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Systemic Therapy in Metastatic Melanoma
Melanoma is the most aggressive form of skin cancer, contributing to about 76,000 new cases and more than 9,000 deaths in 2014.1 Depending on the stage of the disease, 5-year melanoma survival can range from 15% to 97%. Patients with local and distant metastases have a 5-year survival of about 60% and 15%, respectively.2
The incidence of melanoma is rising, partly because of the increasing number of skin biopsies being performed.3 If melanoma is diagnosed early, surgical excision is the treatment of choice. In patients with oligometastatic disease (cancer that has spread, but only to 1 or a small number of sites), complete surgical excision of the metastases may provide prolonged overall survival (OS) and delay the need to use systemic therapy.4
Recently, many new drug therapies have shown promising results in clinical trials, which may improve the prognosis of metastatic disease. This article reviews currently available systemic treatment options for the management of metastatic melanoma, the role of cytotoxic chemotherapy and interleukin-2 (IL-2), and the latest therapies available, including immune checkpoint inhibitors.
Cytotoxic Chemotherapy and Interleukin-2
Cytotoxic chemotherapy does not have an established role in the initial treatment of metastatic melanoma. Currently, cytotoxic chemotherapy is used in patients who have not responded to immunotherapy or molecular targeted therapy. The most commonly used drugs include dacarbazine and its prodrug, temozolomide. Several studies have failed to demonstrate a survival benefit using a single-agent chemotherapy with either dacarbazine or temozolomide.5,6
Other agents used in metastatic melanoma include nitrosoureas (fotemustine), platinum compounds (cisplatin, carboplatin), vinca alkaloids (vincristine),
and taxanes (paclitaxel). None of these agents provide a survival benefit, but an objective response may be seen in a minority of cases. Combination chemotherapy regimens have not shown an advantage over singleagent dacarbazine or temozolomide.7,8
High-dose IL-2 has been used in cases of metastatic melanoma with good performance status (PS) and organ function. Studies have shown a complete response rate of 3% to 7% and a prolonged disease-free survival in a minority of patients.9-11 The use of highdose IL-2, however, is limited by the high incidence of adverse effects (AEs), which include bacterial sepsis, pulmonary edema, arrhythmias, fever, and on some occasions, death due to complications.10 The use of IL-2 requires admission of the patient to a specialized unit for AE monitoring and management. Because of its ability to “cure” a minority of patients, a role still exists for IL-2 therapy in the treatment of younger, healthy patients with no evidence of organ dysfunction at baseline.
Immune Checkpoint Inhibitors
Checkpoint inhibitors are a class of drugs that unmask the immune system to fight against cancer cells. This class of drugs has shown significant activity and survival advantage in recent phase 2 and 3 trials. The class includes the anticytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody ipilimumab and monoclonal antibodies targeting the programmed death 1 protein (PD-1) or its ligand (PD-L1).
Anti-CTLA-4 Antibodies: Ipilimumab
Cytotoxic T-lymphocyte antigen 4 is the antigen responsible for inhibition of cytotoxic T-cell-mediated immunity against foreign antigens presented by the antigen presenting cells (APCs). The APCs cause activation of the T cells when peptide fragments of intracellular proteins are presented in combination with mixed histocompatibility complex molecules. This step requires interaction of a costimulatory molecule (B7) on the APCs with a cluster of differentiation 28 protein (CD28) receptor located on T cells. CTLA-4 competes with CD28 to bind with the B7 molecule, thereby inhibiting the activation of the cytotoxic T cells (Figure 1). This pathway is thought to help with development of tolerance to host tissue antigens. Ipilimumab is a human monoclonal antibody that inhibits this CTLA-4 molecule and facilitates T-cell mediated antitumor activity.12 By blocking the CTLA-4 molecule, ipilimumab also mediates its autoimmune AEs on the host tissues.
Hodi and colleagues conducted a phase 3 trial of ipilimumab, including 676 patients who progressed after prior treatment for stage III or IV melanoma, and found that median OS was significantly better in the ipilimumab groups: 10 months in the ipilimumab plus gp100 peptide vaccine group vs 6.4 months in the gp100 vaccine alone group; 10.1 months in the ipilimumab alone group vs 6.4 months in the gp100 vaccine alone group.13 In another phase 3 trial comparing ipilimumab plus dacarbazine to dacarbazine alone, the ipilimumab group had a significantly improved OS (11.2 months vs 9.1 months).1 Survival rates with ipilimumab were prolonged for up to 3 years compared with the dacarbazine plus placebo group. However, the combination was associated with increased incidence of hepatotoxicity, thereby limiting its use.
A long-term survival analysis of 10 prospective and 2 retrospective studies of ipilimumab showed a median OS of 11.4 months and a long-term survival that began at 3 years with a plateau at 10 years of 21%, which was independent of prior therapy or ipilimumab dose.14 The immune-related AEs of ipilimumab are secondary to its activity against the host antigens and include dermatitis, enterocolitis, hepatitis, and endocrinopathies.15
A recent phase 2 trial studied the combination of ipilimumab with granulocyte-macrophage colonystimulating factor in 245 patients with stage III and IV melanoma. Median OS after 13 months was significantly higher with the combination compared with ipilimumab alone. The 1-year survival rate was 69% with
the combination and 53% with ipilimumab alone. There was no difference in the overall response rate (ORR) or progression-free survival (PFS) between the 2 groups. However, the AEs were significantly reduced with the combination (45% vs 58%).16 The dose of ipilimumab used in the trial was higher than the approved dose, making it difficult to apply the results in practice without further studies on the combination.
Anti-PD-1 Antibodies
Programmed death 1 ligands (PD-L1 and PD-L2) are expressed by tumor or stromal cells to inhibit the T-cell mediated antitumor activity. These ligands bind to the PD-1 protein on the surface of activated T cells to mediate their immunosuppressive effects. Interruption of this interaction by either anti-PD-1 antibodies or anti-PD-L1 antibodies facilitates tumor cell killing by activated T cells.17
Pembrozilumab and nivolumab are the 2 anti-PD-1 monoclonal antibodies that have been approved for treatment of metastatic melanoma. In a phase 1 trial
of pembrolizumab, 411 patients with advanced melanoma (consisting of both ipilimumab-naïve [IPI-N] and ipilimumab-treated [IPI-T] patients), ORR was 40% in IPI-N and 28% in IPI-T patients with a 1-year OS of 71% in all patients. Median PFS was 24 weeks in IPI-N and 23 weeks in IPI-T pts.18 There was no difference in outcomes and safety profiles across the various dosing regimens.18,19 Of note, pembrolizumab had antitumor activity irrespective of the PS, lactate dehydrogenase levels, BRAF (B-Raf proto-oncogene, serine/threonine kinase) gene mutation, metastatic stage, and number and type of prior therapy. In a subgroup analysis, 173 patients who had progression after treatment with ipilimumab were randomly assigned to pembrolizumab 2 mg/kg every 3 weeks (q3w) or 10 mg/kg q3w dosing regimens. Both groups had no significant difference in the ORR (26% in both) and safety profiles.20
In the 2012 KEYNOTE-002 clinical trial, a randomized phase 2 trial involving 540 patients with ipilimumab-refractory advanced melanoma, patients were randomized 1:1:1 to pembrolizumab 2 mg/kg or 10 mg/kg q3w or investigator-choice chemotherapy (control arm consisting of carboplatin plus paclitaxel, carboplatin, paclitaxel, dacarbazine, or temozolomide). The 6-month PFS was significantly improved with pembrolizumab (34% and 38% for pembrolizumab 2 mg/kg and 10 mg/kg, respectively) compared with 16% with chemotherapy. The ORR was significantly better with pembrolizumab (21% at 2 mg/kg, 25% at 10 mg/kg) compared with the control arm (4%).21 These findings led to the approval of pembrolizumab by the FDA for treatment of patients with advanced melanoma who have progressed on ipilimumab. Pembrolizumab is generally well tolerated. The most common AEs include fatigue, pruritus, and rash.
Nivolumab was studied in a recent phase 1 trial in which 107 patients with previously treated advanced melanoma were treated with escalated doses every
2 weeks.22 The 2-year and 3-year OS rates were 48% and 41%, respectively. Objective responses were seen in 32% of the patients. The median response duration was 23 months.23
The first phase 3 trial was conducted in 418 patients with previously untreated metastatic melanoma BRAF mutation. Patients were randomized to receive either nivolumab or dacarbazine. The PFS and OS were significantly better with nivolumab compared with dacarbazine (PFS 5.1 months vs 2.2 months; OS 73% vs 42% at 1 year).24 The AE profile of nivolumab is similar to pembrolizumab and includes lung, skin, endocrine, renal, and gastrointestinal tract toxicities.
Preliminary results of another phase 3 trial were presented at the European Society of Medical Oncology 2014 meeting. Patients with previously treated metastatic melanoma (ipilimumab or BRAF inhibitor) were randomized in a 2:1 ratio to receive either nivolumab or investigators’ choice chemotherapy (dacarbazine or carboplatin plus paclitaxel). The ORR was significantly better with nivolumab (32% vs 11%), and 95% of patients were still responding after 6 months. The nivolumab group showed a complete remission in 3% of the patients with 34% of the responses lasting ≥ 6 months.25 This led to the recent approval of nivolumab for patients with metastatic melanoma with a BRAF mutation who have advanced on ipilimumab. In the phase 3 NCT01844505 trial patients are being randomized to receive ipilimumab, nivolumab, or both.
A newer PD-1 inhibitor, pidilizumab, was studied in a phase 2 trial that included 103 patients with metastatic melanoma, 51% of whom had received therapy with ipilimumab. The ORR in the study group was relatively lower (6%), but the OS at 1 year was 64.5%.26 Further studies are underway to evaluate the role of this drug in metastatic melanoma.
The response with both nivolumab and pembrolizumab is durable as well as sustained, even after discontinuation of therapy. None of the deaths in the aforementioned studies were atributed to drug-related toxicities. As evidenced by current data, these 2 drugs hold a great promise for the management of patients who progress after therapy with anti-CTLA-4 antibodies.
Anti-PD-L1 Antibodies
The anti-PD-L1 monoclonal antibodies work in a similar way to the PD-1 inhibitors and block the interaction between the PD-1 and its ligand, PD-L1. This causes sustained activation of cytotoxic T cells and facilitates their antitumor activity. Two of PD-L1 inhibitors have shown clinical activity against metastatic melanoma.
BMS-936559, the first PD-L1 antibody, is being studied in a phase 1 trial that includes 55 patients with advanced melanoma along with 152 patients with other solid malignancies. Three patients achieved a complete response, and 5 patients had an objective response lasting 1 year. The ORR for melanoma was 17%, with disease stabilization of ≥ 24 weeks in 27% of the patients.27 Common AEs included infusion reactions, diarrhea, fatigue, rash, hypothyroidism, and hepatitis.
The second PD-L1 antibody, MPDL3280A, was studied in a phase 1 trial of 45 patients with metastatic melanoma. An ORR of 29% was observed, along with a 24-week PFS of 43%.28 Commonly noted AEs included hyperglycemia and elevated liver aminotransferases.
A newer PD-L1 inhibitor, MEDI4736, is being studied for advanced malignancies in 8 patients with melanoma. In preliminary analysis, MEDI4736 demonstrated a partial response in 1 out of 8 melanoma patients with a disease control rate of 46%.29 Although the PD-L1 inhibitors seem promising, more information will help discern their role in the management of metastatic melanoma.
Combined Anti-CTLA-4 Plus Anti-PD-1 Antibody
The combination of ipilimumab and the PD-1 inhibitor nivolumab was tested in a phase 1 trial in which both drugs were used concurrently as well as sequentially in metastatic melanoma.30 The 1- and 2-year OS in patients who were treated concurrently was 82% and 75%, respectively. Complete remission was seen in 17% of the patients, and the responses were seen irrespective of the BRAF mutation status. The responses were durable, and about 64% of the objective responses remain in remission at last follow-up.31 Grade 3 to grade 4 AEs were noted in 53% of the patients, with 11 patients requiring discontinuation of the medications. More studies are required to ascertain the optimum dosage of the combination prior to its approval for use in metastatic melanoma.
Molecular Targeted Therapy
The RAS-RAF–mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway is activated in almost 90% of patients
with melanoma.32 This pathway is normally required for the growth and survival of nonmalignant cells. In malignant transformation, mutations and/or overexpression is seen at various levels including KIT, NRAS, BRAF, and the MEK protein. This leads to activation of serine and threonine protein kinases, which lead to uncontrolled cell proliferation and survival.33
Novel therapeutic approaches have tried inhibiting one or more of these pathways for melanoma treatment. The most important mediator of tumorigenesis is BRAF, which is a downstream receptor of NRAS, and is mutated in almost 50% of melanoma cases.34 NRAS mutations are seen in 15% to 20% of cutaneous melanomas.35,36 After its activation, the RAF enzyme—coded by the BRAF gene—causes phosphorylation of the MEK protein, which activates ERK. This ERK activation leads to growth signaling and is the final pathway in several malignancies (Figure 2).37,38
BRAF Inhibitors
BRAF is the first mediator whose inhibition led to clinically significant outcomes in patients with melanoma. The most common BRAF mutation consists of the
substitution of glutamic acid for valine at amino acid 600 (V600E mutation) with majority of the remainder consisting of an alternate substitution (V600V or V600K).34 Vemurafenib and dabrafenib are the 2 BRAF inhibitors that have been shown to improve tumor regression, PFS, and OS considerably, especially in combination with a MEK protein inhibitor. In the phase 3 BRIM-3 trial, the vemurafenib group had a significantly prolonged PFS and OS compared with dacarbazine (13.6 months vs 9.7 months; 6.9 months vs 1.6 months, respectively). It was the first study to show improved survival with vemurafenib in both the V600E and V600K BRAF mutant melanomas.39
Another BRAF inhibitor, dabrafenib, was approved by the FDA for treatment of advanced melanoma with BRAF V600E mutation. It was tested in a phase 3 trial in which it was compared with dacarbazine in patients with advanced melanoma. Median OS in the dabrafenib arm was > 18 months and in dacarbazine arm > 15 months.40 Fifty-seven percent of the patients in dacarbazine arm were crossed over to the dabrafenib arm, thereby confounding the survival data for the former group. Another multicenter, phase 2 trial showed dabrafenib to have activity in melanoma patients with brain metastases, irrespective of previous therapy for the brain metastases.41 The long-term analysis of the BREAK-2 trial, which included 92 patients with metastatic melanoma treated with dabrafenib, showed a median OS of 12.9 months in BRAF V600K group and 13.1 months in BRAF V600E group.42
Adverse effects associated with BRAF inhibition include fatigue, rash, arthralgia, and photosensitivity reactions.43 Dermatologic complications may also include squamous cell carcinoma (SCC) (19%-26%), with keratoacanthoma being the most common subtype.44 These are believed to be likely secondary to the paradoxical activation of the MAPK signaling, since most of these lesions are found to have mutations in the RAS molecule.45 Other specific AEs of dabrafenib include hyperkeratosis (33%) and pyrexia (29%).42
Most patients treated with a BRAF inhibitor eventually have disease progression, likely secondary to reactivation of the MAPK pathway.46,47 This result has led to a heightened interest in combination therapies in an effort to improve outcomes. Combination therapy with ipilimumab and vemurafenib was studied and resulted in a higher incidence of hepatotoxicity (50%).48 However, no hepatotoxicity was seen in a phase 1 trial of combined dabrafenib and ipilimumab.49
Some studies have also suggested that extended BRAF inhibition after progression on a BRAF inhibitor may prolong survival.50,51 The phase 2 trial NCT01983124 is being conducted to evaluate the survival benefit with a combination of vemurafenib and a nitrosourea alkylating agent, fotemustine, in patients who have progressed on vemurafenib alone.
MEK Inhibitors
The inhibition of MEK can halt cell proliferation and induce apoptosis. The phase 3 METRIC trial, which compared the oral MEK inhibitor (trametinib) with chemotherapy, was conducted in 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation. The PFS and 6-month OS were significantly better with trametinib (4.8 months vs 1.5 months, 81% vs 66%) despite the crossover between the 2 groups.52 The AEs associated with trametinib included rash, diarrhea, and peripheral edema. Another phase 2 trial of trametinib including patients pretreated with a BRAF inhibitor showed no confirmed objective responses, 28% patients with stable disease, and minimal improvement in PFS (2 months). Among patients treated with prior chemotherapy and/or immunotherapy, trametinib showed significant improvement in complete responses, partial responses, stable disease, and the median PFS (2%, 23%, 51%, 4 months, respectively).53
The second MEK inhibitor, binimetinib, was studied in a phase 2 trial of advanced melanoma cases harboring a BRAF V600E or NRAS. Bimetinib demonstrated a PR in 20% cases of both the BRAF and NRAS mutant melanomas. Durable disease control was seen in 43% of the NRAS group and 32% of the BRAF group.54 The AE profile was similar to that seen with trametinib. Bimetinib is being studied in phase 1 and 2 trials with the CDK4/6 inhibitor as well as in the phase 3 trial NCT01763164 compared with dacarbazine in NRAS mutation positive melanomas.55
Selumetinib is a MEK inhibitor that has been compared with dacarbazine and temozolomide with no significant OS advantage. A novel highly specific inhibitor of MEK, cobimetinib, is currently being studied in combination with BRAF inhibitors.
Combined BRAF and MEK Inhibition
A randomized, double-blind, phase 3 study comparing the combination of dabrafenib and trametinib with dabrafenib and placebo in patients with advanced melanoma with a BRAF V600E mutation was presented at the 2014 American Society of Clinical Oncology meeting. Researchers found that after a median follow-up period of 9 months, there was a significant improvement with the combination in the PFS (9.3 months vs 8.8 months) and the ORR (67% vs 51%), with a similar incidence of AEs.56 The combination therapy group had fewer incidences of SCC of the skin but more incidence of pyrexia.
The combination of dabrafenib and trametinib was compared with vemurafenib monotherapy in a recent randomized phase 3 trial among 704 metastatic melanoma patients with a BRAF V600 mutation. Median PFS and ORR were significantly better with combination therapy compared with vemurafenib alone (11.4 months vs 7.3 months, 64% vs 51%, respectively). Overall survival rate at 1 year was significantly improved in the combination group as well (72% vs 65%).57 The incidence of SCC and keratoacanthoma was less in the combination (1%) compared with vemurafenib alone (18%). Another study investigating the coadministration and sequential administration of vemurafenib and trametinib is underway.58
The vemurafenib and cobimetinib combination was studied in a phase 3 trial of previously untreated unresectable locally advanced or metastatic BRAF V600
mutation-positive melanoma. The median PFS was 9.9 months in the combination group and 6.2 months in the control group. The interim analysis showed a 9-month survival rate of 81% in the combination group and 73% in the control group, with no significantly higher incidence of AEs in either arm.59 A longer follow-up will be needed to assess the OS benefit with the combination.
Encorafenib, a selective BRAF inhibitor, has been studied in a phase 1 trial in combination with binimetinib.60 This trial has paved the way to the initiation of a currently ongoing phase 3 trial (NCT01909453) comparing the combination with vemurafenib or encorafenib alone.
C-KIT Inhibitors
Mutations of c-KIT are seen more commonly in chronic sun damage-induced cutaneous melanomas, along with acral and mucosal melanomas.61,62 Earlier trials involving patients without selection for c-KIT mutation positivity failed to show benefit with imatinib. A single-arm, phase 2 trial of imatinib mesylate in patients with metastatic melanoma harboring the c-KIT mutation, an ORR of 23% was achieved, with a median PFS of 3.5 months.63 Imatinib showed an ORR of 29% in a phase 2 trial of mucosal, acral, and in chronic sun damage-induced melanoma patients with c-KIT amplifications and/or mutations. It was demonstrated that c-KIT amplification alone is not as responsive to imatinib compared with c-KIT mutation, suggesting that all patients with these specific melanomas should be tested for KIT mutation status.64
A second-generation c-KIT inhibitor, nilotinib, has shown some promising results with a favorable AE profile in small phase 2 trials.65,66 However, more clinical research will be needed before definite recommendations on its use in cutaneous melanomas can be made. Currently, its role seems to be limited to the management of acral, mucosal, and chronic sun damage-related melanomas with c-KIT mutations.
Future Directions
Angiogenesis promoters, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor, fibroblast growth factor, and interleukin-8, are overexpressed in melanoma. Bevacizumab, an anti-VEGF antibody, has been shown to have some benefit in combination with carboplatin and paclitaxel as a triple therapy.67 However, grade 3 AEs were seen in a portion of patients.
The phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway has also been studied as a target for melanoma therapy. Everolimus, an mTOR inhibitor, was studied in a phase 2 trial in combination with bevacizumab for treatment of metastatic melanoma. The combination showed improved median PFS and OS with the combination (4 months and 8.6 months, respectively), with 43% of patients alive after 12 months of follow-up.68 This study points to the direction of possible benefits with the combination of anti-VEGF and immunotherapy. A recent study failed to show survival advantage with combination of bevacizumab and temozolomide.69
Buparlisib (BKM120), a PI3K inhibitor, has been shown to have activity in vivo and in vitro against melanoma brain metastases.70 More studies need to be done to assess the possible combination with other established therapies.
Oblimersen is an antisense oligonucleotide that suppresses B-cell lymphoma-2, thereby suppressing its anti-apoptotic effect. The triple combination of oblimersen with temozolomide and albumin-bound paclitaxel has shown to be safe and efficacious in a phase 1 trial, thereby creating a need for further clinical trials.71
Treatment Approach
Systemic therapy for metastatic melanoma depends on several factors, including BRAF mutation status, functional status of the patient, disease burden, and severity of symptoms. Assessing the BRAF mutation status has become an important component in the management of patients with metastatic melanoma. It can help recognize patients who will benefit from molecular targeted therapy. In case of a BRAF-positive melanoma, treatment can be initiated with either immunotherapy or BRAF inhibitors. There are no randomized studies comparing immunotherapy to molecular targeted therapy.
Patients who have good PS and lymph node metastases can be treated initially with IL-2, which has the advantage of inducing cure in a minority of patients but should only be considered in patients with well-preserved organ function who can be monitored in an intensive care setting. On the other hand, patients who have bulky, symptomatic disease and poor PS should be treated initially with BRAF inhibitors. Combination of BRAF and MEK inhibitors can also be used and has an improved PFS and OS with potential to cause early tumor regression. There are studies to suggest suboptimal outcomes in patients who are treated with ipilimumab after progression on a BRAF inhibitor compared with initial treatment with ipilimumab followed by a BRAF inhibitor.72-74 However, all these studies are retrospective and there is no prospective data to suggest the above. BRAF mutation-positive patients who progress on a BRAF inhibitor
can be treated with PD-1 inhibitors.
