Results From the Phase 3 CheckMate 238 Trial for Stage III/IV Melanoma

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Rapids Readouts: Phase 3 CheckMate 238 Trial 

Jeffrey S. Weber, MD, PhD, deputy director and co-director of the melanoma program, Laura and Isaac Perlmutter Professor of Oncology, Department of Medicine, NYU Langone’s Perlmutter Cancer Center, 2016 Giant of Cancer Care

 in Melanoma, discusses emerging immunotherapy combinations in melanoma.

The combination of ipilimumab (Yervoy) and nivolumab (Opdivo) is being evaluated in the ongoing phase III CheckMate-915 trial, which enrolled over 1,900 patients with resectable stage IIIB/C/D or stage IV melanoma. Patients will be randomized to receive either the combination or nivolumab alone, says Weber.

Notably, the trial has 2 cohorts of patients: patients with PD-L1—positive tumors and those with PD-L1–negative tumors. The PD-L1–negative cohort was unblinded a couple of months ago; those patients did not benefit from the combination. However, because at least half of the patients enrolled on the trial have PD-L1–positive tumors, the trial will continue, says Weber. The results for this cohort are expected at the end of 2020 or in early 2021, concludes Weber.

Jeffrey S. Weber, MD, PhD, deputy director and co-director of the melanoma program, Laura and Isaac Perlmutter Professor of Oncology, Department of Medicine, NYU Langone’s Perlmutter Cancer Center, 2016 Giant of Cancer Care® in Melanoma, discusses emerging immunotherapy combinations in melanoma.

Dr. Weber on Emerging Immunotherapy Combinations in Melanoma

, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, 

 covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

But today, we had the pleasure of sitting down with Jeffrey S. Weber, MD, PhD, deputy director of NYU Langone Health’s Perlmutter Cancer Center, where is also codirector of the Melanoma Research Program. Dr. Weber has been instrumental in key immunotherapeutic developments in oncology with a special focus in melanoma. To start, he’s led several studies of targeted therapies with dabrafenib and trametinib in the disease, as well as combinations with nivolumab and ipilimumab. He’s also aimed to advance a deeper understanding of immunotherapy-related adverse events and how to best manage them, as well as explore novel immunotherapy concepts.

For these reasons and many others, Weber was recognized as the 2016 

In our exclusive interview, Dr. Weber shared with us his journey into the melanoma field and the lessons he has learned along the way, some of the key studies that have significantly impacted his career and clinical practice, and what lies ahead in the melanoma pipeline.

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In our exclusive interview, Jeffrey S. Weber, MD, PhD, shares with us his journey into the melanoma field and the lessons he has learned along the way, some of the key studies that have significantly impacted his career and clinical practice, and what lies ahead in the melanoma pipeline.

Jeffrey Weber, MD, PhD: Charting New Territories in Melanoma

Jeffrey S. Weber, MD, PhD, deputy director and co-director of the melanoma program, NYU Langone’s Perlmutter Cancer Center, 2016 Giant of Cancer Care® in Melanoma, discusses adjuvant approaches in stage III melanoma.

Dabrafenib (Tafinlar) and trametinib (Mekinist) was the first BRAF/MEK combination that was approved for patients with metastatic melanoma. The combination showed a significantly prolonged survival compared with single-agent dabrafenib or vemurafenib (Zelboraf). Subsequently, the combination of vemurafenib and cobimetinib (Cotellic) was approved in the metastatic setting. The combination of encorafenib (Braftovi)and binimetinib (Mektovi) is also approved in the metastatic setting. The phase III COMBI-AD trial was the first trial that evaluated these drugs in the adjuvant setting.

The double-blind, placebo-controlled trial enrolled 870 patients with resected, stage III melanoma who harbored BRAF V600E or V600K mutations. Patients were randomized to the combination of dabrafenib and trametinib or two matched placebo tablets. The estimated 3-year rate of relapse-free survival was 58% in the combination arm versus 39% in the placebo arm (HR, 0.47; 95% CI, 0.39-0.58; 

 <.001). The 3-year overall survival rate was 86% in the combination arm versus 77% in the placebo arm (HR, 0.57; 95% CI,0.42-0.79; 

The most common reason for treatment discontinuation was the occurrence of adverse events and disease recurrence in the combination and placebo arms, respectively. Regardless, dabrafenib and trametinib is a beneficial treatment for patients with resected, stage III melanoma, concludes Weber.

