Immuno-oncology

CHICAGO – Pembrolizumab monotherapy is associated with antitumor activity in patients with advanced recurrent ovarian cancer, interim results from the phase 2 KEYNOTE-100 study suggest.

Notably, objective response rates among study subjects increased in tandem with increased programmed death-ligand 1 (PD-L1) expression, which helps define the population most likely to benefit from single agent pembrolizumab (Keytruda), Ursula A. Matulonis reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.

Further, no new safety signals were identified, said Dr. Matulonis, medical director and program leader of the Medical Gynecologic Oncology Program at of Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston.

All patients received intravenous pembrolizumab at 200 mg every 3 weeks for 2 years or until progression, death, unacceptable toxicity, or consent withdrawal, and tumor imaging was performed every 9 weeks for a year, then every 12 weeks thereafter until progressive disease, death, or study completion.

The overall response rate (ORR) among 285 patients in Cohort A, who had one to three prior chemotherapy lines for recurrent advanced ovarian cancer and a platinum-free or treatment-free interval of 3-12 months, was 7.4%, with mean duration of response of 8.2 months. The ORR among 91 patients in Cohort B, who had four to six prior chemotherapy lines and a platinum-free or treatment-free interval of at least 3 months, was 9.9%; the mean duration of response was not reached in Cohort B.

Among all-comers, the ORR was 8.0%, including 7 complete responses and 23 partial responses. Mean duration of response was 8.2 months, and 65.5% of responses lasted at least 6 months. Further, responses were observed across all subgroups, Dr. Matulonis said, noting that responses were seen regardless of age, prior lines of treatment, progression-free/treatment-free interval duration, platinum sensitivity, and histology.

“The one factor that did predict response was a [combined positive score] of 10 or higher, where there were more responses,” she said.

The ORRs among those with PD-L1 expression as measured using the combined positive score (CPS), which is defined as the number of PD-L1–positive cells out of the total number of tumor cells x 100, was 5.0% in those with CPS less than 1, 10.2% in those with CPS of 1 or greater, and 17.1% in those with CPS of 10 or greater (vs. the 8.0% ORR in the study), she explained, noting that all complete responses occurred in those with CPS of 10 or higher.

Grade 3-4 treatment-related adverse events occurred in 19.7% of patients, and included fatigue in 2.7%, and anemia, colitis, increased amylase, increased blood alkaline phosphatase, ascites, and diarrhea in 0.8-1.3%. One treatment-related death occurred in a patient with Stevens-Johnson syndrome, and another occurred in a patient with hypoaldosteronism. Immune-mediated adverse events and infusion reactions were most commonly hyperthyroidism and hypothyroidism, and most cases were grade 1-2, she said.

KEYNOTE-100 is an ongoing study that followed KEYNOTE-028, which demonstrated the clinical activity of pembrolizumab in patients with advanced ovarian cancer. To date, KEYNOTE-100 has enrolled 376 patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer and confirmed recurrence after frontline platinum-based therapy. All had a tumor sample available for biomarker analysis.

The patients had a mean age of 61 years, 64% and 35% had performance status scores of 0 and 1, respectively, and 75% had high-grade serous disease.

Median follow-up in Cohort A at the time of the current analysis was 16.7 months, and in Cohort B, the median follow-up was 17.3 months. Treatment was ongoing in 15 and 6 patients in the cohorts, respectively. Reasons for discontinuation included radiographic progression (204 and 62 patients), clinical progression (24 and 17 patients), adverse events (22 and 3 patients), and patient withdrawal (9 and 3 patients). Complete responses occurred in 1 and 0 patients in the groups, respectively.

Median progression-free survival in both cohorts was 2.1 months, and overall survival was not reached in Cohort A, while it was 17.6 months in the more heavily pretreated Cohort B.

“Recurrent ovarian cancer is the leading cause of death from gynecologic cancer. The majority of our patients relapse after first-line platinum and taxane-based chemotherapy, and the degree of platinum sensitivity will predict the tumor response rates with platinum, as well as survival time,” she said, noting that subsequent recurrences become increasingly platinum and treatment resistant.

Current treatment options in these patients include chemotherapy with or without bevacizumab; the ORRs with single-agent immune checkpoint blockade are about 10%, but in KEYNOTE-028, patients with PD-L1–positive advanced recurrent ovarian cancer had an ORR of 11.5% with pembrolizumab treatment, she said.

“With 16.9 months median follow-up, the results confirm that pembrolizumab monotherapy in recurrent ovarian cancer elicits modest antitumor efficacy,” Dr. Matulonis concluded, noting that further analysis for biomarkers predictive of pembrolizumab response are ongoing.

Invited discussant Janos Laszlo Tanyi, MD, of the University of Pennsylvania, Philadelphia, said the findings underscore the overall modest ORRs of 5.9%-15% seen with anti-PD-1 or PD-L1 monotherapy in patients with advanced recurrent ovarian cancer, but noted the importance of the finding that the subpopulation of patients with increased PD-L1 expression may experience greater benefit.

Dr. Matulonis reported consulting or advisory roles with 2X Oncology, Clovis Oncology, Fujifilm, Geneos Therapeutics, Lilly, Merck, and Myriad Genetics, and research funding from Merck and Novartis. Dr .Tanyi reported having no disclosures.

SOURCE: Matulonis UA et al. ASCO 2018, Abstract 5511.

CHICAGO – Pembrolizumab monotherapy is associated with antitumor activity in patients with advanced recurrent ovarian cancer, interim results from the phase 2 KEYNOTE-100 study suggest.

Notably, objective response rates among study subjects increased in tandem with increased programmed death-ligand 1 (PD-L1) expression, which helps define the population most likely to benefit from single agent pembrolizumab (Keytruda), Ursula A. Matulonis reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.

Further, no new safety signals were identified, said Dr. Matulonis, medical director and program leader of the Medical Gynecologic Oncology Program at of Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston.

All patients received intravenous pembrolizumab at 200 mg every 3 weeks for 2 years or until progression, death, unacceptable toxicity, or consent withdrawal, and tumor imaging was performed every 9 weeks for a year, then every 12 weeks thereafter until progressive disease, death, or study completion.

The overall response rate (ORR) among 285 patients in Cohort A, who had one to three prior chemotherapy lines for recurrent advanced ovarian cancer and a platinum-free or treatment-free interval of 3-12 months, was 7.4%, with mean duration of response of 8.2 months. The ORR among 91 patients in Cohort B, who had four to six prior chemotherapy lines and a platinum-free or treatment-free interval of at least 3 months, was 9.9%; the mean duration of response was not reached in Cohort B.

Among all-comers, the ORR was 8.0%, including 7 complete responses and 23 partial responses. Mean duration of response was 8.2 months, and 65.5% of responses lasted at least 6 months. Further, responses were observed across all subgroups, Dr. Matulonis said, noting that responses were seen regardless of age, prior lines of treatment, progression-free/treatment-free interval duration, platinum sensitivity, and histology.

“The one factor that did predict response was a [combined positive score] of 10 or higher, where there were more responses,” she said.

The ORRs among those with PD-L1 expression as measured using the combined positive score (CPS), which is defined as the number of PD-L1–positive cells out of the total number of tumor cells x 100, was 5.0% in those with CPS less than 1, 10.2% in those with CPS of 1 or greater, and 17.1% in those with CPS of 10 or greater (vs. the 8.0% ORR in the study), she explained, noting that all complete responses occurred in those with CPS of 10 or higher.

Grade 3-4 treatment-related adverse events occurred in 19.7% of patients, and included fatigue in 2.7%, and anemia, colitis, increased amylase, increased blood alkaline phosphatase, ascites, and diarrhea in 0.8-1.3%. One treatment-related death occurred in a patient with Stevens-Johnson syndrome, and another occurred in a patient with hypoaldosteronism. Immune-mediated adverse events and infusion reactions were most commonly hyperthyroidism and hypothyroidism, and most cases were grade 1-2, she said.

KEYNOTE-100 is an ongoing study that followed KEYNOTE-028, which demonstrated the clinical activity of pembrolizumab in patients with advanced ovarian cancer. To date, KEYNOTE-100 has enrolled 376 patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer and confirmed recurrence after frontline platinum-based therapy. All had a tumor sample available for biomarker analysis.

The patients had a mean age of 61 years, 64% and 35% had performance status scores of 0 and 1, respectively, and 75% had high-grade serous disease.

Median follow-up in Cohort A at the time of the current analysis was 16.7 months, and in Cohort B, the median follow-up was 17.3 months. Treatment was ongoing in 15 and 6 patients in the cohorts, respectively. Reasons for discontinuation included radiographic progression (204 and 62 patients), clinical progression (24 and 17 patients), adverse events (22 and 3 patients), and patient withdrawal (9 and 3 patients). Complete responses occurred in 1 and 0 patients in the groups, respectively.

Median progression-free survival in both cohorts was 2.1 months, and overall survival was not reached in Cohort A, while it was 17.6 months in the more heavily pretreated Cohort B.

“Recurrent ovarian cancer is the leading cause of death from gynecologic cancer. The majority of our patients relapse after first-line platinum and taxane-based chemotherapy, and the degree of platinum sensitivity will predict the tumor response rates with platinum, as well as survival time,” she said, noting that subsequent recurrences become increasingly platinum and treatment resistant.

Current treatment options in these patients include chemotherapy with or without bevacizumab; the ORRs with single-agent immune checkpoint blockade are about 10%, but in KEYNOTE-028, patients with PD-L1–positive advanced recurrent ovarian cancer had an ORR of 11.5% with pembrolizumab treatment, she said.

“With 16.9 months median follow-up, the results confirm that pembrolizumab monotherapy in recurrent ovarian cancer elicits modest antitumor efficacy,” Dr. Matulonis concluded, noting that further analysis for biomarkers predictive of pembrolizumab response are ongoing.

Invited discussant Janos Laszlo Tanyi, MD, of the University of Pennsylvania, Philadelphia, said the findings underscore the overall modest ORRs of 5.9%-15% seen with anti-PD-1 or PD-L1 monotherapy in patients with advanced recurrent ovarian cancer, but noted the importance of the finding that the subpopulation of patients with increased PD-L1 expression may experience greater benefit.