Patients who do not have a BRAF mutation are unlikely to benefit from a BRAF inhibitor and primarily receive immunotherapy with ipilimumab or IL-2. Whenever possible, such patients should be enrolled in a clinical trial, as they have a poor prognosis. Patients who progress on ipilimumab can be treated with one of the PD-1 inhibitors (pembrolizumab, nivolumab). These PD-L1 inhibitors are still being investigated for use in such situations.
The role of chemotherapy in the management of metastatic melanoma has been limited by numerous studies showing significantly better survival with immunotherapy and molecular targeted therapy. Dacarbazine is the only FDA-approved drug for the treatment of melanoma. Its use is reserved mainly for patients who are not candidates for any of the other therapies available, including enrollment in a clinical trial.
Conclusion
Therapies for metastatic melanoma are in a state of flux. In the past decade, several new therapeutic agents have been introduced for the management of this potentially lethal disease. The treatment of metastatic melanoma has gradually shifted from cytotoxic chemotherapy toward a more individualized treatment that has a definite survival advantage over traditional counterparts. The advent of novel therapies has led to initiation of further studies to determine their role in the treatment of advanced melanoma, singly or in combination with other agents. In addition to evaluating new agents, more studies are needed to compare existing treatment modalities so that definitive treatment protocols can be formulated.
Acknowledgement
The authors would like to thank Felicia Ratnaraj, MD, for her assistance in creating the figures.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
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31. Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL) (abstract LBA9003). Paper presented at: 2014 American Society of Clinical Oncology (ASCO) meeting; May-June 2014; Chicago, IL.
32. Omholt K, Platz A, Kanter L, Ringborg U, Hansson J. NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res. 2003;9(17):6483-6488.
33. Wellbrock C, Hurlstone A. BRAF as therapeutic target in melanoma. Biochem Pharmacol. 2010;80(5):561-567.
34. Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29(10):1239-1246.
35. Ball NJ, Yohn JJ, Morelli JG, et al. Ras mutations in human melanoma: a marker of malignant progression. J Invest Dermatol. 1994;102(3):285-290.
36. Platz A, Ringborg U, Brahme EM, Lagerlöf B. Melanoma metastases from patients with hereditary cutaneous malignant melanoma contain a high frequency of N-ras activating mutations. Melanoma Res. 1994;4(3):169-177.
37. Beeram M, Patnaik A, Rowinsky EK. Raf: a strategic target for therapeutic development against cancer. J Clin Oncol. 2005;23(27):6771-6790.
38. Terai K, Matsuda M. The amino-terminal B-Raf-specific region mediates calcium-dependent homo- and hetero-dimerization of Raf. EMBO J. 2006;25(15):3556-3564.
39. McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;15(3):323-332.
40. Hauschild A, Grob JJ, Demidov LV, et al. An update on BREAK-3, a phase III, randomized trial: dabrafenib versus dacarbazine in patients with BRAF V600E-positive mutation metastatic melanoma (Abstract 9013). Paper presented at: American Society of Clinical Oncology 2013 meeting; May-June 2013; Chicago, IL.
41. Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(11):1087-1095.
42. Ascierto PA, Minor DR, Ribas A, et. al., Long-term safety and overall survival update for BREAK-2, a phase 2, single-arm, open-label study of dabrafenib in previously treated metastatic melanoma (NCT01153763). J Clin Oncol. 2014;32(15)(suppl): Abstract 9034.
43. Larkin J, Del Vecchio M, Ascierto PA, et al. Vemurafenib in patients with
BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety
study. Lancet Oncol. 2014;15(4):436-444.
44. Lacouture ME, Duvic M, Hauschild A, et al. Analysis of dermatologic events in vemurafenib-treated patients with melanoma. Oncologist. 2013;18(3):314-322.
45. Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366(3):207-215.
46. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-2516.
47. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358-365.
48. Ribas A, Hodi FS, Callahan M, et. al. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2014;368(14):1365-1366.
49. Linette GP, Puzanov I, Callahan MK, et al. Phase 1 study of the BRAF inhibitor dabrafenib (D) with or without the MEK inhibitor trametinib (T) in combination with ipilimumab (Ipi) for V600E/K mutation–positive unresectable or metastatic melanoma (MM). J Clin Oncol. 2014;32(15)(suppl): Abstract 2511.
50. Chan MMK, Haydu LE, Menzies AM, et al. The nature and management of metastatic melanoma after progression on BRAF inhibitors: effects of extended BRAF inhibition. Cancer. 2014;120(20):3142-3153.
51. Carlino MS, Gowrishankar K, Saunders CAB, et al. Antiproliferative effects of continued mitogen-activated protein kinase pathway inhibition following acquired resistance to BRAF and/or MEK inhibition in melanoma. Mol Cancer Ther. 2013;12(7):1332-1342.
52. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107-114.
53. Kim KB, Kefford R, Pavlick AC, et. al. Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol. 2013;31(1):482-489.
54. Ascierto PA, Schadendorf D, Berking C, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 2013;14(3):249-256.
55. Sosman JA, Kittaneh M, Lolkema MP, et al. A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRAS-mutant melanoma: early encouraging clinical activity (abstract 9009). Paper presented at: 2014 American Society of Clinical Oncology meeting ; May-June 2014; Chicago, IL.
56. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877-1888.
57. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30-39.
58. Gogas H, Schadendorf D, Dummer R. Vemurafenib treatment in patients with BRAF-mutated melanoma failing MEK inhibition with trametinib. J Clin Oncol. 2014;32(15)(suppl): Abstract 9061.
59. Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867-1876.
60. Kefford R, Miller WH, Tan DS, et al. Preliminary results from a phase Ib/II, openlabel, dose-escalation study of the oral BRAF inhibitor LGX818 in combination with the oral MEK1/2 inhibitor MEK162 in BRAF V600-dependent advanced solid tumors (abstract 9019). Paper presented at: 2013 American Society of Clinical Oncology meeting; May-June 2014; Chicago, IL.
61. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct
subtypes of melanoma. J Clin Oncol. 2006;24(26):4340-4346.
62. Jin SA, Chun SM, Choi YD, et al. BRAF mutations and KIT aberrations and their clinicopathological correlation in 202 Korean melanomas. J Invest Dermatol. 2013;133(2):579-582.
63. Guo J, Si L, Kong Y et. al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol. 2011;29(21):2904-2909.
64. Hodi FS, Corless CL, Giobbie-Hurder A, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol. 2013;31(26):3182-3190.
65. Cho JH, Kim KM, Kwon M, Kim JH, Lee J. Nilotinib in patients with metastatic melanoma harboring KIT gene aberration. Invest New Drugs. 2012;30(5): 2008-2014.
66. Lebbe C, Chevret S, Jouary T, et. al. Phase II multicentric uncontrolled national trial assessing the efficacy of nilotinib in the treatment of advanced melanomas with c-KIT mutation or amplification. J Clin Oncol. 2014;32(15)(suppl): Abstract 9032.
67. Perez DG, Suman VJ, Fitch TR, et al. Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N047A. Cancer. 2009;115(1):119-127.
68. Hainsworth JD, Infante JR, Spigel DR, et al. Bevacizumab and everolimus in the treatment of patients with metastatic melanoma. Cancer. 2010;116(17): 4122-4129.
69. Dronca RS, Allred JB, Perez DG, et. al. Phase II study of temozolomide (TMZ) and everolimus (RAD001) therapy for metastatic melanoma: a North Central Cancer Treatment Group study, N0675. Am J Clin Oncol. 2014;37(4):369-376.
70. Meier FE, Niessner H, Schmitz J, et al. The PI3K inhibitor BKM120 has potent antitumor activity in melanoma brain metastases in vitro and in vivo. J Clin Oncol. 2013;31(15)(suppl): Abstract e20050.
71. Ott PA, Chang J, Madden K, et al. Oblimersen in combination with temozolomide and albumin-bound paclitaxel in patients with advanced melanoma: a phase I trial. Cancer Chemother Pharmacol. 2013;71(1);183-191.
72. Ackerman A, Klein O, McDermott DF, et al. Outcomes of patients with metastatic
melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer. 2014;120(11):1695-1701.
73. Ascierto PA, Margolin K. Ipilimumab before BRAF inhibitor treatment may be
more beneficial than vice versa for the majority of patients with advanced melanoma.
Cancer. 2014;120(11):1617-1619.
74. Ascierto PA, Simeone E, Sileni VC, et al. Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from the Italian cohort of the ipilimumab expanded access program. Cancer Invest. 2014;32(4):144-149.
Melanoma is the most aggressive form of skin cancer, contributing to about 76,000 new cases and more than 9,000 deaths in 2014.1 Depending on the stage of the disease, 5-year melanoma survival can range from 15% to 97%. Patients with local and distant metastases have a 5-year survival of about 60% and 15%, respectively.2
The incidence of melanoma is rising, partly because of the increasing number of skin biopsies being performed.3 If melanoma is diagnosed early, surgical excision is the treatment of choice. In patients with oligometastatic disease (cancer that has spread, but only to 1 or a small number of sites), complete surgical excision of the metastases may provide prolonged overall survival (OS) and delay the need to use systemic therapy.4
Recently, many new drug therapies have shown promising results in clinical trials, which may improve the prognosis of metastatic disease. This article reviews currently available systemic treatment options for the management of metastatic melanoma, the role of cytotoxic chemotherapy and interleukin-2 (IL-2), and the latest therapies available, including immune checkpoint inhibitors.
Cytotoxic Chemotherapy and Interleukin-2
Cytotoxic chemotherapy does not have an established role in the initial treatment of metastatic melanoma. Currently, cytotoxic chemotherapy is used in patients who have not responded to immunotherapy or molecular targeted therapy. The most commonly used drugs include dacarbazine and its prodrug, temozolomide. Several studies have failed to demonstrate a survival benefit using a single-agent chemotherapy with either dacarbazine or temozolomide.5,6
Other agents used in metastatic melanoma include nitrosoureas (fotemustine), platinum compounds (cisplatin, carboplatin), vinca alkaloids (vincristine),
and taxanes (paclitaxel). None of these agents provide a survival benefit, but an objective response may be seen in a minority of cases. Combination chemotherapy regimens have not shown an advantage over singleagent dacarbazine or temozolomide.7,8
High-dose IL-2 has been used in cases of metastatic melanoma with good performance status (PS) and organ function. Studies have shown a complete response rate of 3% to 7% and a prolonged disease-free survival in a minority of patients.9-11 The use of highdose IL-2, however, is limited by the high incidence of adverse effects (AEs), which include bacterial sepsis, pulmonary edema, arrhythmias, fever, and on some occasions, death due to complications.10 The use of IL-2 requires admission of the patient to a specialized unit for AE monitoring and management. Because of its ability to “cure” a minority of patients, a role still exists for IL-2 therapy in the treatment of younger, healthy patients with no evidence of organ dysfunction at baseline.
Immune Checkpoint Inhibitors
Checkpoint inhibitors are a class of drugs that unmask the immune system to fight against cancer cells. This class of drugs has shown significant activity and survival advantage in recent phase 2 and 3 trials. The class includes the anticytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody ipilimumab and monoclonal antibodies targeting the programmed death 1 protein (PD-1) or its ligand (PD-L1).
Anti-CTLA-4 Antibodies: Ipilimumab
Cytotoxic T-lymphocyte antigen 4 is the antigen responsible for inhibition of cytotoxic T-cell-mediated immunity against foreign antigens presented by the antigen presenting cells (APCs). The APCs cause activation of the T cells when peptide fragments of intracellular proteins are presented in combination with mixed histocompatibility complex molecules. This step requires interaction of a costimulatory molecule (B7) on the APCs with a cluster of differentiation 28 protein (CD28) receptor located on T cells. CTLA-4 competes with CD28 to bind with the B7 molecule, thereby inhibiting the activation of the cytotoxic T cells (Figure 1). This pathway is thought to help with development of tolerance to host tissue antigens. Ipilimumab is a human monoclonal antibody that inhibits this CTLA-4 molecule and facilitates T-cell mediated antitumor activity.12 By blocking the CTLA-4 molecule, ipilimumab also mediates its autoimmune AEs on the host tissues.
Hodi and colleagues conducted a phase 3 trial of ipilimumab, including 676 patients who progressed after prior treatment for stage III or IV melanoma, and found that median OS was significantly better in the ipilimumab groups: 10 months in the ipilimumab plus gp100 peptide vaccine group vs 6.4 months in the gp100 vaccine alone group; 10.1 months in the ipilimumab alone group vs 6.4 months in the gp100 vaccine alone group.13 In another phase 3 trial comparing ipilimumab plus dacarbazine to dacarbazine alone, the ipilimumab group had a significantly improved OS (11.2 months vs 9.1 months).1 Survival rates with ipilimumab were prolonged for up to 3 years compared with the dacarbazine plus placebo group. However, the combination was associated with increased incidence of hepatotoxicity, thereby limiting its use.
A long-term survival analysis of 10 prospective and 2 retrospective studies of ipilimumab showed a median OS of 11.4 months and a long-term survival that began at 3 years with a plateau at 10 years of 21%, which was independent of prior therapy or ipilimumab dose.14 The immune-related AEs of ipilimumab are secondary to its activity against the host antigens and include dermatitis, enterocolitis, hepatitis, and endocrinopathies.15
A recent phase 2 trial studied the combination of ipilimumab with granulocyte-macrophage colonystimulating factor in 245 patients with stage III and IV melanoma. Median OS after 13 months was significantly higher with the combination compared with ipilimumab alone. The 1-year survival rate was 69% with
the combination and 53% with ipilimumab alone. There was no difference in the overall response rate (ORR) or progression-free survival (PFS) between the 2 groups. However, the AEs were significantly reduced with the combination (45% vs 58%).16 The dose of ipilimumab used in the trial was higher than the approved dose, making it difficult to apply the results in practice without further studies on the combination.
Anti-PD-1 Antibodies
Programmed death 1 ligands (PD-L1 and PD-L2) are expressed by tumor or stromal cells to inhibit the T-cell mediated antitumor activity. These ligands bind to the PD-1 protein on the surface of activated T cells to mediate their immunosuppressive effects. Interruption of this interaction by either anti-PD-1 antibodies or anti-PD-L1 antibodies facilitates tumor cell killing by activated T cells.17
Pembrozilumab and nivolumab are the 2 anti-PD-1 monoclonal antibodies that have been approved for treatment of metastatic melanoma. In a phase 1 trial
of pembrolizumab, 411 patients with advanced melanoma (consisting of both ipilimumab-naïve [IPI-N] and ipilimumab-treated [IPI-T] patients), ORR was 40% in IPI-N and 28% in IPI-T patients with a 1-year OS of 71% in all patients. Median PFS was 24 weeks in IPI-N and 23 weeks in IPI-T pts.18 There was no difference in outcomes and safety profiles across the various dosing regimens.18,19 Of note, pembrolizumab had antitumor activity irrespective of the PS, lactate dehydrogenase levels, BRAF (B-Raf proto-oncogene, serine/threonine kinase) gene mutation, metastatic stage, and number and type of prior therapy. In a subgroup analysis, 173 patients who had progression after treatment with ipilimumab were randomly assigned to pembrolizumab 2 mg/kg every 3 weeks (q3w) or 10 mg/kg q3w dosing regimens. Both groups had no significant difference in the ORR (26% in both) and safety profiles.20
In the 2012 KEYNOTE-002 clinical trial, a randomized phase 2 trial involving 540 patients with ipilimumab-refractory advanced melanoma, patients were randomized 1:1:1 to pembrolizumab 2 mg/kg or 10 mg/kg q3w or investigator-choice chemotherapy (control arm consisting of carboplatin plus paclitaxel, carboplatin, paclitaxel, dacarbazine, or temozolomide). The 6-month PFS was significantly improved with pembrolizumab (34% and 38% for pembrolizumab 2 mg/kg and 10 mg/kg, respectively) compared with 16% with chemotherapy. The ORR was significantly better with pembrolizumab (21% at 2 mg/kg, 25% at 10 mg/kg) compared with the control arm (4%).21 These findings led to the approval of pembrolizumab by the FDA for treatment of patients with advanced melanoma who have progressed on ipilimumab. Pembrolizumab is generally well tolerated. The most common AEs include fatigue, pruritus, and rash.
Nivolumab was studied in a recent phase 1 trial in which 107 patients with previously treated advanced melanoma were treated with escalated doses every
2 weeks.22 The 2-year and 3-year OS rates were 48% and 41%, respectively. Objective responses were seen in 32% of the patients. The median response duration was 23 months.23
The first phase 3 trial was conducted in 418 patients with previously untreated metastatic melanoma BRAF mutation. Patients were randomized to receive either nivolumab or dacarbazine. The PFS and OS were significantly better with nivolumab compared with dacarbazine (PFS 5.1 months vs 2.2 months; OS 73% vs 42% at 1 year).24 The AE profile of nivolumab is similar to pembrolizumab and includes lung, skin, endocrine, renal, and gastrointestinal tract toxicities.
Preliminary results of another phase 3 trial were presented at the European Society of Medical Oncology 2014 meeting. Patients with previously treated metastatic melanoma (ipilimumab or BRAF inhibitor) were randomized in a 2:1 ratio to receive either nivolumab or investigators’ choice chemotherapy (dacarbazine or carboplatin plus paclitaxel). The ORR was significantly better with nivolumab (32% vs 11%), and 95% of patients were still responding after 6 months. The nivolumab group showed a complete remission in 3% of the patients with 34% of the responses lasting ≥ 6 months.25 This led to the recent approval of nivolumab for patients with metastatic melanoma with a BRAF mutation who have advanced on ipilimumab. In the phase 3 NCT01844505 trial patients are being randomized to receive ipilimumab, nivolumab, or both.
A newer PD-1 inhibitor, pidilizumab, was studied in a phase 2 trial that included 103 patients with metastatic melanoma, 51% of whom had received therapy with ipilimumab. The ORR in the study group was relatively lower (6%), but the OS at 1 year was 64.5%.26 Further studies are underway to evaluate the role of this drug in metastatic melanoma.
The response with both nivolumab and pembrolizumab is durable as well as sustained, even after discontinuation of therapy. None of the deaths in the aforementioned studies were atributed to drug-related toxicities. As evidenced by current data, these 2 drugs hold a great promise for the management of patients who progress after therapy with anti-CTLA-4 antibodies.
Anti-PD-L1 Antibodies
The anti-PD-L1 monoclonal antibodies work in a similar way to the PD-1 inhibitors and block the interaction between the PD-1 and its ligand, PD-L1. This causes sustained activation of cytotoxic T cells and facilitates their antitumor activity. Two of PD-L1 inhibitors have shown clinical activity against metastatic melanoma.
BMS-936559, the first PD-L1 antibody, is being studied in a phase 1 trial that includes 55 patients with advanced melanoma along with 152 patients with other solid malignancies. Three patients achieved a complete response, and 5 patients had an objective response lasting 1 year. The ORR for melanoma was 17%, with disease stabilization of ≥ 24 weeks in 27% of the patients.27 Common AEs included infusion reactions, diarrhea, fatigue, rash, hypothyroidism, and hepatitis.
The second PD-L1 antibody, MPDL3280A, was studied in a phase 1 trial of 45 patients with metastatic melanoma. An ORR of 29% was observed, along with a 24-week PFS of 43%.28 Commonly noted AEs included hyperglycemia and elevated liver aminotransferases.
A newer PD-L1 inhibitor, MEDI4736, is being studied for advanced malignancies in 8 patients with melanoma. In preliminary analysis, MEDI4736 demonstrated a partial response in 1 out of 8 melanoma patients with a disease control rate of 46%.29 Although the PD-L1 inhibitors seem promising, more information will help discern their role in the management of metastatic melanoma.
Combined Anti-CTLA-4 Plus Anti-PD-1 Antibody
The combination of ipilimumab and the PD-1 inhibitor nivolumab was tested in a phase 1 trial in which both drugs were used concurrently as well as sequentially in metastatic melanoma.30 The 1- and 2-year OS in patients who were treated concurrently was 82% and 75%, respectively. Complete remission was seen in 17% of the patients, and the responses were seen irrespective of the BRAF mutation status. The responses were durable, and about 64% of the objective responses remain in remission at last follow-up.31 Grade 3 to grade 4 AEs were noted in 53% of the patients, with 11 patients requiring discontinuation of the medications. More studies are required to ascertain the optimum dosage of the combination prior to its approval for use in metastatic melanoma.
