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Tandem transplants provide EFS edge in pediatric neuroblastoma
For young patients with high-risk neuroblastoma, an intensive consolidation regimen with tandem autologous stem cell transplants was associated with significantly better event-free survival, compared with single-transplant consolidation, results of a randomized trial show.
Among 355 patients with high-risk neuroblastoma, the 3-year event-free survival (EFS) rate was 61.6% for patients randomized to tandem (sequential) autologous stem cell transplants, compared with 48.4% for patients randomized to a single transplant (P = .006), reported Julie R. Park, MD from Seattle Children’s Hospital in Washington, and coinvestigators in the Children’s Oncology Group’s ANBL0532 trial.
“Results of the current study are consistent with earlier trials demonstrating that induction chemotherapy followed by consolidation with autologous transplant improved EFS, compared with less intensive consolidation, and that further intensification of consolidation benefits some patients,” they wrote in JAMA.
But of the 652 patients enrolled in the study, only 355 were actually randomized. Although the randomization rate was slightly higher than anticipated, the authors acknowledged that the results may not apply to all patients with high-risk neuroblastoma.
Patients eligible for the trial included those with International Neuroblastoma Staging System (INSS) stage 4 neuroblastoma aged older than 18 months; INSS stage 3 neuroblastoma aged older than 18 months with International Neuroblastoma Pathology Classification of unfavorable histology; INSS stage 2, 3, 4, or 4S neuroblastoma with MYCN amplification; and INSS stage 4 neuroblastoma diagnosed from age 12-18 months whose tumors showed any unfavorable features. Patients initially diagnosed with non–high-risk neuroblastoma (including stage 1) who had not received chemotherapy and whose disease had progressed to high-risk neuroblastoma were also eligible.
Following induction with two cycles of topotecan and cyclophosphamide, patients underwent peripheral blood stem cell collection, followed by four alternating cycles of cisplatin and etoposide and doxorubicin and cyclophosphamide, and vincristine.
For those patients who did not have primary tumors resected at diagnosis, resection was performed after the fourth or fifth cycle.
Those patients who after induction had no disease progression, no uncontrolled infection, sufficient stem cell levels, and adequate organ function were then eligible for randomization. One patient did not receive any therapy, 27 were nonrandomly assigned to single transplant, 62 were not eligible for randomization, and 207 were not randomized because of physician or family preference.
Of the remaining patients (median age at diagnosis, 36.1 months) 176 were randomized to receive tandem transplant with thiotepa and cyclophosphamide followed by dose-reduced carboplatin, etoposide, and melphalan conditioning, and 179 were randomized to single transplant with standard-dose carboplatin, etoposide, and melphalan.
A total of 17 patients died on study from toxicity; 7 during induction and 10 during consolidation. Significant transplant-related toxicities included mucositis in 11.7% of tandem-transplant patients and 15.4% of single-transplant patients, and infections in 17.8% versus 18.3%, respectively.
As noted before, 3-year EFS from the time of randomization, the primary endpoint, was higher for patients in the tandem-transplant arm (61.6% vs. 48.4%, P = .006).
The median duration of follow-up after randomization for patients without relapse, disease progression, second malignancy, or death was 5.6 years.
A post hoc analysis of the randomized patients showed a 3-year overall survival rate of 71.6%, which did not differ significantly between the study arms (74.1% for the tandem-transplant group vs. 68.1% for the single-transplant group). The analysis also showed that 3-year EFS and overall survival was higher in the tandem- versus single-transplant groups among 250 patients who also received immunotherapy with isotretinoin plus an anti-GD2 chimeric antibody and cytokines.
The trial was supported by grants from the National Institutes of Health, National Cancer Institute, National Clinical Trials Network Operations Center, and St. Baldrick’s Foundation. Dr. Park reported no relevant disclosures. Multiple coauthors disclosed grants or personal feeds outside the submitted work.
SOURCE: Park JR et al. JAMA. 2019;322(8):746-55.
The ANBL0532 trial also does not address the important question as to whether tandem high-dose chemotherapy with autologous stem cell transplant results in benefit for all-comers with high-risk neuroblastoma, because just over half of the eligible patients underwent randomization. Although characteristics of the entire cohort and the randomized cohort were similar with respect to age, stage, tumor histology, and MYCN status, there may be differences unrelated to widely accepted neuroblastoma risk variables. A separate but important challenge in interpretation of these results, as with any clinical trial results, is to understand the generalizability of findings to patient populations who may not be enrolling in trials. Previous work in pediatric oncology showed that trial enrollment correlated with race, age, and zip code, and it is difficult to know whether the results of the ANBL0532 trial are applicable to patient groups who may not be well represented.
An additional challenge is that even though a difference in event-free survival was detected between groups assigned to receive single versus tandem transplant, and a difference in overall survival was detected in a post hoc analysis of patients who received immunotherapy, no difference in overall survival was detected in the overall randomized cohort. Overall survival was evaluated as a secondary outcome but the trial was not powered to detect a difference in overall survival. Moreover, as noted by the authors, overall survival can be influenced by therapies delivered after relapse. This is particularly relevant in an era in which relapse therapies have been shown to induce responses, including periods of remission.
Remarks from Rochelle Bagatell, MD, from the University of Pennsylvania, Philadelphia, and Meredith S. Irwin, MD, from the Hospital for Sick Children in Toronto, are adapted and condensed from an editorial accompanying the study by Park et al. Dr. Bagatell is the vice chair of the Children’s Oncology Group Neuroblastoma Disease Committee. Dr. Irwin reported receiving personal fees from Bayer Canada outside the submitted work and is the vice chair of the Children’s Oncology Group Neuroblastoma Biology Committee. Neither Dr. Bagatell nor Dr. Irwin was involved in the design of the ANBL0532 trial or in the analysis of the results.
The ANBL0532 trial also does not address the important question as to whether tandem high-dose chemotherapy with autologous stem cell transplant results in benefit for all-comers with high-risk neuroblastoma, because just over half of the eligible patients underwent randomization. Although characteristics of the entire cohort and the randomized cohort were similar with respect to age, stage, tumor histology, and MYCN status, there may be differences unrelated to widely accepted neuroblastoma risk variables. A separate but important challenge in interpretation of these results, as with any clinical trial results, is to understand the generalizability of findings to patient populations who may not be enrolling in trials. Previous work in pediatric oncology showed that trial enrollment correlated with race, age, and zip code, and it is difficult to know whether the results of the ANBL0532 trial are applicable to patient groups who may not be well represented.
An additional challenge is that even though a difference in event-free survival was detected between groups assigned to receive single versus tandem transplant, and a difference in overall survival was detected in a post hoc analysis of patients who received immunotherapy, no difference in overall survival was detected in the overall randomized cohort. Overall survival was evaluated as a secondary outcome but the trial was not powered to detect a difference in overall survival. Moreover, as noted by the authors, overall survival can be influenced by therapies delivered after relapse. This is particularly relevant in an era in which relapse therapies have been shown to induce responses, including periods of remission.
Remarks from Rochelle Bagatell, MD, from the University of Pennsylvania, Philadelphia, and Meredith S. Irwin, MD, from the Hospital for Sick Children in Toronto, are adapted and condensed from an editorial accompanying the study by Park et al. Dr. Bagatell is the vice chair of the Children’s Oncology Group Neuroblastoma Disease Committee. Dr. Irwin reported receiving personal fees from Bayer Canada outside the submitted work and is the vice chair of the Children’s Oncology Group Neuroblastoma Biology Committee. Neither Dr. Bagatell nor Dr. Irwin was involved in the design of the ANBL0532 trial or in the analysis of the results.
The ANBL0532 trial also does not address the important question as to whether tandem high-dose chemotherapy with autologous stem cell transplant results in benefit for all-comers with high-risk neuroblastoma, because just over half of the eligible patients underwent randomization. Although characteristics of the entire cohort and the randomized cohort were similar with respect to age, stage, tumor histology, and MYCN status, there may be differences unrelated to widely accepted neuroblastoma risk variables. A separate but important challenge in interpretation of these results, as with any clinical trial results, is to understand the generalizability of findings to patient populations who may not be enrolling in trials. Previous work in pediatric oncology showed that trial enrollment correlated with race, age, and zip code, and it is difficult to know whether the results of the ANBL0532 trial are applicable to patient groups who may not be well represented.
An additional challenge is that even though a difference in event-free survival was detected between groups assigned to receive single versus tandem transplant, and a difference in overall survival was detected in a post hoc analysis of patients who received immunotherapy, no difference in overall survival was detected in the overall randomized cohort. Overall survival was evaluated as a secondary outcome but the trial was not powered to detect a difference in overall survival. Moreover, as noted by the authors, overall survival can be influenced by therapies delivered after relapse. This is particularly relevant in an era in which relapse therapies have been shown to induce responses, including periods of remission.
Remarks from Rochelle Bagatell, MD, from the University of Pennsylvania, Philadelphia, and Meredith S. Irwin, MD, from the Hospital for Sick Children in Toronto, are adapted and condensed from an editorial accompanying the study by Park et al. Dr. Bagatell is the vice chair of the Children’s Oncology Group Neuroblastoma Disease Committee. Dr. Irwin reported receiving personal fees from Bayer Canada outside the submitted work and is the vice chair of the Children’s Oncology Group Neuroblastoma Biology Committee. Neither Dr. Bagatell nor Dr. Irwin was involved in the design of the ANBL0532 trial or in the analysis of the results.
For young patients with high-risk neuroblastoma, an intensive consolidation regimen with tandem autologous stem cell transplants was associated with significantly better event-free survival, compared with single-transplant consolidation, results of a randomized trial show.
Among 355 patients with high-risk neuroblastoma, the 3-year event-free survival (EFS) rate was 61.6% for patients randomized to tandem (sequential) autologous stem cell transplants, compared with 48.4% for patients randomized to a single transplant (P = .006), reported Julie R. Park, MD from Seattle Children’s Hospital in Washington, and coinvestigators in the Children’s Oncology Group’s ANBL0532 trial.
“Results of the current study are consistent with earlier trials demonstrating that induction chemotherapy followed by consolidation with autologous transplant improved EFS, compared with less intensive consolidation, and that further intensification of consolidation benefits some patients,” they wrote in JAMA.
But of the 652 patients enrolled in the study, only 355 were actually randomized. Although the randomization rate was slightly higher than anticipated, the authors acknowledged that the results may not apply to all patients with high-risk neuroblastoma.
Patients eligible for the trial included those with International Neuroblastoma Staging System (INSS) stage 4 neuroblastoma aged older than 18 months; INSS stage 3 neuroblastoma aged older than 18 months with International Neuroblastoma Pathology Classification of unfavorable histology; INSS stage 2, 3, 4, or 4S neuroblastoma with MYCN amplification; and INSS stage 4 neuroblastoma diagnosed from age 12-18 months whose tumors showed any unfavorable features. Patients initially diagnosed with non–high-risk neuroblastoma (including stage 1) who had not received chemotherapy and whose disease had progressed to high-risk neuroblastoma were also eligible.
Following induction with two cycles of topotecan and cyclophosphamide, patients underwent peripheral blood stem cell collection, followed by four alternating cycles of cisplatin and etoposide and doxorubicin and cyclophosphamide, and vincristine.
For those patients who did not have primary tumors resected at diagnosis, resection was performed after the fourth or fifth cycle.
Those patients who after induction had no disease progression, no uncontrolled infection, sufficient stem cell levels, and adequate organ function were then eligible for randomization. One patient did not receive any therapy, 27 were nonrandomly assigned to single transplant, 62 were not eligible for randomization, and 207 were not randomized because of physician or family preference.
Of the remaining patients (median age at diagnosis, 36.1 months) 176 were randomized to receive tandem transplant with thiotepa and cyclophosphamide followed by dose-reduced carboplatin, etoposide, and melphalan conditioning, and 179 were randomized to single transplant with standard-dose carboplatin, etoposide, and melphalan.
A total of 17 patients died on study from toxicity; 7 during induction and 10 during consolidation. Significant transplant-related toxicities included mucositis in 11.7% of tandem-transplant patients and 15.4% of single-transplant patients, and infections in 17.8% versus 18.3%, respectively.
As noted before, 3-year EFS from the time of randomization, the primary endpoint, was higher for patients in the tandem-transplant arm (61.6% vs. 48.4%, P = .006).
The median duration of follow-up after randomization for patients without relapse, disease progression, second malignancy, or death was 5.6 years.
A post hoc analysis of the randomized patients showed a 3-year overall survival rate of 71.6%, which did not differ significantly between the study arms (74.1% for the tandem-transplant group vs. 68.1% for the single-transplant group). The analysis also showed that 3-year EFS and overall survival was higher in the tandem- versus single-transplant groups among 250 patients who also received immunotherapy with isotretinoin plus an anti-GD2 chimeric antibody and cytokines.
The trial was supported by grants from the National Institutes of Health, National Cancer Institute, National Clinical Trials Network Operations Center, and St. Baldrick’s Foundation. Dr. Park reported no relevant disclosures. Multiple coauthors disclosed grants or personal feeds outside the submitted work.
SOURCE: Park JR et al. JAMA. 2019;322(8):746-55.
For young patients with high-risk neuroblastoma, an intensive consolidation regimen with tandem autologous stem cell transplants was associated with significantly better event-free survival, compared with single-transplant consolidation, results of a randomized trial show.
Among 355 patients with high-risk neuroblastoma, the 3-year event-free survival (EFS) rate was 61.6% for patients randomized to tandem (sequential) autologous stem cell transplants, compared with 48.4% for patients randomized to a single transplant (P = .006), reported Julie R. Park, MD from Seattle Children’s Hospital in Washington, and coinvestigators in the Children’s Oncology Group’s ANBL0532 trial.