Jeffrey S. Weber, MD, PhD, discusses adjuvant approaches in stage III melanoma.
 

Dr. Weber on Adjuvant Approaches in Stage III Melanoma

Jeffrey S. Weber, MD, PhD, deputy director and co-director of the Melanoma Program, NYU Langone’s Perlmutter Cancer Center, 2016 Giant of Cancer Care

 in Melanoma, discusses the phase III EORTC1325/KEYNOTE-054 trial, which looked at adjuvant pembrolizumab (Keytruda) in patients with stage III melanoma.

In the trial, investigators evaluated pembrolizumab versus placebo as adjuvant therapy in patients with stage III resected high-risk melanoma, as determined by the American Joint Committee on Cancer seventh edition staging criteria, explains Weber. The primary endpoint was recurrence-free survival (RFS). Data from the trial, which were published in 

 as adjuvant therapy in this indication in February 2019, says Weber.

At a median follow-up of 15 months, pembrolizumab showed a 43% reduction in the risk of disease recurrence or death compared with placebo in patients with resected, high-risk stage III melanoma. Notably, the 18-month RFS rate was 71.4% with pembrolizumab versus 53.2% with placebo. These data demonstrate that pembrolizumab is an effective adjuvant therapy for patients with stage III melanoma, concludes Weber.

Jeffrey S. Weber, MD, PhD, discusses the phase III EORTC1325/KEYNOTE-054 trial, which looked at adjuvant pembrolizumab in patients with stage III melanoma.

Dr. Weber on Adjuvant Pembrolizumab in Melanoma

Jeffrey S. Weber, MD, PhD, deputy director and co-director of the Melanoma Program, NYU Langone’s Perlmutter Cancer Center, 2016 Giant of Cancer Care® in Melanoma, discusses biomarker research in the CheckMate-238 trial looking at patients with resected stage III/IV melanoma.

For the first time, researchers collected biomarker data from a significant portion of patients from the CheckMate-238 trial. Researchers looked at 3 tumor-related biomarkers: tumor mutational burden (TMB) by whole-exome sequencing, interferon-gamma—induced genes by shotgun sequencing, and CD8+ T-cell infiltrate by histochemistry, explains Weber.

Additionally, for the first time there was a peripheral blood marker consisting of monocytic myeloid-derived suppressor cells (MDSC) in the peripheral blood by flow cytometry, according to Weber. The tumor markers are above the median for peripheral blood suppressive marker, showing a clear association with outcome for the nivolumab (Opdivo) and ipilimumab (Yervoy) arms, says Weber. The most potent biomarkers with the best hazard ratios were the interferon-gamma—induced genes and TMB.

In combinations of typically independent biomarkers, elevation in TMB above the median, elevation of the interferon-gamma—induced genes above the median, or depression of MDSC resulted in a better hazard ratio for outcome, Weber concludes.

Jeffrey S. Weber, MD, PhD, discusses biomarker research in the CheckMate-238 trial looking at patients with resected stage III/IV melanoma.

Dr. Weber on Biomarker Data From CheckMate-238 for Melanoma

Jeffrey S. Weber, MD, PhD, deputy director and co-director of the Melanoma Research Program, NYU Langone’s Perlmutter Cancer Center, 2016 Giant of Cancer Care

 in Melanoma, discusses the future of checkpoint inhibitors in melanoma. 

Currently, nivolumab (Opdivo), ipilimumab (Yervoy), and pembrolizumab (Keytruda) are approved checkpoint inhibitors in melanoma, explains Weber. The phase III IMspire170 trial evaluated the combination of atezolizumab (Tecentriq) and cobimetinib (Cotellic) in patients with treatment-naïve 

 V600 wild-type melanoma. However, the combination did not meet the trial’s primary endpoint of progression-free survival in patients with 

Although the trial was negative, there are several ongoing phase III studies, one of which is evaluating the combination of a LAG-3-targeting monoclonal antibody and nivolumab versus nivolumab alone. Moreover, the combination of bempegaldesleukin (NKTR-214), a CD122-preferential interleukin-2 pathway agonist, is being tested in combination with nivolumab versus nivolumab alone, Weber concludes.