Dr. Matulonis reported consulting or advisory roles with 2X Oncology, Clovis Oncology, Fujifilm, Geneos Therapeutics, Lilly, Merck, and Myriad Genetics, and research funding from Merck and Novartis. Dr .Tanyi reported having no disclosures.

SOURCE: Matulonis UA et al. ASCO 2018, Abstract 5511.

CHICAGO – Pembrolizumab monotherapy is associated with antitumor activity in patients with advanced recurrent ovarian cancer, interim results from the phase 2 KEYNOTE-100 study suggest.

Notably, objective response rates among study subjects increased in tandem with increased programmed death-ligand 1 (PD-L1) expression, which helps define the population most likely to benefit from single agent pembrolizumab (Keytruda), Ursula A. Matulonis reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.

Further, no new safety signals were identified, said Dr. Matulonis, medical director and program leader of the Medical Gynecologic Oncology Program at of Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston.

All patients received intravenous pembrolizumab at 200 mg every 3 weeks for 2 years or until progression, death, unacceptable toxicity, or consent withdrawal, and tumor imaging was performed every 9 weeks for a year, then every 12 weeks thereafter until progressive disease, death, or study completion.

The overall response rate (ORR) among 285 patients in Cohort A, who had one to three prior chemotherapy lines for recurrent advanced ovarian cancer and a platinum-free or treatment-free interval of 3-12 months, was 7.4%, with mean duration of response of 8.2 months. The ORR among 91 patients in Cohort B, who had four to six prior chemotherapy lines and a platinum-free or treatment-free interval of at least 3 months, was 9.9%; the mean duration of response was not reached in Cohort B.

Among all-comers, the ORR was 8.0%, including 7 complete responses and 23 partial responses. Mean duration of response was 8.2 months, and 65.5% of responses lasted at least 6 months. Further, responses were observed across all subgroups, Dr. Matulonis said, noting that responses were seen regardless of age, prior lines of treatment, progression-free/treatment-free interval duration, platinum sensitivity, and histology.

“The one factor that did predict response was a [combined positive score] of 10 or higher, where there were more responses,” she said.

The ORRs among those with PD-L1 expression as measured using the combined positive score (CPS), which is defined as the number of PD-L1–positive cells out of the total number of tumor cells x 100, was 5.0% in those with CPS less than 1, 10.2% in those with CPS of 1 or greater, and 17.1% in those with CPS of 10 or greater (vs. the 8.0% ORR in the study), she explained, noting that all complete responses occurred in those with CPS of 10 or higher.

Grade 3-4 treatment-related adverse events occurred in 19.7% of patients, and included fatigue in 2.7%, and anemia, colitis, increased amylase, increased blood alkaline phosphatase, ascites, and diarrhea in 0.8-1.3%. One treatment-related death occurred in a patient with Stevens-Johnson syndrome, and another occurred in a patient with hypoaldosteronism. Immune-mediated adverse events and infusion reactions were most commonly hyperthyroidism and hypothyroidism, and most cases were grade 1-2, she said.

KEYNOTE-100 is an ongoing study that followed KEYNOTE-028, which demonstrated the clinical activity of pembrolizumab in patients with advanced ovarian cancer. To date, KEYNOTE-100 has enrolled 376 patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer and confirmed recurrence after frontline platinum-based therapy. All had a tumor sample available for biomarker analysis.

The patients had a mean age of 61 years, 64% and 35% had performance status scores of 0 and 1, respectively, and 75% had high-grade serous disease.

Median follow-up in Cohort A at the time of the current analysis was 16.7 months, and in Cohort B, the median follow-up was 17.3 months. Treatment was ongoing in 15 and 6 patients in the cohorts, respectively. Reasons for discontinuation included radiographic progression (204 and 62 patients), clinical progression (24 and 17 patients), adverse events (22 and 3 patients), and patient withdrawal (9 and 3 patients). Complete responses occurred in 1 and 0 patients in the groups, respectively.

Median progression-free survival in both cohorts was 2.1 months, and overall survival was not reached in Cohort A, while it was 17.6 months in the more heavily pretreated Cohort B.

“Recurrent ovarian cancer is the leading cause of death from gynecologic cancer. The majority of our patients relapse after first-line platinum and taxane-based chemotherapy, and the degree of platinum sensitivity will predict the tumor response rates with platinum, as well as survival time,” she said, noting that subsequent recurrences become increasingly platinum and treatment resistant.

Current treatment options in these patients include chemotherapy with or without bevacizumab; the ORRs with single-agent immune checkpoint blockade are about 10%, but in KEYNOTE-028, patients with PD-L1–positive advanced recurrent ovarian cancer had an ORR of 11.5% with pembrolizumab treatment, she said.

“With 16.9 months median follow-up, the results confirm that pembrolizumab monotherapy in recurrent ovarian cancer elicits modest antitumor efficacy,” Dr. Matulonis concluded, noting that further analysis for biomarkers predictive of pembrolizumab response are ongoing.

Invited discussant Janos Laszlo Tanyi, MD, of the University of Pennsylvania, Philadelphia, said the findings underscore the overall modest ORRs of 5.9%-15% seen with anti-PD-1 or PD-L1 monotherapy in patients with advanced recurrent ovarian cancer, but noted the importance of the finding that the subpopulation of patients with increased PD-L1 expression may experience greater benefit.

Dr. Matulonis reported consulting or advisory roles with 2X Oncology, Clovis Oncology, Fujifilm, Geneos Therapeutics, Lilly, Merck, and Myriad Genetics, and research funding from Merck and Novartis. Dr .Tanyi reported having no disclosures.

SOURCE: Matulonis UA et al. ASCO 2018, Abstract 5511.

For patients with non–small-cell lung cancer (NSCLC), preexisting autoimmune disease (AID) does not increase the risk of immune-related adverse events (irAEs) with checkpoint inhibitor therapy, according to investigators.

Flares of AID during therapy were generally mild, and toxicity rates were only slightly increased in patients with AID, they wrote in Journal of Clinical Oncology.

Approximately 14%-25% of patients with lung cancer also have AID, but patients with AID are typically excluded from clinical trials. “This presents a tremendous knowledge gap,” wrote lead author Giulia C. Leonardi, MD, of the Dana-Farber Cancer Institute in Boston, and coauthors.

The retrospective study comprised 56 patients with NSCLC and preexisting autoimmune disease from five academic cancer centers. Almost half of the patients had a rheumatologic disorder, 29% had a dermatologic disorder, 16% had an endocrine disorder, 11% had inflammatory bowel disease, 5% had a neurologic condition, 3% had rheumatic fever, and one patient (2%) had autoimmune hemolytic anemia.

Patients received either a programmed death-1 or programmed death-ligand 1 inhibitor as monotherapy. Median treatment time was 3.1 months, and median follow-up time after starting therapy was 17.5 months.

Eleven percent of patients with preexisting AID developed grade 3 or 4 irAEs, which is similar to 7%-15% of patients in clinical trials. Although 23% of patients experienced a flare of their preexisting AID, these flares were generally mild – no patients discontinued immunotherapy because of a flare. In contrast, 14% of patients halted therapy because of toxicity, a marginally higher number than 3%-8% of patients in trials.

Checkpoint inhibitors are now a mainstay treatment for a lung cancer, including three approved drugs: nivolumab, pembrolizumab, and atezolizumab. “Almost every patient with advanced NSCLC will likely receive a [checkpoint] inhibitor at some point over the course of their disease,” the authors noted. As checkpoint inhibitors may lead to fatal irAEs, the possible interplay between these immunotherapies and AID requires investigation.

“Our study adds to the growing body of evidence supporting the use of immunotherapy in patients with cancer with preexisting AID, albeit with close monitoring for adverse events,” the researchers concluded.

SOURCE: Leonardi GC et al. J Clin Oncol. 2018* May 20. doi: 10.1200/JCO.2017.77.0305.

*Correction, 5/22/18: An earlier version of this article misstated the year in this citation.

For patients with non–small-cell lung cancer (NSCLC), preexisting autoimmune disease (AID) does not increase the risk of immune-related adverse events (irAEs) with checkpoint inhibitor therapy, according to investigators.

Flares of AID during therapy were generally mild, and toxicity rates were only slightly increased in patients with AID, they wrote in Journal of Clinical Oncology.

Approximately 14%-25% of patients with lung cancer also have AID, but patients with AID are typically excluded from clinical trials. “This presents a tremendous knowledge gap,” wrote lead author Giulia C. Leonardi, MD, of the Dana-Farber Cancer Institute in Boston, and coauthors.

The retrospective study comprised 56 patients with NSCLC and preexisting autoimmune disease from five academic cancer centers. Almost half of the patients had a rheumatologic disorder, 29% had a dermatologic disorder, 16% had an endocrine disorder, 11% had inflammatory bowel disease, 5% had a neurologic condition, 3% had rheumatic fever, and one patient (2%) had autoimmune hemolytic anemia.

Patients received either a programmed death-1 or programmed death-ligand 1 inhibitor as monotherapy. Median treatment time was 3.1 months, and median follow-up time after starting therapy was 17.5 months.

Eleven percent of patients with preexisting AID developed grade 3 or 4 irAEs, which is similar to 7%-15% of patients in clinical trials. Although 23% of patients experienced a flare of their preexisting AID, these flares were generally mild – no patients discontinued immunotherapy because of a flare. In contrast, 14% of patients halted therapy because of toxicity, a marginally higher number than 3%-8% of patients in trials.

Checkpoint inhibitors are now a mainstay treatment for a lung cancer, including three approved drugs: nivolumab, pembrolizumab, and atezolizumab. “Almost every patient with advanced NSCLC will likely receive a [checkpoint] inhibitor at some point over the course of their disease,” the authors noted. As checkpoint inhibitors may lead to fatal irAEs, the possible interplay between these immunotherapies and AID requires investigation.

“Our study adds to the growing body of evidence supporting the use of immunotherapy in patients with cancer with preexisting AID, albeit with close monitoring for adverse events,” the researchers concluded.