“Results of the current study are consistent with earlier trials demonstrating that induction chemotherapy followed by consolidation with autologous transplant improved EFS, compared with less intensive consolidation, and that further intensification of consolidation benefits some patients,” they wrote in JAMA.
But of the 652 patients enrolled in the study, only 355 were actually randomized. Although the randomization rate was slightly higher than anticipated, the authors acknowledged that the results may not apply to all patients with high-risk neuroblastoma.
Patients eligible for the trial included those with International Neuroblastoma Staging System (INSS) stage 4 neuroblastoma aged older than 18 months; INSS stage 3 neuroblastoma aged older than 18 months with International Neuroblastoma Pathology Classification of unfavorable histology; INSS stage 2, 3, 4, or 4S neuroblastoma with MYCN amplification; and INSS stage 4 neuroblastoma diagnosed from age 12-18 months whose tumors showed any unfavorable features. Patients initially diagnosed with non–high-risk neuroblastoma (including stage 1) who had not received chemotherapy and whose disease had progressed to high-risk neuroblastoma were also eligible.
Following induction with two cycles of topotecan and cyclophosphamide, patients underwent peripheral blood stem cell collection, followed by four alternating cycles of cisplatin and etoposide and doxorubicin and cyclophosphamide, and vincristine.
For those patients who did not have primary tumors resected at diagnosis, resection was performed after the fourth or fifth cycle.
Those patients who after induction had no disease progression, no uncontrolled infection, sufficient stem cell levels, and adequate organ function were then eligible for randomization. One patient did not receive any therapy, 27 were nonrandomly assigned to single transplant, 62 were not eligible for randomization, and 207 were not randomized because of physician or family preference.
Of the remaining patients (median age at diagnosis, 36.1 months) 176 were randomized to receive tandem transplant with thiotepa and cyclophosphamide followed by dose-reduced carboplatin, etoposide, and melphalan conditioning, and 179 were randomized to single transplant with standard-dose carboplatin, etoposide, and melphalan.
A total of 17 patients died on study from toxicity; 7 during induction and 10 during consolidation. Significant transplant-related toxicities included mucositis in 11.7% of tandem-transplant patients and 15.4% of single-transplant patients, and infections in 17.8% versus 18.3%, respectively.
As noted before, 3-year EFS from the time of randomization, the primary endpoint, was higher for patients in the tandem-transplant arm (61.6% vs. 48.4%, P = .006).
The median duration of follow-up after randomization for patients without relapse, disease progression, second malignancy, or death was 5.6 years.
A post hoc analysis of the randomized patients showed a 3-year overall survival rate of 71.6%, which did not differ significantly between the study arms (74.1% for the tandem-transplant group vs. 68.1% for the single-transplant group). The analysis also showed that 3-year EFS and overall survival was higher in the tandem- versus single-transplant groups among 250 patients who also received immunotherapy with isotretinoin plus an anti-GD2 chimeric antibody and cytokines.
The trial was supported by grants from the National Institutes of Health, National Cancer Institute, National Clinical Trials Network Operations Center, and St. Baldrick’s Foundation. Dr. Park reported no relevant disclosures. Multiple coauthors disclosed grants or personal feeds outside the submitted work.
SOURCE: Park JR et al. JAMA. 2019;322(8):746-55.
FROM JAMA
Molecular profiling a must in advanced NSCLC
All patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) should undergo molecular testing for targetable mutations and for tumor expression of the programmed death–ligand 1 (PD-L1) protein, authors of a review of systemic therapies for NSCLC recommend.
Their opinion is based on evidence showing that 5-year overall survival rate for patients whose tumors have high levels of PD-L1 expression now exceeds 25%, and that patients with ALK-positive tumors have 5-year overall survival rates over 40%. In contrast, 5-year survival rates for patients with metastatic NSCLC prior to the 21st century were less than 5%, according to Kathryn C. Arbour, MD, and Gregory J. Riely, MD, PhD, from Memorial Sloan Kettering Cancer Center in New York.
“Improved understanding of the biology and molecular subtypes of non–small cell lung cancer have led to more biomarker-directed therapies for patients with metastatic disease. These biomarker-directed therapies and newer empirical treatment regimens have improved overall survival for patients with metastatic non–small cell lung cancer,” they wrote in JAMA.
The authors reviewed published studies of clinical trials of medical therapies for NSCLC, including articles on randomized trials, nonrandomized trials leading to practice changes or regulatory approval of new therapies for patients with locally advanced or metastatic NSCLC, and clinical practice guidelines.
Their review showed that approximately 30% of patients with NSCLC have molecular alterations predictive of response to treatment, such as mutations in EGFR, the gene encoding for epidermal growth factor receptor; rearrangements in the ALK (anaplastic lymphoma kinase) and ROS1 genes; and mutations in BRAF V600E.
Patients with somatic activating mutations in EGFR, which occur in approximately 20% of those with advanced NSCLC, have better progression-free survival when treated with an EGFR-target tyrosine kinase inhibitor such as gefitinib (Iressa), erlotinib (Tarceva), or afatinib (Gilotrif), compared with cytotoxic chemotherapy.
Similarly, they noted, patients with ALK rearrangements leading to overexpression of the ALK protein had better overall response rates and progression-free survival when treated with the ALK inhibitor crizotinib (Xalkori), compared with patients with ALK rearrangements treated with pemetrexed and a platinum agent.
For some patients without targetable mutations, immune checkpoint inhibitors either alone or in combination with chemotherapy have resulted in improvements in overall survival.
“These advances are substantial, but long-term durable responses remain uncommon for most patients. These insights into treating metastatic disease have informed the design of trials for new treatment strategies among patients with early-stage disease. The goal of NSCLC research is to understand and address mechanisms of resistant and refractory disease in patients with advanced disease and, ultimately, to increase cure rates,” the reviewers wrote.
The review was supported in part by a grant from the National Cancer Institute to Memorial Sloan Kettering. Dr. Arbour reported serving as a consultant to AstraZeneca and nonfinancial research support from Novartis and Takeda. Dr. Riely reported grants and nonfinancial support from Pfizer, Roche/Genentech/Chugai, Novartis, Merck, and Takeda; a patent pending for an alternate dosing of erlotinib for which he has no right to royalties; and payments from the National Comprehensive Cancer Network to participate in a committee overseeing solicitation and selection of grants to be awarded by AstraZeneca.
SOURCE: Arbour KC and Riely GJ. JAMA. 2019;322(8):764-74.
All patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) should undergo molecular testing for targetable mutations and for tumor expression of the programmed death–ligand 1 (PD-L1) protein, authors of a review of systemic therapies for NSCLC recommend.
Their opinion is based on evidence showing that 5-year overall survival rate for patients whose tumors have high levels of PD-L1 expression now exceeds 25%, and that patients with ALK-positive tumors have 5-year overall survival rates over 40%. In contrast, 5-year survival rates for patients with metastatic NSCLC prior to the 21st century were less than 5%, according to Kathryn C. Arbour, MD, and Gregory J. Riely, MD, PhD, from Memorial Sloan Kettering Cancer Center in New York.
“Improved understanding of the biology and molecular subtypes of non–small cell lung cancer have led to more biomarker-directed therapies for patients with metastatic disease. These biomarker-directed therapies and newer empirical treatment regimens have improved overall survival for patients with metastatic non–small cell lung cancer,” they wrote in JAMA.
The authors reviewed published studies of clinical trials of medical therapies for NSCLC, including articles on randomized trials, nonrandomized trials leading to practice changes or regulatory approval of new therapies for patients with locally advanced or metastatic NSCLC, and clinical practice guidelines.
Their review showed that approximately 30% of patients with NSCLC have molecular alterations predictive of response to treatment, such as mutations in EGFR, the gene encoding for epidermal growth factor receptor; rearrangements in the ALK (anaplastic lymphoma kinase) and ROS1 genes; and mutations in BRAF V600E.
Patients with somatic activating mutations in EGFR, which occur in approximately 20% of those with advanced NSCLC, have better progression-free survival when treated with an EGFR-target tyrosine kinase inhibitor such as gefitinib (Iressa), erlotinib (Tarceva), or afatinib (Gilotrif), compared with cytotoxic chemotherapy.
Similarly, they noted, patients with ALK rearrangements leading to overexpression of the ALK protein had better overall response rates and progression-free survival when treated with the ALK inhibitor crizotinib (Xalkori), compared with patients with ALK rearrangements treated with pemetrexed and a platinum agent.
For some patients without targetable mutations, immune checkpoint inhibitors either alone or in combination with chemotherapy have resulted in improvements in overall survival.
“These advances are substantial, but long-term durable responses remain uncommon for most patients. These insights into treating metastatic disease have informed the design of trials for new treatment strategies among patients with early-stage disease. The goal of NSCLC research is to understand and address mechanisms of resistant and refractory disease in patients with advanced disease and, ultimately, to increase cure rates,” the reviewers wrote.
The review was supported in part by a grant from the National Cancer Institute to Memorial Sloan Kettering. Dr. Arbour reported serving as a consultant to AstraZeneca and nonfinancial research support from Novartis and Takeda. Dr. Riely reported grants and nonfinancial support from Pfizer, Roche/Genentech/Chugai, Novartis, Merck, and Takeda; a patent pending for an alternate dosing of erlotinib for which he has no right to royalties; and payments from the National Comprehensive Cancer Network to participate in a committee overseeing solicitation and selection of grants to be awarded by AstraZeneca.
SOURCE: Arbour KC and Riely GJ. JAMA. 2019;322(8):764-74.
All patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) should undergo molecular testing for targetable mutations and for tumor expression of the programmed death–ligand 1 (PD-L1) protein, authors of a review of systemic therapies for NSCLC recommend.
Their opinion is based on evidence showing that 5-year overall survival rate for patients whose tumors have high levels of PD-L1 expression now exceeds 25%, and that patients with ALK-positive tumors have 5-year overall survival rates over 40%. In contrast, 5-year survival rates for patients with metastatic NSCLC prior to the 21st century were less than 5%, according to Kathryn C. Arbour, MD, and Gregory J. Riely, MD, PhD, from Memorial Sloan Kettering Cancer Center in New York.
“Improved understanding of the biology and molecular subtypes of non–small cell lung cancer have led to more biomarker-directed therapies for patients with metastatic disease. These biomarker-directed therapies and newer empirical treatment regimens have improved overall survival for patients with metastatic non–small cell lung cancer,” they wrote in JAMA.
The authors reviewed published studies of clinical trials of medical therapies for NSCLC, including articles on randomized trials, nonrandomized trials leading to practice changes or regulatory approval of new therapies for patients with locally advanced or metastatic NSCLC, and clinical practice guidelines.
Their review showed that approximately 30% of patients with NSCLC have molecular alterations predictive of response to treatment, such as mutations in EGFR, the gene encoding for epidermal growth factor receptor; rearrangements in the ALK (anaplastic lymphoma kinase) and ROS1 genes; and mutations in BRAF V600E.
Patients with somatic activating mutations in EGFR, which occur in approximately 20% of those with advanced NSCLC, have better progression-free survival when treated with an EGFR-target tyrosine kinase inhibitor such as gefitinib (Iressa), erlotinib (Tarceva), or afatinib (Gilotrif), compared with cytotoxic chemotherapy.
Similarly, they noted, patients with ALK rearrangements leading to overexpression of the ALK protein had better overall response rates and progression-free survival when treated with the ALK inhibitor crizotinib (Xalkori), compared with patients with ALK rearrangements treated with pemetrexed and a platinum agent.
For some patients without targetable mutations, immune checkpoint inhibitors either alone or in combination with chemotherapy have resulted in improvements in overall survival.
“These advances are substantial, but long-term durable responses remain uncommon for most patients. These insights into treating metastatic disease have informed the design of trials for new treatment strategies among patients with early-stage disease. The goal of NSCLC research is to understand and address mechanisms of resistant and refractory disease in patients with advanced disease and, ultimately, to increase cure rates,” the reviewers wrote.
The review was supported in part by a grant from the National Cancer Institute to Memorial Sloan Kettering. Dr. Arbour reported serving as a consultant to AstraZeneca and nonfinancial research support from Novartis and Takeda. Dr. Riely reported grants and nonfinancial support from Pfizer, Roche/Genentech/Chugai, Novartis, Merck, and Takeda; a patent pending for an alternate dosing of erlotinib for which he has no right to royalties; and payments from the National Comprehensive Cancer Network to participate in a committee overseeing solicitation and selection of grants to be awarded by AstraZeneca.
SOURCE: Arbour KC and Riely GJ. JAMA. 2019;322(8):764-74.
FROM JAMA
Ibrutinib-rituximab induction yields ‘unprecedented’ responses in MCL
LUGANO, Switzerland – In younger patients with previously untreated mantle cell lymphoma, the chemotherapy-free combination of ibrutinib and rituximab followed by a short course of chemotherapy was associated with an “unprecedented” 3-year progression-free survival rate, investigators in the phase 2 WINDOW-1 trial reported.
Among 50 patients aged 65 years and younger who received ibrutinib and rituximab until they achieved a complete or partial response, followed by four cycles of chemotherapy with rituximab plus hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) and rituximab plus methotrexate, the 3-year progression-free survival (PFS) rate was 88%, said Michael Wang, MD, from the University of Texas MD Anderson Cancer Center in Houston.
Additionally, for patients with the low-risk features, the 3-year PFS rate was 90%.
