The emergence of immune checkpoint inhibitors has revolutionized the treatment of advanced melanoma. Nivolumab (Opdivo®, Bristol Myers-Squibb, New York, NY, US) and pembrolizumab (Keytruda®, Merck & Co., Kenilworth, NJ, US), human IgG4 monoclonal antibodies against programmed death-1 (PD-1), and ipilimumab (Yervoy®, Bristol Myers-Squibb, New York, NY, US), an antibody against cytotoxic T-lymphocyte antigen 4 (CTLA-4) are approved for the treatment of metastatic melanoma, and their use is now being extended to the adjuvant setting help prevent the recurrence of melanoma.
When melanoma is surgically removed, further adjuvant treatment is not always given although some patients will subsequently relapse with disseminated disease. The decision of whether or not to recommend adjuvant therapy depends upon the risk of disease recurrence, based on the clinical stage at diagnosis, as well as patient factors such as age, comorbidities, and personal preferences. Before the development of checkpoint inhibitor immunotherapy, high-dose interferon alfa (IFNα) was the only option for adjuvant treatment of high-risk melanoma to show an improvement in overall survival.1,2
Ipilimumab was approved as adjuvant therapy in patients with resected stage III melanoma following a phase III trial that found higher rates of recurrence-free survival (RFS) and overall survival with ipilimumab compared with placebo.3 However, high toxicity led to treatment discontinuation for most patients during the induction phase of ipilimumab administration and, by 5 years, more than half of all ipilimumab-treated patients had relapsed and more than one-third had died.4 Since anti-PD-1 antibodies have shown a better safety profile, efficacy, and durability than those reported with ipilimumab in unresectable stage III and IV melanoma,5 nivolumab and pembrolizumab have been investigated in the adjuvant setting.
The CheckMate 238 study (NCT02388906) is a phase III study designed to compare the efficacy and safety of nivolumab with that of ipilimumab for resected stage III or IV melanoma at high risk of recurrence. In this randomized, double-blind trial, 906 patients, who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma were randomly assigned to receive an intravenous infusion of either nivolumab (3 mg/kg body weight, n=453) every 2 weeks or ipilimumab at a (10 mg/kg body weight, n=453) every 3 weeks for 4 doses and then every 12 weeks. The patients received treatment for up to 1 year or until disease recurrence, any reported unacceptable adverse events, or withdrawal of consent.
The results were published last year in the New England Journal of Medicine to great excitement.6 At a minimum follow-up of 18 months, the 12-month rate of RFS was 70.5% in the nivolumab group and 60.8% in the ipilimumab group; a 35% reduction in the risk of recurrence or death (p<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group. Treatment discontinuation because of any adverse event occurred in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment.6 These impressive findings led to US Food and Drug Administration approval in December 2017 of nivolumab as an adjuvant treatment for patients with completely resected melanoma with lymph node involvement or metastatic disease.
Updated results of the study with an additional 6 months of follow-up were presented at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO), which was held in Chicago from June 1–5, 2018. At a minimum follow-up of 24 months, the RFS continued to be significantly longer for nivolumab than for ipilimumab, with a 34% reduction in the risk of recurrence or death in the nivolumab group (p<0.0001). These benefits were seen regardless of disease stage, PD-L1 expression, and BRAF mutation status. No additional safety assessment was included in this analysis since all patients had been off study treatment for more than 100 days at the time of the previous data cutoff.
Recently, results of the KEYNOTE-054 phase III trial (NCT02362594), which compared pembolizumab with placebo as adjuvant therapy in resected stage III melanoma, have been published. Pembrolizumab (200 mg) administered every 3 weeks for up to 1 year resulted in a 43% reduction in the risk of recurrence or death compared with placebo, with no new toxicities reported.7 Results of another phase III study (NCT02506153), comparing pembrolizumab with high-dose IFN, or high-dose ipilimumab, in patients with completely resected high-risk stage III or IVA disease, are expected soon.
A targeted therapy—the combination of dabrafenib plus trametinib—has also recently been approved for adjuvant use after significantly reducing the risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations compared with placebo.8 Physicians therefore have a difficult choice to make when selecting adjuvant therapy. Clearly, we need to consider mutation status, since patients must have a BRAF V600 mutation to be eligible for dabrafenib plus trametinib. However, we need to establish clinical characteristics, and ideally biomarkers, that can help with the choice of first-line treatment. Immunotherapy combinations or targeted therapy/immunotherapy combinations may also play a valuable role in the future. Other important questions to be addressed include whether adjuvant immunotherapy may play a role in stage II melanoma. The coming years will bring more clinical trial data, which will hopefully address these questions and simplify clinical decision making. What is evident, however, is that we have seen a significant change in the therapeutic landscape for advanced melanoma, and this is likely to continue to evolve.
touchONCOLOGY talks to Jeffrey S Weber from the Laura and Isaac Perlmutter Cancer Cente and NYU Langone Medical Center about the limitations of ipilimumab for the treatment of resected stage III melanoma and how the findings of the CheckMate238 trial can improve the safety profile of this patient population. Watch the interview here.
References
1. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14:7–17.
2. Mocellin S, Pasquali S, Rossi CR, et al. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst. 2010;102:493–501.
3. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16:522–30.
4. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375:1845–55.
5. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.
6. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377:1824–35.
7. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378:1789–801.
8. Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377:1813–23.