SOURCE: Leonardi GC et al. J Clin Oncol. 2018* May 20. doi: 10.1200/JCO.2017.77.0305.

*Correction, 5/22/18: An earlier version of this article misstated the year in this citation.

For patients with non–small-cell lung cancer (NSCLC), preexisting autoimmune disease (AID) does not increase the risk of immune-related adverse events (irAEs) with checkpoint inhibitor therapy, according to investigators.

Flares of AID during therapy were generally mild, and toxicity rates were only slightly increased in patients with AID, they wrote in Journal of Clinical Oncology.

Approximately 14%-25% of patients with lung cancer also have AID, but patients with AID are typically excluded from clinical trials. “This presents a tremendous knowledge gap,” wrote lead author Giulia C. Leonardi, MD, of the Dana-Farber Cancer Institute in Boston, and coauthors.

The retrospective study comprised 56 patients with NSCLC and preexisting autoimmune disease from five academic cancer centers. Almost half of the patients had a rheumatologic disorder, 29% had a dermatologic disorder, 16% had an endocrine disorder, 11% had inflammatory bowel disease, 5% had a neurologic condition, 3% had rheumatic fever, and one patient (2%) had autoimmune hemolytic anemia.

Patients received either a programmed death-1 or programmed death-ligand 1 inhibitor as monotherapy. Median treatment time was 3.1 months, and median follow-up time after starting therapy was 17.5 months.

Eleven percent of patients with preexisting AID developed grade 3 or 4 irAEs, which is similar to 7%-15% of patients in clinical trials. Although 23% of patients experienced a flare of their preexisting AID, these flares were generally mild – no patients discontinued immunotherapy because of a flare. In contrast, 14% of patients halted therapy because of toxicity, a marginally higher number than 3%-8% of patients in trials.

Checkpoint inhibitors are now a mainstay treatment for a lung cancer, including three approved drugs: nivolumab, pembrolizumab, and atezolizumab. “Almost every patient with advanced NSCLC will likely receive a [checkpoint] inhibitor at some point over the course of their disease,” the authors noted. As checkpoint inhibitors may lead to fatal irAEs, the possible interplay between these immunotherapies and AID requires investigation.

“Our study adds to the growing body of evidence supporting the use of immunotherapy in patients with cancer with preexisting AID, albeit with close monitoring for adverse events,” the researchers concluded.

SOURCE: Leonardi GC et al. J Clin Oncol. 2018* May 20. doi: 10.1200/JCO.2017.77.0305.

*Correction, 5/22/18: An earlier version of this article misstated the year in this citation.

CHICAGO – The investigational programmed cell death protein 1 checkpoint inhibitor cemiplimab proved highly effective for the treatment of locally advanced or metastatic cutaneous squamous cell carcinoma in a phase 1 clinical trial, Michael R. Migden, MD, reported at the annual meeting of the American College of Mohs Surgery.

And this was no ordinary phase 1 study, he noted. Because there is no Food and Drug Administration–approved treatment for advanced cutaneous squamous cell carcinoma (CSCC), cemiplimab has been granted both Breakthrough Drug and Orphan Drug status by the FDA and the European Medicines Agency.

Bruce Jancin/MDedge News

The complete response rate at 48 weeks was 12.5%, with tumor clearance occurring as quickly as 14 weeks. Another 25% of patients had a partial response, for an overall response rate of 37.5%. But that’s not the full success story, as another 31% of patients had stable disease. Thus, 11 of 16 patients, or 69%, experienced disease control.

“A disease-control rate of nearly 70% is really important because these are patients with life-threatening tumors. To be able to hold them steady is a big deal,” Dr. Migden observed.

One-quarter of study participants experienced progressive disease. The remainder weren’t evaluated for various reasons.

The dermatologist pointed out that locally advanced disease was particularly responsive to cemiplimab, with four of nine affected patients experiencing complete or partial response, for an overall response rate of 44%. This is consistent with the preliminary results of the pivotal phase 2 study, in which the overall response rate in the 78 participants with unresectable, locally advanced CSCC was 46%.

The phase 2 trial also includes another 59 patients with metastatic CSCC on 3 mg/kg IV cemiplimab every 14 days, as well as 56 patients with metastatic disease assigned to flat-dose 350-mg IV cemiplimab every 21 days.

Treatment side effects

In the phase 1 study, immunotherapy with cemiplimab was far better tolerated than in traditional cancer chemotherapy. There were two grade 3 cases of elevated liver enzymes and one of arthralgia, but no significant fatigue or nausea and no hypothyroidism. However, judging from the cumulative experience accrued with the five PD-1 checkpoint inhibitors already approved for treatment of other cancers, one must be prepared to encounter hypothyroidism and other endocrinopathies, pneumonitis, hepatitis, and rashes.

“The clinician must have a very high index of suspicion for these immune-related adverse events and a low threshold to consult with colleagues in other specialties – pulmonary, endocrine, and medical oncology – for evaluation and management of these possible side effects. I tell all the patients who are on cemiplimab, ‘Any new anything – a slight cough, mild diarrhea – you’re coming in and you’re getting checked,’ ” according to Dr. Migden.

That being said, the majority of immune-related adverse events because of PD-1 inhibitors are mild to moderate. Of the few that reach grade 3 or above, most can be successfully managed by pausing or discontinuing anti–PD-1 therapy coupled with prompt initiation of immunosuppressive therapy, typically with high-dose steroids, he added.
 

Look sharp for pseudoprogression

Pseudoprogression is a phenomenon whereby immunotherapy results in inflammatory changes bringing about a temporary increase in tumor size that precedes tumor shrinkage. It’s uncommon, occurring in 3 of 16 patients in the phase 1 study. The mechanism probably involves tumor infiltration by massive numbers of activated T cells. And there is evidence from other PD-1 inhibitor studies in advanced cancers that pseudoprogression may actually be a marker for increased likelihood of survival beyond 1 year.

“Pseudoprogression is important to recognize because the patients you treat with cemiplimab can get worse before they get better,” the dermatologist explained. “So you don’t want to prematurely discontinue treatment because you’re misclassifying it as tumor progression.”
 

The rationale for anti-PD-1 therapy in CSCC

Tumors that express PD-1 bind to PD–ligand 1 on T cells, switching off T-cell mediated tumor destruction and thereby allowing the malignancy to thrive.

“Simplified, the strategy here is to interfere with the interaction at the T-cell off switch, either with an antibody to PD–ligand 1, such as atezolizumab [Tecentriq], or an antibody to the PD-1 receptor, where cemiplimab works. By turning off the off switch, we get a T cell fully on and attacking the tumor cell,” Dr. Migden said.

“The more the tumor mutation burden, the better immunotherapy works – and CSCC has the highest tumor mutation burden of any tumor type in the Cancer Genome Atlas, several times higher than melanoma. Interestingly, basal cell carcinoma has an even higher tumor mutation burden than CSCC, but it’s not part of the atlas,” he continued.

Although the proportion of CSCCs that are locally advanced hasn’t been well established, it’s clear that CSCC is the deadliest nonmelanoma skin cancer, accounting for 3,900-8,800 deaths annually in the United States.

The cemiplimab phase 1 and 2 clinical trials for CSCC were jointly sponsored by Regeneron and Sanofi. The monoclonal antibody is also being developed for treatment of myeloma and lung cancer. Dr. Migden reported receiving honoraria from Regeneron and Sanofi, as well as from Genentech, Lilly, Novartis, and Sun Pharmaceuticals.

bjancin@mdedge.com

CHICAGO – The investigational programmed cell death protein 1 checkpoint inhibitor cemiplimab proved highly effective for the treatment of locally advanced or metastatic cutaneous squamous cell carcinoma in a phase 1 clinical trial, Michael R. Migden, MD, reported at the annual meeting of the American College of Mohs Surgery.

And this was no ordinary phase 1 study, he noted. Because there is no Food and Drug Administration–approved treatment for advanced cutaneous squamous cell carcinoma (CSCC), cemiplimab has been granted both Breakthrough Drug and Orphan Drug status by the FDA and the European Medicines Agency.

Bruce Jancin/MDedge News

The complete response rate at 48 weeks was 12.5%, with tumor clearance occurring as quickly as 14 weeks. Another 25% of patients had a partial response, for an overall response rate of 37.5%. But that’s not the full success story, as another 31% of patients had stable disease. Thus, 11 of 16 patients, or 69%, experienced disease control.

“A disease-control rate of nearly 70% is really important because these are patients with life-threatening tumors. To be able to hold them steady is a big deal,” Dr. Migden observed.

One-quarter of study participants experienced progressive disease. The remainder weren’t evaluated for various reasons.

The dermatologist pointed out that locally advanced disease was particularly responsive to cemiplimab, with four of nine affected patients experiencing complete or partial response, for an overall response rate of 44%. This is consistent with the preliminary results of the pivotal phase 2 study, in which the overall response rate in the 78 participants with unresectable, locally advanced CSCC was 46%.

The phase 2 trial also includes another 59 patients with metastatic CSCC on 3 mg/kg IV cemiplimab every 14 days, as well as 56 patients with metastatic disease assigned to flat-dose 350-mg IV cemiplimab every 21 days.

Treatment side effects

In the phase 1 study, immunotherapy with cemiplimab was far better tolerated than in traditional cancer chemotherapy. There were two grade 3 cases of elevated liver enzymes and one of arthralgia, but no significant fatigue or nausea and no hypothyroidism. However, judging from the cumulative experience accrued with the five PD-1 checkpoint inhibitors already approved for treatment of other cancers, one must be prepared to encounter hypothyroidism and other endocrinopathies, pneumonitis, hepatitis, and rashes.

“The clinician must have a very high index of suspicion for these immune-related adverse events and a low threshold to consult with colleagues in other specialties – pulmonary, endocrine, and medical oncology – for evaluation and management of these possible side effects. I tell all the patients who are on cemiplimab, ‘Any new anything – a slight cough, mild diarrhea – you’re coming in and you’re getting checked,’ ” according to Dr. Migden.