“Chemo-free ibrutinib-rituximab induced unprecedented – unprecedented – efficacy before chemo consolidation,” he said at the International Conference on Malignant Lymphoma.
Dr. Wang presented data from an interim analysis of the investigator-initiated single-center trial. Fifty patients aged 65 years or younger with untreated mantle cell lymphoma (MCL), good performance status, and good organ function were enrolled.
The patients were treated with ibrutinib and rituximab for two cycles and then evaluated for response with PET-CT scan, bone marrow biopsy, and for some patients, esophagogastroduodenoscopy (EGD) and colonoscopy with random biopsies.
In the induction phase, patients received ibrutinib daily on days 1-28 and rituximab intravenously over 6-8 hours on days 1, 8, 15, and 22 of cycle 1, and then over 4 hours on day 1 of cycles 3-12. The treatment was repeated every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity, or until patients achieved a complete response.
In the consolidation phase, patients received rituximab IV over 6 hours on day 1; oral or IV dexamethasone on days 1-4; cyclophosphamide IV over 3 hours twice daily on days 2-4; doxorubicin IV over 15-30 minutes on day 5; and vincristine IV over 15-30 minutes on day 5 of cycles one, three, five, and seven. Patients also received rituximab IV over 6 hours on day 1; methotrexate IV over 24 hours on day 2; and cytarabine IV over 2 hours twice daily on days 3 and 4 of cycles two, four, six, and eight. Treatments were repeated every 28 days for up to eight cycles in the absence of disease progression or unacceptable toxicity.
Patients who had a complete response (CR) after two cycles of induction and those who had disease progression on induction went on to consolidation. Patients with partial responses (PR) to induction continued on ibrutinib/rituximab until either the loss of a PR or best response for up to 12 cycles, with those who achieved a CR then moving on to consolidation.
Patients who had a CR after induction received four cycles of R-hyperCVAD, no subsequent stem cell transplant, and no maintenance therapy. Patients who had a PR after induction received two cycles of R-hyperCVAD, were reassessed, and then continued on R-hyperCVAD until CR or for up to eight total cycles.
Patients with either stable disease or progression during R-hyperCVAD were taken off the study.
Of the 50 patients enrolled, all 50 were evaluable for part A (induction), and 48 were evaluable after induction and consolidation (two patients withdrew for personal reasons).
After a median follow-up of 36 months, the overall response rate (ORR) following induction was 100%, consisting of 46 CRs (92%) and four PRs (8%).
In an intention-to-treat analysis (including the two patients who withdrew), the ORR was 96%, consisting of CRs in 47 patients (94%) and a PR in 1 patient (2%).
Neither the median PFS nor median overall survival had been reached at the time of data cutoff, and no patients have died.
Of the 50 enrolled patients, four experienced disease progression after 17, 24, 34, and 35 months of treatment. The patients with disease progression included one with Ki-67 of less than 30%, and three with KI-67 of 30% or greater.
Grade 3-4 toxicities during induction including myelosuppression in 4%; fatigue, myalgia, and rashes in 8% each; and oral mucositis in 4%.
Dr. Wang said that future studies on minimal residual disease and clonal evolution are ongoing, and that data on more patients will be presented at the next annual meeting of the American Society of Hematology, scheduled for December 2019.
He also noted that the WINDOW-2 trial, in which ibrutinib and rituximab are followed by veneotclax and hyper-CVAD chemotherapy in patients with newly diagnosed MCL, is open and rapidly enrolling patients.
The study is supported by the National Cancer Institute. Dr. Wang reported financial relationships with Janssen, Pharmacyclics, and other companies.
SOURCE: Wang M et al. ICML-15, Abstract 12.
LUGANO, Switzerland – In younger patients with previously untreated mantle cell lymphoma, the chemotherapy-free combination of ibrutinib and rituximab followed by a short course of chemotherapy was associated with an “unprecedented” 3-year progression-free survival rate, investigators in the phase 2 WINDOW-1 trial reported.
Among 50 patients aged 65 years and younger who received ibrutinib and rituximab until they achieved a complete or partial response, followed by four cycles of chemotherapy with rituximab plus hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) and rituximab plus methotrexate, the 3-year progression-free survival (PFS) rate was 88%, said Michael Wang, MD, from the University of Texas MD Anderson Cancer Center in Houston.
Additionally, for patients with the low-risk features, the 3-year PFS rate was 90%.
“Chemo-free ibrutinib-rituximab induced unprecedented – unprecedented – efficacy before chemo consolidation,” he said at the International Conference on Malignant Lymphoma.
Dr. Wang presented data from an interim analysis of the investigator-initiated single-center trial. Fifty patients aged 65 years or younger with untreated mantle cell lymphoma (MCL), good performance status, and good organ function were enrolled.
The patients were treated with ibrutinib and rituximab for two cycles and then evaluated for response with PET-CT scan, bone marrow biopsy, and for some patients, esophagogastroduodenoscopy (EGD) and colonoscopy with random biopsies.
In the induction phase, patients received ibrutinib daily on days 1-28 and rituximab intravenously over 6-8 hours on days 1, 8, 15, and 22 of cycle 1, and then over 4 hours on day 1 of cycles 3-12. The treatment was repeated every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity, or until patients achieved a complete response.
In the consolidation phase, patients received rituximab IV over 6 hours on day 1; oral or IV dexamethasone on days 1-4; cyclophosphamide IV over 3 hours twice daily on days 2-4; doxorubicin IV over 15-30 minutes on day 5; and vincristine IV over 15-30 minutes on day 5 of cycles one, three, five, and seven. Patients also received rituximab IV over 6 hours on day 1; methotrexate IV over 24 hours on day 2; and cytarabine IV over 2 hours twice daily on days 3 and 4 of cycles two, four, six, and eight. Treatments were repeated every 28 days for up to eight cycles in the absence of disease progression or unacceptable toxicity.
Patients who had a complete response (CR) after two cycles of induction and those who had disease progression on induction went on to consolidation. Patients with partial responses (PR) to induction continued on ibrutinib/rituximab until either the loss of a PR or best response for up to 12 cycles, with those who achieved a CR then moving on to consolidation.
Patients who had a CR after induction received four cycles of R-hyperCVAD, no subsequent stem cell transplant, and no maintenance therapy. Patients who had a PR after induction received two cycles of R-hyperCVAD, were reassessed, and then continued on R-hyperCVAD until CR or for up to eight total cycles.
Patients with either stable disease or progression during R-hyperCVAD were taken off the study.
Of the 50 patients enrolled, all 50 were evaluable for part A (induction), and 48 were evaluable after induction and consolidation (two patients withdrew for personal reasons).
After a median follow-up of 36 months, the overall response rate (ORR) following induction was 100%, consisting of 46 CRs (92%) and four PRs (8%).
In an intention-to-treat analysis (including the two patients who withdrew), the ORR was 96%, consisting of CRs in 47 patients (94%) and a PR in 1 patient (2%).
Neither the median PFS nor median overall survival had been reached at the time of data cutoff, and no patients have died.
Of the 50 enrolled patients, four experienced disease progression after 17, 24, 34, and 35 months of treatment. The patients with disease progression included one with Ki-67 of less than 30%, and three with KI-67 of 30% or greater.
Grade 3-4 toxicities during induction including myelosuppression in 4%; fatigue, myalgia, and rashes in 8% each; and oral mucositis in 4%.
Dr. Wang said that future studies on minimal residual disease and clonal evolution are ongoing, and that data on more patients will be presented at the next annual meeting of the American Society of Hematology, scheduled for December 2019.
He also noted that the WINDOW-2 trial, in which ibrutinib and rituximab are followed by veneotclax and hyper-CVAD chemotherapy in patients with newly diagnosed MCL, is open and rapidly enrolling patients.
The study is supported by the National Cancer Institute. Dr. Wang reported financial relationships with Janssen, Pharmacyclics, and other companies.
SOURCE: Wang M et al. ICML-15, Abstract 12.
LUGANO, Switzerland – In younger patients with previously untreated mantle cell lymphoma, the chemotherapy-free combination of ibrutinib and rituximab followed by a short course of chemotherapy was associated with an “unprecedented” 3-year progression-free survival rate, investigators in the phase 2 WINDOW-1 trial reported.
Among 50 patients aged 65 years and younger who received ibrutinib and rituximab until they achieved a complete or partial response, followed by four cycles of chemotherapy with rituximab plus hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) and rituximab plus methotrexate, the 3-year progression-free survival (PFS) rate was 88%, said Michael Wang, MD, from the University of Texas MD Anderson Cancer Center in Houston.
Additionally, for patients with the low-risk features, the 3-year PFS rate was 90%.
“Chemo-free ibrutinib-rituximab induced unprecedented – unprecedented – efficacy before chemo consolidation,” he said at the International Conference on Malignant Lymphoma.
Dr. Wang presented data from an interim analysis of the investigator-initiated single-center trial. Fifty patients aged 65 years or younger with untreated mantle cell lymphoma (MCL), good performance status, and good organ function were enrolled.
The patients were treated with ibrutinib and rituximab for two cycles and then evaluated for response with PET-CT scan, bone marrow biopsy, and for some patients, esophagogastroduodenoscopy (EGD) and colonoscopy with random biopsies.
In the induction phase, patients received ibrutinib daily on days 1-28 and rituximab intravenously over 6-8 hours on days 1, 8, 15, and 22 of cycle 1, and then over 4 hours on day 1 of cycles 3-12. The treatment was repeated every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity, or until patients achieved a complete response.
In the consolidation phase, patients received rituximab IV over 6 hours on day 1; oral or IV dexamethasone on days 1-4; cyclophosphamide IV over 3 hours twice daily on days 2-4; doxorubicin IV over 15-30 minutes on day 5; and vincristine IV over 15-30 minutes on day 5 of cycles one, three, five, and seven. Patients also received rituximab IV over 6 hours on day 1; methotrexate IV over 24 hours on day 2; and cytarabine IV over 2 hours twice daily on days 3 and 4 of cycles two, four, six, and eight. Treatments were repeated every 28 days for up to eight cycles in the absence of disease progression or unacceptable toxicity.
Patients who had a complete response (CR) after two cycles of induction and those who had disease progression on induction went on to consolidation. Patients with partial responses (PR) to induction continued on ibrutinib/rituximab until either the loss of a PR or best response for up to 12 cycles, with those who achieved a CR then moving on to consolidation.
Patients who had a CR after induction received four cycles of R-hyperCVAD, no subsequent stem cell transplant, and no maintenance therapy. Patients who had a PR after induction received two cycles of R-hyperCVAD, were reassessed, and then continued on R-hyperCVAD until CR or for up to eight total cycles.
Patients with either stable disease or progression during R-hyperCVAD were taken off the study.
Of the 50 patients enrolled, all 50 were evaluable for part A (induction), and 48 were evaluable after induction and consolidation (two patients withdrew for personal reasons).
After a median follow-up of 36 months, the overall response rate (ORR) following induction was 100%, consisting of 46 CRs (92%) and four PRs (8%).
In an intention-to-treat analysis (including the two patients who withdrew), the ORR was 96%, consisting of CRs in 47 patients (94%) and a PR in 1 patient (2%).
Neither the median PFS nor median overall survival had been reached at the time of data cutoff, and no patients have died.
Of the 50 enrolled patients, four experienced disease progression after 17, 24, 34, and 35 months of treatment. The patients with disease progression included one with Ki-67 of less than 30%, and three with KI-67 of 30% or greater.
Grade 3-4 toxicities during induction including myelosuppression in 4%; fatigue, myalgia, and rashes in 8% each; and oral mucositis in 4%.
Dr. Wang said that future studies on minimal residual disease and clonal evolution are ongoing, and that data on more patients will be presented at the next annual meeting of the American Society of Hematology, scheduled for December 2019.
He also noted that the WINDOW-2 trial, in which ibrutinib and rituximab are followed by veneotclax and hyper-CVAD chemotherapy in patients with newly diagnosed MCL, is open and rapidly enrolling patients.
The study is supported by the National Cancer Institute. Dr. Wang reported financial relationships with Janssen, Pharmacyclics, and other companies.
SOURCE: Wang M et al. ICML-15, Abstract 12.
REPORTING FROM 15-ICML
Diet, exercise don’t improve breast cancer-related lymphedema
Neither weight-loss nor home-based exercise programs improved outcomes for women with breast cancer–related lymphedema, investigators found.
Among 351 overweight breast cancer survivors with breast cancer–related lymphedema (BCRL), there were no significant differences at 1 year of follow-up in the percentage difference between limb volumes from baseline, regardless of whether patients had been randomly assigned to a home-based exercise program, weight-loss program, combined interventions, or to a facility-based lymphedema care–only program, reported Kathryn H. Schmitz, PhD, MPH, from Penn State University, Hershey, and colleagues.
“Our findings are contradictory to our own clinical experience, as we have received reports from patients with BCRL who have noted improvements in their lymphedema symptoms after weight loss. Possible explanations for this mismatch of clinical experience and empirical evidence include alterations in aspects of lymphedema, such as tissue composition, that remain challenging to measure with high reliability and validity,” they wrote in JAMA Oncology.
The findings suggest that breast cancer survivors with lymphedema may benefit more from facility-based exercise than home-based lymphedema care, the investigators wrote.
In the randomized Women in Steady Exercise Research (WISER) Survivor trial, the investigators enrolled 351 overweight breast cancer survivors with lymphedema and randomly assigned them to a 52-week home-based exercise program consisting of strength and resistance training twice per week and 180 minutes per week of walking (87 patients), a weight-loss program consisting of 20 weeks of meal replacement and 1 year of lifestyle-modification counseling (87 patients), a combination of the two programs (87 patients), or a facility-based lymphedema care program only (90 patients, control group).
