Adjuvant pembrolizumab reduces the risk for distant metastasis in patients with resected stage IIB/C melanoma

Previously reported results of the phase III KEYNOTE-716 trial demonstrated that adjuvant pembrolizumab improves the recurrence-free survival (RFS) compared to placebo in patients with resected stage IIB/C melanoma. Updated results of this trial, presented at ASCO 2022, show that adjuvant pembrolizumab also significantly improves the distant metastasis-free survival (DMFS), with continued reduction in the risk of recurrence, compared with placebo.

Introduction

Patients with stage IIB and IIC melanoma have a deep or ulcerated primary tumor and have a similar risk of recurrence and death as patients with stage IIIA and IIIB melanoma. Despite this equivalent risk, observation has been standard of care for patients with stage IIB/C disease, whereas patients with stage III A/B melanoma routinely receive adjuvant therapy after their resection. At ESMO 2021, results of the phase III KEYNOTE-716 trial showed that adjuvant therapy with pembrolizumab resulted in a significant, 35% reduction in the risk of disease recurrence compared to placebo in patients with stage IIB/C melanoma.

Study design

The KEYNOTE-716 trial is a double-blind, randomized, placebo-controlled phase III study recruited a total of 976 patients (≥12 years of age) with newly diagnosed, completely resected stage IIB or IIC melanoma (TNM stage T3b or T4 with a negative sentinel lymph node biopsy). Patients were randomly assigned (1:1) to intravenous pembrolizumab 200 mg (2 mg/kg in pediatric patients) or placebo every 3 weeks for 17 cycles or until disease recurrence or unacceptable toxicity. The primary endpoint of the trial was RFS, with DMS, overall survival and safety as secondary objectives. The median follow-up for the presented analysis was 27.4 months. At the time of the analysis, 320/487 patients assigned to pembrolizumab had completed their treatment as compared to 368/489 in the placebo arm. The most common reasons for treatment discontinuation in the experimental arm was toxicity (N=85) and patient withdrawal (N=40).

Results

The median age of patients in KEYNOTE-716 was 60 years, with about 40% of patients being ≥65 years of age. Most patients in the study (92%) had an ECOG performance status of 0, with 41%, 23% and 35% of patients having T3b, T4a or T4b disease, respectively. About two thirds of patients had stage IIB disease, while the remaining 35% was diagnosed with stage IIC. At the time of the analysis, the median DMFS was not reached in either arm. However, at the 24 month landmark, the DMFS rate was 88.1% for the pembrolizumab arm as compared to 82.2% with placebo, translating into a significant 36% reduced risk for the development of distant metastases in patients treated with pembrolizumab (HR[95%CI]: 0.64[0.47-0.88]; p= 0.0029). The benefit in DMFS in favor of pembrolizumab was consistently seen across T-stages. In both arms, the lung was the most common site of metastasis (49% with pembrolizumab vs. 73% with placebo).

An updated analysis of the RFS confirmed the previously reported findings of KEYNOTE-716 with a sustained and statistically significant RFS benefit for patients treated with pembrolizumab (HR[95%CI]: 0.64[0.50-0.84]). At 24-months, patients receiving pembrolizumab had a RFS rate of 81.2%, as compared to 72.8% in the control arm.

The benefit in RFS and DMFS observed with adjuvant pembrolizumab did come at the price of an increased incidence of grade ≥3 adverse events (17% vs. 5%), leading to a higher discontinuation rate (16% vs. 2%). Immune-mediated events and infusion reactions were observed in 38% of patients in the pembrolizumab arm as compared to 9% with placebo. The nature of the adverse events was in line with the known safety profile of pembrolizumab.

Conclusions

Updated results of KEYNOTE-716 further solidify the significant RFS benefit obtained with adjuvant pembrolizumab in patients with resected stage IIB/C melanoma. In addition, adjuvant pembrolizumab effectively reduces the risk for distant metastasis. The safety profile was consistent with earlier reports of pembrolizumab.

Reference

Long G, et al. Distant metastasis-free survival with pembrolizumab versus placebo as adjuvant therapy in stage IIB or IIC melanoma: The phase 3 KEYNOTE-716 study. Presented at ASCO 2022; Abstract 9500.