Molecular Targeted Therapy
The RAS-RAF–mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway is activated in almost 90% of patients
with melanoma.32 This pathway is normally required for the growth and survival of nonmalignant cells. In malignant transformation, mutations and/or overexpression is seen at various levels including KIT, NRAS, BRAF, and the MEK protein. This leads to activation of serine and threonine protein kinases, which lead to uncontrolled cell proliferation and survival.33
Novel therapeutic approaches have tried inhibiting one or more of these pathways for melanoma treatment. The most important mediator of tumorigenesis is BRAF, which is a downstream receptor of NRAS, and is mutated in almost 50% of melanoma cases.34 NRAS mutations are seen in 15% to 20% of cutaneous melanomas.35,36 After its activation, the RAF enzyme—coded by the BRAF gene—causes phosphorylation of the MEK protein, which activates ERK. This ERK activation leads to growth signaling and is the final pathway in several malignancies (Figure 2).37,38
BRAF Inhibitors
BRAF is the first mediator whose inhibition led to clinically significant outcomes in patients with melanoma. The most common BRAF mutation consists of the
substitution of glutamic acid for valine at amino acid 600 (V600E mutation) with majority of the remainder consisting of an alternate substitution (V600V or V600K).34 Vemurafenib and dabrafenib are the 2 BRAF inhibitors that have been shown to improve tumor regression, PFS, and OS considerably, especially in combination with a MEK protein inhibitor. In the phase 3 BRIM-3 trial, the vemurafenib group had a significantly prolonged PFS and OS compared with dacarbazine (13.6 months vs 9.7 months; 6.9 months vs 1.6 months, respectively). It was the first study to show improved survival with vemurafenib in both the V600E and V600K BRAF mutant melanomas.39
Another BRAF inhibitor, dabrafenib, was approved by the FDA for treatment of advanced melanoma with BRAF V600E mutation. It was tested in a phase 3 trial in which it was compared with dacarbazine in patients with advanced melanoma. Median OS in the dabrafenib arm was > 18 months and in dacarbazine arm > 15 months.40 Fifty-seven percent of the patients in dacarbazine arm were crossed over to the dabrafenib arm, thereby confounding the survival data for the former group. Another multicenter, phase 2 trial showed dabrafenib to have activity in melanoma patients with brain metastases, irrespective of previous therapy for the brain metastases.41 The long-term analysis of the BREAK-2 trial, which included 92 patients with metastatic melanoma treated with dabrafenib, showed a median OS of 12.9 months in BRAF V600K group and 13.1 months in BRAF V600E group.42
Adverse effects associated with BRAF inhibition include fatigue, rash, arthralgia, and photosensitivity reactions.43 Dermatologic complications may also include squamous cell carcinoma (SCC) (19%-26%), with keratoacanthoma being the most common subtype.44 These are believed to be likely secondary to the paradoxical activation of the MAPK signaling, since most of these lesions are found to have mutations in the RAS molecule.45 Other specific AEs of dabrafenib include hyperkeratosis (33%) and pyrexia (29%).42
Most patients treated with a BRAF inhibitor eventually have disease progression, likely secondary to reactivation of the MAPK pathway.46,47 This result has led to a heightened interest in combination therapies in an effort to improve outcomes. Combination therapy with ipilimumab and vemurafenib was studied and resulted in a higher incidence of hepatotoxicity (50%).48 However, no hepatotoxicity was seen in a phase 1 trial of combined dabrafenib and ipilimumab.49
Some studies have also suggested that extended BRAF inhibition after progression on a BRAF inhibitor may prolong survival.50,51 The phase 2 trial NCT01983124 is being conducted to evaluate the survival benefit with a combination of vemurafenib and a nitrosourea alkylating agent, fotemustine, in patients who have progressed on vemurafenib alone.
MEK Inhibitors
The inhibition of MEK can halt cell proliferation and induce apoptosis. The phase 3 METRIC trial, which compared the oral MEK inhibitor (trametinib) with chemotherapy, was conducted in 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation. The PFS and 6-month OS were significantly better with trametinib (4.8 months vs 1.5 months, 81% vs 66%) despite the crossover between the 2 groups.52 The AEs associated with trametinib included rash, diarrhea, and peripheral edema. Another phase 2 trial of trametinib including patients pretreated with a BRAF inhibitor showed no confirmed objective responses, 28% patients with stable disease, and minimal improvement in PFS (2 months). Among patients treated with prior chemotherapy and/or immunotherapy, trametinib showed significant improvement in complete responses, partial responses, stable disease, and the median PFS (2%, 23%, 51%, 4 months, respectively).53
The second MEK inhibitor, binimetinib, was studied in a phase 2 trial of advanced melanoma cases harboring a BRAF V600E or NRAS. Bimetinib demonstrated a PR in 20% cases of both the BRAF and NRAS mutant melanomas. Durable disease control was seen in 43% of the NRAS group and 32% of the BRAF group.54 The AE profile was similar to that seen with trametinib. Bimetinib is being studied in phase 1 and 2 trials with the CDK4/6 inhibitor as well as in the phase 3 trial NCT01763164 compared with dacarbazine in NRAS mutation positive melanomas.55
Selumetinib is a MEK inhibitor that has been compared with dacarbazine and temozolomide with no significant OS advantage. A novel highly specific inhibitor of MEK, cobimetinib, is currently being studied in combination with BRAF inhibitors.
Combined BRAF and MEK Inhibition
A randomized, double-blind, phase 3 study comparing the combination of dabrafenib and trametinib with dabrafenib and placebo in patients with advanced melanoma with a BRAF V600E mutation was presented at the 2014 American Society of Clinical Oncology meeting. Researchers found that after a median follow-up period of 9 months, there was a significant improvement with the combination in the PFS (9.3 months vs 8.8 months) and the ORR (67% vs 51%), with a similar incidence of AEs.56 The combination therapy group had fewer incidences of SCC of the skin but more incidence of pyrexia.
The combination of dabrafenib and trametinib was compared with vemurafenib monotherapy in a recent randomized phase 3 trial among 704 metastatic melanoma patients with a BRAF V600 mutation. Median PFS and ORR were significantly better with combination therapy compared with vemurafenib alone (11.4 months vs 7.3 months, 64% vs 51%, respectively). Overall survival rate at 1 year was significantly improved in the combination group as well (72% vs 65%).57 The incidence of SCC and keratoacanthoma was less in the combination (1%) compared with vemurafenib alone (18%). Another study investigating the coadministration and sequential administration of vemurafenib and trametinib is underway.58
The vemurafenib and cobimetinib combination was studied in a phase 3 trial of previously untreated unresectable locally advanced or metastatic BRAF V600
mutation-positive melanoma. The median PFS was 9.9 months in the combination group and 6.2 months in the control group. The interim analysis showed a 9-month survival rate of 81% in the combination group and 73% in the control group, with no significantly higher incidence of AEs in either arm.59 A longer follow-up will be needed to assess the OS benefit with the combination.
Encorafenib, a selective BRAF inhibitor, has been studied in a phase 1 trial in combination with binimetinib.60 This trial has paved the way to the initiation of a currently ongoing phase 3 trial (NCT01909453) comparing the combination with vemurafenib or encorafenib alone.
C-KIT Inhibitors
Mutations of c-KIT are seen more commonly in chronic sun damage-induced cutaneous melanomas, along with acral and mucosal melanomas.61,62 Earlier trials involving patients without selection for c-KIT mutation positivity failed to show benefit with imatinib. A single-arm, phase 2 trial of imatinib mesylate in patients with metastatic melanoma harboring the c-KIT mutation, an ORR of 23% was achieved, with a median PFS of 3.5 months.63 Imatinib showed an ORR of 29% in a phase 2 trial of mucosal, acral, and in chronic sun damage-induced melanoma patients with c-KIT amplifications and/or mutations. It was demonstrated that c-KIT amplification alone is not as responsive to imatinib compared with c-KIT mutation, suggesting that all patients with these specific melanomas should be tested for KIT mutation status.64
A second-generation c-KIT inhibitor, nilotinib, has shown some promising results with a favorable AE profile in small phase 2 trials.65,66 However, more clinical research will be needed before definite recommendations on its use in cutaneous melanomas can be made. Currently, its role seems to be limited to the management of acral, mucosal, and chronic sun damage-related melanomas with c-KIT mutations.
Future Directions
Angiogenesis promoters, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor, fibroblast growth factor, and interleukin-8, are overexpressed in melanoma. Bevacizumab, an anti-VEGF antibody, has been shown to have some benefit in combination with carboplatin and paclitaxel as a triple therapy.67 However, grade 3 AEs were seen in a portion of patients.
The phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway has also been studied as a target for melanoma therapy. Everolimus, an mTOR inhibitor, was studied in a phase 2 trial in combination with bevacizumab for treatment of metastatic melanoma. The combination showed improved median PFS and OS with the combination (4 months and 8.6 months, respectively), with 43% of patients alive after 12 months of follow-up.68 This study points to the direction of possible benefits with the combination of anti-VEGF and immunotherapy. A recent study failed to show survival advantage with combination of bevacizumab and temozolomide.69
Buparlisib (BKM120), a PI3K inhibitor, has been shown to have activity in vivo and in vitro against melanoma brain metastases.70 More studies need to be done to assess the possible combination with other established therapies.
Oblimersen is an antisense oligonucleotide that suppresses B-cell lymphoma-2, thereby suppressing its anti-apoptotic effect. The triple combination of oblimersen with temozolomide and albumin-bound paclitaxel has shown to be safe and efficacious in a phase 1 trial, thereby creating a need for further clinical trials.71
Treatment Approach
Systemic therapy for metastatic melanoma depends on several factors, including BRAF mutation status, functional status of the patient, disease burden, and severity of symptoms. Assessing the BRAF mutation status has become an important component in the management of patients with metastatic melanoma. It can help recognize patients who will benefit from molecular targeted therapy. In case of a BRAF-positive melanoma, treatment can be initiated with either immunotherapy or BRAF inhibitors. There are no randomized studies comparing immunotherapy to molecular targeted therapy.
Patients who have good PS and lymph node metastases can be treated initially with IL-2, which has the advantage of inducing cure in a minority of patients but should only be considered in patients with well-preserved organ function who can be monitored in an intensive care setting. On the other hand, patients who have bulky, symptomatic disease and poor PS should be treated initially with BRAF inhibitors. Combination of BRAF and MEK inhibitors can also be used and has an improved PFS and OS with potential to cause early tumor regression. There are studies to suggest suboptimal outcomes in patients who are treated with ipilimumab after progression on a BRAF inhibitor compared with initial treatment with ipilimumab followed by a BRAF inhibitor.72-74 However, all these studies are retrospective and there is no prospective data to suggest the above. BRAF mutation-positive patients who progress on a BRAF inhibitor
can be treated with PD-1 inhibitors.
Patients who do not have a BRAF mutation are unlikely to benefit from a BRAF inhibitor and primarily receive immunotherapy with ipilimumab or IL-2. Whenever possible, such patients should be enrolled in a clinical trial, as they have a poor prognosis. Patients who progress on ipilimumab can be treated with one of the PD-1 inhibitors (pembrolizumab, nivolumab). These PD-L1 inhibitors are still being investigated for use in such situations.
The role of chemotherapy in the management of metastatic melanoma has been limited by numerous studies showing significantly better survival with immunotherapy and molecular targeted therapy. Dacarbazine is the only FDA-approved drug for the treatment of melanoma. Its use is reserved mainly for patients who are not candidates for any of the other therapies available, including enrollment in a clinical trial.
Conclusion
Therapies for metastatic melanoma are in a state of flux. In the past decade, several new therapeutic agents have been introduced for the management of this potentially lethal disease. The treatment of metastatic melanoma has gradually shifted from cytotoxic chemotherapy toward a more individualized treatment that has a definite survival advantage over traditional counterparts. The advent of novel therapies has led to initiation of further studies to determine their role in the treatment of advanced melanoma, singly or in combination with other agents. In addition to evaluating new agents, more studies are needed to compare existing treatment modalities so that definitive treatment protocols can be formulated.
Acknowledgement
The authors would like to thank Felicia Ratnaraj, MD, for her assistance in creating the figures.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Click here to read the digital edition.
Melanoma is the most aggressive form of skin cancer, contributing to about 76,000 new cases and more than 9,000 deaths in 2014.1 Depending on the stage of the disease, 5-year melanoma survival can range from 15% to 97%. Patients with local and distant metastases have a 5-year survival of about 60% and 15%, respectively.2
The incidence of melanoma is rising, partly because of the increasing number of skin biopsies being performed.3 If melanoma is diagnosed early, surgical excision is the treatment of choice. In patients with oligometastatic disease (cancer that has spread, but only to 1 or a small number of sites), complete surgical excision of the metastases may provide prolonged overall survival (OS) and delay the need to use systemic therapy.4
Recently, many new drug therapies have shown promising results in clinical trials, which may improve the prognosis of metastatic disease. This article reviews currently available systemic treatment options for the management of metastatic melanoma, the role of cytotoxic chemotherapy and interleukin-2 (IL-2), and the latest therapies available, including immune checkpoint inhibitors.
Cytotoxic Chemotherapy and Interleukin-2
Cytotoxic chemotherapy does not have an established role in the initial treatment of metastatic melanoma. Currently, cytotoxic chemotherapy is used in patients who have not responded to immunotherapy or molecular targeted therapy. The most commonly used drugs include dacarbazine and its prodrug, temozolomide. Several studies have failed to demonstrate a survival benefit using a single-agent chemotherapy with either dacarbazine or temozolomide.5,6
Other agents used in metastatic melanoma include nitrosoureas (fotemustine), platinum compounds (cisplatin, carboplatin), vinca alkaloids (vincristine),
and taxanes (paclitaxel). None of these agents provide a survival benefit, but an objective response may be seen in a minority of cases. Combination chemotherapy regimens have not shown an advantage over singleagent dacarbazine or temozolomide.7,8
High-dose IL-2 has been used in cases of metastatic melanoma with good performance status (PS) and organ function. Studies have shown a complete response rate of 3% to 7% and a prolonged disease-free survival in a minority of patients.9-11 The use of highdose IL-2, however, is limited by the high incidence of adverse effects (AEs), which include bacterial sepsis, pulmonary edema, arrhythmias, fever, and on some occasions, death due to complications.10 The use of IL-2 requires admission of the patient to a specialized unit for AE monitoring and management. Because of its ability to “cure” a minority of patients, a role still exists for IL-2 therapy in the treatment of younger, healthy patients with no evidence of organ dysfunction at baseline.
Immune Checkpoint Inhibitors
Checkpoint inhibitors are a class of drugs that unmask the immune system to fight against cancer cells. This class of drugs has shown significant activity and survival advantage in recent phase 2 and 3 trials. The class includes the anticytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody ipilimumab and monoclonal antibodies targeting the programmed death 1 protein (PD-1) or its ligand (PD-L1).
Anti-CTLA-4 Antibodies: Ipilimumab
Cytotoxic T-lymphocyte antigen 4 is the antigen responsible for inhibition of cytotoxic T-cell-mediated immunity against foreign antigens presented by the antigen presenting cells (APCs). The APCs cause activation of the T cells when peptide fragments of intracellular proteins are presented in combination with mixed histocompatibility complex molecules. This step requires interaction of a costimulatory molecule (B7) on the APCs with a cluster of differentiation 28 protein (CD28) receptor located on T cells. CTLA-4 competes with CD28 to bind with the B7 molecule, thereby inhibiting the activation of the cytotoxic T cells (Figure 1). This pathway is thought to help with development of tolerance to host tissue antigens. Ipilimumab is a human monoclonal antibody that inhibits this CTLA-4 molecule and facilitates T-cell mediated antitumor activity.12 By blocking the CTLA-4 molecule, ipilimumab also mediates its autoimmune AEs on the host tissues.
Hodi and colleagues conducted a phase 3 trial of ipilimumab, including 676 patients who progressed after prior treatment for stage III or IV melanoma, and found that median OS was significantly better in the ipilimumab groups: 10 months in the ipilimumab plus gp100 peptide vaccine group vs 6.4 months in the gp100 vaccine alone group; 10.1 months in the ipilimumab alone group vs 6.4 months in the gp100 vaccine alone group.13 In another phase 3 trial comparing ipilimumab plus dacarbazine to dacarbazine alone, the ipilimumab group had a significantly improved OS (11.2 months vs 9.1 months).1 Survival rates with ipilimumab were prolonged for up to 3 years compared with the dacarbazine plus placebo group. However, the combination was associated with increased incidence of hepatotoxicity, thereby limiting its use.
A long-term survival analysis of 10 prospective and 2 retrospective studies of ipilimumab showed a median OS of 11.4 months and a long-term survival that began at 3 years with a plateau at 10 years of 21%, which was independent of prior therapy or ipilimumab dose.14 The immune-related AEs of ipilimumab are secondary to its activity against the host antigens and include dermatitis, enterocolitis, hepatitis, and endocrinopathies.15
A recent phase 2 trial studied the combination of ipilimumab with granulocyte-macrophage colonystimulating factor in 245 patients with stage III and IV melanoma. Median OS after 13 months was significantly higher with the combination compared with ipilimumab alone. The 1-year survival rate was 69% with
the combination and 53% with ipilimumab alone. There was no difference in the overall response rate (ORR) or progression-free survival (PFS) between the 2 groups. However, the AEs were significantly reduced with the combination (45% vs 58%).16 The dose of ipilimumab used in the trial was higher than the approved dose, making it difficult to apply the results in practice without further studies on the combination.
Anti-PD-1 Antibodies
Programmed death 1 ligands (PD-L1 and PD-L2) are expressed by tumor or stromal cells to inhibit the T-cell mediated antitumor activity. These ligands bind to the PD-1 protein on the surface of activated T cells to mediate their immunosuppressive effects. Interruption of this interaction by either anti-PD-1 antibodies or anti-PD-L1 antibodies facilitates tumor cell killing by activated T cells.17
Pembrozilumab and nivolumab are the 2 anti-PD-1 monoclonal antibodies that have been approved for treatment of metastatic melanoma. In a phase 1 trial
of pembrolizumab, 411 patients with advanced melanoma (consisting of both ipilimumab-naïve [IPI-N] and ipilimumab-treated [IPI-T] patients), ORR was 40% in IPI-N and 28% in IPI-T patients with a 1-year OS of 71% in all patients. Median PFS was 24 weeks in IPI-N and 23 weeks in IPI-T pts.18 There was no difference in outcomes and safety profiles across the various dosing regimens.18,19 Of note, pembrolizumab had antitumor activity irrespective of the PS, lactate dehydrogenase levels, BRAF (B-Raf proto-oncogene, serine/threonine kinase) gene mutation, metastatic stage, and number and type of prior therapy. In a subgroup analysis, 173 patients who had progression after treatment with ipilimumab were randomly assigned to pembrolizumab 2 mg/kg every 3 weeks (q3w) or 10 mg/kg q3w dosing regimens. Both groups had no significant difference in the ORR (26% in both) and safety profiles.20
In the 2012 KEYNOTE-002 clinical trial, a randomized phase 2 trial involving 540 patients with ipilimumab-refractory advanced melanoma, patients were randomized 1:1:1 to pembrolizumab 2 mg/kg or 10 mg/kg q3w or investigator-choice chemotherapy (control arm consisting of carboplatin plus paclitaxel, carboplatin, paclitaxel, dacarbazine, or temozolomide). The 6-month PFS was significantly improved with pembrolizumab (34% and 38% for pembrolizumab 2 mg/kg and 10 mg/kg, respectively) compared with 16% with chemotherapy. The ORR was significantly better with pembrolizumab (21% at 2 mg/kg, 25% at 10 mg/kg) compared with the control arm (4%).21 These findings led to the approval of pembrolizumab by the FDA for treatment of patients with advanced melanoma who have progressed on ipilimumab. Pembrolizumab is generally well tolerated. The most common AEs include fatigue, pruritus, and rash.
Nivolumab was studied in a recent phase 1 trial in which 107 patients with previously treated advanced melanoma were treated with escalated doses every
2 weeks.22 The 2-year and 3-year OS rates were 48% and 41%, respectively. Objective responses were seen in 32% of the patients. The median response duration was 23 months.23
The first phase 3 trial was conducted in 418 patients with previously untreated metastatic melanoma BRAF mutation. Patients were randomized to receive either nivolumab or dacarbazine. The PFS and OS were significantly better with nivolumab compared with dacarbazine (PFS 5.1 months vs 2.2 months; OS 73% vs 42% at 1 year).24 The AE profile of nivolumab is similar to pembrolizumab and includes lung, skin, endocrine, renal, and gastrointestinal tract toxicities.
Preliminary results of another phase 3 trial were presented at the European Society of Medical Oncology 2014 meeting. Patients with previously treated metastatic melanoma (ipilimumab or BRAF inhibitor) were randomized in a 2:1 ratio to receive either nivolumab or investigators’ choice chemotherapy (dacarbazine or carboplatin plus paclitaxel). The ORR was significantly better with nivolumab (32% vs 11%), and 95% of patients were still responding after 6 months. The nivolumab group showed a complete remission in 3% of the patients with 34% of the responses lasting ≥ 6 months.25 This led to the recent approval of nivolumab for patients with metastatic melanoma with a BRAF mutation who have advanced on ipilimumab. In the phase 3 NCT01844505 trial patients are being randomized to receive ipilimumab, nivolumab, or both.
A newer PD-1 inhibitor, pidilizumab, was studied in a phase 2 trial that included 103 patients with metastatic melanoma, 51% of whom had received therapy with ipilimumab. The ORR in the study group was relatively lower (6%), but the OS at 1 year was 64.5%.26 Further studies are underway to evaluate the role of this drug in metastatic melanoma.
The response with both nivolumab and pembrolizumab is durable as well as sustained, even after discontinuation of therapy. None of the deaths in the aforementioned studies were atributed to drug-related toxicities. As evidenced by current data, these 2 drugs hold a great promise for the management of patients who progress after therapy with anti-CTLA-4 antibodies.
Anti-PD-L1 Antibodies
The anti-PD-L1 monoclonal antibodies work in a similar way to the PD-1 inhibitors and block the interaction between the PD-1 and its ligand, PD-L1. This causes sustained activation of cytotoxic T cells and facilitates their antitumor activity. Two of PD-L1 inhibitors have shown clinical activity against metastatic melanoma.
BMS-936559, the first PD-L1 antibody, is being studied in a phase 1 trial that includes 55 patients with advanced melanoma along with 152 patients with other solid malignancies. Three patients achieved a complete response, and 5 patients had an objective response lasting 1 year. The ORR for melanoma was 17%, with disease stabilization of ≥ 24 weeks in 27% of the patients.27 Common AEs included infusion reactions, diarrhea, fatigue, rash, hypothyroidism, and hepatitis.
The second PD-L1 antibody, MPDL3280A, was studied in a phase 1 trial of 45 patients with metastatic melanoma. An ORR of 29% was observed, along with a 24-week PFS of 43%.28 Commonly noted AEs included hyperglycemia and elevated liver aminotransferases.
A newer PD-L1 inhibitor, MEDI4736, is being studied for advanced malignancies in 8 patients with melanoma. In preliminary analysis, MEDI4736 demonstrated a partial response in 1 out of 8 melanoma patients with a disease control rate of 46%.29 Although the PD-L1 inhibitors seem promising, more information will help discern their role in the management of metastatic melanoma.
Combined Anti-CTLA-4 Plus Anti-PD-1 Antibody
The combination of ipilimumab and the PD-1 inhibitor nivolumab was tested in a phase 1 trial in which both drugs were used concurrently as well as sequentially in metastatic melanoma.30 The 1- and 2-year OS in patients who were treated concurrently was 82% and 75%, respectively. Complete remission was seen in 17% of the patients, and the responses were seen irrespective of the BRAF mutation status. The responses were durable, and about 64% of the objective responses remain in remission at last follow-up.31 Grade 3 to grade 4 AEs were noted in 53% of the patients, with 11 patients requiring discontinuation of the medications. More studies are required to ascertain the optimum dosage of the combination prior to its approval for use in metastatic melanoma.