That being said, the majority of immune-related adverse events because of PD-1 inhibitors are mild to moderate. Of the few that reach grade 3 or above, most can be successfully managed by pausing or discontinuing anti–PD-1 therapy coupled with prompt initiation of immunosuppressive therapy, typically with high-dose steroids, he added.
 

Look sharp for pseudoprogression

Pseudoprogression is a phenomenon whereby immunotherapy results in inflammatory changes bringing about a temporary increase in tumor size that precedes tumor shrinkage. It’s uncommon, occurring in 3 of 16 patients in the phase 1 study. The mechanism probably involves tumor infiltration by massive numbers of activated T cells. And there is evidence from other PD-1 inhibitor studies in advanced cancers that pseudoprogression may actually be a marker for increased likelihood of survival beyond 1 year.

“Pseudoprogression is important to recognize because the patients you treat with cemiplimab can get worse before they get better,” the dermatologist explained. “So you don’t want to prematurely discontinue treatment because you’re misclassifying it as tumor progression.”
 

The rationale for anti-PD-1 therapy in CSCC

Tumors that express PD-1 bind to PD–ligand 1 on T cells, switching off T-cell mediated tumor destruction and thereby allowing the malignancy to thrive.

“Simplified, the strategy here is to interfere with the interaction at the T-cell off switch, either with an antibody to PD–ligand 1, such as atezolizumab [Tecentriq], or an antibody to the PD-1 receptor, where cemiplimab works. By turning off the off switch, we get a T cell fully on and attacking the tumor cell,” Dr. Migden said.

“The more the tumor mutation burden, the better immunotherapy works – and CSCC has the highest tumor mutation burden of any tumor type in the Cancer Genome Atlas, several times higher than melanoma. Interestingly, basal cell carcinoma has an even higher tumor mutation burden than CSCC, but it’s not part of the atlas,” he continued.

Although the proportion of CSCCs that are locally advanced hasn’t been well established, it’s clear that CSCC is the deadliest nonmelanoma skin cancer, accounting for 3,900-8,800 deaths annually in the United States.

The cemiplimab phase 1 and 2 clinical trials for CSCC were jointly sponsored by Regeneron and Sanofi. The monoclonal antibody is also being developed for treatment of myeloma and lung cancer. Dr. Migden reported receiving honoraria from Regeneron and Sanofi, as well as from Genentech, Lilly, Novartis, and Sun Pharmaceuticals.

bjancin@mdedge.com

CHICAGO – The investigational programmed cell death protein 1 checkpoint inhibitor cemiplimab proved highly effective for the treatment of locally advanced or metastatic cutaneous squamous cell carcinoma in a phase 1 clinical trial, Michael R. Migden, MD, reported at the annual meeting of the American College of Mohs Surgery.

And this was no ordinary phase 1 study, he noted. Because there is no Food and Drug Administration–approved treatment for advanced cutaneous squamous cell carcinoma (CSCC), cemiplimab has been granted both Breakthrough Drug and Orphan Drug status by the FDA and the European Medicines Agency.

Bruce Jancin/MDedge News

The complete response rate at 48 weeks was 12.5%, with tumor clearance occurring as quickly as 14 weeks. Another 25% of patients had a partial response, for an overall response rate of 37.5%. But that’s not the full success story, as another 31% of patients had stable disease. Thus, 11 of 16 patients, or 69%, experienced disease control.

“A disease-control rate of nearly 70% is really important because these are patients with life-threatening tumors. To be able to hold them steady is a big deal,” Dr. Migden observed.

One-quarter of study participants experienced progressive disease. The remainder weren’t evaluated for various reasons.

The dermatologist pointed out that locally advanced disease was particularly responsive to cemiplimab, with four of nine affected patients experiencing complete or partial response, for an overall response rate of 44%. This is consistent with the preliminary results of the pivotal phase 2 study, in which the overall response rate in the 78 participants with unresectable, locally advanced CSCC was 46%.

The phase 2 trial also includes another 59 patients with metastatic CSCC on 3 mg/kg IV cemiplimab every 14 days, as well as 56 patients with metastatic disease assigned to flat-dose 350-mg IV cemiplimab every 21 days.

Treatment side effects

In the phase 1 study, immunotherapy with cemiplimab was far better tolerated than in traditional cancer chemotherapy. There were two grade 3 cases of elevated liver enzymes and one of arthralgia, but no significant fatigue or nausea and no hypothyroidism. However, judging from the cumulative experience accrued with the five PD-1 checkpoint inhibitors already approved for treatment of other cancers, one must be prepared to encounter hypothyroidism and other endocrinopathies, pneumonitis, hepatitis, and rashes.

“The clinician must have a very high index of suspicion for these immune-related adverse events and a low threshold to consult with colleagues in other specialties – pulmonary, endocrine, and medical oncology – for evaluation and management of these possible side effects. I tell all the patients who are on cemiplimab, ‘Any new anything – a slight cough, mild diarrhea – you’re coming in and you’re getting checked,’ ” according to Dr. Migden.

That being said, the majority of immune-related adverse events because of PD-1 inhibitors are mild to moderate. Of the few that reach grade 3 or above, most can be successfully managed by pausing or discontinuing anti–PD-1 therapy coupled with prompt initiation of immunosuppressive therapy, typically with high-dose steroids, he added.
 

Look sharp for pseudoprogression

Pseudoprogression is a phenomenon whereby immunotherapy results in inflammatory changes bringing about a temporary increase in tumor size that precedes tumor shrinkage. It’s uncommon, occurring in 3 of 16 patients in the phase 1 study. The mechanism probably involves tumor infiltration by massive numbers of activated T cells. And there is evidence from other PD-1 inhibitor studies in advanced cancers that pseudoprogression may actually be a marker for increased likelihood of survival beyond 1 year.

“Pseudoprogression is important to recognize because the patients you treat with cemiplimab can get worse before they get better,” the dermatologist explained. “So you don’t want to prematurely discontinue treatment because you’re misclassifying it as tumor progression.”
 

The rationale for anti-PD-1 therapy in CSCC

Tumors that express PD-1 bind to PD–ligand 1 on T cells, switching off T-cell mediated tumor destruction and thereby allowing the malignancy to thrive.

“Simplified, the strategy here is to interfere with the interaction at the T-cell off switch, either with an antibody to PD–ligand 1, such as atezolizumab [Tecentriq], or an antibody to the PD-1 receptor, where cemiplimab works. By turning off the off switch, we get a T cell fully on and attacking the tumor cell,” Dr. Migden said.

“The more the tumor mutation burden, the better immunotherapy works – and CSCC has the highest tumor mutation burden of any tumor type in the Cancer Genome Atlas, several times higher than melanoma. Interestingly, basal cell carcinoma has an even higher tumor mutation burden than CSCC, but it’s not part of the atlas,” he continued.

Although the proportion of CSCCs that are locally advanced hasn’t been well established, it’s clear that CSCC is the deadliest nonmelanoma skin cancer, accounting for 3,900-8,800 deaths annually in the United States.

The cemiplimab phase 1 and 2 clinical trials for CSCC were jointly sponsored by Regeneron and Sanofi. The monoclonal antibody is also being developed for treatment of myeloma and lung cancer. Dr. Migden reported receiving honoraria from Regeneron and Sanofi, as well as from Genentech, Lilly, Novartis, and Sun Pharmaceuticals.

bjancin@mdedge.com

PITTSBURGH – Call it the CAR of the future – an investigational chimeric antigen receptor–T cell construct targeted against an antigen highly expressed on pediatric solid tumors has shown promising efficacy in preclinical studies.

Investigators found that the antigen, labeled B7-H3, was expressed on 84% of microarrays of pediatric solid tumors. More importantly, a single dose of CAR targeted to B7-H3 caused complete regression of osteosarcoma and Ewing sarcoma xenografts and improved survival over an untransduced, CD19-targeted CAR in mice, Robbie Majzner, MD, reported at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Neil Osterweil/MDedge News

In contrast, B7-H3 is highly expressed on many different pediatric solid tumors, including rhabdomyosarcoma (95% of tumors stained), Ewing sarcoma (89%), Wilms tumor (100%), neuroblastoma (82%), ganglioneuroblastoma and ganglioneuroma (53%), medulloblastoma (96%), glioblastoma multiforme (84%), and diffuse intrinsic pontine glioma (100%).

To see whether CAR T therapy might have better efficacy than checkpoint inhibitors in this population, the investigators created a B7-H3 CAR using the B7-H3 tumor–specific monoclonal antibody MGA271, which has been shown to be safe in both adults and children in early clinical trials.

In human tumor xenograft models of osteosarcoma, all mice who received a single dose of the B7-H3 CAR survived at least 70 days after tumor engraftment, whereas all control mice, who received the CD19 CAR, died by day 60 (P = .0067). Similarly, in a model of Ewing sarcoma, all mice treated with B7-H3 survived at least 100 days, whereas all controls were dead by day 50 (P = .0015).

The B7-H3 construct also showed good activity against a model of medulloblastoma, showing that it was capable of crossing the blood-brain barrier.

Since B7-H3 has been reported to be expressed on both myeloid and lymphoid leukemia cells, the investigators also tested the CAR against a murine model of leukemia generated by injection of K562, a well-characterized line of myeloid leukemia cells.

“While we found some increase in survival in the mice that received the B7-H3 CAR T cells, compared to mice that received untransduced CAR T cells, this clearly is not as effective as in our solid tumor models,” Dr. Majzner said.

Going back to the cell line, they discovered that expression of B7-H3 was considerably lower in the K562 cells than in either the osteosarcoma or medulloblastoma cell lines used in their other models.

They found that both in vitro and in vivo, high levels of B7-H3 expression were necessary to provoke the immune system into releasing cytokines necessary for an adequate antitumor response.

The investigators are currently planning clinical trials using the B7-H3 CAR T-cell construct in patients with solid tumors.

The work is supported by the Sarcoma Alliance for Research through Collaboration, the St. Baldrick’s Foundation, and Stand Up to Cancer. Dr. Majzner reported having no financial disclosures.

SOURCE: Majzner RG et al. ASPHO 2018, Abstract #PS2003.

