Adjuvant anti–PD-1 antibody therapy is widely used for stage III melanoma, given the approvals of pembrolizumab and nivolumab. These approvals were based on significantly improved relapse-free survival in the CheckMate 238 trial of nivolumab compared with ipilimumab and the EORTC 1325/KEYNOTE-054 trial comparing pembrolizumab with placebo. Recently, a significant improvement in the secondary endpoint of distant metastasis–free survival in the EORTC 1325/KEYNOTE-054 trial was reported in The Lancet Oncology by Eggermont et al¹ (reviewed in this issue of The ASCO Post), adding an additional clinically meaningful endpoint to support the benefit of adjuvant anti–PD-1 antibody in stage III melanoma.

Ravi Amaravadi, MD

Lynn Schuchter, MD

New data from this study were also presented at the 2021 ASCO Annual Meeting by Eggermont et al.² These findings detailed outcomes in patients who crossed over from placebo to pembrolizumab at the time of first relapse as well as patients who chose to be re-treated with pembrolizumab if relapse occurred more than 6 months after completing adjuvant pembrolizumab. Together, these data shed light on major unanswered questions for adjuvant therapy in melanoma: Is there a benefit to treatment immediately following surgical resection, or is it equally effective to wait until recurrence to treat, given the steady advancement of effective therapeutic regimens for stage IV melanoma?

Distant Metastasis–Free Survival Benefit With Pembrolizumab

EORTC 1325/KEYNOTE-054 is a double-blind placebo-controlled trial involving 1,019 patients in 23 countries who had American Joint Committee on Cancer staging system–7th edition stage IIIA, IIIB, or IIIC disease. The co-primary endpoints were recurrence-free survival in the intention-to-treat population and in patients with PD-L1–positive (> 1%) tumors. The secondary endpoint was distant metastasis–free survival in the intention-to-treat and PD-L1–positive populations.

With a median follow-up of 42.3 months, distant metastasis–free survival at 3.5 years was 65.3% (95% confidence interval [CI] = 60.9%–69.5%) in the pembrolizumab group vs 49.4% (95% CI = 44.8%–53.8%) in the placebo group in the intention-to-treat population. There was a similar benefit in patients with PD-L1–positive and PD-L1–negative status.

Patients with stage IIIB and stage IIIC—but not those with stage IIIA disease—had a significant difference in favor of pembrolizumab. There was a significant benefit favoring pembrolizumab in patients with BRAF-mutant disease, but not in those with BRAF wild-type disease. Taken together, these findings support the use of adjuvant pembrolizumab therapy in patients with high-risk stage III melanoma.

Role of Delayed Pembrolizumab

EORTC 1325/KEYNOTE-054 is the only large, global, randomized phase III trial that has a placebo control arm in the modern era, with a growing number of options for patients with metastatic disease. It is also unique because it allows for crossover in patients who were assigned to placebo and experienced disease progression, as well as retreatment with pembrolizumab if patients experienced disease progression more than 6 months after completing adjuvant pembrolizumab.

Only about half of patients who recurred on the placebo arm (n = 298) and were eligible for crossover actually crossed over on study (n = 155), raising the possibility that many patients received other treatments, such as surgical resection, radiation, dual checkpoint inhibition, or BRAF and MEK inhibitor therapy, rather than single-agent pembrolizumab. The crossover patients from the placebo arm who were treated with pembrolizumab for relapsed disease had a response rate of 39%, with a median progression-free survival of 8.5 months.

The discussant for the oral session at the ASCO meeting, Dr. -Alexander Menzies, pointed out that the patients who recurred on the placebo arm of this trial presented with more localized stage IV disease (M1a, M1b) compared with benchmark trials for stage IV front-line pembrolizumab (KEYNOTE-006); so, one might have expected higher response rates and longer progression-free survival. Salvage pembrolizumab (retreatment following disease progression on adjuvant pembrolizumab) yielded poor outcomes and limited efficacy, with a response rate of 11% and a median progression-free survival of 4 months. Thus, rechallenge with pembrolizumab seems to have little benefit, and alternative therapeutic approaches are needed for these patients.

Will Outcomes Observed in Adjuvant Trials Translate to Survival Benefit?

Thus far, no trial has reported survival data for adjuvant anti–PD-1 antibody treatment in patients with stage III melanoma. Although the EORTC 1325/KEYNOTE-054 trial now shows that pembrolizumab provides a significant improvement in recurrence-free and distant metastasis–free survival compared with placebo, it is not clear this trial will demonstrate a benefit in overall survival. The event rate for the overall survival endpoint is coming in so slowly that it will be years before survival data will be available.

Potential reasons there may not be a difference in overall survival between the arms in this study include the crossover design, improving stage IV regimens (such as multiple BRAF and MEK inhibitor combinations, nivolumab, and ipilimumab), and newer regimens such as nivolumab and relatlimab; these newer options are showing a benefit in clinical trials and will likely be evaluated for regulatory approval.

To underscore this point, the CheckMate 238 trial, which compared nivolumab and ipilimumab in patients with stage IIIB/C and IV melanoma and did not include a crossover design, showed significant recurrence-free and distant metastasis–free survival benefits with nivolumab but no overall survival benefit. There are ongoing efforts to identify predictors of relapse in the stage III setting, which may allow for more accurate risk stratification and more precise decision-making for adjuvant therapy.

Anti–PD-1 Therapy: Now or Later?

Fundamental questions remain: Is it better for patients to be treated with PD-1 inhibitors in the adjuvant setting, or can we safely wait and reserve treatment only for those patients who relapse and develop metastatic melanoma? The EORTC 1325/KEYNOTE-054 trial is boldly attempting to answer this question. However, at this time, it remains unanswered. Although there is no doubt we are overtreating some patients with stage III melanoma who may be cured with surgery alone, current data still strongly favor the use of adjuvant anti–PD-1 antibody for patients with stage III disease as a mainstay of adjuvant therapy. Ongoing trials are also examining the role of neoadjuvant therapy for patients with stage III melanoma. 

DISCLOSURE: Dr. Amaravadi is Founder of Pinpoint Therapeutics; serves as a consultant for Merck, Deciphera, Sprint Biosciences, and Immune Cell; and receives research funding from Novartis, BMS, Pfizer, and Pinpoint Therapeutics. Dr. Schuchter has served as a consultant or advisor to Incyte; has received institutional research funding from Bristol Myers Squibb, GlaxoSmithKline, and Merck; has provided expert testimony on behalf of Pfizer; and has been reimbursed for travel, accommodations, or other expenses by Stand Up To Cancer.

Dr. Amaravadi works in the Division of Hematology Oncology, and Dr. Schuchter is Chief of the Division of Hematology Oncology at the Abramson Cancer Center, University of Pennsylvania, Philadelphia.

REFERENCES

1. Eggermont AMM, Blank CU, Mandalà M, et al: Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): Distant metastasis-free survival results from a double-blind, randomised controlled phase 3 trial. Lancet Oncol 22:643-654, 2021.

2. Eggermont AM, Meshcheryakov A, Atkinson V, et al: Crossover and rechallenge with pembrolizumab in recurrent patients from EORTC 1325-MG/KEYNOTE-054 phase 3 trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma. 2021 ASCO Annual Meeting. Abstract 9500. Presented June 4, 2021.