Molecular Targeted Therapy
The RAS-RAF–mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway is activated in almost 90% of patients
with melanoma.32 This pathway is normally required for the growth and survival of nonmalignant cells. In malignant transformation, mutations and/or overexpression is seen at various levels including KIT, NRAS, BRAF, and the MEK protein. This leads to activation of serine and threonine protein kinases, which lead to uncontrolled cell proliferation and survival.33
Novel therapeutic approaches have tried inhibiting one or more of these pathways for melanoma treatment. The most important mediator of tumorigenesis is BRAF, which is a downstream receptor of NRAS, and is mutated in almost 50% of melanoma cases.34 NRAS mutations are seen in 15% to 20% of cutaneous melanomas.35,36 After its activation, the RAF enzyme—coded by the BRAF gene—causes phosphorylation of the MEK protein, which activates ERK. This ERK activation leads to growth signaling and is the final pathway in several malignancies (Figure 2).37,38
BRAF Inhibitors
BRAF is the first mediator whose inhibition led to clinically significant outcomes in patients with melanoma. The most common BRAF mutation consists of the
substitution of glutamic acid for valine at amino acid 600 (V600E mutation) with majority of the remainder consisting of an alternate substitution (V600V or V600K).34 Vemurafenib and dabrafenib are the 2 BRAF inhibitors that have been shown to improve tumor regression, PFS, and OS considerably, especially in combination with a MEK protein inhibitor. In the phase 3 BRIM-3 trial, the vemurafenib group had a significantly prolonged PFS and OS compared with dacarbazine (13.6 months vs 9.7 months; 6.9 months vs 1.6 months, respectively). It was the first study to show improved survival with vemurafenib in both the V600E and V600K BRAF mutant melanomas.39
Another BRAF inhibitor, dabrafenib, was approved by the FDA for treatment of advanced melanoma with BRAF V600E mutation. It was tested in a phase 3 trial in which it was compared with dacarbazine in patients with advanced melanoma. Median OS in the dabrafenib arm was > 18 months and in dacarbazine arm > 15 months.40 Fifty-seven percent of the patients in dacarbazine arm were crossed over to the dabrafenib arm, thereby confounding the survival data for the former group. Another multicenter, phase 2 trial showed dabrafenib to have activity in melanoma patients with brain metastases, irrespective of previous therapy for the brain metastases.41 The long-term analysis of the BREAK-2 trial, which included 92 patients with metastatic melanoma treated with dabrafenib, showed a median OS of 12.9 months in BRAF V600K group and 13.1 months in BRAF V600E group.42
Adverse effects associated with BRAF inhibition include fatigue, rash, arthralgia, and photosensitivity reactions.43 Dermatologic complications may also include squamous cell carcinoma (SCC) (19%-26%), with keratoacanthoma being the most common subtype.44 These are believed to be likely secondary to the paradoxical activation of the MAPK signaling, since most of these lesions are found to have mutations in the RAS molecule.45 Other specific AEs of dabrafenib include hyperkeratosis (33%) and pyrexia (29%).42
Most patients treated with a BRAF inhibitor eventually have disease progression, likely secondary to reactivation of the MAPK pathway.46,47 This result has led to a heightened interest in combination therapies in an effort to improve outcomes. Combination therapy with ipilimumab and vemurafenib was studied and resulted in a higher incidence of hepatotoxicity (50%).48 However, no hepatotoxicity was seen in a phase 1 trial of combined dabrafenib and ipilimumab.49
Some studies have also suggested that extended BRAF inhibition after progression on a BRAF inhibitor may prolong survival.50,51 The phase 2 trial NCT01983124 is being conducted to evaluate the survival benefit with a combination of vemurafenib and a nitrosourea alkylating agent, fotemustine, in patients who have progressed on vemurafenib alone.
MEK Inhibitors
The inhibition of MEK can halt cell proliferation and induce apoptosis. The phase 3 METRIC trial, which compared the oral MEK inhibitor (trametinib) with chemotherapy, was conducted in 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation. The PFS and 6-month OS were significantly better with trametinib (4.8 months vs 1.5 months, 81% vs 66%) despite the crossover between the 2 groups.52 The AEs associated with trametinib included rash, diarrhea, and peripheral edema. Another phase 2 trial of trametinib including patients pretreated with a BRAF inhibitor showed no confirmed objective responses, 28% patients with stable disease, and minimal improvement in PFS (2 months). Among patients treated with prior chemotherapy and/or immunotherapy, trametinib showed significant improvement in complete responses, partial responses, stable disease, and the median PFS (2%, 23%, 51%, 4 months, respectively).53
The second MEK inhibitor, binimetinib, was studied in a phase 2 trial of advanced melanoma cases harboring a BRAF V600E or NRAS. Bimetinib demonstrated a PR in 20% cases of both the BRAF and NRAS mutant melanomas. Durable disease control was seen in 43% of the NRAS group and 32% of the BRAF group.54 The AE profile was similar to that seen with trametinib. Bimetinib is being studied in phase 1 and 2 trials with the CDK4/6 inhibitor as well as in the phase 3 trial NCT01763164 compared with dacarbazine in NRAS mutation positive melanomas.55
Selumetinib is a MEK inhibitor that has been compared with dacarbazine and temozolomide with no significant OS advantage. A novel highly specific inhibitor of MEK, cobimetinib, is currently being studied in combination with BRAF inhibitors.
Combined BRAF and MEK Inhibition
A randomized, double-blind, phase 3 study comparing the combination of dabrafenib and trametinib with dabrafenib and placebo in patients with advanced melanoma with a BRAF V600E mutation was presented at the 2014 American Society of Clinical Oncology meeting. Researchers found that after a median follow-up period of 9 months, there was a significant improvement with the combination in the PFS (9.3 months vs 8.8 months) and the ORR (67% vs 51%), with a similar incidence of AEs.56 The combination therapy group had fewer incidences of SCC of the skin but more incidence of pyrexia.
The combination of dabrafenib and trametinib was compared with vemurafenib monotherapy in a recent randomized phase 3 trial among 704 metastatic melanoma patients with a BRAF V600 mutation. Median PFS and ORR were significantly better with combination therapy compared with vemurafenib alone (11.4 months vs 7.3 months, 64% vs 51%, respectively). Overall survival rate at 1 year was significantly improved in the combination group as well (72% vs 65%).57 The incidence of SCC and keratoacanthoma was less in the combination (1%) compared with vemurafenib alone (18%). Another study investigating the coadministration and sequential administration of vemurafenib and trametinib is underway.58
The vemurafenib and cobimetinib combination was studied in a phase 3 trial of previously untreated unresectable locally advanced or metastatic BRAF V600
mutation-positive melanoma. The median PFS was 9.9 months in the combination group and 6.2 months in the control group. The interim analysis showed a 9-month survival rate of 81% in the combination group and 73% in the control group, with no significantly higher incidence of AEs in either arm.59 A longer follow-up will be needed to assess the OS benefit with the combination.
Encorafenib, a selective BRAF inhibitor, has been studied in a phase 1 trial in combination with binimetinib.60 This trial has paved the way to the initiation of a currently ongoing phase 3 trial (NCT01909453) comparing the combination with vemurafenib or encorafenib alone.
C-KIT Inhibitors
Mutations of c-KIT are seen more commonly in chronic sun damage-induced cutaneous melanomas, along with acral and mucosal melanomas.61,62 Earlier trials involving patients without selection for c-KIT mutation positivity failed to show benefit with imatinib. A single-arm, phase 2 trial of imatinib mesylate in patients with metastatic melanoma harboring the c-KIT mutation, an ORR of 23% was achieved, with a median PFS of 3.5 months.63 Imatinib showed an ORR of 29% in a phase 2 trial of mucosal, acral, and in chronic sun damage-induced melanoma patients with c-KIT amplifications and/or mutations. It was demonstrated that c-KIT amplification alone is not as responsive to imatinib compared with c-KIT mutation, suggesting that all patients with these specific melanomas should be tested for KIT mutation status.64
A second-generation c-KIT inhibitor, nilotinib, has shown some promising results with a favorable AE profile in small phase 2 trials.65,66 However, more clinical research will be needed before definite recommendations on its use in cutaneous melanomas can be made. Currently, its role seems to be limited to the management of acral, mucosal, and chronic sun damage-related melanomas with c-KIT mutations.
Future Directions
Angiogenesis promoters, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor, fibroblast growth factor, and interleukin-8, are overexpressed in melanoma. Bevacizumab, an anti-VEGF antibody, has been shown to have some benefit in combination with carboplatin and paclitaxel as a triple therapy.67 However, grade 3 AEs were seen in a portion of patients.
The phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway has also been studied as a target for melanoma therapy. Everolimus, an mTOR inhibitor, was studied in a phase 2 trial in combination with bevacizumab for treatment of metastatic melanoma. The combination showed improved median PFS and OS with the combination (4 months and 8.6 months, respectively), with 43% of patients alive after 12 months of follow-up.68 This study points to the direction of possible benefits with the combination of anti-VEGF and immunotherapy. A recent study failed to show survival advantage with combination of bevacizumab and temozolomide.69
Buparlisib (BKM120), a PI3K inhibitor, has been shown to have activity in vivo and in vitro against melanoma brain metastases.70 More studies need to be done to assess the possible combination with other established therapies.
Oblimersen is an antisense oligonucleotide that suppresses B-cell lymphoma-2, thereby suppressing its anti-apoptotic effect. The triple combination of oblimersen with temozolomide and albumin-bound paclitaxel has shown to be safe and efficacious in a phase 1 trial, thereby creating a need for further clinical trials.71
Treatment Approach
Systemic therapy for metastatic melanoma depends on several factors, including BRAF mutation status, functional status of the patient, disease burden, and severity of symptoms. Assessing the BRAF mutation status has become an important component in the management of patients with metastatic melanoma. It can help recognize patients who will benefit from molecular targeted therapy. In case of a BRAF-positive melanoma, treatment can be initiated with either immunotherapy or BRAF inhibitors. There are no randomized studies comparing immunotherapy to molecular targeted therapy.
Patients who have good PS and lymph node metastases can be treated initially with IL-2, which has the advantage of inducing cure in a minority of patients but should only be considered in patients with well-preserved organ function who can be monitored in an intensive care setting. On the other hand, patients who have bulky, symptomatic disease and poor PS should be treated initially with BRAF inhibitors. Combination of BRAF and MEK inhibitors can also be used and has an improved PFS and OS with potential to cause early tumor regression. There are studies to suggest suboptimal outcomes in patients who are treated with ipilimumab after progression on a BRAF inhibitor compared with initial treatment with ipilimumab followed by a BRAF inhibitor.72-74 However, all these studies are retrospective and there is no prospective data to suggest the above. BRAF mutation-positive patients who progress on a BRAF inhibitor
can be treated with PD-1 inhibitors.
Patients who do not have a BRAF mutation are unlikely to benefit from a BRAF inhibitor and primarily receive immunotherapy with ipilimumab or IL-2. Whenever possible, such patients should be enrolled in a clinical trial, as they have a poor prognosis. Patients who progress on ipilimumab can be treated with one of the PD-1 inhibitors (pembrolizumab, nivolumab). These PD-L1 inhibitors are still being investigated for use in such situations.
The role of chemotherapy in the management of metastatic melanoma has been limited by numerous studies showing significantly better survival with immunotherapy and molecular targeted therapy. Dacarbazine is the only FDA-approved drug for the treatment of melanoma. Its use is reserved mainly for patients who are not candidates for any of the other therapies available, including enrollment in a clinical trial.
Conclusion
Therapies for metastatic melanoma are in a state of flux. In the past decade, several new therapeutic agents have been introduced for the management of this potentially lethal disease. The treatment of metastatic melanoma has gradually shifted from cytotoxic chemotherapy toward a more individualized treatment that has a definite survival advantage over traditional counterparts. The advent of novel therapies has led to initiation of further studies to determine their role in the treatment of advanced melanoma, singly or in combination with other agents. In addition to evaluating new agents, more studies are needed to compare existing treatment modalities so that definitive treatment protocols can be formulated.
Acknowledgement
The authors would like to thank Felicia Ratnaraj, MD, for her assistance in creating the figures.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Click here to read the digital edition.
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14. Schadendorf D, Hodi FS, Robert C, et. al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma [published online ahead of print February 9, 2015]. J Clin Oncol. pii:JCO.2014.56.2736.
15. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-2697.
16. Hodi FS, Lee S, McDermott DF, et al. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA. 2014;312(17):1744-1753.
17. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-2454.
18. Ribas A, Hodi FS, Kefford R, et al. Efficacy and safety of the anti-PD-1 monoclonal antibody pembrolizumab (MK-3475) in 411 patients (pts) with melanoma (MEL) (Abstract LBA9000). Paper presented at: 2014 American Society of Clinical Oncology (ASCO) meeting; May-June 2014; Chicago, IL.
19. Hamid O, Robert C, Ribas A, et al. Randomized comparison of two doses of the anti-PD-1 monoclonal antibody MK-3475 for ipilimumab-refractory (IPI-R) and IPI-naive (IPI-N) melanoma (MEL) (abstract 3000). Paper presented at: 2014 American Society of Clinical Oncology (ASCO) meeting; May-June 2014; Chicago, IL.
20. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014; 384(9948):1109-1117.
21. Dummer R, Daud A, Puzanov I, et. al. A randomized controlled comparison of pembrolizumab and chemotherapy in patients with ipilimumab-refractory melanoma. J Transl Med. 2015;13(suppl 1):O5.
22. Topalian SL, Sznol M, McDermott DF, et. al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32(10):1020-1030.
23. Hodi FS, Sznol M, Kluger HM, et al. Long-term survival of ipilimumab-naive patients with advanced melanoma (MEL) treated with nivolumab (anti-PD-1, BMS-936558, ONO-4538) in a phase I trial (abstract 9002). Paper presented at: 2014 American Society of Clinical Oncology (ASCO) meeting; May-June 2014; Chicago, IL.
24. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320-330.
25. Weber J, D’Angelo S, Gutzmer R, et al. A phase 3 randomized, open-label study of nivolumab versus investigator’s choice of chemotherapy in patients with advanced melanoma after prior anti-CTLA4 therapy (abstract LBA3). Paper presented at: European Society of Medical Oncology 2014 meeting; September 2014; Madrid, Spain.
26. Atkins MB, Kudchadkar RR, Sznol M, et al. Phase 2, multicenter, safety and efficacy study of pidilizumab in patients with metastatic melanoma (abstract 9001). Paper presented at: 2014 American Society of Clinical Oncology (ASCO) meeting; May-June 2014; Chicago, IL.
27. Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455-2465.
28. Hamid O, Sosman JA, Lawrence DP, et. al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mM). J Clin Oncol. 2013;31(15)(suppl): Abstract 9010.
29. Lutzky J, Antonia SJ, Blake-Haskins A, et. al. A phase 1 study of MEDI4736, an anti–PD-L1 antibody, in patients with advanced solid tumors. J Clin Oncol. 2014;32(15)(suppl): Abstract 3001.
30. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced
melanoma. N Engl J Med. 2013;369(2):122-133.
31. Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL) (abstract LBA9003). Paper presented at: 2014 American Society of Clinical Oncology (ASCO) meeting; May-June 2014; Chicago, IL.
32. Omholt K, Platz A, Kanter L, Ringborg U, Hansson J. NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res. 2003;9(17):6483-6488.
33. Wellbrock C, Hurlstone A. BRAF as therapeutic target in melanoma. Biochem Pharmacol. 2010;80(5):561-567.
34. Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29(10):1239-1246.
35. Ball NJ, Yohn JJ, Morelli JG, et al. Ras mutations in human melanoma: a marker of malignant progression. J Invest Dermatol. 1994;102(3):285-290.
36. Platz A, Ringborg U, Brahme EM, Lagerlöf B. Melanoma metastases from patients with hereditary cutaneous malignant melanoma contain a high frequency of N-ras activating mutations. Melanoma Res. 1994;4(3):169-177.
37. Beeram M, Patnaik A, Rowinsky EK. Raf: a strategic target for therapeutic development against cancer. J Clin Oncol. 2005;23(27):6771-6790.
38. Terai K, Matsuda M. The amino-terminal B-Raf-specific region mediates calcium-dependent homo- and hetero-dimerization of Raf. EMBO J. 2006;25(15):3556-3564.
39. McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;15(3):323-332.
40. Hauschild A, Grob JJ, Demidov LV, et al. An update on BREAK-3, a phase III, randomized trial: dabrafenib versus dacarbazine in patients with BRAF V600E-positive mutation metastatic melanoma (Abstract 9013). Paper presented at: American Society of Clinical Oncology 2013 meeting; May-June 2013; Chicago, IL.
41. Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(11):1087-1095.
42. Ascierto PA, Minor DR, Ribas A, et. al., Long-term safety and overall survival update for BREAK-2, a phase 2, single-arm, open-label study of dabrafenib in previously treated metastatic melanoma (NCT01153763). J Clin Oncol. 2014;32(15)(suppl): Abstract 9034.
43. Larkin J, Del Vecchio M, Ascierto PA, et al. Vemurafenib in patients with
BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety
study. Lancet Oncol. 2014;15(4):436-444.
44. Lacouture ME, Duvic M, Hauschild A, et al. Analysis of dermatologic events in vemurafenib-treated patients with melanoma. Oncologist. 2013;18(3):314-322.
45. Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366(3):207-215.
46. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-2516.
47. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358-365.
48. Ribas A, Hodi FS, Callahan M, et. al. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2014;368(14):1365-1366.
49. Linette GP, Puzanov I, Callahan MK, et al. Phase 1 study of the BRAF inhibitor dabrafenib (D) with or without the MEK inhibitor trametinib (T) in combination with ipilimumab (Ipi) for V600E/K mutation–positive unresectable or metastatic melanoma (MM). J Clin Oncol. 2014;32(15)(suppl): Abstract 2511.
50. Chan MMK, Haydu LE, Menzies AM, et al. The nature and management of metastatic melanoma after progression on BRAF inhibitors: effects of extended BRAF inhibition. Cancer. 2014;120(20):3142-3153.
51. Carlino MS, Gowrishankar K, Saunders CAB, et al. Antiproliferative effects of continued mitogen-activated protein kinase pathway inhibition following acquired resistance to BRAF and/or MEK inhibition in melanoma. Mol Cancer Ther. 2013;12(7):1332-1342.
52. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107-114.
53. Kim KB, Kefford R, Pavlick AC, et. al. Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol. 2013;31(1):482-489.
54. Ascierto PA, Schadendorf D, Berking C, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 2013;14(3):249-256.
55. Sosman JA, Kittaneh M, Lolkema MP, et al. A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRAS-mutant melanoma: early encouraging clinical activity (abstract 9009). Paper presented at: 2014 American Society of Clinical Oncology meeting ; May-June 2014; Chicago, IL.
56. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877-1888.
57. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30-39.
58. Gogas H, Schadendorf D, Dummer R. Vemurafenib treatment in patients with BRAF-mutated melanoma failing MEK inhibition with trametinib. J Clin Oncol. 2014;32(15)(suppl): Abstract 9061.
59. Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867-1876.
60. Kefford R, Miller WH, Tan DS, et al. Preliminary results from a phase Ib/II, openlabel, dose-escalation study of the oral BRAF inhibitor LGX818 in combination with the oral MEK1/2 inhibitor MEK162 in BRAF V600-dependent advanced solid tumors (abstract 9019). Paper presented at: 2013 American Society of Clinical Oncology meeting; May-June 2014; Chicago, IL.
61. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct
subtypes of melanoma. J Clin Oncol. 2006;24(26):4340-4346.
62. Jin SA, Chun SM, Choi YD, et al. BRAF mutations and KIT aberrations and their clinicopathological correlation in 202 Korean melanomas. J Invest Dermatol. 2013;133(2):579-582.
63. Guo J, Si L, Kong Y et. al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol. 2011;29(21):2904-2909.
64. Hodi FS, Corless CL, Giobbie-Hurder A, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol. 2013;31(26):3182-3190.
65. Cho JH, Kim KM, Kwon M, Kim JH, Lee J. Nilotinib in patients with metastatic melanoma harboring KIT gene aberration. Invest New Drugs. 2012;30(5): 2008-2014.
66. Lebbe C, Chevret S, Jouary T, et. al. Phase II multicentric uncontrolled national trial assessing the efficacy of nilotinib in the treatment of advanced melanomas with c-KIT mutation or amplification. J Clin Oncol. 2014;32(15)(suppl): Abstract 9032.
67. Perez DG, Suman VJ, Fitch TR, et al. Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N047A. Cancer. 2009;115(1):119-127.
68. Hainsworth JD, Infante JR, Spigel DR, et al. Bevacizumab and everolimus in the treatment of patients with metastatic melanoma. Cancer. 2010;116(17): 4122-4129.
69. Dronca RS, Allred JB, Perez DG, et. al. Phase II study of temozolomide (TMZ) and everolimus (RAD001) therapy for metastatic melanoma: a North Central Cancer Treatment Group study, N0675. Am J Clin Oncol. 2014;37(4):369-376.
70. Meier FE, Niessner H, Schmitz J, et al. The PI3K inhibitor BKM120 has potent antitumor activity in melanoma brain metastases in vitro and in vivo. J Clin Oncol. 2013;31(15)(suppl): Abstract e20050.
71. Ott PA, Chang J, Madden K, et al. Oblimersen in combination with temozolomide and albumin-bound paclitaxel in patients with advanced melanoma: a phase I trial. Cancer Chemother Pharmacol. 2013;71(1);183-191.
72. Ackerman A, Klein O, McDermott DF, et al. Outcomes of patients with metastatic
melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer. 2014;120(11):1695-1701.
73. Ascierto PA, Margolin K. Ipilimumab before BRAF inhibitor treatment may be
more beneficial than vice versa for the majority of patients with advanced melanoma.
Cancer. 2014;120(11):1617-1619.
74. Ascierto PA, Simeone E, Sileni VC, et al. Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from the Italian cohort of the ipilimumab expanded access program. Cancer Invest. 2014;32(4):144-149.
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or without sorafenib in metastatic melanoma. J Clin Oncol. 2013;31(3):373-379.
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11. Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000;6(suppl 1):S11-S14.
12. Hoos A, Ibrahim R, Korman A, et al. Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy. Semin Oncol. 2010;37(5):533-546.
13. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723.
14. Schadendorf D, Hodi FS, Robert C, et. al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma [published online ahead of print February 9, 2015]. J Clin Oncol. pii:JCO.2014.56.2736.
15. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-2697.
16. Hodi FS, Lee S, McDermott DF, et al. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA. 2014;312(17):1744-1753.
17. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-2454.
