Nivolumab Increases Response Rate vs Chemotherapy in Advanced Melanoma With Progression After Anti–CTLA-4 Treatment
In the phase III CheckMate 037 trial reported in The Lancet Oncology, Weber et al found that treatment with the PD-1 inhibitor nivolumab (Opdivo) resulted in a significantly greater response rate vs chemotherapy as second- or later-line treatment in patients with advanced melanoma progressing after anti–CTLA-4 treatment. Findings in this trial supported the accelerated approval of nivolumab in this setting in December 2014.
Study Details
In this open-label trial, 405 patients with unresectable or metastatic melanoma from 90 sites in 14 countries were randomly assigned 2:1 between December 2010 and January 2014 to receive nivolumab (n = 272) or chemotherapy (n = 133). Patients had to have progressed after treatment with ipilimumab (Yervoy) or with ipilimumab and a BRAF inhibitor if they were BRAF V600 mutation–positive. Nivolumab was given at 3 mg/kg intravenously every 2 weeks. Dose delay but not reduction was permitted in nivolumab patients. Investigator’s choice of chemotherapy consisted of dacarbazine 1,000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 combined with carboplatin area under the curve = 6 every 3 weeks. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoints of the trial are objective response and overall survival. In the current report of the first interim analysis, objective response was assessed after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks.
Among all randomized patients, the nivolumab and chemotherapy groups were generally balanced for age (median 59 and 62 years), gender (65% and 64% male), Eastern Cooperative Oncology Group performance status (0 for 60% and 63%, 1 for 40% and 36%), stage M1c disease (75% and 77%), stage 4 disease (96% and 98%), history of brain metastases (19% vs 14%), elevated lactate dehydrogenase (51% vs 35%), number of prior systemic treatments (one in 28% and 26%, two in 51% in both, more than two in 21% and 23%), previous treatment other than ipilimumab (chemotherapy in 53% and 54%, vemurafenib (Zelboraf) in 18% and 17%, other immunotherapy in 14% and 26%), PD-L1–positive status (49% and 50%), BRAF-mutant disease (22% in both), and no benefit (best overall response of progressive disease) from prior ipilimumab (64% and 65%).
Objective Response Rate
Patients received nivolumab for a median of 5.3 months and chemotherapy for a median of 2.0 months. Confirmed objective response was observed in 38 (31.7%, 95% confidence interval [CI] = 23.5%–40.8%) of the first 120 patients in the nivolumab group (including complete response in four patients, 3.3%) vs 5 (10.6%, 95% CI = 3.5%–23.1%) of 47 patients in the chemotherapy group. Median duration of response had not been reached (range = 1.4+ to 10.0+ months) in the nivolumab group and was 3.5 months (range = 1.3+ to 3.5) months in the chemotherapy group. Median time to response was 2.1 months (range = 1.6–7.4 months) vs 3.5 months (range = 2.1–6.1 months).
At the time of analysis, 33 (87%) of 38 nivolumab patients with response had continuing response without disease progression on treatment. Nivolumab was continued beyond disease progression in 37 patients (31%), with 10 (8%) exhibiting > 30% reduction in the sum of the longest diameters of target lesions.
Predefined Subgroups
In exploratory subgroup analyses, a higher response rate was observed with nivolumab vs chemotherapy irrespective of BRAF mutation status or previous anti–CTLA-4 treatment benefit. Response was observed in 23.1% (6/26) vs 9.1% (1/11) of BRAF V600 mutation–positive patients and 34.0% (32/94) vs 11.1% (4/36) of BRAF wild-type patients. Response was observed in 30.0% (12/40) vs 13.3% (2/15) of patients with prior anti–CTLA-4 treatment benefit and in 32.5% (26/80) vs 9.4% (3/32) with no benefit. Response was observed in 43.6% (24/55) vs 9.1% (2/22) of patients with PD-L1–positive tumors and in 20.3% (13/64) vs 13.0% (3/23) of those with PD-L1–negative tumors.
Among the 182 patients who had been randomly assigned at the time of the first planned assessment of objective response, median progression-free survival was 4.7 months (95% CI = 2.3–6.5 months) vs 4.2 months (95% CI = 2.1–6.3 months; hazard ratio = 0.82, 99.99% CI = 0.32–2.05), and 6-month progression-free survival was 48% (95% CI = 38%–56%) vs 34% (95% CI = 18%–51%).
Adverse Events
The reported safety analysis included 268 nivolumab patients and 102 chemotherapy patients who received at least one dose of study treatment at the time of objective response analysis. The most frequent treatment-related adverse events of any grade in the nivolumab group were fatigue (25% vs 34% in the chemotherapy group), pruritus (16% vs 2%), and diarrhea (11% vs 15%); the most frequent in the chemotherapy group were nausea (37%), fatigue, and alopecia (27%). Grade 3 or 4 treatment-related adverse events occurred in 9% vs 31% of patients, with the most common in the nivolumab group being increased lipase (1%), elevated alanine transaminase (1%), fatigue (1%), and anemia (1%); the most common in the chemotherapy group were neutropenia (14%), thrombocytopenia (6%), and anemia (5%).
Treatment-related serious adverse events occurred in 5% vs 9% of patients. Adverse events led to discontinuation of treatment in 3% vs 7%. No treatment-related deaths were observed.
The investigators concluded: “Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need.”
Jeffrey S. Weber, MD, of the Moffitt Cancer Center, is the corresponding author of The Lancet Oncology article.
The study was funded by Bristol-Myers Squibb. For full disclosures of the study authors, visit www.thelancet.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
