Nivolumab Earns FDA Approval as Adjuvant Therapy for Melanoma Based on Checkmate-238 Trial
Based on the outcomes of Checkmate-238, the Food and Drug Administration approved nivolumab as adjuvant therapy for the treatment of melanoma.
According to the National Cancer Institute, about 2.2% of people will be diagnosed with melanoma at a point in their lifetime.1 For those requiring surgery, the goal of adjuvant therapy is to increase relapse-free survival. Considering that patients with resected stage IV melanoma are often excluded from phase 3 trials of adjuvant therapy, it is imperative that researchers conduct studies to address outcomes in this population.
CheckMate 238 is a randomized, double-blind, phase 3 trial assessing the use of nivolumab (Opdivo, Bristol-Myers Squibb Company), a CTLA-4 immune checkpoint inhibitor, versus ipilimumab (Yervoy, Bristol-Myers Squibb Company), a PD-1 inhibitor, in resected stage IIIB, IIIC, or IV melanoma. An interim analysis published in the New England Journal of Medicine reports the safety and efficacy data from the trial.2
The trial included data from 130 centers in 25 countries. Patients were assigned in a 1:1 ratio to receive an IV infusion of nivolumab at 10 mg/kg every 2 weeks or ipilimumab at 10 mg/kg every 2 weeks for 4 doses and then every 12 weeks thereafter with corresponding matching placebo. This occurred for up to 1 year or until recurrence, unacceptable toxicity, or withdrawal of patient consent.
Statistical analyses included all 906 patients who underwent randomization, with 453 subjects in each arm of the study. The median age was 56 years for nivolumab recipients and 54 years for ipilimumab recipients. Among other criteria available in the supplementary appendix, patients with ocular or uveal melanoma were excluded.
Endpoint and Outcomes
The primary endpoint was recurrence-free survival (RFS). At the time of this report, median RFS had yet to be reached in either arm. At 1 year, the primary outcome RFS was 70.5% (95% CI, 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56 to 65.2) in the ipilimumab group. The nivolumab arm delivered significantly longer RFS than ipiliumamb, with recurrence or death in 34% and 45.5%, respectively (HR 0.65; 97.56% CI, 0.51 to 0.83; P<0.001).
Secondary endpoints included overall survival (OS), safety, RFS according to PD-L1 expression, and health-related quality of life (HRQoL). Benefit for nivolumab was detected in each subgroup (e.g., age, sex, disease stage, and BRAF status) with the exception of mucosal subtype melanoma, in which ipilimumab was better with respect to RFS. In patients with PD-L1 expression of <5% and those with PD-L1 expression >5%, the RFS rate was higher in the nivolumab group. Quality of life scores did not result in any clinically meaningful changes and remained near baseline scores, as gauged by the European Organization for Research and Treatment of Cancer QLQ-C30 Questionnaire and the European Quality of Life-5 Dimensions index and scale.
The most common adverse events (>20%) of any grade reported for nivolumab include fatigue (34.5%), diarrhea (24.3%) and pruritus (23.2%). For ipilimumab, >20% of patients reported fatigue (32.9%), diarrhea (45.9%), pruritus (33.6%), rash (29.4%) and nausea (20.1%).
Although the total percentage for adverse events of any cause was similar in the nivolumab and ipilimumab groups (96.6% versus 98.5%, respectively), a look at the adverse events table from the study more clearly conveys differences in toxicity. In other specifics, Grade 3 or 4 events deemed related to the trial drug occurred in 14.4% of patients in the nivolumab arm, as compared to 45.9% of patients in the ipilimumab arm. Serious adverse events that resulted in discontinuation occurred in 9.7% of nivolumab patients, as compared to 42.6% of ipilimumab patients. Two deaths occurred as a result of marrow aplasia and colitis, both of which were in the ipilimumab group and occurred more than 100 days after the last treatment dose.
The data safety monitoring committee determined that the trial be stopped early due to nivolumab showing substantial benefit over ipilimumab. Based on the results from this trial, the Food and Drug Administration approved nivolumab as adjuvant treatment for patients with melanoma with involvement of lymph nodes or metastatic disease with complete resection.
1. Cancer Stat Facts: Melanoma of the Skin. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Retrieved from https://seer.cancer.gov/statfacts/html/melan.html. Accessed Jan 5, 2018.
2. Weber J, Mandala M, Del Vecchio M, et al.; CheckMate 238 Collaborators. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med. 2017 Nov 9;377(19):1824-1835. doi: 10.1056/NEJMoa1709030.