The primary endpoint was originally intended to be lymphedema clinical events such as incident flare-ups or cellulitis, but was changed to the percentage of interlimb difference (that is, between the affected and unaffected limb) because of a reduction in funding that led to a reduction in the sample size.
There were no significant between-group differences at either baseline or 12 months in either the percentage of interlimb differences or in absolute differences, the investigators found.
Women assigned to the diet and exercise intervention lost significantly more weight than controls (P less than .001), but saw significant improvements in fitness only in the maximum amount of weight they could lift (P = .01).
“Multiple national organizations currently advise overweight women to achieve and maintain a healthy weight to improve the outcomes of previously diagnosed BCRL. The empirical evidence base, including data from the present study, does not support the assertion that weight loss as an intervention improves the hallmark measure of BCRL severity, percentage of interlimb difference,” Dr. Schmitz and colleagues wrote.
They acknowledged that BCRL is a long-term condition and that the 1-year follow-up period may have been too short to observe lymphedema exacerbation or related clinical events; therefore, the results may not apply to women with severe lymphedema, such as those with interlimb differences of greater than 30%.
The study was supported by various National Institutes of Health grants. Compression garments were supplied by BSN Medical. Dr. Schmitz reported receiving grants from the National Cancer Institute and nonfinancial support from BSN Medical during the conduct of the study, personal fees from Klose Training outside the submitted work, and a licensed patent for a Strength After Breast Cancer course.
SOURCE: Schmitz KH et al. JAMA Oncol. 2019 Aug 15. doi: 10.1001/jamaoncol.2019.2109..
Neither weight-loss nor home-based exercise programs improved outcomes for women with breast cancer–related lymphedema, investigators found.
Among 351 overweight breast cancer survivors with breast cancer–related lymphedema (BCRL), there were no significant differences at 1 year of follow-up in the percentage difference between limb volumes from baseline, regardless of whether patients had been randomly assigned to a home-based exercise program, weight-loss program, combined interventions, or to a facility-based lymphedema care–only program, reported Kathryn H. Schmitz, PhD, MPH, from Penn State University, Hershey, and colleagues.
“Our findings are contradictory to our own clinical experience, as we have received reports from patients with BCRL who have noted improvements in their lymphedema symptoms after weight loss. Possible explanations for this mismatch of clinical experience and empirical evidence include alterations in aspects of lymphedema, such as tissue composition, that remain challenging to measure with high reliability and validity,” they wrote in JAMA Oncology.
The findings suggest that breast cancer survivors with lymphedema may benefit more from facility-based exercise than home-based lymphedema care, the investigators wrote.
In the randomized Women in Steady Exercise Research (WISER) Survivor trial, the investigators enrolled 351 overweight breast cancer survivors with lymphedema and randomly assigned them to a 52-week home-based exercise program consisting of strength and resistance training twice per week and 180 minutes per week of walking (87 patients), a weight-loss program consisting of 20 weeks of meal replacement and 1 year of lifestyle-modification counseling (87 patients), a combination of the two programs (87 patients), or a facility-based lymphedema care program only (90 patients, control group).
The primary endpoint was originally intended to be lymphedema clinical events such as incident flare-ups or cellulitis, but was changed to the percentage of interlimb difference (that is, between the affected and unaffected limb) because of a reduction in funding that led to a reduction in the sample size.
There were no significant between-group differences at either baseline or 12 months in either the percentage of interlimb differences or in absolute differences, the investigators found.
Women assigned to the diet and exercise intervention lost significantly more weight than controls (P less than .001), but saw significant improvements in fitness only in the maximum amount of weight they could lift (P = .01).
“Multiple national organizations currently advise overweight women to achieve and maintain a healthy weight to improve the outcomes of previously diagnosed BCRL. The empirical evidence base, including data from the present study, does not support the assertion that weight loss as an intervention improves the hallmark measure of BCRL severity, percentage of interlimb difference,” Dr. Schmitz and colleagues wrote.
They acknowledged that BCRL is a long-term condition and that the 1-year follow-up period may have been too short to observe lymphedema exacerbation or related clinical events; therefore, the results may not apply to women with severe lymphedema, such as those with interlimb differences of greater than 30%.
The study was supported by various National Institutes of Health grants. Compression garments were supplied by BSN Medical. Dr. Schmitz reported receiving grants from the National Cancer Institute and nonfinancial support from BSN Medical during the conduct of the study, personal fees from Klose Training outside the submitted work, and a licensed patent for a Strength After Breast Cancer course.
SOURCE: Schmitz KH et al. JAMA Oncol. 2019 Aug 15. doi: 10.1001/jamaoncol.2019.2109..
Neither weight-loss nor home-based exercise programs improved outcomes for women with breast cancer–related lymphedema, investigators found.
Among 351 overweight breast cancer survivors with breast cancer–related lymphedema (BCRL), there were no significant differences at 1 year of follow-up in the percentage difference between limb volumes from baseline, regardless of whether patients had been randomly assigned to a home-based exercise program, weight-loss program, combined interventions, or to a facility-based lymphedema care–only program, reported Kathryn H. Schmitz, PhD, MPH, from Penn State University, Hershey, and colleagues.
“Our findings are contradictory to our own clinical experience, as we have received reports from patients with BCRL who have noted improvements in their lymphedema symptoms after weight loss. Possible explanations for this mismatch of clinical experience and empirical evidence include alterations in aspects of lymphedema, such as tissue composition, that remain challenging to measure with high reliability and validity,” they wrote in JAMA Oncology.
The findings suggest that breast cancer survivors with lymphedema may benefit more from facility-based exercise than home-based lymphedema care, the investigators wrote.
In the randomized Women in Steady Exercise Research (WISER) Survivor trial, the investigators enrolled 351 overweight breast cancer survivors with lymphedema and randomly assigned them to a 52-week home-based exercise program consisting of strength and resistance training twice per week and 180 minutes per week of walking (87 patients), a weight-loss program consisting of 20 weeks of meal replacement and 1 year of lifestyle-modification counseling (87 patients), a combination of the two programs (87 patients), or a facility-based lymphedema care program only (90 patients, control group).
The primary endpoint was originally intended to be lymphedema clinical events such as incident flare-ups or cellulitis, but was changed to the percentage of interlimb difference (that is, between the affected and unaffected limb) because of a reduction in funding that led to a reduction in the sample size.
There were no significant between-group differences at either baseline or 12 months in either the percentage of interlimb differences or in absolute differences, the investigators found.
Women assigned to the diet and exercise intervention lost significantly more weight than controls (P less than .001), but saw significant improvements in fitness only in the maximum amount of weight they could lift (P = .01).
“Multiple national organizations currently advise overweight women to achieve and maintain a healthy weight to improve the outcomes of previously diagnosed BCRL. The empirical evidence base, including data from the present study, does not support the assertion that weight loss as an intervention improves the hallmark measure of BCRL severity, percentage of interlimb difference,” Dr. Schmitz and colleagues wrote.
They acknowledged that BCRL is a long-term condition and that the 1-year follow-up period may have been too short to observe lymphedema exacerbation or related clinical events; therefore, the results may not apply to women with severe lymphedema, such as those with interlimb differences of greater than 30%.
The study was supported by various National Institutes of Health grants. Compression garments were supplied by BSN Medical. Dr. Schmitz reported receiving grants from the National Cancer Institute and nonfinancial support from BSN Medical during the conduct of the study, personal fees from Klose Training outside the submitted work, and a licensed patent for a Strength After Breast Cancer course.
SOURCE: Schmitz KH et al. JAMA Oncol. 2019 Aug 15. doi: 10.1001/jamaoncol.2019.2109..
FROM JAMA ONCOLOGY
EHR-derived data on tumor progression may predict survival
Real-world electronic health record data on tumor progression appears to be a good surrogate for overall survival, a finding that could help to improve estimates of benefit for complex cancer therapy regimens for use in both clinical trials and treatment planning, investigators say.
A study of electronic health record (EHR) data on more than 30,000 patients with non–small cell lung cancer (NSCLC) showed that real-world data on progression-free survival (PFS) showed a high degree of correlation with overall survival (OS), reported Sandra D. Griffith, PhD, of Flatiron Health, New York, and colleagues.
“As survival rates have improved and more than one therapy line has become typical, OS has become an inadequate metric for ascertaining the benefit of some cancer treatment interventions. Intermediate endpoints are essential for evaluating treatment benefits in real-world contexts. This study presents a scalable, feasible, and replicable approach to yield an EHR-generated progression variable ready for incorporation into large, contemporary real-world analyses,” they wrote in JCO Clinical Cancer Informatics.
The investigators studied retrospectively whether it would be feasible on a large scale to extract clinically relevant endpoints from an EHR-derived database that relies on technology-assisted abstraction of data from patient charts.
Their cohort included 30,276 patients diagnosed with advanced NSCLC from January 2011 through February 2018 who had two or more visits documented on EHR and who had been started on one or more lines of systemic therapy. Of this group, 16,606 had one or more documented tumor progression events, and 11,366 either died, discontinued therapy, or started on a new therapy.
The investigators found that among 20,000 evaluable patients, correlation of real-word PFS with OS was moderately high (Spearman’s P = .076), although for 11,902 patients with a progression event who died the correlation of EHR data with actual OS was somewhat lower (Spearman’s P = .069).
The strength of the correlations was verified in an duplicate random sample reviewed by independent abstractors.
The median time to abstract data on disease progression from individual electronic health records was 18 minutes.
“More work is needed to document how real-world progression under different treatments relates to treatment effects observed in clinical trials; understand the impact of different imaging and assessment cadences—for example, informative censoring; and clarify the relationship between real-world progression and other endpoints, such as real-world tumor response. Similar work is also needed in other tumor types,” Dr. Griffiths and colleagues wrote.
The study was supported by Flatiron Health, a subsidiary of Roche. Dr. Griffith and multiple co-authors are employees and stockholders of Flatiron Health and/or Roche.
SOURCE: Griffith SD et al. JCO Clinical Informatics. 2019 Aug 12. doi: 10.1200/CCI.19.00013.
Real-world electronic health record data on tumor progression appears to be a good surrogate for overall survival, a finding that could help to improve estimates of benefit for complex cancer therapy regimens for use in both clinical trials and treatment planning, investigators say.
A study of electronic health record (EHR) data on more than 30,000 patients with non–small cell lung cancer (NSCLC) showed that real-world data on progression-free survival (PFS) showed a high degree of correlation with overall survival (OS), reported Sandra D. Griffith, PhD, of Flatiron Health, New York, and colleagues.
“As survival rates have improved and more than one therapy line has become typical, OS has become an inadequate metric for ascertaining the benefit of some cancer treatment interventions. Intermediate endpoints are essential for evaluating treatment benefits in real-world contexts. This study presents a scalable, feasible, and replicable approach to yield an EHR-generated progression variable ready for incorporation into large, contemporary real-world analyses,” they wrote in JCO Clinical Cancer Informatics.
The investigators studied retrospectively whether it would be feasible on a large scale to extract clinically relevant endpoints from an EHR-derived database that relies on technology-assisted abstraction of data from patient charts.
Their cohort included 30,276 patients diagnosed with advanced NSCLC from January 2011 through February 2018 who had two or more visits documented on EHR and who had been started on one or more lines of systemic therapy. Of this group, 16,606 had one or more documented tumor progression events, and 11,366 either died, discontinued therapy, or started on a new therapy.
The investigators found that among 20,000 evaluable patients, correlation of real-word PFS with OS was moderately high (Spearman’s P = .076), although for 11,902 patients with a progression event who died the correlation of EHR data with actual OS was somewhat lower (Spearman’s P = .069).
The strength of the correlations was verified in an duplicate random sample reviewed by independent abstractors.
The median time to abstract data on disease progression from individual electronic health records was 18 minutes.
“More work is needed to document how real-world progression under different treatments relates to treatment effects observed in clinical trials; understand the impact of different imaging and assessment cadences—for example, informative censoring; and clarify the relationship between real-world progression and other endpoints, such as real-world tumor response. Similar work is also needed in other tumor types,” Dr. Griffiths and colleagues wrote.
The study was supported by Flatiron Health, a subsidiary of Roche. Dr. Griffith and multiple co-authors are employees and stockholders of Flatiron Health and/or Roche.
SOURCE: Griffith SD et al. JCO Clinical Informatics. 2019 Aug 12. doi: 10.1200/CCI.19.00013.
Real-world electronic health record data on tumor progression appears to be a good surrogate for overall survival, a finding that could help to improve estimates of benefit for complex cancer therapy regimens for use in both clinical trials and treatment planning, investigators say.
A study of electronic health record (EHR) data on more than 30,000 patients with non–small cell lung cancer (NSCLC) showed that real-world data on progression-free survival (PFS) showed a high degree of correlation with overall survival (OS), reported Sandra D. Griffith, PhD, of Flatiron Health, New York, and colleagues.
“As survival rates have improved and more than one therapy line has become typical, OS has become an inadequate metric for ascertaining the benefit of some cancer treatment interventions. Intermediate endpoints are essential for evaluating treatment benefits in real-world contexts. This study presents a scalable, feasible, and replicable approach to yield an EHR-generated progression variable ready for incorporation into large, contemporary real-world analyses,” they wrote in JCO Clinical Cancer Informatics.
The investigators studied retrospectively whether it would be feasible on a large scale to extract clinically relevant endpoints from an EHR-derived database that relies on technology-assisted abstraction of data from patient charts.