PITTSBURGH – Call it the CAR of the future – an investigational chimeric antigen receptor–T cell construct targeted against an antigen highly expressed on pediatric solid tumors has shown promising efficacy in preclinical studies.

Investigators found that the antigen, labeled B7-H3, was expressed on 84% of microarrays of pediatric solid tumors. More importantly, a single dose of CAR targeted to B7-H3 caused complete regression of osteosarcoma and Ewing sarcoma xenografts and improved survival over an untransduced, CD19-targeted CAR in mice, Robbie Majzner, MD, reported at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Neil Osterweil/MDedge News

In contrast, B7-H3 is highly expressed on many different pediatric solid tumors, including rhabdomyosarcoma (95% of tumors stained), Ewing sarcoma (89%), Wilms tumor (100%), neuroblastoma (82%), ganglioneuroblastoma and ganglioneuroma (53%), medulloblastoma (96%), glioblastoma multiforme (84%), and diffuse intrinsic pontine glioma (100%).

To see whether CAR T therapy might have better efficacy than checkpoint inhibitors in this population, the investigators created a B7-H3 CAR using the B7-H3 tumor–specific monoclonal antibody MGA271, which has been shown to be safe in both adults and children in early clinical trials.

In human tumor xenograft models of osteosarcoma, all mice who received a single dose of the B7-H3 CAR survived at least 70 days after tumor engraftment, whereas all control mice, who received the CD19 CAR, died by day 60 (P = .0067). Similarly, in a model of Ewing sarcoma, all mice treated with B7-H3 survived at least 100 days, whereas all controls were dead by day 50 (P = .0015).

The B7-H3 construct also showed good activity against a model of medulloblastoma, showing that it was capable of crossing the blood-brain barrier.

Since B7-H3 has been reported to be expressed on both myeloid and lymphoid leukemia cells, the investigators also tested the CAR against a murine model of leukemia generated by injection of K562, a well-characterized line of myeloid leukemia cells.

“While we found some increase in survival in the mice that received the B7-H3 CAR T cells, compared to mice that received untransduced CAR T cells, this clearly is not as effective as in our solid tumor models,” Dr. Majzner said.

Going back to the cell line, they discovered that expression of B7-H3 was considerably lower in the K562 cells than in either the osteosarcoma or medulloblastoma cell lines used in their other models.

They found that both in vitro and in vivo, high levels of B7-H3 expression were necessary to provoke the immune system into releasing cytokines necessary for an adequate antitumor response.

The investigators are currently planning clinical trials using the B7-H3 CAR T-cell construct in patients with solid tumors.

The work is supported by the Sarcoma Alliance for Research through Collaboration, the St. Baldrick’s Foundation, and Stand Up to Cancer. Dr. Majzner reported having no financial disclosures.

SOURCE: Majzner RG et al. ASPHO 2018, Abstract #PS2003.

PITTSBURGH – Call it the CAR of the future – an investigational chimeric antigen receptor–T cell construct targeted against an antigen highly expressed on pediatric solid tumors has shown promising efficacy in preclinical studies.

Investigators found that the antigen, labeled B7-H3, was expressed on 84% of microarrays of pediatric solid tumors. More importantly, a single dose of CAR targeted to B7-H3 caused complete regression of osteosarcoma and Ewing sarcoma xenografts and improved survival over an untransduced, CD19-targeted CAR in mice, Robbie Majzner, MD, reported at the annual meeting of the American Society of Pediatric Hematology/Oncology.

Neil Osterweil/MDedge News

In contrast, B7-H3 is highly expressed on many different pediatric solid tumors, including rhabdomyosarcoma (95% of tumors stained), Ewing sarcoma (89%), Wilms tumor (100%), neuroblastoma (82%), ganglioneuroblastoma and ganglioneuroma (53%), medulloblastoma (96%), glioblastoma multiforme (84%), and diffuse intrinsic pontine glioma (100%).

To see whether CAR T therapy might have better efficacy than checkpoint inhibitors in this population, the investigators created a B7-H3 CAR using the B7-H3 tumor–specific monoclonal antibody MGA271, which has been shown to be safe in both adults and children in early clinical trials.

In human tumor xenograft models of osteosarcoma, all mice who received a single dose of the B7-H3 CAR survived at least 70 days after tumor engraftment, whereas all control mice, who received the CD19 CAR, died by day 60 (P = .0067). Similarly, in a model of Ewing sarcoma, all mice treated with B7-H3 survived at least 100 days, whereas all controls were dead by day 50 (P = .0015).

The B7-H3 construct also showed good activity against a model of medulloblastoma, showing that it was capable of crossing the blood-brain barrier.

Since B7-H3 has been reported to be expressed on both myeloid and lymphoid leukemia cells, the investigators also tested the CAR against a murine model of leukemia generated by injection of K562, a well-characterized line of myeloid leukemia cells.

“While we found some increase in survival in the mice that received the B7-H3 CAR T cells, compared to mice that received untransduced CAR T cells, this clearly is not as effective as in our solid tumor models,” Dr. Majzner said.

Going back to the cell line, they discovered that expression of B7-H3 was considerably lower in the K562 cells than in either the osteosarcoma or medulloblastoma cell lines used in their other models.

They found that both in vitro and in vivo, high levels of B7-H3 expression were necessary to provoke the immune system into releasing cytokines necessary for an adequate antitumor response.

The investigators are currently planning clinical trials using the B7-H3 CAR T-cell construct in patients with solid tumors.

The work is supported by the Sarcoma Alliance for Research through Collaboration, the St. Baldrick’s Foundation, and Stand Up to Cancer. Dr. Majzner reported having no financial disclosures.

SOURCE: Majzner RG et al. ASPHO 2018, Abstract #PS2003.

Cancer immunotherapy using checkpoint inhibitors may achieve greater mortality reductions in men than they do in women, new research has suggested.

In a meta-analysis and systematic review published in Lancet Oncology, researchers analyzed 20 randomized, controlled trials of immune checkpoint inhibitors that included detail on overall survival and patients’ sex; altogether, these studies involved 11,351 patients with advanced or metastatic cancers.

They found that while men treated with checkpoint inhibitors had a significant 28% reduced risk of death, compared with male controls, the survival benefit in women was smaller (14% reduced risk of death, compared with female controls).

Fabio Conforti, MD, from the European Institute of Oncology, Milan, and coauthors commented that the magnitude of the difference between the effect seen men and that in women was clinically significant.

“The pooled reduction of risk of death was double the size for male patients than for female patients – a difference that is similar to the size of the difference in survival benefit observed between patients with non–small cell lung cancer with PD-L1 positive (greater than 1%) tumors versus negative tumors, who were treated with anti-PD-1,” they wrote.

This difference between the benefit seen men and that in women was evident across all the subgroups in the study, which included subgroups based on cancer histotype, line of treatment, drugs used, and type of control.

However there was greater heterogeneity in the magnitude of the effect of checkpoint inhibitors on mortality in men than there was in women. The authors suggested this could be explained by the fact that the drugs have lower efficacy in women and this may therefore reduce the variability of results when compared with those in men.

SOURCE: Conforti F et al. Lancet Oncol. 2018 May 16. doi: 10.1016/S1470-2045(18)30261-4.

Cancer immunotherapy using checkpoint inhibitors may achieve greater mortality reductions in men than they do in women, new research has suggested.

In a meta-analysis and systematic review published in Lancet Oncology, researchers analyzed 20 randomized, controlled trials of immune checkpoint inhibitors that included detail on overall survival and patients’ sex; altogether, these studies involved 11,351 patients with advanced or metastatic cancers.

They found that while men treated with checkpoint inhibitors had a significant 28% reduced risk of death, compared with male controls, the survival benefit in women was smaller (14% reduced risk of death, compared with female controls).

Fabio Conforti, MD, from the European Institute of Oncology, Milan, and coauthors commented that the magnitude of the difference between the effect seen men and that in women was clinically significant.

“The pooled reduction of risk of death was double the size for male patients than for female patients – a difference that is similar to the size of the difference in survival benefit observed between patients with non–small cell lung cancer with PD-L1 positive (greater than 1%) tumors versus negative tumors, who were treated with anti-PD-1,” they wrote.

This difference between the benefit seen men and that in women was evident across all the subgroups in the study, which included subgroups based on cancer histotype, line of treatment, drugs used, and type of control.

However there was greater heterogeneity in the magnitude of the effect of checkpoint inhibitors on mortality in men than there was in women. The authors suggested this could be explained by the fact that the drugs have lower efficacy in women and this may therefore reduce the variability of results when compared with those in men.

SOURCE: Conforti F et al. Lancet Oncol. 2018 May 16. doi: 10.1016/S1470-2045(18)30261-4.

Cancer immunotherapy using checkpoint inhibitors may achieve greater mortality reductions in men than they do in women, new research has suggested.

In a meta-analysis and systematic review published in Lancet Oncology, researchers analyzed 20 randomized, controlled trials of immune checkpoint inhibitors that included detail on overall survival and patients’ sex; altogether, these studies involved 11,351 patients with advanced or metastatic cancers.

They found that while men treated with checkpoint inhibitors had a significant 28% reduced risk of death, compared with male controls, the survival benefit in women was smaller (14% reduced risk of death, compared with female controls).

Fabio Conforti, MD, from the European Institute of Oncology, Milan, and coauthors commented that the magnitude of the difference between the effect seen men and that in women was clinically significant.

“The pooled reduction of risk of death was double the size for male patients than for female patients – a difference that is similar to the size of the difference in survival benefit observed between patients with non–small cell lung cancer with PD-L1 positive (greater than 1%) tumors versus negative tumors, who were treated with anti-PD-1,” they wrote.

This difference between the benefit seen men and that in women was evident across all the subgroups in the study, which included subgroups based on cancer histotype, line of treatment, drugs used, and type of control.

However there was greater heterogeneity in the magnitude of the effect of checkpoint inhibitors on mortality in men than there was in women. The authors suggested this could be explained by the fact that the drugs have lower efficacy in women and this may therefore reduce the variability of results when compared with those in men.