Jeffrey S. Weber, MD, PhD, discusses the future of checkpoint inhibitors in melanoma. 
 

Dr. Weber on the Future of Checkpoint Inhibitors in Melanoma

Jeffrey S. Weber, MD, PhD, deputy director and co-director of the Melanoma Research Program, NYU Langone’s Perlmutter Cancer Center, 2016 Giant of Cancer Care® in Melanoma, shares toxicity data from the randomized, double-blind, phase III CheckMate-238 trial in resected stage III or IV melanoma.

The toxicity data have not been updated since the presentation on the trial at the 2017 ESMO Congress, which included all patients who were followed up to 100 days after treatment, says Weber.

At the meeting, Weber reported that 8% of patients in the nivolumab (Opdivo) arm had to stop treatment due to toxicity. Furthermore, around 10% to 15% of patients experienced grade 3 or 4 immune-related adverse events that were determined to be of significance. The data, according to Weber, were in line with what would be seen in the metastatic setting when single-agent PD-1 drugs like nivolumab or pembrolizumab (Keytruda) are used, Weber concludes.

Jeffrey S. Weber, MD, PhD, shares toxicity data from the randomized, double-blind, phase III CheckMate-238 trial in resected stage III or IV melanoma.

Dr. Weber on Toxicity Data From CheckMate-238 Trial in Melanoma

Jeffrey S. Weber, MD, PhD, deputy director and co-director of the Melanoma Program, NYU Langone’s Perlmutter Cancer Center, 2016 Giant of Cancer Care in Melanoma, discusses the rationale behind the randomized, double-blind, phase III CheckMate-238 trial in resected stage III or IV melanoma. 

In 2014, the FDA approved nivolumab (Opdivo) and pembrolizumab (Keytruda) for the treatment of patients with metastatic melanoma. Given the activity of these agents in the metastatic setting, investigators wanted to evaluate their activity in the adjuvant setting. To that end, Weber conducted a pilot study of 33 patients with resected stage IIIC or IV melanoma who received adjuvant treatment with a peptide vaccine and nivolumab.

Based on highly encouraging data from the pilot study, the CheckMate-238 trial was designed to explore these drugs on a larger scale. Ultimately, results from the CheckMate-238 trial demonstrated an improvement in relapse-free survival with adjuvant nivolumab versus ipilimumab (Yervoy) in patients with resected stage III or IV melanoma.

Jeffrey S. Weber, MD, PhD, discusses the rationale behind the randomized, double-blind, phase III CheckMate-238 trial in resected stage III or IV melanoma. 

Dr. Weber on Rationale for the CheckMate-238 Trial in Melanoma

Jeffrey S. Weber, MD, PhD, deputy director and co-director of the Melanoma Program, NYU Langone’s Perlmutter Cancer Center, 2016 Giant of Cancer Care in Melanoma, discusses the updated analysis of the phase III CheckMate-238 trial in patients with resected stage III/IV melanoma.

Initials results of the trial demonstrated an improvement in relapse-free survival (RFS) with nivolumab (Opdivo) versus ipilimumab (Yervoy) in patients with resected stage III/IV melanoma. The efficacy of nivolumab was maintained at 24 months of follow-up. At 36 months of follow-up, nivolumab showed a sustained benefit in RFS that compared favorably to what was seen with ipilimumab (HR, 0.68; 

&thinsp;<0.0001), says Weber. In addition to RFS, updated distant metastasis-free survival data similarly demonstrated an improvement with nivolumab versus ipilimumab (HR, 0.78; 

At 3 years, the RFS rates were 58% in the nivolumab arm and 45% in the ipilimumab arm. Moreover, interferon-gamma gene expression signature, tumor mutational burden, and CD8+ T-cell infiltration were associated with an improvement in RFS for nivolumab and ipilimumab. 

Jeffrey S. Weber, MD, PhD, discusses the updated analysis of the phase III CheckMate-238 trial in patients with resected stage III/IV melanoma.

Jeffrey Weber, MD, PhD, NYU Langone Health, Perlmutter Cancer Center

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