Their cohort included 30,276 patients diagnosed with advanced NSCLC from January 2011 through February 2018 who had two or more visits documented on EHR and who had been started on one or more lines of systemic therapy. Of this group, 16,606 had one or more documented tumor progression events, and 11,366 either died, discontinued therapy, or started on a new therapy.
The investigators found that among 20,000 evaluable patients, correlation of real-word PFS with OS was moderately high (Spearman’s P = .076), although for 11,902 patients with a progression event who died the correlation of EHR data with actual OS was somewhat lower (Spearman’s P = .069).
The strength of the correlations was verified in an duplicate random sample reviewed by independent abstractors.
The median time to abstract data on disease progression from individual electronic health records was 18 minutes.
“More work is needed to document how real-world progression under different treatments relates to treatment effects observed in clinical trials; understand the impact of different imaging and assessment cadences—for example, informative censoring; and clarify the relationship between real-world progression and other endpoints, such as real-world tumor response. Similar work is also needed in other tumor types,” Dr. Griffiths and colleagues wrote.
The study was supported by Flatiron Health, a subsidiary of Roche. Dr. Griffith and multiple co-authors are employees and stockholders of Flatiron Health and/or Roche.
SOURCE: Griffith SD et al. JCO Clinical Informatics. 2019 Aug 12. doi: 10.1200/CCI.19.00013.
FROM JCO CLINICAL INFORMATICS
Ibrutinib/rituximab effective, safe as frontline treatment for older patients with MCL
LUGANO, SWITZERLAND – The chemotherapy-free combination of ibrutinib (Imbruvica) and rituximab is highly effective as frontline therapy for older, transplant-ineligible patients with nonblastoid mantle cell lymphoma, according to investigators.
In a phase 2 study of patients with a median age of 71 years, 38 of 41 patients (93%) had an objective response, and the regimen was both safe and easy to administer, reported Preetesh Jain, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.
“The adverse event profile was generally favorable, with specific monitoring recommended for patients with cardiovascular comorbidities and a history of atrial fibrillation,” he said at the International Conference on Malignant Lymphoma.
The investigators enrolled 48 patients aged 65 years and older with previously untreated mantle cell lymphoma (MCL), of whom 41 were evaluable for the primary endpoints of overall response rate (ORR) and safety. The patients had good performance status and normal organ function, with the largest tumor size less than 10 cm. Patients with atrial fibrillation could participate, if the fibrillation was controlled. Patients with Ki-67 protein levels of 50% or greater and blastoid/pleomorphic histology were excluded.
Patients were treated with ibrutinib 560 mg orally daily for each 28-day cycle, with therapy continued until disease progression, or until therapy was stopped for any other reason. Patients also received intravenous rituximab 375 mg/m2 on days 1, 8, 15 and 22, plus or minus one day for cycle 1, on day 1 of cycles 3-8, and on day 1 of every other cycle for up to 2 years.
Of the 41 patients evaluable for response, 26 (64%) had a complete response (CR) and 12 (29%) had a partial response. Three additional patients had stable disease, for an objective response rate of 93%.
Of 34 patients with PET scans, all had negative scans. Of 37 patients evaluable for minimal residual disease (MRD) by flow cytometry, 21 (58%) were MRD negative.
Patients with low or intermediate Mantle Cell Lymphoma International Prognostic Index (MIPI) scores had a higher ORR (100% vs. 89% for patients with high MIPI scores), and patients with low Ki-67 levels had a higher response rate than that of patients with KI-67 of 30% or greater (80% vs. 87%).
Neither median 3-year progression-free survival nor median 3-year overall survival have been reached, with respective 3-year rates of 87% and 95%.
Four patients experienced disease progression at 4, 10, 13 and 33 months of treatment. Three of these patients had disease that had transformed to blastoid/pleomorphic variant, two had Ki-67 of 30% or greater, one had mutations in TP53, and one had FAT1 and SF3B1 mutations.
Two patients died after ibrutinib therapy, one who had discontinued therapy because of bleeding, and the other who died on treatment at 13 months from transformed disease. Both of these patients had high Ki-67 levels.
Grade 3 or 4 hematological adverse events were neutropenia in four patients, and thrombocytopenia in two patients. There were no cases of grade 3 or 4 anemia.
Grade 3 or 4 nonhematological adverse events were fatigue, myalgia, and atrial fibrillation in seven patients each, diarrhea in six patients, and petechiae/bleeding in three patients.
Patients will continue to be followed for late adverse events, secondary cancers, and relapses, and further studies on clonal evolution, mutation profiling, and MRD are ongoing and will be reported at a later date, Dr. Jain said.
The National Cancer Institute supported the study. Dr. Jain reported having no financial disclosures.
SOURCE: Jain P et al. 15-ICML. Abstract 011.
LUGANO, SWITZERLAND – The chemotherapy-free combination of ibrutinib (Imbruvica) and rituximab is highly effective as frontline therapy for older, transplant-ineligible patients with nonblastoid mantle cell lymphoma, according to investigators.
In a phase 2 study of patients with a median age of 71 years, 38 of 41 patients (93%) had an objective response, and the regimen was both safe and easy to administer, reported Preetesh Jain, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.
“The adverse event profile was generally favorable, with specific monitoring recommended for patients with cardiovascular comorbidities and a history of atrial fibrillation,” he said at the International Conference on Malignant Lymphoma.
The investigators enrolled 48 patients aged 65 years and older with previously untreated mantle cell lymphoma (MCL), of whom 41 were evaluable for the primary endpoints of overall response rate (ORR) and safety. The patients had good performance status and normal organ function, with the largest tumor size less than 10 cm. Patients with atrial fibrillation could participate, if the fibrillation was controlled. Patients with Ki-67 protein levels of 50% or greater and blastoid/pleomorphic histology were excluded.
Patients were treated with ibrutinib 560 mg orally daily for each 28-day cycle, with therapy continued until disease progression, or until therapy was stopped for any other reason. Patients also received intravenous rituximab 375 mg/m2 on days 1, 8, 15 and 22, plus or minus one day for cycle 1, on day 1 of cycles 3-8, and on day 1 of every other cycle for up to 2 years.
Of the 41 patients evaluable for response, 26 (64%) had a complete response (CR) and 12 (29%) had a partial response. Three additional patients had stable disease, for an objective response rate of 93%.
Of 34 patients with PET scans, all had negative scans. Of 37 patients evaluable for minimal residual disease (MRD) by flow cytometry, 21 (58%) were MRD negative.
Patients with low or intermediate Mantle Cell Lymphoma International Prognostic Index (MIPI) scores had a higher ORR (100% vs. 89% for patients with high MIPI scores), and patients with low Ki-67 levels had a higher response rate than that of patients with KI-67 of 30% or greater (80% vs. 87%).
Neither median 3-year progression-free survival nor median 3-year overall survival have been reached, with respective 3-year rates of 87% and 95%.
Four patients experienced disease progression at 4, 10, 13 and 33 months of treatment. Three of these patients had disease that had transformed to blastoid/pleomorphic variant, two had Ki-67 of 30% or greater, one had mutations in TP53, and one had FAT1 and SF3B1 mutations.
Two patients died after ibrutinib therapy, one who had discontinued therapy because of bleeding, and the other who died on treatment at 13 months from transformed disease. Both of these patients had high Ki-67 levels.
Grade 3 or 4 hematological adverse events were neutropenia in four patients, and thrombocytopenia in two patients. There were no cases of grade 3 or 4 anemia.
Grade 3 or 4 nonhematological adverse events were fatigue, myalgia, and atrial fibrillation in seven patients each, diarrhea in six patients, and petechiae/bleeding in three patients.
Patients will continue to be followed for late adverse events, secondary cancers, and relapses, and further studies on clonal evolution, mutation profiling, and MRD are ongoing and will be reported at a later date, Dr. Jain said.
The National Cancer Institute supported the study. Dr. Jain reported having no financial disclosures.
SOURCE: Jain P et al. 15-ICML. Abstract 011.
LUGANO, SWITZERLAND – The chemotherapy-free combination of ibrutinib (Imbruvica) and rituximab is highly effective as frontline therapy for older, transplant-ineligible patients with nonblastoid mantle cell lymphoma, according to investigators.
In a phase 2 study of patients with a median age of 71 years, 38 of 41 patients (93%) had an objective response, and the regimen was both safe and easy to administer, reported Preetesh Jain, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.
“The adverse event profile was generally favorable, with specific monitoring recommended for patients with cardiovascular comorbidities and a history of atrial fibrillation,” he said at the International Conference on Malignant Lymphoma.
The investigators enrolled 48 patients aged 65 years and older with previously untreated mantle cell lymphoma (MCL), of whom 41 were evaluable for the primary endpoints of overall response rate (ORR) and safety. The patients had good performance status and normal organ function, with the largest tumor size less than 10 cm. Patients with atrial fibrillation could participate, if the fibrillation was controlled. Patients with Ki-67 protein levels of 50% or greater and blastoid/pleomorphic histology were excluded.
Patients were treated with ibrutinib 560 mg orally daily for each 28-day cycle, with therapy continued until disease progression, or until therapy was stopped for any other reason. Patients also received intravenous rituximab 375 mg/m2 on days 1, 8, 15 and 22, plus or minus one day for cycle 1, on day 1 of cycles 3-8, and on day 1 of every other cycle for up to 2 years.
Of the 41 patients evaluable for response, 26 (64%) had a complete response (CR) and 12 (29%) had a partial response. Three additional patients had stable disease, for an objective response rate of 93%.
Of 34 patients with PET scans, all had negative scans. Of 37 patients evaluable for minimal residual disease (MRD) by flow cytometry, 21 (58%) were MRD negative.
Patients with low or intermediate Mantle Cell Lymphoma International Prognostic Index (MIPI) scores had a higher ORR (100% vs. 89% for patients with high MIPI scores), and patients with low Ki-67 levels had a higher response rate than that of patients with KI-67 of 30% or greater (80% vs. 87%).
Neither median 3-year progression-free survival nor median 3-year overall survival have been reached, with respective 3-year rates of 87% and 95%.
Four patients experienced disease progression at 4, 10, 13 and 33 months of treatment. Three of these patients had disease that had transformed to blastoid/pleomorphic variant, two had Ki-67 of 30% or greater, one had mutations in TP53, and one had FAT1 and SF3B1 mutations.
Two patients died after ibrutinib therapy, one who had discontinued therapy because of bleeding, and the other who died on treatment at 13 months from transformed disease. Both of these patients had high Ki-67 levels.
Grade 3 or 4 hematological adverse events were neutropenia in four patients, and thrombocytopenia in two patients. There were no cases of grade 3 or 4 anemia.
Grade 3 or 4 nonhematological adverse events were fatigue, myalgia, and atrial fibrillation in seven patients each, diarrhea in six patients, and petechiae/bleeding in three patients.
Patients will continue to be followed for late adverse events, secondary cancers, and relapses, and further studies on clonal evolution, mutation profiling, and MRD are ongoing and will be reported at a later date, Dr. Jain said.
The National Cancer Institute supported the study. Dr. Jain reported having no financial disclosures.
SOURCE: Jain P et al. 15-ICML. Abstract 011.
REPORTING FROM 15-ICML
HDAC/HMA combo shows ‘remarkable’ activity in PTCL
LUGANO, SWITZERLAND – A combination of 5-azacytidine and romidepsin showed promising activity in patients with peripheral T cell lymphomas, particularly angioimmunoblastic T-cell lymphoma (AITL) and primary cutaneous follicular helper T-cell lymphoma (PTCL-TFH), results of a phase 2 study showed.
Of 16 patients with AITL or PTCL-TFH, 11 (69%) had a clinical response to the 5-azacytidine (AZA)/romidepsin combination, including 8 (50%) with complete responses (CRs), and 3 with partial responses (PRs), reported Lorenzo Falchi, MD, of Columbia University Medical Center and New York Presbyterian Hospital, New York, and colleagues.
“We show that the combination of oral AZA/romidepsin is remarkably active in patients with T-cell lymphomas. Clearly more patients with other subtypes are needed to better evaluate this combination,” Dr. Falchi said at the International Conference on Malignant Lymphoma.
The combination is intended to target epigenetic changes in PTCLs, which often bear mutations in TET2, DNMT3A, and IDH2. These mutations create global hypermethylation and cause transcriptional silencing of tumor suppressor genes, Dr. Falchi said.
Both histone deacetylase inhibitors such as romidepsin, and hypomethylating agents such as AZA have been shown to have single-agent activity against PTCL, and as previously reported at the 2018 T-cell Lymphoma Forum, the combination produced a higher overall response rate (ORR) and prolonged progression-free survival (PFS) in patients with T-cell lymphomas.
Dr. Falchi presented the phase 2 results at 15-ICML. A total of 25 patients with newly diagnosed or relapsed/refractory PTCL were treated with AZA 300 mg daily on days 1-14 and romidepsin 14 mg/m2 on days 8, 15, and 22, every 35 days.
A total of 24 patients were evaluable for response. The ORR – the primary endpoint – was achieved in 14 patients (58%), and included 10 CRs and 4 PRs. Three additional patients had stable disease, and six patients experienced disease progression (response data for one patient was not complete at the time of the presentation).
In total, 11 of 16 patients with AITL/PTCL-TFH had responses, compared with 3 of 8 patients with other histologies.
A secondary analysis of 16 patients with information on mutational status showed that 10 of 12 patients with TET2 mutations (83%) had responses, including 8 CRs and 2 PRs. Two additional patients with TET2 mutations had disease progression. In contrast, among four patients without TET2 mutations, one had a CR, one a PR, and two had disease progression.