SOURCE: Conforti F et al. Lancet Oncol. 2018 May 16. doi: 10.1016/S1470-2045(18)30261-4.

Checkpoint inhibitors got to melanoma, non–small cell lung cancer, and renal cell carcinoma patients quickly in clinical practice after Food and Drug Administration approval – usually within 4 months – but the patients treated in clinical settings tended to be older than those treated in trials, which has caused concern about whether real-world efficacy will prove to be the same, according to a study in JAMA Oncology.

“Such rapid adoption stands in contrast to older estimates that suggest it takes years or even decades for new treatments to be adopted,” wrote lead author Cary Gross, MD, professor of medicine at Yale University, New Haven, and his coauthors. “We found significant differences in age between patients treated in practice and those treated in trials, which highlights the need to clarify the risks and benefits of checkpoint inhibitors in general populations of patients.”

Researchers drew data on nivolumab and pembrolizumab use from the Flatiron Health longitudinal EHR database, which included 233 academic and community oncology practices. In each of the three disease cohorts, adoption was seen within 4 months for at least 60% of patients. Uptake was quickest for the melanoma patients, 76% of whom received a checkpoint inhibitor within 4 months, investigators wrote. Factors for the fast adoption could include high disease severity, a preference for novelty, perceived gains over existing treatments, and promotional activities, such as media reports and advertising directly to consumers, they wrote.

More patients in real-world practice were aged 65 years or older, ranging from as little as 61% at the lowest end of the range at one center to as much as 64% at the highest end at another. In the clinical trials, the percentage of patients aged 65 years or older ranged from 32% in one trial to 41% in another. Researchers wrote that these higher real-world rates are concerning because there are still questions regarding whether differences in immune responses will cause differences in efficacy between older and younger patients, as well as safety considerations among different age groups.

“Although data suggest that outcomes are similar between older and younger patients receiving anti–PD-1 agents for melanoma, there is little evidence to guide anti–PD-1 treatment of older patients with NSCLC [non–small cell lung cancer],” Dr. Gross and his coinvestigators wrote.

Investigators wrote that the findings are cause for caution.

“As FDA officials develop more flexible standards for approval, which the 21st Century Cures Act requires them to do, it is possible that many patients will receive drugs before much is known about clinical outcomes,” Dr. Gross said. “Further integrations of real-world evidence might allow the FDA to better assess the drugs that they approve on the basis of nonrepresentative trial participants.”

SOURCE: Gross C et al. JAMA Oncol. 2018 May 10. doi: 10.1001/jamaoncol.2018.0798.






 

Checkpoint inhibitors got to melanoma, non–small cell lung cancer, and renal cell carcinoma patients quickly in clinical practice after Food and Drug Administration approval – usually within 4 months – but the patients treated in clinical settings tended to be older than those treated in trials, which has caused concern about whether real-world efficacy will prove to be the same, according to a study in JAMA Oncology.

“Such rapid adoption stands in contrast to older estimates that suggest it takes years or even decades for new treatments to be adopted,” wrote lead author Cary Gross, MD, professor of medicine at Yale University, New Haven, and his coauthors. “We found significant differences in age between patients treated in practice and those treated in trials, which highlights the need to clarify the risks and benefits of checkpoint inhibitors in general populations of patients.”

Researchers drew data on nivolumab and pembrolizumab use from the Flatiron Health longitudinal EHR database, which included 233 academic and community oncology practices. In each of the three disease cohorts, adoption was seen within 4 months for at least 60% of patients. Uptake was quickest for the melanoma patients, 76% of whom received a checkpoint inhibitor within 4 months, investigators wrote. Factors for the fast adoption could include high disease severity, a preference for novelty, perceived gains over existing treatments, and promotional activities, such as media reports and advertising directly to consumers, they wrote.

More patients in real-world practice were aged 65 years or older, ranging from as little as 61% at the lowest end of the range at one center to as much as 64% at the highest end at another. In the clinical trials, the percentage of patients aged 65 years or older ranged from 32% in one trial to 41% in another. Researchers wrote that these higher real-world rates are concerning because there are still questions regarding whether differences in immune responses will cause differences in efficacy between older and younger patients, as well as safety considerations among different age groups.

“Although data suggest that outcomes are similar between older and younger patients receiving anti–PD-1 agents for melanoma, there is little evidence to guide anti–PD-1 treatment of older patients with NSCLC [non–small cell lung cancer],” Dr. Gross and his coinvestigators wrote.

Investigators wrote that the findings are cause for caution.

“As FDA officials develop more flexible standards for approval, which the 21st Century Cures Act requires them to do, it is possible that many patients will receive drugs before much is known about clinical outcomes,” Dr. Gross said. “Further integrations of real-world evidence might allow the FDA to better assess the drugs that they approve on the basis of nonrepresentative trial participants.”

SOURCE: Gross C et al. JAMA Oncol. 2018 May 10. doi: 10.1001/jamaoncol.2018.0798.






 

Checkpoint inhibitors got to melanoma, non–small cell lung cancer, and renal cell carcinoma patients quickly in clinical practice after Food and Drug Administration approval – usually within 4 months – but the patients treated in clinical settings tended to be older than those treated in trials, which has caused concern about whether real-world efficacy will prove to be the same, according to a study in JAMA Oncology.

“Such rapid adoption stands in contrast to older estimates that suggest it takes years or even decades for new treatments to be adopted,” wrote lead author Cary Gross, MD, professor of medicine at Yale University, New Haven, and his coauthors. “We found significant differences in age between patients treated in practice and those treated in trials, which highlights the need to clarify the risks and benefits of checkpoint inhibitors in general populations of patients.”

Researchers drew data on nivolumab and pembrolizumab use from the Flatiron Health longitudinal EHR database, which included 233 academic and community oncology practices. In each of the three disease cohorts, adoption was seen within 4 months for at least 60% of patients. Uptake was quickest for the melanoma patients, 76% of whom received a checkpoint inhibitor within 4 months, investigators wrote. Factors for the fast adoption could include high disease severity, a preference for novelty, perceived gains over existing treatments, and promotional activities, such as media reports and advertising directly to consumers, they wrote.

More patients in real-world practice were aged 65 years or older, ranging from as little as 61% at the lowest end of the range at one center to as much as 64% at the highest end at another. In the clinical trials, the percentage of patients aged 65 years or older ranged from 32% in one trial to 41% in another. Researchers wrote that these higher real-world rates are concerning because there are still questions regarding whether differences in immune responses will cause differences in efficacy between older and younger patients, as well as safety considerations among different age groups.

“Although data suggest that outcomes are similar between older and younger patients receiving anti–PD-1 agents for melanoma, there is little evidence to guide anti–PD-1 treatment of older patients with NSCLC [non–small cell lung cancer],” Dr. Gross and his coinvestigators wrote.

Investigators wrote that the findings are cause for caution.

“As FDA officials develop more flexible standards for approval, which the 21st Century Cures Act requires them to do, it is possible that many patients will receive drugs before much is known about clinical outcomes,” Dr. Gross said. “Further integrations of real-world evidence might allow the FDA to better assess the drugs that they approve on the basis of nonrepresentative trial participants.”

SOURCE: Gross C et al. JAMA Oncol. 2018 May 10. doi: 10.1001/jamaoncol.2018.0798.






 

PHILADELPHIA – Recent approvals and investigations of targeted and immune treatments for advanced hepatocellular carcinoma (HCC) are encouraging, Nikolaos Pyrsopoulos, MD, MBA, said at Digestive Diseases: New Advances, jointly provided by Rutgers and Global Academy for Medical Education.

“I am excited, because a few years ago, there was only one [Food and Drug Administration] approved medication,” Dr. Pyrsopoulos, division director for gastroenterology and hepatology at Rutgers New Jersey Medical School, Newark, said in an interview. “We are on the cusp where new compounds not only are being tested, but they are being approved.”

In one of the most recent developments, the multikinase inhibitor cabozantinib significantly improved the primary endpoint of overall survival versus placebo in HCC patients in the randomized phase 3 CELESTIAL trial.

Median overall survival in CELESTIAL was 10.2 months for cabozantinib versus 8.0 for placebo (P = .0049), according to the published report, and investigators also reported significant improvements in progression-free survival and response versus placebo.

“It is very encouraging,” Dr. Pyrsopoulos said of the cabozantinib results in a presentation on advances in HCC that he gave at the conference.

For years, the only FDA-approved treatment for advanced HCC was sorafenib. In the randomized phase 3 SHARP trial, published in the New England Journal of Medicine in 2008, patients receiving the multikinase inhibitor had a median survival of 10.7 months, versus 7.9 months for placebo (P less than .001).

In April 2017, the FDA approved regorafenib for patients with HCC previously treated with sorafenib. In the randomized phase 3 RESORCE trial, published in The Lancet in 2017, median overall survival was 10.6 months for regorafenib-treated patients versus 7.8 months in the placebo group. Investigators reported that regorafenib improved overall survival with a hazard ratio of 0.63 (P less than .0001).

Dr. Pyrsopoulos noted that a strategy of sorafenib followed by regorafenib would combine two treatments, each of which in clinical trials had a median overall survival approaching 11 months.

“In essence, you have an approximate 2-year survival,” he said.

More agents are under investigation, including lenvatinib, another multikinase inhibitor. In results of a phase 3 randomized trial presented at the 2017 meeting of the American Society of Clinical Oncology, lenvatinib was noninferior to sorafenib in overall survival, with treatment-related adverse effects such as hypertension and diarrhea that were expected based on previous experience with the drug, investigators said.

Cancer immunotherapy is making inroads into HCC. Just a few months after approving regorafenib, the FDA granted approval to nivolumab, a PD-1 inhibitor, for patients with HCC previously treated with sorafenib. The September 2017 approval of this checkpoint inhibitor was based in part on data from the CheckMate-040 trial that included a 14.3% response rate in the 154-patient subgroup of patients who had progressive disease on sorafenib or were intolerant of the treatment.

Dr. Pyrsopoulos highlighted another checkpoint inhibitor, known as BGB-A317, or tislelizumab. In January, BeiGene announced the initiation of a global phase 3 trial of this anti-PD-1 antibody versus sorafenib as first-line treatment of patients with unresectable HCC.