18. Ribas A, Hodi FS, Kefford R, et al. Efficacy and safety of the anti-PD-1 monoclonal antibody pembrolizumab (MK-3475) in 411 patients (pts) with melanoma (MEL) (Abstract LBA9000). Paper presented at: 2014 American Society of Clinical Oncology (ASCO) meeting; May-June 2014; Chicago, IL.
19. Hamid O, Robert C, Ribas A, et al. Randomized comparison of two doses of the anti-PD-1 monoclonal antibody MK-3475 for ipilimumab-refractory (IPI-R) and IPI-naive (IPI-N) melanoma (MEL) (abstract 3000). Paper presented at: 2014 American Society of Clinical Oncology (ASCO) meeting; May-June 2014; Chicago, IL.
20. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014; 384(9948):1109-1117.
21. Dummer R, Daud A, Puzanov I, et. al. A randomized controlled comparison of pembrolizumab and chemotherapy in patients with ipilimumab-refractory melanoma. J Transl Med. 2015;13(suppl 1):O5.
22. Topalian SL, Sznol M, McDermott DF, et. al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32(10):1020-1030.
23. Hodi FS, Sznol M, Kluger HM, et al. Long-term survival of ipilimumab-naive patients with advanced melanoma (MEL) treated with nivolumab (anti-PD-1, BMS-936558, ONO-4538) in a phase I trial (abstract 9002). Paper presented at: 2014 American Society of Clinical Oncology (ASCO) meeting; May-June 2014; Chicago, IL.
24. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320-330.
25. Weber J, D’Angelo S, Gutzmer R, et al. A phase 3 randomized, open-label study of nivolumab versus investigator’s choice of chemotherapy in patients with advanced melanoma after prior anti-CTLA4 therapy (abstract LBA3). Paper presented at: European Society of Medical Oncology 2014 meeting; September 2014; Madrid, Spain.
26. Atkins MB, Kudchadkar RR, Sznol M, et al. Phase 2, multicenter, safety and efficacy study of pidilizumab in patients with metastatic melanoma (abstract 9001). Paper presented at: 2014 American Society of Clinical Oncology (ASCO) meeting; May-June 2014; Chicago, IL.
27. Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455-2465.
28. Hamid O, Sosman JA, Lawrence DP, et. al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mM). J Clin Oncol. 2013;31(15)(suppl): Abstract 9010.
29. Lutzky J, Antonia SJ, Blake-Haskins A, et. al. A phase 1 study of MEDI4736, an anti–PD-L1 antibody, in patients with advanced solid tumors. J Clin Oncol. 2014;32(15)(suppl): Abstract 3001.
30. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced
melanoma. N Engl J Med. 2013;369(2):122-133.
31. Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL) (abstract LBA9003). Paper presented at: 2014 American Society of Clinical Oncology (ASCO) meeting; May-June 2014; Chicago, IL.
32. Omholt K, Platz A, Kanter L, Ringborg U, Hansson J. NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res. 2003;9(17):6483-6488.
33. Wellbrock C, Hurlstone A. BRAF as therapeutic target in melanoma. Biochem Pharmacol. 2010;80(5):561-567.
34. Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29(10):1239-1246.
35. Ball NJ, Yohn JJ, Morelli JG, et al. Ras mutations in human melanoma: a marker of malignant progression. J Invest Dermatol. 1994;102(3):285-290.
36. Platz A, Ringborg U, Brahme EM, Lagerlöf B. Melanoma metastases from patients with hereditary cutaneous malignant melanoma contain a high frequency of N-ras activating mutations. Melanoma Res. 1994;4(3):169-177.
37. Beeram M, Patnaik A, Rowinsky EK. Raf: a strategic target for therapeutic development against cancer. J Clin Oncol. 2005;23(27):6771-6790.
38. Terai K, Matsuda M. The amino-terminal B-Raf-specific region mediates calcium-dependent homo- and hetero-dimerization of Raf. EMBO J. 2006;25(15):3556-3564.
39. McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;15(3):323-332.
40. Hauschild A, Grob JJ, Demidov LV, et al. An update on BREAK-3, a phase III, randomized trial: dabrafenib versus dacarbazine in patients with BRAF V600E-positive mutation metastatic melanoma (Abstract 9013). Paper presented at: American Society of Clinical Oncology 2013 meeting; May-June 2013; Chicago, IL.
41. Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(11):1087-1095.
42. Ascierto PA, Minor DR, Ribas A, et. al., Long-term safety and overall survival update for BREAK-2, a phase 2, single-arm, open-label study of dabrafenib in previously treated metastatic melanoma (NCT01153763). J Clin Oncol. 2014;32(15)(suppl): Abstract 9034.
43. Larkin J, Del Vecchio M, Ascierto PA, et al. Vemurafenib in patients with
BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety
study. Lancet Oncol. 2014;15(4):436-444.
44. Lacouture ME, Duvic M, Hauschild A, et al. Analysis of dermatologic events in vemurafenib-treated patients with melanoma. Oncologist. 2013;18(3):314-322.
45. Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366(3):207-215.
46. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-2516.
47. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358-365.
48. Ribas A, Hodi FS, Callahan M, et. al. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2014;368(14):1365-1366.
49. Linette GP, Puzanov I, Callahan MK, et al. Phase 1 study of the BRAF inhibitor dabrafenib (D) with or without the MEK inhibitor trametinib (T) in combination with ipilimumab (Ipi) for V600E/K mutation–positive unresectable or metastatic melanoma (MM). J Clin Oncol. 2014;32(15)(suppl): Abstract 2511.
50. Chan MMK, Haydu LE, Menzies AM, et al. The nature and management of metastatic melanoma after progression on BRAF inhibitors: effects of extended BRAF inhibition. Cancer. 2014;120(20):3142-3153.
51. Carlino MS, Gowrishankar K, Saunders CAB, et al. Antiproliferative effects of continued mitogen-activated protein kinase pathway inhibition following acquired resistance to BRAF and/or MEK inhibition in melanoma. Mol Cancer Ther. 2013;12(7):1332-1342.
52. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107-114.
53. Kim KB, Kefford R, Pavlick AC, et. al. Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol. 2013;31(1):482-489.
54. Ascierto PA, Schadendorf D, Berking C, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 2013;14(3):249-256.
55. Sosman JA, Kittaneh M, Lolkema MP, et al. A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRAS-mutant melanoma: early encouraging clinical activity (abstract 9009). Paper presented at: 2014 American Society of Clinical Oncology meeting ; May-June 2014; Chicago, IL.
56. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877-1888.
57. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30-39.
58. Gogas H, Schadendorf D, Dummer R. Vemurafenib treatment in patients with BRAF-mutated melanoma failing MEK inhibition with trametinib. J Clin Oncol. 2014;32(15)(suppl): Abstract 9061.
59. Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867-1876.
60. Kefford R, Miller WH, Tan DS, et al. Preliminary results from a phase Ib/II, openlabel, dose-escalation study of the oral BRAF inhibitor LGX818 in combination with the oral MEK1/2 inhibitor MEK162 in BRAF V600-dependent advanced solid tumors (abstract 9019). Paper presented at: 2013 American Society of Clinical Oncology meeting; May-June 2014; Chicago, IL.
61. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct
subtypes of melanoma. J Clin Oncol. 2006;24(26):4340-4346.
62. Jin SA, Chun SM, Choi YD, et al. BRAF mutations and KIT aberrations and their clinicopathological correlation in 202 Korean melanomas. J Invest Dermatol. 2013;133(2):579-582.
63. Guo J, Si L, Kong Y et. al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol. 2011;29(21):2904-2909.
64. Hodi FS, Corless CL, Giobbie-Hurder A, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol. 2013;31(26):3182-3190.
65. Cho JH, Kim KM, Kwon M, Kim JH, Lee J. Nilotinib in patients with metastatic melanoma harboring KIT gene aberration. Invest New Drugs. 2012;30(5): 2008-2014.
66. Lebbe C, Chevret S, Jouary T, et. al. Phase II multicentric uncontrolled national trial assessing the efficacy of nilotinib in the treatment of advanced melanomas with c-KIT mutation or amplification. J Clin Oncol. 2014;32(15)(suppl): Abstract 9032.
67. Perez DG, Suman VJ, Fitch TR, et al. Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N047A. Cancer. 2009;115(1):119-127.
68. Hainsworth JD, Infante JR, Spigel DR, et al. Bevacizumab and everolimus in the treatment of patients with metastatic melanoma. Cancer. 2010;116(17): 4122-4129.
69. Dronca RS, Allred JB, Perez DG, et. al. Phase II study of temozolomide (TMZ) and everolimus (RAD001) therapy for metastatic melanoma: a North Central Cancer Treatment Group study, N0675. Am J Clin Oncol. 2014;37(4):369-376.
70. Meier FE, Niessner H, Schmitz J, et al. The PI3K inhibitor BKM120 has potent antitumor activity in melanoma brain metastases in vitro and in vivo. J Clin Oncol. 2013;31(15)(suppl): Abstract e20050.
71. Ott PA, Chang J, Madden K, et al. Oblimersen in combination with temozolomide and albumin-bound paclitaxel in patients with advanced melanoma: a phase I trial. Cancer Chemother Pharmacol. 2013;71(1);183-191.
72. Ackerman A, Klein O, McDermott DF, et al. Outcomes of patients with metastatic
melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer. 2014;120(11):1695-1701.
73. Ascierto PA, Margolin K. Ipilimumab before BRAF inhibitor treatment may be
more beneficial than vice versa for the majority of patients with advanced melanoma.
Cancer. 2014;120(11):1617-1619.
74. Ascierto PA, Simeone E, Sileni VC, et al. Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from the Italian cohort of the ipilimumab expanded access program. Cancer Invest. 2014;32(4):144-149.
For Latinos, misperceptions and lack of medical care make preventing melanoma risky business
ORLANDO – Ignorance and exposure are teaming up to put Latinos in the bull’s-eye of skin cancer.
Many believe that they are not at risk for either melanoma or nonmelanoma skin cancers – and too often, their physicians believe the same, Maritza Perez, MD, said at the annual meeting of the American Academy of Dermatology. Because of such incorrect perceptions, Latino patients get little counseling about risky behaviors, and so their exposure to those dangers continues unabated.
“The behavior of many Hispanic patients is very risky,” said Dr. Perez, a clinical professor of dermatology, at Mount Sinai Medical Center, New York. “They don’t wear sunscreen. They don’t do skin self-exams. They use tanning beds. And because of these beliefs, they don’t educate their children about sun safety.”
A research letter published in the Journal of the American Academy of Dermatology in 2011 broke down levels of skin cancer awareness by race and ethnicity among 165 whites, Hispanics, blacks, and Asians surveyed in New York City (64[1]:198-200). Compared with whites, Hispanics were significantly less likely to have ever had a doctor perform a full body skin exam (21% vs. 61%) or to have performed a self-exam (37% vs. 54%). Significantly fewer believed that skin cancer could occur in darker skin (78% vs. 91%). Only 8% had heard of the ABCDs of early melanoma detection, compared with 27% of whites. And about half as many Hispanics said they wore sunscreen (55% vs. 96%).
Unfortunately, Dr. Perez said, doctors aren’t correcting these misperceptions. Many physicians display a similar lack of understanding. They may correctly believe that the risk for skin cancer is less among Hispanics than it is among whites overall, but fail to communicate individual risk.
What these physicians may not understand, Dr. Perez said, is that the Hispanic population comprises an incredible variety of ethnic backgrounds. The population’s centuries-long genetic mixing bowl means there is no “typical” Hispanic skin. Instead, it includes every Fitzpatrick skin type, from fair-skinned redheads to the darkest brown and black skins.
Inadequate healthcare access exerts yet another damaging force. Like other ethnic minorities, many Hispanic patients lack insurance or adequate access to medical care. Instead of seeking regular primary care that would include skin cancer screenings, they tend to rely on urgent care or emergency departments to address emergent health issues, Dr. Perez said. When primary and preventive care falls by the wayside, melanomas that could be diagnosed at a curable stage invariably progress.
“We know that the only way of curing melanoma is with a scalpel. And the only way to remove it is by treating early disease. We’re not doing that. Our melanoma patients are diagnosed at younger ages with more advanced disease with more lymph node involvement than Caucasians, so there is also more mortality. We achieve early-stage diagnosis in 91% of Caucasians, but only 74% of Hispanics.”
A 2011 paper on racial and ethnic variations in the incidence and survival of melanoma, based on national cancer registry data covering almost 70% of the U.S. population, from 1999-2006, provided more information on the differences between the white and Hispanic populations (J Am Acad Dermatol. 2011 Nov;65[5 Suppl 1]:S26-37). Compared with non-Hispanic whites, Hispanics presented with thicker tumors (more than 1 mm, 35% vs. 25%), more regional involvement (12% vs. 8%), and more distant metastasis (7% vs. 4%).
Because adult Hispanic patients lack knowledge about their melanoma risk, they aren’t improving the outlook for their children, Dr. Perez said. The Hispanic demographic in the United States is already a young one. According on 2014 data cited by the Pew Research Center, 58% of Hispanics in the United States are aged 33 years or younger; 32% are younger than 18 years.
These young people are already endangering their health with unsafe sun behavior, Dr. Perez said. A 2007 study surveyed 369 white Hispanic and white non-Hispanic high school students in Miami about sun protection behaviors and skin cancer risk. The Hispanic teens were 2.5 times more likely to have used a tanning bed in the previous year; they were also less likely to wear sunscreen and protective clothing. The Hispanic students generally believed they were less likely to get skin cancer than the Caucasian students. They were 60% less likely to have heard of a skin self-exam and 70% less likely to have been told how to do one (Arch Dermatol. 2007;143[8]:983-8).
The oil to calm these troubled waters is education, Dr. Perez said. She takes this commitment very seriously, and said a simple conversation is the first step.
“I tell all my patients, no matter what ethnicity you are or what skin type you have, you can get skin cancer and you need regular, complete skin exams. And I teach them to do this for themselves.”
A senior vice-president for the Skin Cancer Foundation, Dr. Perez is coauthor of “Understanding Melanoma: What You Need to Know,” which is now in its fifth edition.
The book, originally published in 1996, is aimed at melanoma patients and their families. It covers the four types of melanoma and their causes and risk factors. Information on melanoma diagnosis, staging, treatment options, prognosis, and hereditary and genetic factors is also included, as well as guidelines for prevention.
The updated edition contains information on the latest immunotherapy and genetically targeted treatments, including ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), vemurafenib (Zelboraf), dabrafenib (Tafinlar) and trametinib (Mekinist). The book is available for download for a nominal fee.
She has also committed to educating physicians about the issue.
“If we want to decrease the incidence of melanoma in Latinos, decrease the tumor depth at diagnosis and bring down the higher mortality, we have to first educate the doctors who are taking care of these patients and correct the message delivered to Latinos by telling them that they are as prone to skin cancer as Caucasians. We simply have to get the message across that, just like everyone else, they need protection from the sun by applying sunblocks, using sunglasses, and covering their bodies with sun-protective clothing and large-rim hats. And we have to make medical care more accessible so that these people can be diagnosed and saved. This is what we need to do now. But I don’t know how many decades it will take to turn the tables.”
Dr. Perez had no disclosures relevant to her lecture.
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
ORLANDO – Ignorance and exposure are teaming up to put Latinos in the bull’s-eye of skin cancer.
Many believe that they are not at risk for either melanoma or nonmelanoma skin cancers – and too often, their physicians believe the same, Maritza Perez, MD, said at the annual meeting of the American Academy of Dermatology. Because of such incorrect perceptions, Latino patients get little counseling about risky behaviors, and so their exposure to those dangers continues unabated.
“The behavior of many Hispanic patients is very risky,” said Dr. Perez, a clinical professor of dermatology, at Mount Sinai Medical Center, New York. “They don’t wear sunscreen. They don’t do skin self-exams. They use tanning beds. And because of these beliefs, they don’t educate their children about sun safety.”
A research letter published in the Journal of the American Academy of Dermatology in 2011 broke down levels of skin cancer awareness by race and ethnicity among 165 whites, Hispanics, blacks, and Asians surveyed in New York City (64[1]:198-200). Compared with whites, Hispanics were significantly less likely to have ever had a doctor perform a full body skin exam (21% vs. 61%) or to have performed a self-exam (37% vs. 54%). Significantly fewer believed that skin cancer could occur in darker skin (78% vs. 91%). Only 8% had heard of the ABCDs of early melanoma detection, compared with 27% of whites. And about half as many Hispanics said they wore sunscreen (55% vs. 96%).
Unfortunately, Dr. Perez said, doctors aren’t correcting these misperceptions. Many physicians display a similar lack of understanding. They may correctly believe that the risk for skin cancer is less among Hispanics than it is among whites overall, but fail to communicate individual risk.
What these physicians may not understand, Dr. Perez said, is that the Hispanic population comprises an incredible variety of ethnic backgrounds. The population’s centuries-long genetic mixing bowl means there is no “typical” Hispanic skin. Instead, it includes every Fitzpatrick skin type, from fair-skinned redheads to the darkest brown and black skins.
Inadequate healthcare access exerts yet another damaging force. Like other ethnic minorities, many Hispanic patients lack insurance or adequate access to medical care. Instead of seeking regular primary care that would include skin cancer screenings, they tend to rely on urgent care or emergency departments to address emergent health issues, Dr. Perez said. When primary and preventive care falls by the wayside, melanomas that could be diagnosed at a curable stage invariably progress.
“We know that the only way of curing melanoma is with a scalpel. And the only way to remove it is by treating early disease. We’re not doing that. Our melanoma patients are diagnosed at younger ages with more advanced disease with more lymph node involvement than Caucasians, so there is also more mortality. We achieve early-stage diagnosis in 91% of Caucasians, but only 74% of Hispanics.”
A 2011 paper on racial and ethnic variations in the incidence and survival of melanoma, based on national cancer registry data covering almost 70% of the U.S. population, from 1999-2006, provided more information on the differences between the white and Hispanic populations (J Am Acad Dermatol. 2011 Nov;65[5 Suppl 1]:S26-37). Compared with non-Hispanic whites, Hispanics presented with thicker tumors (more than 1 mm, 35% vs. 25%), more regional involvement (12% vs. 8%), and more distant metastasis (7% vs. 4%).
Because adult Hispanic patients lack knowledge about their melanoma risk, they aren’t improving the outlook for their children, Dr. Perez said. The Hispanic demographic in the United States is already a young one. According on 2014 data cited by the Pew Research Center, 58% of Hispanics in the United States are aged 33 years or younger; 32% are younger than 18 years.
These young people are already endangering their health with unsafe sun behavior, Dr. Perez said. A 2007 study surveyed 369 white Hispanic and white non-Hispanic high school students in Miami about sun protection behaviors and skin cancer risk. The Hispanic teens were 2.5 times more likely to have used a tanning bed in the previous year; they were also less likely to wear sunscreen and protective clothing. The Hispanic students generally believed they were less likely to get skin cancer than the Caucasian students. They were 60% less likely to have heard of a skin self-exam and 70% less likely to have been told how to do one (Arch Dermatol. 2007;143[8]:983-8).
The oil to calm these troubled waters is education, Dr. Perez said. She takes this commitment very seriously, and said a simple conversation is the first step.
“I tell all my patients, no matter what ethnicity you are or what skin type you have, you can get skin cancer and you need regular, complete skin exams. And I teach them to do this for themselves.”
A senior vice-president for the Skin Cancer Foundation, Dr. Perez is coauthor of “Understanding Melanoma: What You Need to Know,” which is now in its fifth edition.
The book, originally published in 1996, is aimed at melanoma patients and their families. It covers the four types of melanoma and their causes and risk factors. Information on melanoma diagnosis, staging, treatment options, prognosis, and hereditary and genetic factors is also included, as well as guidelines for prevention.
The updated edition contains information on the latest immunotherapy and genetically targeted treatments, including ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), vemurafenib (Zelboraf), dabrafenib (Tafinlar) and trametinib (Mekinist). The book is available for download for a nominal fee.
She has also committed to educating physicians about the issue.
“If we want to decrease the incidence of melanoma in Latinos, decrease the tumor depth at diagnosis and bring down the higher mortality, we have to first educate the doctors who are taking care of these patients and correct the message delivered to Latinos by telling them that they are as prone to skin cancer as Caucasians. We simply have to get the message across that, just like everyone else, they need protection from the sun by applying sunblocks, using sunglasses, and covering their bodies with sun-protective clothing and large-rim hats. And we have to make medical care more accessible so that these people can be diagnosed and saved. This is what we need to do now. But I don’t know how many decades it will take to turn the tables.”
Dr. Perez had no disclosures relevant to her lecture.
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
ORLANDO – Ignorance and exposure are teaming up to put Latinos in the bull’s-eye of skin cancer.
Many believe that they are not at risk for either melanoma or nonmelanoma skin cancers – and too often, their physicians believe the same, Maritza Perez, MD, said at the annual meeting of the American Academy of Dermatology. Because of such incorrect perceptions, Latino patients get little counseling about risky behaviors, and so their exposure to those dangers continues unabated.
“The behavior of many Hispanic patients is very risky,” said Dr. Perez, a clinical professor of dermatology, at Mount Sinai Medical Center, New York. “They don’t wear sunscreen. They don’t do skin self-exams. They use tanning beds. And because of these beliefs, they don’t educate their children about sun safety.”
A research letter published in the Journal of the American Academy of Dermatology in 2011 broke down levels of skin cancer awareness by race and ethnicity among 165 whites, Hispanics, blacks, and Asians surveyed in New York City (64[1]:198-200). Compared with whites, Hispanics were significantly less likely to have ever had a doctor perform a full body skin exam (21% vs. 61%) or to have performed a self-exam (37% vs. 54%). Significantly fewer believed that skin cancer could occur in darker skin (78% vs. 91%). Only 8% had heard of the ABCDs of early melanoma detection, compared with 27% of whites. And about half as many Hispanics said they wore sunscreen (55% vs. 96%).
Unfortunately, Dr. Perez said, doctors aren’t correcting these misperceptions. Many physicians display a similar lack of understanding. They may correctly believe that the risk for skin cancer is less among Hispanics than it is among whites overall, but fail to communicate individual risk.
What these physicians may not understand, Dr. Perez said, is that the Hispanic population comprises an incredible variety of ethnic backgrounds. The population’s centuries-long genetic mixing bowl means there is no “typical” Hispanic skin. Instead, it includes every Fitzpatrick skin type, from fair-skinned redheads to the darkest brown and black skins.