Of the 10 patients overall with CRs, 5 patients were receiving the combination in the first line, and 5 patients were receiving it for relapsed/refractory disease.
Median PFS among all patients was 8.7 months. The median overall survival has not been reached. Among patients with the AITL or PTCL-TFH subtypes, median PFS was 8.7 months, compared with 2.3 months for patients with other histologies.
The most frequent hematologic grade 3 or 4 adverse events were thrombocytopenia and neutropenia. The most frequent nonhematologic grade 3 or 4 events included lung infection and febrile neutropenia. Common grade 1 or 2 toxicities included anemia, diarrhea, fatigue, nausea, and vomiting. No patients discontinued therapy because of adverse events.
Dr. Falchi noted that a phase 1 trial evaluating the immune checkpoint inhibitor durvalumab (Imfinzi) with AZA or romidepsin alone or in combination, or pralatrexate and romidepsin, is currently recruiting.
Dr. Falchi reported having no financial disclosures. Other investigators reported funding from Celgene, which supported the study.
SOURCE: Falchi L et al. 15-ICML, Abstract 129.
LUGANO, SWITZERLAND – A combination of 5-azacytidine and romidepsin showed promising activity in patients with peripheral T cell lymphomas, particularly angioimmunoblastic T-cell lymphoma (AITL) and primary cutaneous follicular helper T-cell lymphoma (PTCL-TFH), results of a phase 2 study showed.
Of 16 patients with AITL or PTCL-TFH, 11 (69%) had a clinical response to the 5-azacytidine (AZA)/romidepsin combination, including 8 (50%) with complete responses (CRs), and 3 with partial responses (PRs), reported Lorenzo Falchi, MD, of Columbia University Medical Center and New York Presbyterian Hospital, New York, and colleagues.
“We show that the combination of oral AZA/romidepsin is remarkably active in patients with T-cell lymphomas. Clearly more patients with other subtypes are needed to better evaluate this combination,” Dr. Falchi said at the International Conference on Malignant Lymphoma.
The combination is intended to target epigenetic changes in PTCLs, which often bear mutations in TET2, DNMT3A, and IDH2. These mutations create global hypermethylation and cause transcriptional silencing of tumor suppressor genes, Dr. Falchi said.
Both histone deacetylase inhibitors such as romidepsin, and hypomethylating agents such as AZA have been shown to have single-agent activity against PTCL, and as previously reported at the 2018 T-cell Lymphoma Forum, the combination produced a higher overall response rate (ORR) and prolonged progression-free survival (PFS) in patients with T-cell lymphomas.
Dr. Falchi presented the phase 2 results at 15-ICML. A total of 25 patients with newly diagnosed or relapsed/refractory PTCL were treated with AZA 300 mg daily on days 1-14 and romidepsin 14 mg/m2 on days 8, 15, and 22, every 35 days.
A total of 24 patients were evaluable for response. The ORR – the primary endpoint – was achieved in 14 patients (58%), and included 10 CRs and 4 PRs. Three additional patients had stable disease, and six patients experienced disease progression (response data for one patient was not complete at the time of the presentation).
In total, 11 of 16 patients with AITL/PTCL-TFH had responses, compared with 3 of 8 patients with other histologies.
A secondary analysis of 16 patients with information on mutational status showed that 10 of 12 patients with TET2 mutations (83%) had responses, including 8 CRs and 2 PRs. Two additional patients with TET2 mutations had disease progression. In contrast, among four patients without TET2 mutations, one had a CR, one a PR, and two had disease progression.
Of the 10 patients overall with CRs, 5 patients were receiving the combination in the first line, and 5 patients were receiving it for relapsed/refractory disease.
Median PFS among all patients was 8.7 months. The median overall survival has not been reached. Among patients with the AITL or PTCL-TFH subtypes, median PFS was 8.7 months, compared with 2.3 months for patients with other histologies.
The most frequent hematologic grade 3 or 4 adverse events were thrombocytopenia and neutropenia. The most frequent nonhematologic grade 3 or 4 events included lung infection and febrile neutropenia. Common grade 1 or 2 toxicities included anemia, diarrhea, fatigue, nausea, and vomiting. No patients discontinued therapy because of adverse events.
Dr. Falchi noted that a phase 1 trial evaluating the immune checkpoint inhibitor durvalumab (Imfinzi) with AZA or romidepsin alone or in combination, or pralatrexate and romidepsin, is currently recruiting.
Dr. Falchi reported having no financial disclosures. Other investigators reported funding from Celgene, which supported the study.
SOURCE: Falchi L et al. 15-ICML, Abstract 129.
LUGANO, SWITZERLAND – A combination of 5-azacytidine and romidepsin showed promising activity in patients with peripheral T cell lymphomas, particularly angioimmunoblastic T-cell lymphoma (AITL) and primary cutaneous follicular helper T-cell lymphoma (PTCL-TFH), results of a phase 2 study showed.
Of 16 patients with AITL or PTCL-TFH, 11 (69%) had a clinical response to the 5-azacytidine (AZA)/romidepsin combination, including 8 (50%) with complete responses (CRs), and 3 with partial responses (PRs), reported Lorenzo Falchi, MD, of Columbia University Medical Center and New York Presbyterian Hospital, New York, and colleagues.
“We show that the combination of oral AZA/romidepsin is remarkably active in patients with T-cell lymphomas. Clearly more patients with other subtypes are needed to better evaluate this combination,” Dr. Falchi said at the International Conference on Malignant Lymphoma.
The combination is intended to target epigenetic changes in PTCLs, which often bear mutations in TET2, DNMT3A, and IDH2. These mutations create global hypermethylation and cause transcriptional silencing of tumor suppressor genes, Dr. Falchi said.
Both histone deacetylase inhibitors such as romidepsin, and hypomethylating agents such as AZA have been shown to have single-agent activity against PTCL, and as previously reported at the 2018 T-cell Lymphoma Forum, the combination produced a higher overall response rate (ORR) and prolonged progression-free survival (PFS) in patients with T-cell lymphomas.
Dr. Falchi presented the phase 2 results at 15-ICML. A total of 25 patients with newly diagnosed or relapsed/refractory PTCL were treated with AZA 300 mg daily on days 1-14 and romidepsin 14 mg/m2 on days 8, 15, and 22, every 35 days.
A total of 24 patients were evaluable for response. The ORR – the primary endpoint – was achieved in 14 patients (58%), and included 10 CRs and 4 PRs. Three additional patients had stable disease, and six patients experienced disease progression (response data for one patient was not complete at the time of the presentation).
In total, 11 of 16 patients with AITL/PTCL-TFH had responses, compared with 3 of 8 patients with other histologies.
A secondary analysis of 16 patients with information on mutational status showed that 10 of 12 patients with TET2 mutations (83%) had responses, including 8 CRs and 2 PRs. Two additional patients with TET2 mutations had disease progression. In contrast, among four patients without TET2 mutations, one had a CR, one a PR, and two had disease progression.
Of the 10 patients overall with CRs, 5 patients were receiving the combination in the first line, and 5 patients were receiving it for relapsed/refractory disease.
Median PFS among all patients was 8.7 months. The median overall survival has not been reached. Among patients with the AITL or PTCL-TFH subtypes, median PFS was 8.7 months, compared with 2.3 months for patients with other histologies.
The most frequent hematologic grade 3 or 4 adverse events were thrombocytopenia and neutropenia. The most frequent nonhematologic grade 3 or 4 events included lung infection and febrile neutropenia. Common grade 1 or 2 toxicities included anemia, diarrhea, fatigue, nausea, and vomiting. No patients discontinued therapy because of adverse events.
Dr. Falchi noted that a phase 1 trial evaluating the immune checkpoint inhibitor durvalumab (Imfinzi) with AZA or romidepsin alone or in combination, or pralatrexate and romidepsin, is currently recruiting.
Dr. Falchi reported having no financial disclosures. Other investigators reported funding from Celgene, which supported the study.
SOURCE: Falchi L et al. 15-ICML, Abstract 129.
REPORTING FROM 15-ICML
Bevacizumab or pemetrexed, but not both, efficacious for NSCLC maintenance
Single-agent therapy with either bevacizumab or pemetrexed is efficacious as maintenance therapy for patients with advanced nonsquamous non–small cell lung cancer (NSCLC), but the combination of the two agents offers no survival benefit and is more toxic, results of the randomized ECOG-ACRIN 5508 study show.
For patients with no disease progression after four cycles of induction chemotherapy who were assigned to one of three maintenance therapy strategies, there were no differences in overall survival between those randomized to monotherapy with pemetrexed or bevacizumab or to a combination of the two agents, although progression-free survival (PFS) was better with the combination, reported Suresh S. Ramalingam, MD, from the Winship Cancer Institute of Emory University, Atlanta, and colleagues.
The incidence of grade 3 or greater adverse events was also significantly higher with the combination, compared with bevacizumab monotherapy.
Even in the age of immune checkpoint inhibitor therapy in the front line, “[i]t is clear that maintenance therapy will remain an integral part of the treatment approach to advanced nonsquamous NSCLC. The results of ECOG-ACRIN 5508 support the use of either pemetrexed or bevacizumab as a single agent in this setting,” the investigators wrote in the Journal of Clinical Oncology.
Although the combination of bevacizumab and pemetrexed was associated with a significant improvement in PFS in a randomized trial, the three maintenance strategies have never before been directly compared, Dr. Ramalingam and associates noted.
In ECOG-ACRIN 5508, 1,516 patients with advanced nonsquamous NSCLC who had not received prior systemic therapy were given standard induction chemotherapy, consisting of carboplatin to an area under the curve of 6, paclitaxel 200 mg/m2, and bevacizumab 15 mg/kg for up to four cycles.
Patients without progression after four cycles (874) were randomly assigned to maintenance therapy with bevacizumab at 15 mg/kg , pemetrexed 500 mg/m2, or a combination of the two agents.
For the primary endpoint of overall survival, with bevacizumab serving as the control group for comparison, the investigators found that, at a median follow-up of 50.6 months, median survival was 15.9 months with pemetrexed, compared with 14.4 months with bevacizumab, a difference that was not statistically significant. Median survival with the combination was 16.4 months and was also not significantly different from bevacizumab.
Median PFS was 4.2 months and 5.1 months for the pemetrexed and bevacizumab groups, respectively, with no significant difference. In contrast, median was 7.5 months with the combination, which was significantly better than controls, with a hazard ratio of 0.67 (P less than .001).
Patients received a median of six maintenance therapy cycles for each of the single agents, and a median of eight for the combinations. The incidence of grade 3-4 toxicity was 29% with bevacizumab, 37% with pemetrexed, and 51% with the combination. The combination was associated with a significantly greater incidence of toxicities, compared with bevacizumab (P less than .001).
The study was supported by grants from the National Cancer Institute. Dr. Ramalingam reported a consulting/advisory role for bevacizumab maker Genentech/Roche and others. Multiple coauthors reported similar disclosures.
SOURCE: Ramalingam SS et al. J Clin Oncol. 2019 Jul 30. doi: 10.1200/JCO.19.01006.
Single-agent therapy with either bevacizumab or pemetrexed is efficacious as maintenance therapy for patients with advanced nonsquamous non–small cell lung cancer (NSCLC), but the combination of the two agents offers no survival benefit and is more toxic, results of the randomized ECOG-ACRIN 5508 study show.
For patients with no disease progression after four cycles of induction chemotherapy who were assigned to one of three maintenance therapy strategies, there were no differences in overall survival between those randomized to monotherapy with pemetrexed or bevacizumab or to a combination of the two agents, although progression-free survival (PFS) was better with the combination, reported Suresh S. Ramalingam, MD, from the Winship Cancer Institute of Emory University, Atlanta, and colleagues.
The incidence of grade 3 or greater adverse events was also significantly higher with the combination, compared with bevacizumab monotherapy.
Even in the age of immune checkpoint inhibitor therapy in the front line, “[i]t is clear that maintenance therapy will remain an integral part of the treatment approach to advanced nonsquamous NSCLC. The results of ECOG-ACRIN 5508 support the use of either pemetrexed or bevacizumab as a single agent in this setting,” the investigators wrote in the Journal of Clinical Oncology.
Although the combination of bevacizumab and pemetrexed was associated with a significant improvement in PFS in a randomized trial, the three maintenance strategies have never before been directly compared, Dr. Ramalingam and associates noted.
In ECOG-ACRIN 5508, 1,516 patients with advanced nonsquamous NSCLC who had not received prior systemic therapy were given standard induction chemotherapy, consisting of carboplatin to an area under the curve of 6, paclitaxel 200 mg/m2, and bevacizumab 15 mg/kg for up to four cycles.
Patients without progression after four cycles (874) were randomly assigned to maintenance therapy with bevacizumab at 15 mg/kg , pemetrexed 500 mg/m2, or a combination of the two agents.
For the primary endpoint of overall survival, with bevacizumab serving as the control group for comparison, the investigators found that, at a median follow-up of 50.6 months, median survival was 15.9 months with pemetrexed, compared with 14.4 months with bevacizumab, a difference that was not statistically significant. Median survival with the combination was 16.4 months and was also not significantly different from bevacizumab.
Median PFS was 4.2 months and 5.1 months for the pemetrexed and bevacizumab groups, respectively, with no significant difference. In contrast, median was 7.5 months with the combination, which was significantly better than controls, with a hazard ratio of 0.67 (P less than .001).
Patients received a median of six maintenance therapy cycles for each of the single agents, and a median of eight for the combinations. The incidence of grade 3-4 toxicity was 29% with bevacizumab, 37% with pemetrexed, and 51% with the combination. The combination was associated with a significantly greater incidence of toxicities, compared with bevacizumab (P less than .001).