Although cancer immunotherapy holds great promise for HCC and other cancers, the treatments are associated with unique immune-related adverse events (irAEs) including immune-related hepatitis that may require corticosteroid treatment, according to Dr. Pyrsopoulos.

Dr. Pyrsopoulos reported disclosures related to AbbVie, Bayer, Genfit, Gilead Sciences, Hologic, Merck, Prometheus, Shire, and Vital Therapies.

Global Academy for Medical Education and this news organization are owned by the same company.

PHILADELPHIA – Recent approvals and investigations of targeted and immune treatments for advanced hepatocellular carcinoma (HCC) are encouraging, Nikolaos Pyrsopoulos, MD, MBA, said at Digestive Diseases: New Advances, jointly provided by Rutgers and Global Academy for Medical Education.

“I am excited, because a few years ago, there was only one [Food and Drug Administration] approved medication,” Dr. Pyrsopoulos, division director for gastroenterology and hepatology at Rutgers New Jersey Medical School, Newark, said in an interview. “We are on the cusp where new compounds not only are being tested, but they are being approved.”

In one of the most recent developments, the multikinase inhibitor cabozantinib significantly improved the primary endpoint of overall survival versus placebo in HCC patients in the randomized phase 3 CELESTIAL trial.

Median overall survival in CELESTIAL was 10.2 months for cabozantinib versus 8.0 for placebo (P = .0049), according to the published report, and investigators also reported significant improvements in progression-free survival and response versus placebo.

“It is very encouraging,” Dr. Pyrsopoulos said of the cabozantinib results in a presentation on advances in HCC that he gave at the conference.

For years, the only FDA-approved treatment for advanced HCC was sorafenib. In the randomized phase 3 SHARP trial, published in the New England Journal of Medicine in 2008, patients receiving the multikinase inhibitor had a median survival of 10.7 months, versus 7.9 months for placebo (P less than .001).

In April 2017, the FDA approved regorafenib for patients with HCC previously treated with sorafenib. In the randomized phase 3 RESORCE trial, published in The Lancet in 2017, median overall survival was 10.6 months for regorafenib-treated patients versus 7.8 months in the placebo group. Investigators reported that regorafenib improved overall survival with a hazard ratio of 0.63 (P less than .0001).

Dr. Pyrsopoulos noted that a strategy of sorafenib followed by regorafenib would combine two treatments, each of which in clinical trials had a median overall survival approaching 11 months.

“In essence, you have an approximate 2-year survival,” he said.

More agents are under investigation, including lenvatinib, another multikinase inhibitor. In results of a phase 3 randomized trial presented at the 2017 meeting of the American Society of Clinical Oncology, lenvatinib was noninferior to sorafenib in overall survival, with treatment-related adverse effects such as hypertension and diarrhea that were expected based on previous experience with the drug, investigators said.

Cancer immunotherapy is making inroads into HCC. Just a few months after approving regorafenib, the FDA granted approval to nivolumab, a PD-1 inhibitor, for patients with HCC previously treated with sorafenib. The September 2017 approval of this checkpoint inhibitor was based in part on data from the CheckMate-040 trial that included a 14.3% response rate in the 154-patient subgroup of patients who had progressive disease on sorafenib or were intolerant of the treatment.

Dr. Pyrsopoulos highlighted another checkpoint inhibitor, known as BGB-A317, or tislelizumab. In January, BeiGene announced the initiation of a global phase 3 trial of this anti-PD-1 antibody versus sorafenib as first-line treatment of patients with unresectable HCC.

Although cancer immunotherapy holds great promise for HCC and other cancers, the treatments are associated with unique immune-related adverse events (irAEs) including immune-related hepatitis that may require corticosteroid treatment, according to Dr. Pyrsopoulos.

Dr. Pyrsopoulos reported disclosures related to AbbVie, Bayer, Genfit, Gilead Sciences, Hologic, Merck, Prometheus, Shire, and Vital Therapies.

Global Academy for Medical Education and this news organization are owned by the same company.

PHILADELPHIA – Recent approvals and investigations of targeted and immune treatments for advanced hepatocellular carcinoma (HCC) are encouraging, Nikolaos Pyrsopoulos, MD, MBA, said at Digestive Diseases: New Advances, jointly provided by Rutgers and Global Academy for Medical Education.

“I am excited, because a few years ago, there was only one [Food and Drug Administration] approved medication,” Dr. Pyrsopoulos, division director for gastroenterology and hepatology at Rutgers New Jersey Medical School, Newark, said in an interview. “We are on the cusp where new compounds not only are being tested, but they are being approved.”

In one of the most recent developments, the multikinase inhibitor cabozantinib significantly improved the primary endpoint of overall survival versus placebo in HCC patients in the randomized phase 3 CELESTIAL trial.

Median overall survival in CELESTIAL was 10.2 months for cabozantinib versus 8.0 for placebo (P = .0049), according to the published report, and investigators also reported significant improvements in progression-free survival and response versus placebo.

“It is very encouraging,” Dr. Pyrsopoulos said of the cabozantinib results in a presentation on advances in HCC that he gave at the conference.

For years, the only FDA-approved treatment for advanced HCC was sorafenib. In the randomized phase 3 SHARP trial, published in the New England Journal of Medicine in 2008, patients receiving the multikinase inhibitor had a median survival of 10.7 months, versus 7.9 months for placebo (P less than .001).

In April 2017, the FDA approved regorafenib for patients with HCC previously treated with sorafenib. In the randomized phase 3 RESORCE trial, published in The Lancet in 2017, median overall survival was 10.6 months for regorafenib-treated patients versus 7.8 months in the placebo group. Investigators reported that regorafenib improved overall survival with a hazard ratio of 0.63 (P less than .0001).

Dr. Pyrsopoulos noted that a strategy of sorafenib followed by regorafenib would combine two treatments, each of which in clinical trials had a median overall survival approaching 11 months.

“In essence, you have an approximate 2-year survival,” he said.

More agents are under investigation, including lenvatinib, another multikinase inhibitor. In results of a phase 3 randomized trial presented at the 2017 meeting of the American Society of Clinical Oncology, lenvatinib was noninferior to sorafenib in overall survival, with treatment-related adverse effects such as hypertension and diarrhea that were expected based on previous experience with the drug, investigators said.

Cancer immunotherapy is making inroads into HCC. Just a few months after approving regorafenib, the FDA granted approval to nivolumab, a PD-1 inhibitor, for patients with HCC previously treated with sorafenib. The September 2017 approval of this checkpoint inhibitor was based in part on data from the CheckMate-040 trial that included a 14.3% response rate in the 154-patient subgroup of patients who had progressive disease on sorafenib or were intolerant of the treatment.

Dr. Pyrsopoulos highlighted another checkpoint inhibitor, known as BGB-A317, or tislelizumab. In January, BeiGene announced the initiation of a global phase 3 trial of this anti-PD-1 antibody versus sorafenib as first-line treatment of patients with unresectable HCC.

Although cancer immunotherapy holds great promise for HCC and other cancers, the treatments are associated with unique immune-related adverse events (irAEs) including immune-related hepatitis that may require corticosteroid treatment, according to Dr. Pyrsopoulos.

Dr. Pyrsopoulos reported disclosures related to AbbVie, Bayer, Genfit, Gilead Sciences, Hologic, Merck, Prometheus, Shire, and Vital Therapies.

Global Academy for Medical Education and this news organization are owned by the same company.

CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.

Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.

For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.

In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.

The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.

“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.

The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.

A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.

Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.

“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.

Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.

It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.

Dr. Milhem had no financial relationships to disclose.

SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.

CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.

Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.

For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.

In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.

The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.

“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.

The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.

A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.

Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.

“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.

Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.

It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.

Dr. Milhem had no financial relationships to disclose.

SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.

CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.

Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.

For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.

In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.

The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.

“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.

The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.

A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.

Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.

“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.

Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.

It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.

Dr. Milhem had no financial relationships to disclose.

SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.

CHICAGO – Adjuvant pembrolizumab for resected high-risk melanoma slowed the rate of recurrence or death by 43% compared with placebo in a phase 3 trial of 1,519 patients.

After 15 months of follow-up, 12-month rates of recurrence-free survival (RFS) were 75% for pembrolizumab and 61% for placebo (hazard ratio, 0.57; P less than .001), Alexander M.M. Eggermont, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

By 18 months, the RFS difference between the arms had widened even more (71% versus 53%), Dr. Eggermont and his associates said at the meeting. The report was published simultaneously in the New England Journal of Medicine.

Adjuvant pembrolizumab was effective irrespective of PD-L1 tumor expression status. In a subgroup of more than 800 patients with PD-L1-positive tumors, 12-month RFS rates were 77% for pembrolizumab and 63% for placebo (HR, 0.54; 95% CI, 0.42 to 0.69; P less than .001). Among 116 patients who were PD-L1-negative, these rates were 72% and 52%, respectively (HR, 0.47; P = .01).

Treatment produced no new safety signals, said Dr. Eggermont of Gustave Roussy Cancer Campus Grand Paris and University Paris-Saclay, Villejuif, France. Grade 3 or higher toxicities affected 15% of pembrolizumab patients. Myositis caused one pembrolizumab-related death.

The findings bolster data suggesting that adjuvant therapy can stop or delay recurrence in resected high-risk melanoma. Previously, adjuvant ipilimumab was approved after significantly extending RFS and overall survival in the placebo-controlled European Organization for Research and Treatment of Cancer 18071 trial. More recently, adjuvant dabrafenib plus trametinib reduced the risk of recurrence compared with placebo in completely resected stage III melanoma with BRAF mutations (COMBI-AD), and adjuvant nivolumab significantly improved RFS and was less toxic than was ipilimumab in patients with advanced resected BRAF-mutated and BRAF-wild-type melanomas (CheckMate 238).

SOURCE: Eggermont AMM et al. AACR Annual Meeting Abstract CT001.