Inadequate healthcare access exerts yet another damaging force. Like other ethnic minorities, many Hispanic patients lack insurance or adequate access to medical care. Instead of seeking regular primary care that would include skin cancer screenings, they tend to rely on urgent care or emergency departments to address emergent health issues, Dr. Perez said. When primary and preventive care falls by the wayside, melanomas that could be diagnosed at a curable stage invariably progress.
“We know that the only way of curing melanoma is with a scalpel. And the only way to remove it is by treating early disease. We’re not doing that. Our melanoma patients are diagnosed at younger ages with more advanced disease with more lymph node involvement than Caucasians, so there is also more mortality. We achieve early-stage diagnosis in 91% of Caucasians, but only 74% of Hispanics.”
A 2011 paper on racial and ethnic variations in the incidence and survival of melanoma, based on national cancer registry data covering almost 70% of the U.S. population, from 1999-2006, provided more information on the differences between the white and Hispanic populations (J Am Acad Dermatol. 2011 Nov;65[5 Suppl 1]:S26-37). Compared with non-Hispanic whites, Hispanics presented with thicker tumors (more than 1 mm, 35% vs. 25%), more regional involvement (12% vs. 8%), and more distant metastasis (7% vs. 4%).
Because adult Hispanic patients lack knowledge about their melanoma risk, they aren’t improving the outlook for their children, Dr. Perez said. The Hispanic demographic in the United States is already a young one. According on 2014 data cited by the Pew Research Center, 58% of Hispanics in the United States are aged 33 years or younger; 32% are younger than 18 years.
These young people are already endangering their health with unsafe sun behavior, Dr. Perez said. A 2007 study surveyed 369 white Hispanic and white non-Hispanic high school students in Miami about sun protection behaviors and skin cancer risk. The Hispanic teens were 2.5 times more likely to have used a tanning bed in the previous year; they were also less likely to wear sunscreen and protective clothing. The Hispanic students generally believed they were less likely to get skin cancer than the Caucasian students. They were 60% less likely to have heard of a skin self-exam and 70% less likely to have been told how to do one (Arch Dermatol. 2007;143[8]:983-8).
The oil to calm these troubled waters is education, Dr. Perez said. She takes this commitment very seriously, and said a simple conversation is the first step.
“I tell all my patients, no matter what ethnicity you are or what skin type you have, you can get skin cancer and you need regular, complete skin exams. And I teach them to do this for themselves.”
A senior vice-president for the Skin Cancer Foundation, Dr. Perez is coauthor of “Understanding Melanoma: What You Need to Know,” which is now in its fifth edition.
The book, originally published in 1996, is aimed at melanoma patients and their families. It covers the four types of melanoma and their causes and risk factors. Information on melanoma diagnosis, staging, treatment options, prognosis, and hereditary and genetic factors is also included, as well as guidelines for prevention.
The updated edition contains information on the latest immunotherapy and genetically targeted treatments, including ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), vemurafenib (Zelboraf), dabrafenib (Tafinlar) and trametinib (Mekinist). The book is available for download for a nominal fee.
She has also committed to educating physicians about the issue.
“If we want to decrease the incidence of melanoma in Latinos, decrease the tumor depth at diagnosis and bring down the higher mortality, we have to first educate the doctors who are taking care of these patients and correct the message delivered to Latinos by telling them that they are as prone to skin cancer as Caucasians. We simply have to get the message across that, just like everyone else, they need protection from the sun by applying sunblocks, using sunglasses, and covering their bodies with sun-protective clothing and large-rim hats. And we have to make medical care more accessible so that these people can be diagnosed and saved. This is what we need to do now. But I don’t know how many decades it will take to turn the tables.”
Dr. Perez had no disclosures relevant to her lecture.
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
EXPERT ANALYSIS FROM AAD 17
Machine learning melanoma
What if an app could diagnose melanoma from a photo? That was my idea. In December 2009, Google introduced Google Goggles, an application that recognized images. At the time, I thought, “Wouldn’t it be neat if we could use this with telederm?” I even pitched it to a friend at the search giant. “Great idea!” he wrote back, placating me. For those uninitiated in innovation, “Great idea!” is a euphemism for “Yeah, we thought of that.”
Yes, it isn’t only mine; no doubt, many of you had this same idea: Let’s use amazing image interpretation capabilities from companies like Google or Apple to help us make diagnoses. Sounds simple. It isn’t. This is why most melanoma-finding apps are for entertainment purposes only – they don’t work.
So can melanoma be diagnosed from an app? A Stanford University team believes so. They trained a machine learning system to make dermatologic diagnoses from photos of skin lesions. To overcome previous barriers, they used open-sourced software from Google and awesome processors. For a start, they pretrained the program on over 1.28 million images. Then they fed it 128,450 images of known diagnoses.
Then, just as when Google’s AlphaGo algorithm challenged Lee Sedol, the world Go champion, the Stanford research team challenged 21 dermatologists. They had to choose if they would biopsy/treat or reassure patients based on photos of benign lesions, keratinocyte carcinomas, clinical melanomas, and dermoscopic melanomas. Guess who won?
In a stunning victory (or defeat, if you’re rooting for our team), the trained algorithm matched or outperformed all the dermatologists when scored on sensitivity-specificity curves. While we dermatologists, of course, use more than just a photo to diagnose skin cancer, many around the globe don’t have access to us. Based on these findings, they might need access only to a smartphone to get potentially life-saving advice.
But, what does this mean? Will we someday be outsourced to AI? Will a future POTUS promise to “bring back the doctor industry?” Not if we adapt. The future is bright – if we learn to apply machine learning in ways that can have an impact. (Brain + Computer > Brain.) Consider the following: An optimized ophthalmologist who reads retinal scans prediagnosed by a computer. A teledermatologist who uses AI to perform perfectly in diagnosing melanoma.
Patients have always wanted high quality and high touch care. In the history of medicine, we’ve never been better at both than we are today. Until tomorrow, when we’ll be better still.
Jeff Benabio, MD, MBA, is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@frontlinemedcom.com. He has no disclosures related to this column.
What if an app could diagnose melanoma from a photo? That was my idea. In December 2009, Google introduced Google Goggles, an application that recognized images. At the time, I thought, “Wouldn’t it be neat if we could use this with telederm?” I even pitched it to a friend at the search giant. “Great idea!” he wrote back, placating me. For those uninitiated in innovation, “Great idea!” is a euphemism for “Yeah, we thought of that.”
Yes, it isn’t only mine; no doubt, many of you had this same idea: Let’s use amazing image interpretation capabilities from companies like Google or Apple to help us make diagnoses. Sounds simple. It isn’t. This is why most melanoma-finding apps are for entertainment purposes only – they don’t work.
So can melanoma be diagnosed from an app? A Stanford University team believes so. They trained a machine learning system to make dermatologic diagnoses from photos of skin lesions. To overcome previous barriers, they used open-sourced software from Google and awesome processors. For a start, they pretrained the program on over 1.28 million images. Then they fed it 128,450 images of known diagnoses.
Then, just as when Google’s AlphaGo algorithm challenged Lee Sedol, the world Go champion, the Stanford research team challenged 21 dermatologists. They had to choose if they would biopsy/treat or reassure patients based on photos of benign lesions, keratinocyte carcinomas, clinical melanomas, and dermoscopic melanomas. Guess who won?
In a stunning victory (or defeat, if you’re rooting for our team), the trained algorithm matched or outperformed all the dermatologists when scored on sensitivity-specificity curves. While we dermatologists, of course, use more than just a photo to diagnose skin cancer, many around the globe don’t have access to us. Based on these findings, they might need access only to a smartphone to get potentially life-saving advice.
But, what does this mean? Will we someday be outsourced to AI? Will a future POTUS promise to “bring back the doctor industry?” Not if we adapt. The future is bright – if we learn to apply machine learning in ways that can have an impact. (Brain + Computer > Brain.) Consider the following: An optimized ophthalmologist who reads retinal scans prediagnosed by a computer. A teledermatologist who uses AI to perform perfectly in diagnosing melanoma.
Patients have always wanted high quality and high touch care. In the history of medicine, we’ve never been better at both than we are today. Until tomorrow, when we’ll be better still.
Jeff Benabio, MD, MBA, is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@frontlinemedcom.com. He has no disclosures related to this column.
What if an app could diagnose melanoma from a photo? That was my idea. In December 2009, Google introduced Google Goggles, an application that recognized images. At the time, I thought, “Wouldn’t it be neat if we could use this with telederm?” I even pitched it to a friend at the search giant. “Great idea!” he wrote back, placating me. For those uninitiated in innovation, “Great idea!” is a euphemism for “Yeah, we thought of that.”
Yes, it isn’t only mine; no doubt, many of you had this same idea: Let’s use amazing image interpretation capabilities from companies like Google or Apple to help us make diagnoses. Sounds simple. It isn’t. This is why most melanoma-finding apps are for entertainment purposes only – they don’t work.
So can melanoma be diagnosed from an app? A Stanford University team believes so. They trained a machine learning system to make dermatologic diagnoses from photos of skin lesions. To overcome previous barriers, they used open-sourced software from Google and awesome processors. For a start, they pretrained the program on over 1.28 million images. Then they fed it 128,450 images of known diagnoses.
Then, just as when Google’s AlphaGo algorithm challenged Lee Sedol, the world Go champion, the Stanford research team challenged 21 dermatologists. They had to choose if they would biopsy/treat or reassure patients based on photos of benign lesions, keratinocyte carcinomas, clinical melanomas, and dermoscopic melanomas. Guess who won?
In a stunning victory (or defeat, if you’re rooting for our team), the trained algorithm matched or outperformed all the dermatologists when scored on sensitivity-specificity curves. While we dermatologists, of course, use more than just a photo to diagnose skin cancer, many around the globe don’t have access to us. Based on these findings, they might need access only to a smartphone to get potentially life-saving advice.
But, what does this mean? Will we someday be outsourced to AI? Will a future POTUS promise to “bring back the doctor industry?” Not if we adapt. The future is bright – if we learn to apply machine learning in ways that can have an impact. (Brain + Computer > Brain.) Consider the following: An optimized ophthalmologist who reads retinal scans prediagnosed by a computer. A teledermatologist who uses AI to perform perfectly in diagnosing melanoma.
Patients have always wanted high quality and high touch care. In the history of medicine, we’ve never been better at both than we are today. Until tomorrow, when we’ll be better still.
Jeff Benabio, MD, MBA, is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. Dr. Benabio is @Dermdoc on Twitter. Write to him at dermnews@frontlinemedcom.com. He has no disclosures related to this column.
Update on Confocal Microscopy and Skin Cancer Imaging: Report from the AAD Meeting
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
VIDEO: Updating the rule of threes for melanoma gene testing
ORLANDO – The rule of threes that has been used to identify patients at risk of hereditary melanoma who may be candidates for genetic testing may be modified soon, according to Sancy Leachman, MD, PhD, professor and chair of the department of dermatology, Oregon Health and Science University, Portland.
Dr. Leachman was the author of a 2009 study that listed three factors as criteria for identifying melanoma: a personal history of at least three invasive melanomas, a combination of at least three melanomas in the individual and in first-degree and second-degree blood relatives – or, in first- or second-degree relatives, a total of at least three diagnoses of melanoma or pancreatic cancer or astrocytoma, which also have been associated with a known susceptibility gene, p16 (J Am Acad Dermatol. 2009 Oct;61[4]:677.e1-14).
But with more genetic testing, it is becoming clear that there are other cancers associated with an increased risk of hereditary melanoma, she explained in a video interview at the annual meeting of the American Academy of Dermatology. “The genes are a little bit different, but if you could identify those patients, you could potentially then screen them for those other cancers,” said Dr. Leachman, who is also director of the melanoma research program at Knight Cancer Institute at OHSU.
In the interview, she discussed a soon-to-be-published literature review that builds upon the rule of threes and suggests a strategy for deciding which patients should be considered for genetic testing, and includes “a suggested list of genes” that should be used in these different subsets of patients.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Leachman had no relevant disclosures.
ORLANDO – The rule of threes that has been used to identify patients at risk of hereditary melanoma who may be candidates for genetic testing may be modified soon, according to Sancy Leachman, MD, PhD, professor and chair of the department of dermatology, Oregon Health and Science University, Portland.
Dr. Leachman was the author of a 2009 study that listed three factors as criteria for identifying melanoma: a personal history of at least three invasive melanomas, a combination of at least three melanomas in the individual and in first-degree and second-degree blood relatives – or, in first- or second-degree relatives, a total of at least three diagnoses of melanoma or pancreatic cancer or astrocytoma, which also have been associated with a known susceptibility gene, p16 (J Am Acad Dermatol. 2009 Oct;61[4]:677.e1-14).
But with more genetic testing, it is becoming clear that there are other cancers associated with an increased risk of hereditary melanoma, she explained in a video interview at the annual meeting of the American Academy of Dermatology. “The genes are a little bit different, but if you could identify those patients, you could potentially then screen them for those other cancers,” said Dr. Leachman, who is also director of the melanoma research program at Knight Cancer Institute at OHSU.
In the interview, she discussed a soon-to-be-published literature review that builds upon the rule of threes and suggests a strategy for deciding which patients should be considered for genetic testing, and includes “a suggested list of genes” that should be used in these different subsets of patients.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Leachman had no relevant disclosures.
ORLANDO – The rule of threes that has been used to identify patients at risk of hereditary melanoma who may be candidates for genetic testing may be modified soon, according to Sancy Leachman, MD, PhD, professor and chair of the department of dermatology, Oregon Health and Science University, Portland.
Dr. Leachman was the author of a 2009 study that listed three factors as criteria for identifying melanoma: a personal history of at least three invasive melanomas, a combination of at least three melanomas in the individual and in first-degree and second-degree blood relatives – or, in first- or second-degree relatives, a total of at least three diagnoses of melanoma or pancreatic cancer or astrocytoma, which also have been associated with a known susceptibility gene, p16 (J Am Acad Dermatol. 2009 Oct;61[4]:677.e1-14).
But with more genetic testing, it is becoming clear that there are other cancers associated with an increased risk of hereditary melanoma, she explained in a video interview at the annual meeting of the American Academy of Dermatology. “The genes are a little bit different, but if you could identify those patients, you could potentially then screen them for those other cancers,” said Dr. Leachman, who is also director of the melanoma research program at Knight Cancer Institute at OHSU.
In the interview, she discussed a soon-to-be-published literature review that builds upon the rule of threes and suggests a strategy for deciding which patients should be considered for genetic testing, and includes “a suggested list of genes” that should be used in these different subsets of patients.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. Leachman had no relevant disclosures.
AT AAD 17
Connective tissue diseases reported in patients receiving immune checkpoint inhibitors
For the first time, new-onset connective tissue disease has been reported in patients who were treated with anti-PD1/PDL-1 agents, according to findings published in the Annals of the Rheumatic Diseases.
In a cohort of 447 cancer patients who received therapy with immune checkpoint inhibitors (ICIs), Sébastien Le Burel, MD, of the Bicêtre Hospital in Le Kremlin-Bicêtre, France, and his colleagues described four patients who developed a connective tissue disease (CTD). There were two cases of Sjögren’s syndrome in patients taking an anti–programmed cell death 1 (anti-PD1) drug, one case of cryoglobulinemic vasculitis as a complication of suspected Sjögren’s syndrome in a patient taking an anti–programmed cell death ligand 1 (PDL-1) agent, and a case of a patient with antinuclear antibody positive myositis who was taking an anti-PDL-1 drug (Ann Rheum Dis. 2017 Feb 27. doi: 10.1136/annrheumdis-2016-210820).
“While the onset of systemic autoimmune disease after ICI treatment remains uncommon, greater awareness of these conditions should enable physicians to provide more effective patient care,” the investigators wrote. “This underlines the need for close collaboration within a network of oncologists and other specialist physicians in the new era of immunotherapy.”
The investigators discovered the cases by screening the French prospective, multicenter, academic REISAMIC registry for reports of CTD among patients being treated with anti-PD1 or anti-PDL-1 agents.
All four of the patients who developed a CTD had metastatic cancer, and their mean age was 62 years. Two patients had been treated with anti-PD1 agents and two with anti-PDL-1 agents. None of the four patients had presented with symptoms of CTD before they began treatment.
The mean time interval between the first treatment dose and the first symptom of CTD was 60 days (range, 24-72), and the mean time interval between the first symptom and subsequent diagnosis of CTD was 40 days (range, 10-74).
Three patients discontinued the ICI agent, and two patients were treated with steroids (1 mg/kg/day).
The estimated prevalence of CTD was 0.7% in the REISAMIC registry, and the authors emphasize that the high proportion of cases of Sjögren’s syndrome is noteworthy, with two of the patients fulfilling the recent American College of Rheumatology/European League Against Rheumatism criteria for Sjögren’s syndrome.
A limitation of the study is that some patients presenting with milder symptoms might not have been investigated by their oncologist.
The findings raise the question of whether asymptomatic patients taking ICIs who are at risk for immune-related adverse events should be screened and monitored closely, the authors explained.
One of the study authors received research funding from Novartis and Pfizer for the current paper. Several authors report relationships with industry.
For the first time, new-onset connective tissue disease has been reported in patients who were treated with anti-PD1/PDL-1 agents, according to findings published in the Annals of the Rheumatic Diseases.
In a cohort of 447 cancer patients who received therapy with immune checkpoint inhibitors (ICIs), Sébastien Le Burel, MD, of the Bicêtre Hospital in Le Kremlin-Bicêtre, France, and his colleagues described four patients who developed a connective tissue disease (CTD). There were two cases of Sjögren’s syndrome in patients taking an anti–programmed cell death 1 (anti-PD1) drug, one case of cryoglobulinemic vasculitis as a complication of suspected Sjögren’s syndrome in a patient taking an anti–programmed cell death ligand 1 (PDL-1) agent, and a case of a patient with antinuclear antibody positive myositis who was taking an anti-PDL-1 drug (Ann Rheum Dis. 2017 Feb 27. doi: 10.1136/annrheumdis-2016-210820).
“While the onset of systemic autoimmune disease after ICI treatment remains uncommon, greater awareness of these conditions should enable physicians to provide more effective patient care,” the investigators wrote. “This underlines the need for close collaboration within a network of oncologists and other specialist physicians in the new era of immunotherapy.”
The investigators discovered the cases by screening the French prospective, multicenter, academic REISAMIC registry for reports of CTD among patients being treated with anti-PD1 or anti-PDL-1 agents.
All four of the patients who developed a CTD had metastatic cancer, and their mean age was 62 years. Two patients had been treated with anti-PD1 agents and two with anti-PDL-1 agents. None of the four patients had presented with symptoms of CTD before they began treatment.
The mean time interval between the first treatment dose and the first symptom of CTD was 60 days (range, 24-72), and the mean time interval between the first symptom and subsequent diagnosis of CTD was 40 days (range, 10-74).
Three patients discontinued the ICI agent, and two patients were treated with steroids (1 mg/kg/day).
The estimated prevalence of CTD was 0.7% in the REISAMIC registry, and the authors emphasize that the high proportion of cases of Sjögren’s syndrome is noteworthy, with two of the patients fulfilling the recent American College of Rheumatology/European League Against Rheumatism criteria for Sjögren’s syndrome.
A limitation of the study is that some patients presenting with milder symptoms might not have been investigated by their oncologist.
The findings raise the question of whether asymptomatic patients taking ICIs who are at risk for immune-related adverse events should be screened and monitored closely, the authors explained.
One of the study authors received research funding from Novartis and Pfizer for the current paper. Several authors report relationships with industry.
For the first time, new-onset connective tissue disease has been reported in patients who were treated with anti-PD1/PDL-1 agents, according to findings published in the Annals of the Rheumatic Diseases.
In a cohort of 447 cancer patients who received therapy with immune checkpoint inhibitors (ICIs), Sébastien Le Burel, MD, of the Bicêtre Hospital in Le Kremlin-Bicêtre, France, and his colleagues described four patients who developed a connective tissue disease (CTD). There were two cases of Sjögren’s syndrome in patients taking an anti–programmed cell death 1 (anti-PD1) drug, one case of cryoglobulinemic vasculitis as a complication of suspected Sjögren’s syndrome in a patient taking an anti–programmed cell death ligand 1 (PDL-1) agent, and a case of a patient with antinuclear antibody positive myositis who was taking an anti-PDL-1 drug (Ann Rheum Dis. 2017 Feb 27. doi: 10.1136/annrheumdis-2016-210820).
“While the onset of systemic autoimmune disease after ICI treatment remains uncommon, greater awareness of these conditions should enable physicians to provide more effective patient care,” the investigators wrote. “This underlines the need for close collaboration within a network of oncologists and other specialist physicians in the new era of immunotherapy.”
The investigators discovered the cases by screening the French prospective, multicenter, academic REISAMIC registry for reports of CTD among patients being treated with anti-PD1 or anti-PDL-1 agents.
All four of the patients who developed a CTD had metastatic cancer, and their mean age was 62 years. Two patients had been treated with anti-PD1 agents and two with anti-PDL-1 agents. None of the four patients had presented with symptoms of CTD before they began treatment.
The mean time interval between the first treatment dose and the first symptom of CTD was 60 days (range, 24-72), and the mean time interval between the first symptom and subsequent diagnosis of CTD was 40 days (range, 10-74).
Three patients discontinued the ICI agent, and two patients were treated with steroids (1 mg/kg/day).
The estimated prevalence of CTD was 0.7% in the REISAMIC registry, and the authors emphasize that the high proportion of cases of Sjögren’s syndrome is noteworthy, with two of the patients fulfilling the recent American College of Rheumatology/European League Against Rheumatism criteria for Sjögren’s syndrome.
A limitation of the study is that some patients presenting with milder symptoms might not have been investigated by their oncologist.
The findings raise the question of whether asymptomatic patients taking ICIs who are at risk for immune-related adverse events should be screened and monitored closely, the authors explained.
One of the study authors received research funding from Novartis and Pfizer for the current paper. Several authors report relationships with industry.
Key clinical point:
Major finding: In a cohort of 447 patients, 4 with metastatic cancer developed connective tissue disease following anti-PD-1/PDL-1 treatment.
Data source: A prospective, multicenter, academic registry was screened for reports of CTD among patients being treated with anti-PD1/PDL-1 agents.
Disclosures: One of the study authors received research funding from Novartis and Pfizer for the current paper. Several authors report relationships with industry.