The study was supported by grants from the National Cancer Institute. Dr. Ramalingam reported a consulting/advisory role for bevacizumab maker Genentech/Roche and others. Multiple coauthors reported similar disclosures.
SOURCE: Ramalingam SS et al. J Clin Oncol. 2019 Jul 30. doi: 10.1200/JCO.19.01006.
Single-agent therapy with either bevacizumab or pemetrexed is efficacious as maintenance therapy for patients with advanced nonsquamous non–small cell lung cancer (NSCLC), but the combination of the two agents offers no survival benefit and is more toxic, results of the randomized ECOG-ACRIN 5508 study show.
For patients with no disease progression after four cycles of induction chemotherapy who were assigned to one of three maintenance therapy strategies, there were no differences in overall survival between those randomized to monotherapy with pemetrexed or bevacizumab or to a combination of the two agents, although progression-free survival (PFS) was better with the combination, reported Suresh S. Ramalingam, MD, from the Winship Cancer Institute of Emory University, Atlanta, and colleagues.
The incidence of grade 3 or greater adverse events was also significantly higher with the combination, compared with bevacizumab monotherapy.
Even in the age of immune checkpoint inhibitor therapy in the front line, “[i]t is clear that maintenance therapy will remain an integral part of the treatment approach to advanced nonsquamous NSCLC. The results of ECOG-ACRIN 5508 support the use of either pemetrexed or bevacizumab as a single agent in this setting,” the investigators wrote in the Journal of Clinical Oncology.
Although the combination of bevacizumab and pemetrexed was associated with a significant improvement in PFS in a randomized trial, the three maintenance strategies have never before been directly compared, Dr. Ramalingam and associates noted.
In ECOG-ACRIN 5508, 1,516 patients with advanced nonsquamous NSCLC who had not received prior systemic therapy were given standard induction chemotherapy, consisting of carboplatin to an area under the curve of 6, paclitaxel 200 mg/m2, and bevacizumab 15 mg/kg for up to four cycles.
Patients without progression after four cycles (874) were randomly assigned to maintenance therapy with bevacizumab at 15 mg/kg , pemetrexed 500 mg/m2, or a combination of the two agents.
For the primary endpoint of overall survival, with bevacizumab serving as the control group for comparison, the investigators found that, at a median follow-up of 50.6 months, median survival was 15.9 months with pemetrexed, compared with 14.4 months with bevacizumab, a difference that was not statistically significant. Median survival with the combination was 16.4 months and was also not significantly different from bevacizumab.
Median PFS was 4.2 months and 5.1 months for the pemetrexed and bevacizumab groups, respectively, with no significant difference. In contrast, median was 7.5 months with the combination, which was significantly better than controls, with a hazard ratio of 0.67 (P less than .001).
Patients received a median of six maintenance therapy cycles for each of the single agents, and a median of eight for the combinations. The incidence of grade 3-4 toxicity was 29% with bevacizumab, 37% with pemetrexed, and 51% with the combination. The combination was associated with a significantly greater incidence of toxicities, compared with bevacizumab (P less than .001).
The study was supported by grants from the National Cancer Institute. Dr. Ramalingam reported a consulting/advisory role for bevacizumab maker Genentech/Roche and others. Multiple coauthors reported similar disclosures.
SOURCE: Ramalingam SS et al. J Clin Oncol. 2019 Jul 30. doi: 10.1200/JCO.19.01006.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
High EPclin score equals chemo benefit in ER+/HER2– breast cancer
A study modeling outcomes for women with estrogen receptor–positive, HER2-negative breast cancer indicates that those with the highest score on a clinicomolecular test would be most likely to benefit from chemotherapy to reduce the risk of distant recurrence.
The model, created by William Gradishar, MD, from the Robert H. Lurie Comprehensive Cancer Center in Chicago, and colleagues, uses validated 10-year risk of distant breast recurrences as a function of the EndoPredict (EPclin) 12-gene clinicomolecular assay score.
The model suggests that for patients with a low EPclin score, chemotherapy would offer no additional benefit over endocrine therapy, whereas those with high scores would have an increase in recurrence-free survival with chemotherapy.
“Overall, this demonstrates that EndoPredict provides guidance on the expected absolute benefit from adjuvant chemotherapy in addition to prognostic information for patients with ER-positive, HER2-negative early-stage breast cancer. Therefore, EndoPredict can identify patients likely to benefit sufficiently from adjuvant chemotherapy to justify associated toxicities,” Dr. Gradishar and associates wrote in Precision Oncology.
The assay has previously been shown to accurately predict the risk of distant metastases in patients with estrogen receptor–positive, human epidermal growth factor receptor–2 negative (ER+/HER2–) breast cancer, but the ability to predict absolute benefit of chemotherapy is less clear, and it would be unethical to conduct a randomized trial with a no-chemotherapy arm, the investigators noted.
Instead, the investigators created a mathematical model to try to answer the question. They determined the average relative benefit of chemotherapy for reducing distant recurrence using a published meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group, and they estimated absolute chemotherapy benefit differences across a range of interaction strengths between relative chemotherapy benefit and the EPclin score. Finally, they calculated average absolute benefit for patients with high and low EPclin scores using the distribution of scores in 2,185 samples tested by Myriad Genetics, maker of the assay.
They found that the average expected absolute benefit of chemotherapy treatment for patients with a low EPclin score was 1.8% assuming no interaction between prognostic factors and chemotherapy benefit, and 1.5% for maximal interaction, suggesting no significant added benefit from chemotherapy.
In contrast, for patients with a high EPclin score, the absolute benefit assuming no interaction was 5.3% and the benefit assuming maximal interaction was 7.3%.
“Overall, these data demonstrate that high EPclin scores are associated with maximal predicted chemotherapy benefit, and low EPclin scores are associated with no clinically meaningful benefit. This association is irrespective of interaction strength between EPclin and predicted chemotherapy benefit, and the impact of any interaction on absolute benefit is much smaller than the ability to accurately estimate absolute risk,” they wrote.
The study was supported by Myriad Genetics. Dr. Gradishar disclosed consulting or advisory roles with Genentech and Roche. Five of the coauthors are employees of Myriad Genetics or Myriad International.
SOURCE: Gradishar W et al. Precision Oncology. 2016 Aug. 6. doi: 10.1200/PO.18.00361.
A study modeling outcomes for women with estrogen receptor–positive, HER2-negative breast cancer indicates that those with the highest score on a clinicomolecular test would be most likely to benefit from chemotherapy to reduce the risk of distant recurrence.
The model, created by William Gradishar, MD, from the Robert H. Lurie Comprehensive Cancer Center in Chicago, and colleagues, uses validated 10-year risk of distant breast recurrences as a function of the EndoPredict (EPclin) 12-gene clinicomolecular assay score.
The model suggests that for patients with a low EPclin score, chemotherapy would offer no additional benefit over endocrine therapy, whereas those with high scores would have an increase in recurrence-free survival with chemotherapy.
“Overall, this demonstrates that EndoPredict provides guidance on the expected absolute benefit from adjuvant chemotherapy in addition to prognostic information for patients with ER-positive, HER2-negative early-stage breast cancer. Therefore, EndoPredict can identify patients likely to benefit sufficiently from adjuvant chemotherapy to justify associated toxicities,” Dr. Gradishar and associates wrote in Precision Oncology.
The assay has previously been shown to accurately predict the risk of distant metastases in patients with estrogen receptor–positive, human epidermal growth factor receptor–2 negative (ER+/HER2–) breast cancer, but the ability to predict absolute benefit of chemotherapy is less clear, and it would be unethical to conduct a randomized trial with a no-chemotherapy arm, the investigators noted.
Instead, the investigators created a mathematical model to try to answer the question. They determined the average relative benefit of chemotherapy for reducing distant recurrence using a published meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group, and they estimated absolute chemotherapy benefit differences across a range of interaction strengths between relative chemotherapy benefit and the EPclin score. Finally, they calculated average absolute benefit for patients with high and low EPclin scores using the distribution of scores in 2,185 samples tested by Myriad Genetics, maker of the assay.
They found that the average expected absolute benefit of chemotherapy treatment for patients with a low EPclin score was 1.8% assuming no interaction between prognostic factors and chemotherapy benefit, and 1.5% for maximal interaction, suggesting no significant added benefit from chemotherapy.
In contrast, for patients with a high EPclin score, the absolute benefit assuming no interaction was 5.3% and the benefit assuming maximal interaction was 7.3%.
“Overall, these data demonstrate that high EPclin scores are associated with maximal predicted chemotherapy benefit, and low EPclin scores are associated with no clinically meaningful benefit. This association is irrespective of interaction strength between EPclin and predicted chemotherapy benefit, and the impact of any interaction on absolute benefit is much smaller than the ability to accurately estimate absolute risk,” they wrote.
The study was supported by Myriad Genetics. Dr. Gradishar disclosed consulting or advisory roles with Genentech and Roche. Five of the coauthors are employees of Myriad Genetics or Myriad International.
SOURCE: Gradishar W et al. Precision Oncology. 2016 Aug. 6. doi: 10.1200/PO.18.00361.
A study modeling outcomes for women with estrogen receptor–positive, HER2-negative breast cancer indicates that those with the highest score on a clinicomolecular test would be most likely to benefit from chemotherapy to reduce the risk of distant recurrence.
The model, created by William Gradishar, MD, from the Robert H. Lurie Comprehensive Cancer Center in Chicago, and colleagues, uses validated 10-year risk of distant breast recurrences as a function of the EndoPredict (EPclin) 12-gene clinicomolecular assay score.
The model suggests that for patients with a low EPclin score, chemotherapy would offer no additional benefit over endocrine therapy, whereas those with high scores would have an increase in recurrence-free survival with chemotherapy.
“Overall, this demonstrates that EndoPredict provides guidance on the expected absolute benefit from adjuvant chemotherapy in addition to prognostic information for patients with ER-positive, HER2-negative early-stage breast cancer. Therefore, EndoPredict can identify patients likely to benefit sufficiently from adjuvant chemotherapy to justify associated toxicities,” Dr. Gradishar and associates wrote in Precision Oncology.
The assay has previously been shown to accurately predict the risk of distant metastases in patients with estrogen receptor–positive, human epidermal growth factor receptor–2 negative (ER+/HER2–) breast cancer, but the ability to predict absolute benefit of chemotherapy is less clear, and it would be unethical to conduct a randomized trial with a no-chemotherapy arm, the investigators noted.
Instead, the investigators created a mathematical model to try to answer the question. They determined the average relative benefit of chemotherapy for reducing distant recurrence using a published meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group, and they estimated absolute chemotherapy benefit differences across a range of interaction strengths between relative chemotherapy benefit and the EPclin score. Finally, they calculated average absolute benefit for patients with high and low EPclin scores using the distribution of scores in 2,185 samples tested by Myriad Genetics, maker of the assay.
They found that the average expected absolute benefit of chemotherapy treatment for patients with a low EPclin score was 1.8% assuming no interaction between prognostic factors and chemotherapy benefit, and 1.5% for maximal interaction, suggesting no significant added benefit from chemotherapy.
In contrast, for patients with a high EPclin score, the absolute benefit assuming no interaction was 5.3% and the benefit assuming maximal interaction was 7.3%.
“Overall, these data demonstrate that high EPclin scores are associated with maximal predicted chemotherapy benefit, and low EPclin scores are associated with no clinically meaningful benefit. This association is irrespective of interaction strength between EPclin and predicted chemotherapy benefit, and the impact of any interaction on absolute benefit is much smaller than the ability to accurately estimate absolute risk,” they wrote.
The study was supported by Myriad Genetics. Dr. Gradishar disclosed consulting or advisory roles with Genentech and Roche. Five of the coauthors are employees of Myriad Genetics or Myriad International.
SOURCE: Gradishar W et al. Precision Oncology. 2016 Aug. 6. doi: 10.1200/PO.18.00361.
FROM PRECISION ONCOLOGY
ctDNA may predict relapse risk in early breast cancer
Following therapy with curative intent for early-stage primary breast care, the presence of circulating tumor DNA may identify those patients at high risk for relapse, investigators reported.
Among 101 women treated for early-stage breast cancer and followed for a median of nearly 3 years, detection of circulating tumor DNA (ctDNA) during follow-up was associated with a 2,400% increased risk for relapse, and detection of ctDNA at diagnosis but before treatment was associated with a nearly 500% risk, wrote Isaac Garcia-Murillas, PhD, of the Institute of Cancer Research, London, and colleagues.
“Prospective clinical trials are now required to assess whether detection of ctDNA can improve outcomes in patients, and a phase 2 interventional trial in TNBC [triple-negative breast cancer] has been initiated. This trial may develop a new treatment paradigm for treating breast cancer, in which treatment is initiated at molecular relapse without waiting for symptomatic incurable metastatic disease to develop,” they wrote in JAMA Oncology.
The investigators conducted a prospective, multicenter validation study of samples collected from women with early-stage breast cancer irrespective of hormone-receptor or HER2 status. The patients were scheduled for neoadjuvant chemotherapy followed by surgery, or surgery followed by adjuvant therapy.
Of 170 women recruited, 101 had tumors with identified mutations and were included in the main cohort. The investigators also conducted secondary analyses with patients in this cohort plus an additional 43 women who had participated in a previous proof-of-principle study.
They first sequenced tumor DNA to identify somatic mutations in primary tumors that could then be tracked using a breast cancer driver gene panel. For each sample, a personalized digital polymerase chain reaction (dPCR) assay was created to identify the mutations in plasma samples.