CHICAGO – Adjuvant pembrolizumab for resected high-risk melanoma slowed the rate of recurrence or death by 43% compared with placebo in a phase 3 trial of 1,519 patients.

After 15 months of follow-up, 12-month rates of recurrence-free survival (RFS) were 75% for pembrolizumab and 61% for placebo (hazard ratio, 0.57; P less than .001), Alexander M.M. Eggermont, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

By 18 months, the RFS difference between the arms had widened even more (71% versus 53%), Dr. Eggermont and his associates said at the meeting. The report was published simultaneously in the New England Journal of Medicine.

Adjuvant pembrolizumab was effective irrespective of PD-L1 tumor expression status. In a subgroup of more than 800 patients with PD-L1-positive tumors, 12-month RFS rates were 77% for pembrolizumab and 63% for placebo (HR, 0.54; 95% CI, 0.42 to 0.69; P less than .001). Among 116 patients who were PD-L1-negative, these rates were 72% and 52%, respectively (HR, 0.47; P = .01).

Treatment produced no new safety signals, said Dr. Eggermont of Gustave Roussy Cancer Campus Grand Paris and University Paris-Saclay, Villejuif, France. Grade 3 or higher toxicities affected 15% of pembrolizumab patients. Myositis caused one pembrolizumab-related death.

The findings bolster data suggesting that adjuvant therapy can stop or delay recurrence in resected high-risk melanoma. Previously, adjuvant ipilimumab was approved after significantly extending RFS and overall survival in the placebo-controlled European Organization for Research and Treatment of Cancer 18071 trial. More recently, adjuvant dabrafenib plus trametinib reduced the risk of recurrence compared with placebo in completely resected stage III melanoma with BRAF mutations (COMBI-AD), and adjuvant nivolumab significantly improved RFS and was less toxic than was ipilimumab in patients with advanced resected BRAF-mutated and BRAF-wild-type melanomas (CheckMate 238).

SOURCE: Eggermont AMM et al. AACR Annual Meeting Abstract CT001.

CHICAGO – Adjuvant pembrolizumab for resected high-risk melanoma slowed the rate of recurrence or death by 43% compared with placebo in a phase 3 trial of 1,519 patients.

After 15 months of follow-up, 12-month rates of recurrence-free survival (RFS) were 75% for pembrolizumab and 61% for placebo (hazard ratio, 0.57; P less than .001), Alexander M.M. Eggermont, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

By 18 months, the RFS difference between the arms had widened even more (71% versus 53%), Dr. Eggermont and his associates said at the meeting. The report was published simultaneously in the New England Journal of Medicine.

Adjuvant pembrolizumab was effective irrespective of PD-L1 tumor expression status. In a subgroup of more than 800 patients with PD-L1-positive tumors, 12-month RFS rates were 77% for pembrolizumab and 63% for placebo (HR, 0.54; 95% CI, 0.42 to 0.69; P less than .001). Among 116 patients who were PD-L1-negative, these rates were 72% and 52%, respectively (HR, 0.47; P = .01).

Treatment produced no new safety signals, said Dr. Eggermont of Gustave Roussy Cancer Campus Grand Paris and University Paris-Saclay, Villejuif, France. Grade 3 or higher toxicities affected 15% of pembrolizumab patients. Myositis caused one pembrolizumab-related death.

The findings bolster data suggesting that adjuvant therapy can stop or delay recurrence in resected high-risk melanoma. Previously, adjuvant ipilimumab was approved after significantly extending RFS and overall survival in the placebo-controlled European Organization for Research and Treatment of Cancer 18071 trial. More recently, adjuvant dabrafenib plus trametinib reduced the risk of recurrence compared with placebo in completely resected stage III melanoma with BRAF mutations (COMBI-AD), and adjuvant nivolumab significantly improved RFS and was less toxic than was ipilimumab in patients with advanced resected BRAF-mutated and BRAF-wild-type melanomas (CheckMate 238).

SOURCE: Eggermont AMM et al. AACR Annual Meeting Abstract CT001.

After treatment with blinatumomab, most patients with minimal residual disease–positive acute lymphoblastic leukemia (ALL) achieved complete MRD response, according to results of a single-arm phase 2 study.

Achieving complete MRD response was associated with significantly longer relapse-free and overall survival in the patients, who were already in hematologic complete remission, researchers reported in the journal Blood.

“Our results suggest that targeted treatment in early stages of MRD is a viable therapeutic strategy for patients with B-cell precursor ALL and that it should also be evaluated in other hematologic malignancies,” Nicola Gökbuget, MD, University Hospital, Frankfurt, Germany, and her coauthors wrote.

This is the first international multicenter study to specifically enroll MRD-positive ALL patients and evaluate them for an MRD-based primary outcome in a cohort of MRD-positive ALL patients, according to the authors.

Preemptively treating low but measurable disease in ALL in remission, instead of waiting for overt relapse, is a strategy that may prolong overall survival, Dr. Gökbuget and her colleagues said in describing the rationale for their study. While there is no standard therapy yet for ALL patients with detectable MRD after intensive chemotherapy, hematopoietic stem cell transplantation (HSCT) is recommended, based on data that it may improve outcomes in patients with persistent MRD. However, other studies suggest detectable MRD before HSCT is associated with higher relapse rates, and many patients relapse while waiting for HSCT, the researchers noted.

To test an MRD-directed treatment strategy, Dr. Gökbuget and colleagues at 46 centers in Europe and Russia conducted an open-label, single-arm, phase 2 study including 116 patients with B-cell precursor ALL in hematologic complete remission. Patients in the study received up to four cycles of blinatumomab, a bispecific, T cell–engager antibody construct that enables T cells to recognize and eliminate CD19-positive cells.

Of 113 evaluable patients, 88 (78%) achieved complete MRD response after one cycle, the primary end point of the study. Relapse-free survival at 18 months was estimated at 54% and median overall survival was 36.5 months in the subset of 110 patients with Philadelphia chromosome–negative ALL in hematologic remission.

SOURCE: Gökbuget N et al. Blood. 2018 Apr 5;131(14):1522-31.

After treatment with blinatumomab, most patients with minimal residual disease–positive acute lymphoblastic leukemia (ALL) achieved complete MRD response, according to results of a single-arm phase 2 study.

Achieving complete MRD response was associated with significantly longer relapse-free and overall survival in the patients, who were already in hematologic complete remission, researchers reported in the journal Blood.

“Our results suggest that targeted treatment in early stages of MRD is a viable therapeutic strategy for patients with B-cell precursor ALL and that it should also be evaluated in other hematologic malignancies,” Nicola Gökbuget, MD, University Hospital, Frankfurt, Germany, and her coauthors wrote.

This is the first international multicenter study to specifically enroll MRD-positive ALL patients and evaluate them for an MRD-based primary outcome in a cohort of MRD-positive ALL patients, according to the authors.

Preemptively treating low but measurable disease in ALL in remission, instead of waiting for overt relapse, is a strategy that may prolong overall survival, Dr. Gökbuget and her colleagues said in describing the rationale for their study. While there is no standard therapy yet for ALL patients with detectable MRD after intensive chemotherapy, hematopoietic stem cell transplantation (HSCT) is recommended, based on data that it may improve outcomes in patients with persistent MRD. However, other studies suggest detectable MRD before HSCT is associated with higher relapse rates, and many patients relapse while waiting for HSCT, the researchers noted.

To test an MRD-directed treatment strategy, Dr. Gökbuget and colleagues at 46 centers in Europe and Russia conducted an open-label, single-arm, phase 2 study including 116 patients with B-cell precursor ALL in hematologic complete remission. Patients in the study received up to four cycles of blinatumomab, a bispecific, T cell–engager antibody construct that enables T cells to recognize and eliminate CD19-positive cells.

Of 113 evaluable patients, 88 (78%) achieved complete MRD response after one cycle, the primary end point of the study. Relapse-free survival at 18 months was estimated at 54% and median overall survival was 36.5 months in the subset of 110 patients with Philadelphia chromosome–negative ALL in hematologic remission.

SOURCE: Gökbuget N et al. Blood. 2018 Apr 5;131(14):1522-31.

After treatment with blinatumomab, most patients with minimal residual disease–positive acute lymphoblastic leukemia (ALL) achieved complete MRD response, according to results of a single-arm phase 2 study.

Achieving complete MRD response was associated with significantly longer relapse-free and overall survival in the patients, who were already in hematologic complete remission, researchers reported in the journal Blood.

“Our results suggest that targeted treatment in early stages of MRD is a viable therapeutic strategy for patients with B-cell precursor ALL and that it should also be evaluated in other hematologic malignancies,” Nicola Gökbuget, MD, University Hospital, Frankfurt, Germany, and her coauthors wrote.

This is the first international multicenter study to specifically enroll MRD-positive ALL patients and evaluate them for an MRD-based primary outcome in a cohort of MRD-positive ALL patients, according to the authors.

Preemptively treating low but measurable disease in ALL in remission, instead of waiting for overt relapse, is a strategy that may prolong overall survival, Dr. Gökbuget and her colleagues said in describing the rationale for their study. While there is no standard therapy yet for ALL patients with detectable MRD after intensive chemotherapy, hematopoietic stem cell transplantation (HSCT) is recommended, based on data that it may improve outcomes in patients with persistent MRD. However, other studies suggest detectable MRD before HSCT is associated with higher relapse rates, and many patients relapse while waiting for HSCT, the researchers noted.

To test an MRD-directed treatment strategy, Dr. Gökbuget and colleagues at 46 centers in Europe and Russia conducted an open-label, single-arm, phase 2 study including 116 patients with B-cell precursor ALL in hematologic complete remission. Patients in the study received up to four cycles of blinatumomab, a bispecific, T cell–engager antibody construct that enables T cells to recognize and eliminate CD19-positive cells.

Of 113 evaluable patients, 88 (78%) achieved complete MRD response after one cycle, the primary end point of the study. Relapse-free survival at 18 months was estimated at 54% and median overall survival was 36.5 months in the subset of 110 patients with Philadelphia chromosome–negative ALL in hematologic remission.

SOURCE: Gökbuget N et al. Blood. 2018 Apr 5;131(14):1522-31.