Soluble PD-L1 correlates with melanoma outcomes
ORLANDO – Patients with metastatic melanoma who have high blood levels of the soluble form of the programmed death-ligand 1 (sPD-L1) have poor clinical outcomes, decreased overall survival, and disease that is resistant to PD-L1 checkpoint inhibitors, compared with patients with low levels of sPD-L1, investigators have found.
High sPD-L1 levels are also associated with an immunosuppressive disease phenotype and with higher levels of pro-inflammatory cytokines, said Roxana S. Dronca, MD, from the Mayo Clinic in Rochester, Minn.
Tumor-induced immune suppression
Membrane-bound, tumor associated PD-L1 has been shown to play a key role in tumor-induced immunosuppression in melanoma and many other malignancies. Expression of PD-L1 on tumors has been shown to be associated with more aggressive tumor biology and with decreased survival in various tumor types, and it was previously thought to be prognostic, she said.
“However, other investigators more recently have found that expression of PD-L1, for instance in metastatic melanoma, is associated with improved survival, possibly reflective of endogenous anti-tumor immunity. So, therefore, the prognostic role of tumor associated PD-L1 is unclear. And also, PD-L1 has been found to be a suboptimal predictive biomarker for response to PD-1 blockade, likely due to heterogeneous and dynamic expression in the tumor tissues, which really cannot be captured with a single-time-point, random tumor biopsy,” she added.
In 2011, Mayo investigators reported on the presence of sPD-L1 (then called B7-H1) in the sera of patients with advanced renal-cell carcinoma and that it was associated with advanced tumor stage and negative clinicopathologic tumor characteristics.
“It seems that the molecule is biologically able to engage PD-1 on circulating T cells, and therefore, it may represent an unanticipated contributing factor to immune homeostasis beyond the tumor microenvironment,” Dr. Dronca said.
Higher levels correlate with outcomes
To see whether sPD-L1 levels are related to outcome and response to immune checkpoint inhibitor therapy in patients with metastatic melanoma, the investigators collected baseline peripheral blood samples from 276 patients with advanced melanoma prior to enrollment in nonimmunotherapy clinical trials, as well as samples from 36 healthy blood donors at their center.
They also evaluated samples from 80 patients who were undergoing anti-PD-1 based immunotherapy, with peripheral blood collected at baseline and each subsequent radiographic tumor evaluation, and serial monthly blood samples from healthy pregnant women (number not specified), with samples taken at 2 hours and at 6 weeks post delivery. Levels of PD-L1 were measured by enzyme-linked immunosorbent assay.
The investigators first observed that sPD-L1 levels rose steadily during pregnancy then fell sharply after delivery, showing the presence of PD-L1 levels in healthy subjects and in a normal model of immune tolerance (that is, pregnancy). This finding is not especially surprising given that PD-L1 was first cloned from human placentas, where it is present in abundant levels and forms a barrier at the fetal-maternal interface, Dr. Dronca said.
They also found that sPD-L1 was significantly higher among melanoma patients than among controls, with a mean level of 1.73 ng/mL, compared with 0.77 ng/mL in controls.
Using receiver operating characteristic analysis, the researchers determined a cutoff value of 0.239 ng/mL to distinguish between low and high levels of sPD-L1.
They found that melanoma patients with levels above 0.293 ng/mL had a median overall survival of 11.3 months, compared with 14.8 months for those with levels of 0.293 ng/mL or lower (P = .04).
They also found that high sPD-L1 levels were associated with resistance to anti-PD-1 therapy. Patients who had complete or partial objective responses had a mean level of 0.3 ng/mL, whereas patients who had unequivocal disease progression at 12 weeks had levels 7.5 times higher.
“Interestingly, at 12 weeks the levels were actually quite stable, both in responders and progressors, suggesting that, maybe, soluble PD-L1 is not only a direct reflection of the tumor load, but as mentioned, it can be released by other immune cells and is possibly a more global marker of immune dysfunction,” Dr. Dronca said.
‘A little bit curious’
Douglas G. McNeel, MD, PhD, from the University of Wisconsin–Madison, the invited discussant, commended the authors for their study and noted that it raises important questions about the role of PD-L1 in healthy and malignant cells.
He added that it’s still unclear, but worth pursuing, whether measuring sPD-L1 levels can identify patients who may benefit from anti-PD1 monotherapy versus combinatorial strategies and agrees with the authors’ conclusion that larger studies are needed to establish whether sPD-L1 can be a prognostic or predictive biomarker.
The study was supported by grants from the National Institutes of Health, Mayo Clinic, and Fraternal Order of Eagles Cancer Research Fund. Dr. Dronca disclosed institution research funding from Merck Sharp & Dohme, and other financial relationship with Elsevier. Dr. McNeel disclosed leadership, stock ownership, and consulting with Madison Vaccines, and consulting and/or institutional research funding from Bristol-Myers Squibb, Dendreon, Janssen, Madison Vaccines, and Medivation.
ORLANDO – Patients with metastatic melanoma who have high blood levels of the soluble form of the programmed death-ligand 1 (sPD-L1) have poor clinical outcomes, decreased overall survival, and disease that is resistant to PD-L1 checkpoint inhibitors, compared with patients with low levels of sPD-L1, investigators have found.
High sPD-L1 levels are also associated with an immunosuppressive disease phenotype and with higher levels of pro-inflammatory cytokines, said Roxana S. Dronca, MD, from the Mayo Clinic in Rochester, Minn.
Tumor-induced immune suppression
Membrane-bound, tumor associated PD-L1 has been shown to play a key role in tumor-induced immunosuppression in melanoma and many other malignancies. Expression of PD-L1 on tumors has been shown to be associated with more aggressive tumor biology and with decreased survival in various tumor types, and it was previously thought to be prognostic, she said.
“However, other investigators more recently have found that expression of PD-L1, for instance in metastatic melanoma, is associated with improved survival, possibly reflective of endogenous anti-tumor immunity. So, therefore, the prognostic role of tumor associated PD-L1 is unclear. And also, PD-L1 has been found to be a suboptimal predictive biomarker for response to PD-1 blockade, likely due to heterogeneous and dynamic expression in the tumor tissues, which really cannot be captured with a single-time-point, random tumor biopsy,” she added.
In 2011, Mayo investigators reported on the presence of sPD-L1 (then called B7-H1) in the sera of patients with advanced renal-cell carcinoma and that it was associated with advanced tumor stage and negative clinicopathologic tumor characteristics.
“It seems that the molecule is biologically able to engage PD-1 on circulating T cells, and therefore, it may represent an unanticipated contributing factor to immune homeostasis beyond the tumor microenvironment,” Dr. Dronca said.
Higher levels correlate with outcomes
To see whether sPD-L1 levels are related to outcome and response to immune checkpoint inhibitor therapy in patients with metastatic melanoma, the investigators collected baseline peripheral blood samples from 276 patients with advanced melanoma prior to enrollment in nonimmunotherapy clinical trials, as well as samples from 36 healthy blood donors at their center.
They also evaluated samples from 80 patients who were undergoing anti-PD-1 based immunotherapy, with peripheral blood collected at baseline and each subsequent radiographic tumor evaluation, and serial monthly blood samples from healthy pregnant women (number not specified), with samples taken at 2 hours and at 6 weeks post delivery. Levels of PD-L1 were measured by enzyme-linked immunosorbent assay.
The investigators first observed that sPD-L1 levels rose steadily during pregnancy then fell sharply after delivery, showing the presence of PD-L1 levels in healthy subjects and in a normal model of immune tolerance (that is, pregnancy). This finding is not especially surprising given that PD-L1 was first cloned from human placentas, where it is present in abundant levels and forms a barrier at the fetal-maternal interface, Dr. Dronca said.
They also found that sPD-L1 was significantly higher among melanoma patients than among controls, with a mean level of 1.73 ng/mL, compared with 0.77 ng/mL in controls.
Using receiver operating characteristic analysis, the researchers determined a cutoff value of 0.239 ng/mL to distinguish between low and high levels of sPD-L1.
They found that melanoma patients with levels above 0.293 ng/mL had a median overall survival of 11.3 months, compared with 14.8 months for those with levels of 0.293 ng/mL or lower (P = .04).
They also found that high sPD-L1 levels were associated with resistance to anti-PD-1 therapy. Patients who had complete or partial objective responses had a mean level of 0.3 ng/mL, whereas patients who had unequivocal disease progression at 12 weeks had levels 7.5 times higher.
“Interestingly, at 12 weeks the levels were actually quite stable, both in responders and progressors, suggesting that, maybe, soluble PD-L1 is not only a direct reflection of the tumor load, but as mentioned, it can be released by other immune cells and is possibly a more global marker of immune dysfunction,” Dr. Dronca said.
‘A little bit curious’
Douglas G. McNeel, MD, PhD, from the University of Wisconsin–Madison, the invited discussant, commended the authors for their study and noted that it raises important questions about the role of PD-L1 in healthy and malignant cells.
He added that it’s still unclear, but worth pursuing, whether measuring sPD-L1 levels can identify patients who may benefit from anti-PD1 monotherapy versus combinatorial strategies and agrees with the authors’ conclusion that larger studies are needed to establish whether sPD-L1 can be a prognostic or predictive biomarker.
The study was supported by grants from the National Institutes of Health, Mayo Clinic, and Fraternal Order of Eagles Cancer Research Fund. Dr. Dronca disclosed institution research funding from Merck Sharp & Dohme, and other financial relationship with Elsevier. Dr. McNeel disclosed leadership, stock ownership, and consulting with Madison Vaccines, and consulting and/or institutional research funding from Bristol-Myers Squibb, Dendreon, Janssen, Madison Vaccines, and Medivation.
ORLANDO – Patients with metastatic melanoma who have high blood levels of the soluble form of the programmed death-ligand 1 (sPD-L1) have poor clinical outcomes, decreased overall survival, and disease that is resistant to PD-L1 checkpoint inhibitors, compared with patients with low levels of sPD-L1, investigators have found.
High sPD-L1 levels are also associated with an immunosuppressive disease phenotype and with higher levels of pro-inflammatory cytokines, said Roxana S. Dronca, MD, from the Mayo Clinic in Rochester, Minn.
Tumor-induced immune suppression
Membrane-bound, tumor associated PD-L1 has been shown to play a key role in tumor-induced immunosuppression in melanoma and many other malignancies. Expression of PD-L1 on tumors has been shown to be associated with more aggressive tumor biology and with decreased survival in various tumor types, and it was previously thought to be prognostic, she said.
“However, other investigators more recently have found that expression of PD-L1, for instance in metastatic melanoma, is associated with improved survival, possibly reflective of endogenous anti-tumor immunity. So, therefore, the prognostic role of tumor associated PD-L1 is unclear. And also, PD-L1 has been found to be a suboptimal predictive biomarker for response to PD-1 blockade, likely due to heterogeneous and dynamic expression in the tumor tissues, which really cannot be captured with a single-time-point, random tumor biopsy,” she added.
In 2011, Mayo investigators reported on the presence of sPD-L1 (then called B7-H1) in the sera of patients with advanced renal-cell carcinoma and that it was associated with advanced tumor stage and negative clinicopathologic tumor characteristics.
“It seems that the molecule is biologically able to engage PD-1 on circulating T cells, and therefore, it may represent an unanticipated contributing factor to immune homeostasis beyond the tumor microenvironment,” Dr. Dronca said.
Higher levels correlate with outcomes
To see whether sPD-L1 levels are related to outcome and response to immune checkpoint inhibitor therapy in patients with metastatic melanoma, the investigators collected baseline peripheral blood samples from 276 patients with advanced melanoma prior to enrollment in nonimmunotherapy clinical trials, as well as samples from 36 healthy blood donors at their center.
They also evaluated samples from 80 patients who were undergoing anti-PD-1 based immunotherapy, with peripheral blood collected at baseline and each subsequent radiographic tumor evaluation, and serial monthly blood samples from healthy pregnant women (number not specified), with samples taken at 2 hours and at 6 weeks post delivery. Levels of PD-L1 were measured by enzyme-linked immunosorbent assay.
The investigators first observed that sPD-L1 levels rose steadily during pregnancy then fell sharply after delivery, showing the presence of PD-L1 levels in healthy subjects and in a normal model of immune tolerance (that is, pregnancy). This finding is not especially surprising given that PD-L1 was first cloned from human placentas, where it is present in abundant levels and forms a barrier at the fetal-maternal interface, Dr. Dronca said.
They also found that sPD-L1 was significantly higher among melanoma patients than among controls, with a mean level of 1.73 ng/mL, compared with 0.77 ng/mL in controls.
Using receiver operating characteristic analysis, the researchers determined a cutoff value of 0.239 ng/mL to distinguish between low and high levels of sPD-L1.
They found that melanoma patients with levels above 0.293 ng/mL had a median overall survival of 11.3 months, compared with 14.8 months for those with levels of 0.293 ng/mL or lower (P = .04).
They also found that high sPD-L1 levels were associated with resistance to anti-PD-1 therapy. Patients who had complete or partial objective responses had a mean level of 0.3 ng/mL, whereas patients who had unequivocal disease progression at 12 weeks had levels 7.5 times higher.
“Interestingly, at 12 weeks the levels were actually quite stable, both in responders and progressors, suggesting that, maybe, soluble PD-L1 is not only a direct reflection of the tumor load, but as mentioned, it can be released by other immune cells and is possibly a more global marker of immune dysfunction,” Dr. Dronca said.
‘A little bit curious’
Douglas G. McNeel, MD, PhD, from the University of Wisconsin–Madison, the invited discussant, commended the authors for their study and noted that it raises important questions about the role of PD-L1 in healthy and malignant cells.
He added that it’s still unclear, but worth pursuing, whether measuring sPD-L1 levels can identify patients who may benefit from anti-PD1 monotherapy versus combinatorial strategies and agrees with the authors’ conclusion that larger studies are needed to establish whether sPD-L1 can be a prognostic or predictive biomarker.
The study was supported by grants from the National Institutes of Health, Mayo Clinic, and Fraternal Order of Eagles Cancer Research Fund. Dr. Dronca disclosed institution research funding from Merck Sharp & Dohme, and other financial relationship with Elsevier. Dr. McNeel disclosed leadership, stock ownership, and consulting with Madison Vaccines, and consulting and/or institutional research funding from Bristol-Myers Squibb, Dendreon, Janssen, Madison Vaccines, and Medivation.
Key clinical point: Soluble PD-L1 may be a predictive or prognostic biomarker for malignant melanoma outcomes.
Major finding: Patients with high levels of sPD-L1 had a median overall survival of 11.3 months, compared with 14.8 months for those with levels below a specified cutoff.
Data source: Prospective study of sPD-L1 in 276 patients with metastatic melanoma, 36 healthy volunteers, and 80 patients who were undergoing anti-PD-1 based immunotherapy.
Disclosures: The study was supported by grants from the National Institutes of Health, Mayo Clinic, and Fraternal Order of Eagles Cancer Research Fund. Dr. Dronca disclosed institution research funding from Merck Sharp & Dohme and another financial relationship with Elsevier. Dr. McNeel disclosed leadership, stock ownership, and consulting with Madison Vaccines and consulting and/or institutional research funding from Bristol-Myers Squibb, Dendreon, Janssen, Madison Vaccines, and Medivation.
Teen indoor tanning drops, but schools fall short on sun safety
Indoor tanning among adolescents in the United States has dropped significantly, but fewer than half of schools in the United States reported sun safety practices to help minimize students’ UV exposure in the school setting, based on data from two studies presented at the annual meeting of the American Academy of Dermatology and published simultaneously in JAMA Dermatology.
“Data suggest that intermittent, recreational exposure (vs. chronic exposure, as with outdoor workers) more often leads to sunburn,” wrote Sherry Everett Jones, PhD, MPH, and Gery P. Guy Jr, PhD, MPH, of the Centers for Disease Control and Prevention. “Although a small proportion of school districts and schools have adopted policies to address sun safety, most have not, even though it is common for students to be outside during the midday hours or after school when the sun is still at peak intensity.”
To characterize sun safety practices at schools, the researchers reviewed data from the 2014 School Health Policies and Practices Study Healthy and Safe School Environment questionnaire including 577 elementary, middle, and high schools (JAMA Dermatol. 2017. doi: 10.1001/jamadermatol.2016.6274).
Overall, 48% of schools reported that teachers allowed students time to apply sunscreen at school (the most frequent sun safety practice). However, only 13% made sunscreen available, 16% asked parents to ensure sunscreen application before school, and 15% made an effort to avoid scheduling outdoor activities during times of peak sun intensity. High schools were less likely than elementary or middle schools to follow sun safety practices.
“None of the sun safety policies or practices were statistically significantly associated with metropolitan status,” the researchers noted. However, the findings were limited by the cross-sectional nature of the study and lack of data about natural shade and man made shade structures in outdoor areas of the schools.
“Interventions driven by the public health and medical community educating school leadership and policy makers about the importance of sun safety are needed regardless of level, location, size, and poverty concentration of the school. These efforts could be instrumental in increasing the adoption of sun safety practices among schools,” Dr. Jones and Dr. Guy emphasized.
However, data from another study showed a significant reduction in the prevalence of indoor tanning among adolescents.
In particular, indoor tanning among non-Hispanic white females (the group at highest risk for skin cancer) dropped from 37% in 2009 to 15% in 2015. CDC researchers led by Dr. Guy pooled data from the 2009, 2011, 2013, and 2015 national Youth Risk Behavior Surveillance System Surveys (JAMA Dermatol. 2017. doi:10.1001/jamadermatol.2016.6273). Overall, the prevalence of indoor tanning among U.S. high school students decreased from 16% in 2009 to 7% in 2015.
“Despite declines in indoor tanning, continued efforts are needed,” the researchers wrote. “Public health efforts could help address the misconception that indoor tanning protects against sunburn. The medical community also can play a key role in counseling adolescents and young adults in accordance with the U.S. Preventive Services Task Force guidelines.”
The findings were limited by several factors including the use of self-reports and the inability to control for skin type, the researchers wrote. However, “Reducing the proportion of youth who engage in indoor tanning and experience sunburns presents an important cancer prevention opportunity.”
None of the researchers on either study had relevant financial conflicts to disclose.
Explore best practices for public education campaigns “For more than 10 years, much effort has been made to educate the public on sun-safety practices, including warnings about the harmful effects of indoor tanning on those at higher risk, such as young adults and children. In this issue of JAMA Dermatology, 2 important articles describe the progress made toward sun safety,” wrote Henry W. Lim, MD, and Samantha L. Schneider, MD, in the accompanying editorial.
Data from a study of indoor tanning showed a significant decrease in prevalence of indoor tanning among adolescents, from 16% in 2009 to 7% in 2015. Although these results are encouraging, public education is needed for further improvement, they said. “One myth is that UV radiation prevents vitamin D deficiency; however, oral vitamin D supplementation is known to be a safer alternative. Another myth is that obtaining a baseline tan before the summer or a vacation reduces the risk of sunburn. However, as Guy and colleagues observed, those who tanned indoors were more likely to develop sunburn than students who did not engage in indoor tanning.”
“Clearly, both the dermatology and medical communities need to continue public awareness campaigns regarding photoprotection, including sun-safety practices such as seeking shade when outdoors and wearing photoprotective clothing, wide-brimmed hats, and sunglasses,” they emphasized.
In addition, “A highly effective means of public education may be to identify a campaign, such as Portugal’s sugar packet initiative, that makes sun-safety awareness and practice a part of everyone’s daily routine,” they said (JAMA Dermatol. 2017. doi: 10.1001/jamadermatol.2016.6272).
Dr. Lim and Dr. Schneider are affiliated with the department of dermatology at Henry Ford Hospital in Detroit. Dr Lim disclosed serving as an investigator or coinvestigator on clinical research projects for Ferndale Pharma, Estée Lauder, and Allergan. Dr. Schneider had no relevant conflicts to disclose.
Explore best practices for public education campaigns “For more than 10 years, much effort has been made to educate the public on sun-safety practices, including warnings about the harmful effects of indoor tanning on those at higher risk, such as young adults and children. In this issue of JAMA Dermatology, 2 important articles describe the progress made toward sun safety,” wrote Henry W. Lim, MD, and Samantha L. Schneider, MD, in the accompanying editorial.
Data from a study of indoor tanning showed a significant decrease in prevalence of indoor tanning among adolescents, from 16% in 2009 to 7% in 2015. Although these results are encouraging, public education is needed for further improvement, they said. “One myth is that UV radiation prevents vitamin D deficiency; however, oral vitamin D supplementation is known to be a safer alternative. Another myth is that obtaining a baseline tan before the summer or a vacation reduces the risk of sunburn. However, as Guy and colleagues observed, those who tanned indoors were more likely to develop sunburn than students who did not engage in indoor tanning.”
“Clearly, both the dermatology and medical communities need to continue public awareness campaigns regarding photoprotection, including sun-safety practices such as seeking shade when outdoors and wearing photoprotective clothing, wide-brimmed hats, and sunglasses,” they emphasized.
In addition, “A highly effective means of public education may be to identify a campaign, such as Portugal’s sugar packet initiative, that makes sun-safety awareness and practice a part of everyone’s daily routine,” they said (JAMA Dermatol. 2017. doi: 10.1001/jamadermatol.2016.6272).
Dr. Lim and Dr. Schneider are affiliated with the department of dermatology at Henry Ford Hospital in Detroit. Dr Lim disclosed serving as an investigator or coinvestigator on clinical research projects for Ferndale Pharma, Estée Lauder, and Allergan. Dr. Schneider had no relevant conflicts to disclose.
Explore best practices for public education campaigns “For more than 10 years, much effort has been made to educate the public on sun-safety practices, including warnings about the harmful effects of indoor tanning on those at higher risk, such as young adults and children. In this issue of JAMA Dermatology, 2 important articles describe the progress made toward sun safety,” wrote Henry W. Lim, MD, and Samantha L. Schneider, MD, in the accompanying editorial.
Data from a study of indoor tanning showed a significant decrease in prevalence of indoor tanning among adolescents, from 16% in 2009 to 7% in 2015. Although these results are encouraging, public education is needed for further improvement, they said. “One myth is that UV radiation prevents vitamin D deficiency; however, oral vitamin D supplementation is known to be a safer alternative. Another myth is that obtaining a baseline tan before the summer or a vacation reduces the risk of sunburn. However, as Guy and colleagues observed, those who tanned indoors were more likely to develop sunburn than students who did not engage in indoor tanning.”
“Clearly, both the dermatology and medical communities need to continue public awareness campaigns regarding photoprotection, including sun-safety practices such as seeking shade when outdoors and wearing photoprotective clothing, wide-brimmed hats, and sunglasses,” they emphasized.