The plasma samples were collected every 3 months for the first year of follow-up, then every 6 months thereafter.
In the main cohort, the median age was 54 years, and the median follow-up was 35.5 months. The investigators found that, for the primary endpoint of relapse-free survival, ctDNA was associated with a hazard ratio for relapse of 25.2 (P less than .001). Detection of ctDNA in samples taken at the time of diagnosis was also associated with worse relapse-free survival, with an HR of 5.8 (P = .01).
In a secondary analysis, ctDNA detection preceded clinical relapse by a median of 10.7 months, and was associated with relapse in all breast cancer subtypes.
Of 29 patients who experienced a relapse, 22 of 23 with extracranial distant metastatic relapse had prior ctDNA detection.
The remaining six patients experienced relapse without ctDNA detection either before or at the time of relapse. Each of these six patients had a relapse at a single site: in the brain in three patients (with no extracranial relapses), in the ovaries in one patient, and solitary locoregional relapses in two patients.
The investigators acknowledged that the results “demonstrate clinical validity for ctDNA mutation tracking with dPCR but do not demonstrate clinical utility. Without evidence that mutation tracking can improve patient outcome, our results should not be recommended yet for routine clinical practice.”
The study was funded by Breast Cancer Now, Le Cure, and National Institute for Health Research funding to the Biomedical Research Centre at the Royal Marsden Hospital and the Institute of Cancer Research. Dr. Garcia-Murillas had no disclosures. Multiple coauthors reported grants and/or fees from various pharmaceutical companies.
SOURCE: Garcia-Murillias I et al. JAMA Oncol. 2019 Aug 1. doi: 10.1001/jamaoncol.2019.1838.
Although a strength of the study is the inclusion of all subtypes of breast cancer, Garcia-Murillas et al. found that the ability to detect circulating tumor DNA (ctDNA) was likely influenced by biologic factors, including receptor subtypes. The study had a median follow-up of 36.3 months (in the combined cohorts); however, because the risk of relapse for luminal estrogen receptor–positive breast cancers is known to persist for decades, these data cannot be applied to late recurrences, which are largely derived from luminal estrogen receptor–positive disease. Longer-term follow-up with serial sampling of ctDNA will be required to demonstrate validation for this patient population.
As addressed by the authors, the clinical utility for ctDNA detection in early-stage breast cancer is still unknown. Proof of clinical utility can be accomplished through prospective, multi-institutional trials randomizing ctDNA-positive patients to therapy versus control and demonstrating reductions in disease-free and overall survival. The use of real-time testing and rapid turnaround time may prove to be challenging if we are to implement ctDNA testing as an integral biomarker for clinical decision making. However, the study by Garcia-Murillas et al. is a major step forward in reaching this goal because the results suggest the feasibility and clinical validation of ctDNA for patients with early-stage disease.
Remarks from Swathi Karthikeyan, MS, of Johns Hopkins University, Baltimore, and Ben Ho Park, MD, PhD, of Johns Hopkins and Vanderbilt University, Nashville, Tenn., are condensed and adapted from an editorial accompanying the study by Garcia-Murillas et al. Dr. Park reported royalties from Horizon Discovery, serving as a scientific advisory board member for Loxo Oncology, having an ownership interest in Loxo Oncology, serving as a recent paid consultant for Foundation Medicine, Jackson Laboratories, H3 Biomedicine, Casdin Capital, Roche, Eli Lilly, and Astra Zeneca, and having research contracts with Abbvie, Foundation Medicine, and Pfizer. No other disclosures were reported.
Although a strength of the study is the inclusion of all subtypes of breast cancer, Garcia-Murillas et al. found that the ability to detect circulating tumor DNA (ctDNA) was likely influenced by biologic factors, including receptor subtypes. The study had a median follow-up of 36.3 months (in the combined cohorts); however, because the risk of relapse for luminal estrogen receptor–positive breast cancers is known to persist for decades, these data cannot be applied to late recurrences, which are largely derived from luminal estrogen receptor–positive disease. Longer-term follow-up with serial sampling of ctDNA will be required to demonstrate validation for this patient population.
As addressed by the authors, the clinical utility for ctDNA detection in early-stage breast cancer is still unknown. Proof of clinical utility can be accomplished through prospective, multi-institutional trials randomizing ctDNA-positive patients to therapy versus control and demonstrating reductions in disease-free and overall survival. The use of real-time testing and rapid turnaround time may prove to be challenging if we are to implement ctDNA testing as an integral biomarker for clinical decision making. However, the study by Garcia-Murillas et al. is a major step forward in reaching this goal because the results suggest the feasibility and clinical validation of ctDNA for patients with early-stage disease.
Remarks from Swathi Karthikeyan, MS, of Johns Hopkins University, Baltimore, and Ben Ho Park, MD, PhD, of Johns Hopkins and Vanderbilt University, Nashville, Tenn., are condensed and adapted from an editorial accompanying the study by Garcia-Murillas et al. Dr. Park reported royalties from Horizon Discovery, serving as a scientific advisory board member for Loxo Oncology, having an ownership interest in Loxo Oncology, serving as a recent paid consultant for Foundation Medicine, Jackson Laboratories, H3 Biomedicine, Casdin Capital, Roche, Eli Lilly, and Astra Zeneca, and having research contracts with Abbvie, Foundation Medicine, and Pfizer. No other disclosures were reported.
Although a strength of the study is the inclusion of all subtypes of breast cancer, Garcia-Murillas et al. found that the ability to detect circulating tumor DNA (ctDNA) was likely influenced by biologic factors, including receptor subtypes. The study had a median follow-up of 36.3 months (in the combined cohorts); however, because the risk of relapse for luminal estrogen receptor–positive breast cancers is known to persist for decades, these data cannot be applied to late recurrences, which are largely derived from luminal estrogen receptor–positive disease. Longer-term follow-up with serial sampling of ctDNA will be required to demonstrate validation for this patient population.
As addressed by the authors, the clinical utility for ctDNA detection in early-stage breast cancer is still unknown. Proof of clinical utility can be accomplished through prospective, multi-institutional trials randomizing ctDNA-positive patients to therapy versus control and demonstrating reductions in disease-free and overall survival. The use of real-time testing and rapid turnaround time may prove to be challenging if we are to implement ctDNA testing as an integral biomarker for clinical decision making. However, the study by Garcia-Murillas et al. is a major step forward in reaching this goal because the results suggest the feasibility and clinical validation of ctDNA for patients with early-stage disease.
Remarks from Swathi Karthikeyan, MS, of Johns Hopkins University, Baltimore, and Ben Ho Park, MD, PhD, of Johns Hopkins and Vanderbilt University, Nashville, Tenn., are condensed and adapted from an editorial accompanying the study by Garcia-Murillas et al. Dr. Park reported royalties from Horizon Discovery, serving as a scientific advisory board member for Loxo Oncology, having an ownership interest in Loxo Oncology, serving as a recent paid consultant for Foundation Medicine, Jackson Laboratories, H3 Biomedicine, Casdin Capital, Roche, Eli Lilly, and Astra Zeneca, and having research contracts with Abbvie, Foundation Medicine, and Pfizer. No other disclosures were reported.
Following therapy with curative intent for early-stage primary breast care, the presence of circulating tumor DNA may identify those patients at high risk for relapse, investigators reported.
Among 101 women treated for early-stage breast cancer and followed for a median of nearly 3 years, detection of circulating tumor DNA (ctDNA) during follow-up was associated with a 2,400% increased risk for relapse, and detection of ctDNA at diagnosis but before treatment was associated with a nearly 500% risk, wrote Isaac Garcia-Murillas, PhD, of the Institute of Cancer Research, London, and colleagues.
“Prospective clinical trials are now required to assess whether detection of ctDNA can improve outcomes in patients, and a phase 2 interventional trial in TNBC [triple-negative breast cancer] has been initiated. This trial may develop a new treatment paradigm for treating breast cancer, in which treatment is initiated at molecular relapse without waiting for symptomatic incurable metastatic disease to develop,” they wrote in JAMA Oncology.
The investigators conducted a prospective, multicenter validation study of samples collected from women with early-stage breast cancer irrespective of hormone-receptor or HER2 status. The patients were scheduled for neoadjuvant chemotherapy followed by surgery, or surgery followed by adjuvant therapy.
Of 170 women recruited, 101 had tumors with identified mutations and were included in the main cohort. The investigators also conducted secondary analyses with patients in this cohort plus an additional 43 women who had participated in a previous proof-of-principle study.
They first sequenced tumor DNA to identify somatic mutations in primary tumors that could then be tracked using a breast cancer driver gene panel. For each sample, a personalized digital polymerase chain reaction (dPCR) assay was created to identify the mutations in plasma samples.
The plasma samples were collected every 3 months for the first year of follow-up, then every 6 months thereafter.
In the main cohort, the median age was 54 years, and the median follow-up was 35.5 months. The investigators found that, for the primary endpoint of relapse-free survival, ctDNA was associated with a hazard ratio for relapse of 25.2 (P less than .001). Detection of ctDNA in samples taken at the time of diagnosis was also associated with worse relapse-free survival, with an HR of 5.8 (P = .01).
In a secondary analysis, ctDNA detection preceded clinical relapse by a median of 10.7 months, and was associated with relapse in all breast cancer subtypes.
Of 29 patients who experienced a relapse, 22 of 23 with extracranial distant metastatic relapse had prior ctDNA detection.
The remaining six patients experienced relapse without ctDNA detection either before or at the time of relapse. Each of these six patients had a relapse at a single site: in the brain in three patients (with no extracranial relapses), in the ovaries in one patient, and solitary locoregional relapses in two patients.
The investigators acknowledged that the results “demonstrate clinical validity for ctDNA mutation tracking with dPCR but do not demonstrate clinical utility. Without evidence that mutation tracking can improve patient outcome, our results should not be recommended yet for routine clinical practice.”
The study was funded by Breast Cancer Now, Le Cure, and National Institute for Health Research funding to the Biomedical Research Centre at the Royal Marsden Hospital and the Institute of Cancer Research. Dr. Garcia-Murillas had no disclosures. Multiple coauthors reported grants and/or fees from various pharmaceutical companies.
SOURCE: Garcia-Murillias I et al. JAMA Oncol. 2019 Aug 1. doi: 10.1001/jamaoncol.2019.1838.
Following therapy with curative intent for early-stage primary breast care, the presence of circulating tumor DNA may identify those patients at high risk for relapse, investigators reported.
Among 101 women treated for early-stage breast cancer and followed for a median of nearly 3 years, detection of circulating tumor DNA (ctDNA) during follow-up was associated with a 2,400% increased risk for relapse, and detection of ctDNA at diagnosis but before treatment was associated with a nearly 500% risk, wrote Isaac Garcia-Murillas, PhD, of the Institute of Cancer Research, London, and colleagues.
“Prospective clinical trials are now required to assess whether detection of ctDNA can improve outcomes in patients, and a phase 2 interventional trial in TNBC [triple-negative breast cancer] has been initiated. This trial may develop a new treatment paradigm for treating breast cancer, in which treatment is initiated at molecular relapse without waiting for symptomatic incurable metastatic disease to develop,” they wrote in JAMA Oncology.
The investigators conducted a prospective, multicenter validation study of samples collected from women with early-stage breast cancer irrespective of hormone-receptor or HER2 status. The patients were scheduled for neoadjuvant chemotherapy followed by surgery, or surgery followed by adjuvant therapy.
Of 170 women recruited, 101 had tumors with identified mutations and were included in the main cohort. The investigators also conducted secondary analyses with patients in this cohort plus an additional 43 women who had participated in a previous proof-of-principle study.
They first sequenced tumor DNA to identify somatic mutations in primary tumors that could then be tracked using a breast cancer driver gene panel. For each sample, a personalized digital polymerase chain reaction (dPCR) assay was created to identify the mutations in plasma samples.
The plasma samples were collected every 3 months for the first year of follow-up, then every 6 months thereafter.
In the main cohort, the median age was 54 years, and the median follow-up was 35.5 months. The investigators found that, for the primary endpoint of relapse-free survival, ctDNA was associated with a hazard ratio for relapse of 25.2 (P less than .001). Detection of ctDNA in samples taken at the time of diagnosis was also associated with worse relapse-free survival, with an HR of 5.8 (P = .01).
In a secondary analysis, ctDNA detection preceded clinical relapse by a median of 10.7 months, and was associated with relapse in all breast cancer subtypes.
Of 29 patients who experienced a relapse, 22 of 23 with extracranial distant metastatic relapse had prior ctDNA detection.
The remaining six patients experienced relapse without ctDNA detection either before or at the time of relapse. Each of these six patients had a relapse at a single site: in the brain in three patients (with no extracranial relapses), in the ovaries in one patient, and solitary locoregional relapses in two patients.
The investigators acknowledged that the results “demonstrate clinical validity for ctDNA mutation tracking with dPCR but do not demonstrate clinical utility. Without evidence that mutation tracking can improve patient outcome, our results should not be recommended yet for routine clinical practice.”
The study was funded by Breast Cancer Now, Le Cure, and National Institute for Health Research funding to the Biomedical Research Centre at the Royal Marsden Hospital and the Institute of Cancer Research. Dr. Garcia-Murillas had no disclosures. Multiple coauthors reported grants and/or fees from various pharmaceutical companies.
SOURCE: Garcia-Murillias I et al. JAMA Oncol. 2019 Aug 1. doi: 10.1001/jamaoncol.2019.1838.
FROM JAMA ONCOLOGY