In addition, “A highly effective means of public education may be to identify a campaign, such as Portugal’s sugar packet initiative, that makes sun-safety awareness and practice a part of everyone’s daily routine,” they said (JAMA Dermatol. 2017. doi: 10.1001/jamadermatol.2016.6272).
Dr. Lim and Dr. Schneider are affiliated with the department of dermatology at Henry Ford Hospital in Detroit. Dr Lim disclosed serving as an investigator or coinvestigator on clinical research projects for Ferndale Pharma, Estée Lauder, and Allergan. Dr. Schneider had no relevant conflicts to disclose.
Indoor tanning among adolescents in the United States has dropped significantly, but fewer than half of schools in the United States reported sun safety practices to help minimize students’ UV exposure in the school setting, based on data from two studies presented at the annual meeting of the American Academy of Dermatology and published simultaneously in JAMA Dermatology.
“Data suggest that intermittent, recreational exposure (vs. chronic exposure, as with outdoor workers) more often leads to sunburn,” wrote Sherry Everett Jones, PhD, MPH, and Gery P. Guy Jr, PhD, MPH, of the Centers for Disease Control and Prevention. “Although a small proportion of school districts and schools have adopted policies to address sun safety, most have not, even though it is common for students to be outside during the midday hours or after school when the sun is still at peak intensity.”
To characterize sun safety practices at schools, the researchers reviewed data from the 2014 School Health Policies and Practices Study Healthy and Safe School Environment questionnaire including 577 elementary, middle, and high schools (JAMA Dermatol. 2017. doi: 10.1001/jamadermatol.2016.6274).
Overall, 48% of schools reported that teachers allowed students time to apply sunscreen at school (the most frequent sun safety practice). However, only 13% made sunscreen available, 16% asked parents to ensure sunscreen application before school, and 15% made an effort to avoid scheduling outdoor activities during times of peak sun intensity. High schools were less likely than elementary or middle schools to follow sun safety practices.
“None of the sun safety policies or practices were statistically significantly associated with metropolitan status,” the researchers noted. However, the findings were limited by the cross-sectional nature of the study and lack of data about natural shade and man made shade structures in outdoor areas of the schools.
“Interventions driven by the public health and medical community educating school leadership and policy makers about the importance of sun safety are needed regardless of level, location, size, and poverty concentration of the school. These efforts could be instrumental in increasing the adoption of sun safety practices among schools,” Dr. Jones and Dr. Guy emphasized.
However, data from another study showed a significant reduction in the prevalence of indoor tanning among adolescents.
In particular, indoor tanning among non-Hispanic white females (the group at highest risk for skin cancer) dropped from 37% in 2009 to 15% in 2015. CDC researchers led by Dr. Guy pooled data from the 2009, 2011, 2013, and 2015 national Youth Risk Behavior Surveillance System Surveys (JAMA Dermatol. 2017. doi:10.1001/jamadermatol.2016.6273). Overall, the prevalence of indoor tanning among U.S. high school students decreased from 16% in 2009 to 7% in 2015.
“Despite declines in indoor tanning, continued efforts are needed,” the researchers wrote. “Public health efforts could help address the misconception that indoor tanning protects against sunburn. The medical community also can play a key role in counseling adolescents and young adults in accordance with the U.S. Preventive Services Task Force guidelines.”
The findings were limited by several factors including the use of self-reports and the inability to control for skin type, the researchers wrote. However, “Reducing the proportion of youth who engage in indoor tanning and experience sunburns presents an important cancer prevention opportunity.”
None of the researchers on either study had relevant financial conflicts to disclose.
Indoor tanning among adolescents in the United States has dropped significantly, but fewer than half of schools in the United States reported sun safety practices to help minimize students’ UV exposure in the school setting, based on data from two studies presented at the annual meeting of the American Academy of Dermatology and published simultaneously in JAMA Dermatology.
“Data suggest that intermittent, recreational exposure (vs. chronic exposure, as with outdoor workers) more often leads to sunburn,” wrote Sherry Everett Jones, PhD, MPH, and Gery P. Guy Jr, PhD, MPH, of the Centers for Disease Control and Prevention. “Although a small proportion of school districts and schools have adopted policies to address sun safety, most have not, even though it is common for students to be outside during the midday hours or after school when the sun is still at peak intensity.”
To characterize sun safety practices at schools, the researchers reviewed data from the 2014 School Health Policies and Practices Study Healthy and Safe School Environment questionnaire including 577 elementary, middle, and high schools (JAMA Dermatol. 2017. doi: 10.1001/jamadermatol.2016.6274).
Overall, 48% of schools reported that teachers allowed students time to apply sunscreen at school (the most frequent sun safety practice). However, only 13% made sunscreen available, 16% asked parents to ensure sunscreen application before school, and 15% made an effort to avoid scheduling outdoor activities during times of peak sun intensity. High schools were less likely than elementary or middle schools to follow sun safety practices.
“None of the sun safety policies or practices were statistically significantly associated with metropolitan status,” the researchers noted. However, the findings were limited by the cross-sectional nature of the study and lack of data about natural shade and man made shade structures in outdoor areas of the schools.
“Interventions driven by the public health and medical community educating school leadership and policy makers about the importance of sun safety are needed regardless of level, location, size, and poverty concentration of the school. These efforts could be instrumental in increasing the adoption of sun safety practices among schools,” Dr. Jones and Dr. Guy emphasized.
However, data from another study showed a significant reduction in the prevalence of indoor tanning among adolescents.
In particular, indoor tanning among non-Hispanic white females (the group at highest risk for skin cancer) dropped from 37% in 2009 to 15% in 2015. CDC researchers led by Dr. Guy pooled data from the 2009, 2011, 2013, and 2015 national Youth Risk Behavior Surveillance System Surveys (JAMA Dermatol. 2017. doi:10.1001/jamadermatol.2016.6273). Overall, the prevalence of indoor tanning among U.S. high school students decreased from 16% in 2009 to 7% in 2015.
“Despite declines in indoor tanning, continued efforts are needed,” the researchers wrote. “Public health efforts could help address the misconception that indoor tanning protects against sunburn. The medical community also can play a key role in counseling adolescents and young adults in accordance with the U.S. Preventive Services Task Force guidelines.”
The findings were limited by several factors including the use of self-reports and the inability to control for skin type, the researchers wrote. However, “Reducing the proportion of youth who engage in indoor tanning and experience sunburns presents an important cancer prevention opportunity.”
None of the researchers on either study had relevant financial conflicts to disclose.
FROM AAD 2017
Key clinical point:
Major finding: Fewer than half (48%) of schools in the United States allowed time for sunscreen application, and fewer than 15% provided sunscreen. However, overall prevalence of indoor tanning among U.S. adolescents dropped from 16% in 2009 to 7% in 2015.
Data source: Data were taken from the 2014 School Health Policies and Practices Study in the first study and from the 2009, 2011, 2013, and 2015 national Youth Risk Behavior Surveys in the second.
Disclosures: The researchers had no financial conflicts to disclose.
Pigmented skin lesions lightened during melanoma immunotherapy
Treatment with pembrolizumab, a humanized antibody used in cancer immunotherapy, may affect the pigmentation of some benign skin lesions, according to a case study in British Journal of Dermatology.
Pembrolizumab works by targeting the programmed cell death-1 (PD-1) receptor and is used in the treatment of metastatic melanoma and some other cancers.
The case report, by Zachary J. Wolner, MD, of Memorial Sloan Kettering Cancer Center in New York, and his colleagues, describes a male patient in his 60s with HRAS mutant metastatic melanoma who was treated with pembrolizumab 2 mg/kg every 3 weeks for 13 months, and had received no previous systematic treatment. At 4 months after starting pembrolizumab, the patient experienced whitening of eyebrows and eyelashes, along with scalp and body hair, followed by lighter overall skin pigmentation and the fading of pigmented skin lesions. Baseline (pre-pembrolizumab) and 1-year follow-up skin photography confirmed lightening or disappearance of solar lentigines, seborrheic keratoses, and melanocytic nevi along with overall lightening of the skin (Br J. Dermatol. 2017 doi: 10.1111/bjd.15354).
Dr. Wolner and his colleagues noted that while changing skin lesions have not been reported in clinical trials of anti-PD-1 therapies, one study in patients treated with an anti-PD-1 therapy for metastatic melanoma found changes to nevi in 6 of 34 (18%) patients. Patients using a melanoma website also have self-reported disappearing nevi after immunotherapy treatment, the authors noted.
Expression of the coinhibitory molecule PD-L1 “is not limited to malignant tumors,” the researchers wrote, adding that previous studies have identified PD-L1 expression in melanocytes of benign melanocytic nevi. “Therefore it is biologically plausible that PD-1 inhibition may affect the natural history of benign melanocytic neoplasms.”
Also, they wrote, “the co-occurrence of vitiligo and poliosis in our patient suggests a role for autoimmunity in the fading/disappearance of his pigmented lesions.” The investigators cited a recent study in 67 patients with metastatic melanoma receiving pembrolizumab, which found that 25% developed vitiligo. Response to treatment also was significantly associated with occurrence of vitiligo (JAMA Dermatol. 2016;152[1]:45-51).
Dr. Wolner and his colleagues cautioned that their findings were limited to a single case report, and also by “lack of histological sampling and molecular characterization of fading/disappearing nevi.” An alternative explanation for the observed changes “includes fading/disappearance not related to PD-1 inhibition or due to chance alone.”
A National Institutes of Health/National Cancer Institute Cancer Center grant was used to help fund the study. Two of Dr. Wolner’s coauthors disclosed consultant or advisory board relationships with Merck and other pharmaceutical manufacturers.
Treatment with pembrolizumab, a humanized antibody used in cancer immunotherapy, may affect the pigmentation of some benign skin lesions, according to a case study in British Journal of Dermatology.
Pembrolizumab works by targeting the programmed cell death-1 (PD-1) receptor and is used in the treatment of metastatic melanoma and some other cancers.
The case report, by Zachary J. Wolner, MD, of Memorial Sloan Kettering Cancer Center in New York, and his colleagues, describes a male patient in his 60s with HRAS mutant metastatic melanoma who was treated with pembrolizumab 2 mg/kg every 3 weeks for 13 months, and had received no previous systematic treatment. At 4 months after starting pembrolizumab, the patient experienced whitening of eyebrows and eyelashes, along with scalp and body hair, followed by lighter overall skin pigmentation and the fading of pigmented skin lesions. Baseline (pre-pembrolizumab) and 1-year follow-up skin photography confirmed lightening or disappearance of solar lentigines, seborrheic keratoses, and melanocytic nevi along with overall lightening of the skin (Br J. Dermatol. 2017 doi: 10.1111/bjd.15354).
Dr. Wolner and his colleagues noted that while changing skin lesions have not been reported in clinical trials of anti-PD-1 therapies, one study in patients treated with an anti-PD-1 therapy for metastatic melanoma found changes to nevi in 6 of 34 (18%) patients. Patients using a melanoma website also have self-reported disappearing nevi after immunotherapy treatment, the authors noted.
Expression of the coinhibitory molecule PD-L1 “is not limited to malignant tumors,” the researchers wrote, adding that previous studies have identified PD-L1 expression in melanocytes of benign melanocytic nevi. “Therefore it is biologically plausible that PD-1 inhibition may affect the natural history of benign melanocytic neoplasms.”
Also, they wrote, “the co-occurrence of vitiligo and poliosis in our patient suggests a role for autoimmunity in the fading/disappearance of his pigmented lesions.” The investigators cited a recent study in 67 patients with metastatic melanoma receiving pembrolizumab, which found that 25% developed vitiligo. Response to treatment also was significantly associated with occurrence of vitiligo (JAMA Dermatol. 2016;152[1]:45-51).
Dr. Wolner and his colleagues cautioned that their findings were limited to a single case report, and also by “lack of histological sampling and molecular characterization of fading/disappearing nevi.” An alternative explanation for the observed changes “includes fading/disappearance not related to PD-1 inhibition or due to chance alone.”
A National Institutes of Health/National Cancer Institute Cancer Center grant was used to help fund the study. Two of Dr. Wolner’s coauthors disclosed consultant or advisory board relationships with Merck and other pharmaceutical manufacturers.
Treatment with pembrolizumab, a humanized antibody used in cancer immunotherapy, may affect the pigmentation of some benign skin lesions, according to a case study in British Journal of Dermatology.
Pembrolizumab works by targeting the programmed cell death-1 (PD-1) receptor and is used in the treatment of metastatic melanoma and some other cancers.
The case report, by Zachary J. Wolner, MD, of Memorial Sloan Kettering Cancer Center in New York, and his colleagues, describes a male patient in his 60s with HRAS mutant metastatic melanoma who was treated with pembrolizumab 2 mg/kg every 3 weeks for 13 months, and had received no previous systematic treatment. At 4 months after starting pembrolizumab, the patient experienced whitening of eyebrows and eyelashes, along with scalp and body hair, followed by lighter overall skin pigmentation and the fading of pigmented skin lesions. Baseline (pre-pembrolizumab) and 1-year follow-up skin photography confirmed lightening or disappearance of solar lentigines, seborrheic keratoses, and melanocytic nevi along with overall lightening of the skin (Br J. Dermatol. 2017 doi: 10.1111/bjd.15354).
Dr. Wolner and his colleagues noted that while changing skin lesions have not been reported in clinical trials of anti-PD-1 therapies, one study in patients treated with an anti-PD-1 therapy for metastatic melanoma found changes to nevi in 6 of 34 (18%) patients. Patients using a melanoma website also have self-reported disappearing nevi after immunotherapy treatment, the authors noted.
Expression of the coinhibitory molecule PD-L1 “is not limited to malignant tumors,” the researchers wrote, adding that previous studies have identified PD-L1 expression in melanocytes of benign melanocytic nevi. “Therefore it is biologically plausible that PD-1 inhibition may affect the natural history of benign melanocytic neoplasms.”
Also, they wrote, “the co-occurrence of vitiligo and poliosis in our patient suggests a role for autoimmunity in the fading/disappearance of his pigmented lesions.” The investigators cited a recent study in 67 patients with metastatic melanoma receiving pembrolizumab, which found that 25% developed vitiligo. Response to treatment also was significantly associated with occurrence of vitiligo (JAMA Dermatol. 2016;152[1]:45-51).
Dr. Wolner and his colleagues cautioned that their findings were limited to a single case report, and also by “lack of histological sampling and molecular characterization of fading/disappearing nevi.” An alternative explanation for the observed changes “includes fading/disappearance not related to PD-1 inhibition or due to chance alone.”
A National Institutes of Health/National Cancer Institute Cancer Center grant was used to help fund the study. Two of Dr. Wolner’s coauthors disclosed consultant or advisory board relationships with Merck and other pharmaceutical manufacturers.
Key clinical point:
Major finding: Pembrolizumab and other PD-1 inhibitors may affect benign pigmented lesions.
Data source: A single-center, single-patient case report.
Disclosures: A National Institutes of Health/National Cancer Institute Cancer Center grant was used to help fund the study. Two of Dr. Wolner’s coauthors disclosed consultant or advisory board relationships with Merck and other pharmaceutical manufacturers.
Use of IHC stains on rise in melanoma diagnosis
While there is little consensus on the ideal role of immunohistochemical (IHC) stains in the diagnosis of melanoma, their use increased dramatically over a 15-year period, according to results from a study.
Randie H. Kim, MD, PhD, and Shane A. Meehan, MD, of New York University, reviewed nearly 6,300 pathology reports from patients with melanomas, all referred (along with tissue samples) to their center from other institutions during 2001-2015. One or more IHC stains were used diagnostically in 871 cases during the study period, with use increasing from 5% of patients in 2001 to 25% in 2015 (P less than .0001). Usage increased gradually over time, although the number of stains used per case did not increase significantly (J Cutan Pathol. 2017 Mar;44[3]:221-7).
IHC stain use was associated with melanomas occurring on the head or neck (odds ratio = 1.6; 95% confidence interval, 1.4-1.9), acral melanomas (OR = 1.5; 95% CI 1.1-2.0) and melanomas thicker than 4 mm (OR = 2.5; 95% CI 1.7-3.6). The most common stain used in the study was Melan-A/MART-1 (melanoma antigen recognized by T cells), the most specific of the IHC markers available and the one “largely responsible for the increased incidence in overall immunostain use in our study,” the researchers wrote. “The perception that melanocytic markers, such as Melan-A, can more accurately stage melanomas, is a potential explanation for its increased usage over the duration of the study period.”
The higher use of immunostains in thicker melanomas may be because these “exhibit greater morphological heterogeneity, such as nodular, spindled and desmoplastic subtypes, that lead to additional confirmational testing,” Dr. Kim and Dr. Meehan noted. However, they cautioned that extrinsic factors, including reimbursement fees and concerns about malpractice claims, could also influence the use of IHC stains in the diagnosis of melanomas.
“While Melan-A/MART-1 is a useful adjunct for determining melanocytic density or the presence of invasion in difficult cases, its routine use on melanomas has not been validated,” the researchers wrote in their analysis. “A consensus conference delineating the appropriate use of IHC in the diagnosis of melanoma may be of value in this regard.”
Dr. Kim and Dr. Meehan also noted that while a greater proportion of the melanomas seen in the study were thick (greater than 4 mm) compared with most population-based studies, this may reflect patient management practices in which thinner melanomas are treated in outpatient centers while thicker ones get referred to tertiary care centers such as theirs.
The researchers disclosed no outside funding or conflicts of interest.
While there is little consensus on the ideal role of immunohistochemical (IHC) stains in the diagnosis of melanoma, their use increased dramatically over a 15-year period, according to results from a study.
Randie H. Kim, MD, PhD, and Shane A. Meehan, MD, of New York University, reviewed nearly 6,300 pathology reports from patients with melanomas, all referred (along with tissue samples) to their center from other institutions during 2001-2015. One or more IHC stains were used diagnostically in 871 cases during the study period, with use increasing from 5% of patients in 2001 to 25% in 2015 (P less than .0001). Usage increased gradually over time, although the number of stains used per case did not increase significantly (J Cutan Pathol. 2017 Mar;44[3]:221-7).
IHC stain use was associated with melanomas occurring on the head or neck (odds ratio = 1.6; 95% confidence interval, 1.4-1.9), acral melanomas (OR = 1.5; 95% CI 1.1-2.0) and melanomas thicker than 4 mm (OR = 2.5; 95% CI 1.7-3.6). The most common stain used in the study was Melan-A/MART-1 (melanoma antigen recognized by T cells), the most specific of the IHC markers available and the one “largely responsible for the increased incidence in overall immunostain use in our study,” the researchers wrote. “The perception that melanocytic markers, such as Melan-A, can more accurately stage melanomas, is a potential explanation for its increased usage over the duration of the study period.”
The higher use of immunostains in thicker melanomas may be because these “exhibit greater morphological heterogeneity, such as nodular, spindled and desmoplastic subtypes, that lead to additional confirmational testing,” Dr. Kim and Dr. Meehan noted. However, they cautioned that extrinsic factors, including reimbursement fees and concerns about malpractice claims, could also influence the use of IHC stains in the diagnosis of melanomas.
“While Melan-A/MART-1 is a useful adjunct for determining melanocytic density or the presence of invasion in difficult cases, its routine use on melanomas has not been validated,” the researchers wrote in their analysis. “A consensus conference delineating the appropriate use of IHC in the diagnosis of melanoma may be of value in this regard.”
Dr. Kim and Dr. Meehan also noted that while a greater proportion of the melanomas seen in the study were thick (greater than 4 mm) compared with most population-based studies, this may reflect patient management practices in which thinner melanomas are treated in outpatient centers while thicker ones get referred to tertiary care centers such as theirs.
The researchers disclosed no outside funding or conflicts of interest.
While there is little consensus on the ideal role of immunohistochemical (IHC) stains in the diagnosis of melanoma, their use increased dramatically over a 15-year period, according to results from a study.
Randie H. Kim, MD, PhD, and Shane A. Meehan, MD, of New York University, reviewed nearly 6,300 pathology reports from patients with melanomas, all referred (along with tissue samples) to their center from other institutions during 2001-2015. One or more IHC stains were used diagnostically in 871 cases during the study period, with use increasing from 5% of patients in 2001 to 25% in 2015 (P less than .0001). Usage increased gradually over time, although the number of stains used per case did not increase significantly (J Cutan Pathol. 2017 Mar;44[3]:221-7).
IHC stain use was associated with melanomas occurring on the head or neck (odds ratio = 1.6; 95% confidence interval, 1.4-1.9), acral melanomas (OR = 1.5; 95% CI 1.1-2.0) and melanomas thicker than 4 mm (OR = 2.5; 95% CI 1.7-3.6). The most common stain used in the study was Melan-A/MART-1 (melanoma antigen recognized by T cells), the most specific of the IHC markers available and the one “largely responsible for the increased incidence in overall immunostain use in our study,” the researchers wrote. “The perception that melanocytic markers, such as Melan-A, can more accurately stage melanomas, is a potential explanation for its increased usage over the duration of the study period.”
The higher use of immunostains in thicker melanomas may be because these “exhibit greater morphological heterogeneity, such as nodular, spindled and desmoplastic subtypes, that lead to additional confirmational testing,” Dr. Kim and Dr. Meehan noted. However, they cautioned that extrinsic factors, including reimbursement fees and concerns about malpractice claims, could also influence the use of IHC stains in the diagnosis of melanomas.
“While Melan-A/MART-1 is a useful adjunct for determining melanocytic density or the presence of invasion in difficult cases, its routine use on melanomas has not been validated,” the researchers wrote in their analysis. “A consensus conference delineating the appropriate use of IHC in the diagnosis of melanoma may be of value in this regard.”
Dr. Kim and Dr. Meehan also noted that while a greater proportion of the melanomas seen in the study were thick (greater than 4 mm) compared with most population-based studies, this may reflect patient management practices in which thinner melanomas are treated in outpatient centers while thicker ones get referred to tertiary care centers such as theirs.
The researchers disclosed no outside funding or conflicts of interest.
FROM THE JOURNAL OF CUTANEOUS PATHOLOGY
Key clinical point:
Major finding: One or more stains was used diagnostically in 5% of melanoma cases in 2001, compared with 25% in 2015 (P less than .0001).
Data source: A retrospective review of more than 6,000 case records referred after diagnosis to a tertiary care center during 2001-2015.
Disclosures: The researchers disclosed no outside funding or conflicts of interest.