Research Summary

Adjuvant Pembrolizumab and Risk of New Skin Cancers in Stage IIB/IIC Melanoma: A Secondary Analysis of KEYNOTE-716

Edited by:
Ashton L. Stahl

Key Highlights

  • Incidence of new primary melanoma was similar between pembrolizumab and placebo.
  • Nonmelanoma skin cancers, including basal cell carcinoma and cutaneous squamous cell carcinoma, were more common with placebo.
  • Recurrence-free survival benefit with pembrolizumab persisted when new primary melanoma was counted as an event.
  • Immune-mediated severe skin reactions were infrequent and generally manageable.

In a secondary analysis of the randomized phase 3 KEYNOTE-716 trial published in JAMA Network Open, investigators examined the incidence of new skin cancers among patients with completely resected stage IIB or IIC cutaneous melanoma treated with adjuvant pembrolizumab vs placebo. The analysis included 976 participants enrolled between September 2018 and November 2020, with follow-up completed in February 2024.

KEYNOTE-716 was a multicenter, double-blind trial that randomly assigned patients 12 years or older to intravenous pembrolizumab 200 mg (2 mg/kg in pediatric participants) or placebo every 3 weeks for up to 17 cycles (approximately 1 year). This post hoc analysis assessed the incidence and time to diagnosis of new invasive primary melanoma, melanoma in situ, basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (cSCC). A sensitivity analysis of recurrence-free survival (RFS) was conducted in which a new primary melanoma was counted as an event.

Study Findings

Among 487 patients assigned to pembrolizumab and 489 to placebo, the median follow-up was 52.8 months. New skin cancers were diagnosed in 37 patients (7.6%) in the pembrolizumab group and 56 patients (11.5%) in the placebo group, corresponding to a percent risk difference of −3.9% (95% CI, −7.6% to −0.2%).

Invasive primary melanoma occurred in 12 patients (2.5%) treated with pembrolizumab and 9 (1.8%) receiving placebo. Melanoma in situ was diagnosed in 6 (1.2%) and 9 (1.8%) patients, respectively. BCC occurred in 19 patients (3.9%) in the pembrolizumab arm vs 26 (5.3%) in the placebo arm, while cSCC occurred in 9 (1.8%) vs 17 (3.5%), respectively. The median time to diagnosis of any new skin cancer was 168 days with pembrolizumab and 177 days with placebo.

In the RFS sensitivity analysis, counting new primary melanoma as an event, 146 events (30.0%) occurred in the pembrolizumab group vs 207 (42.3%) in the placebo group (hazard ratio, 0.65; 95% CI, 0.52-0.80). Median RFS was not reached with pembrolizumab (59.2 months; 95% CI, 53.9 months to not reached) and was 59.2 months (95% CI, 53.9 months to not reached) with placebo. The 48-month RFS rates were 68.7% and 56.5%, respectively.

Immune-mediated adverse events or infusion reactions occurred in 38.3% of patients receiving pembrolizumab vs 9.5% with placebo; grade 3 or 4 events occurred in 11.0% vs 1.2%, respectively. Immune-mediated severe skin reactions were reported in 3.3% vs 0.6%, with most events resolving and few leading to treatment discontinuation.

Clinical Implications

According to the study authors, patients with resected stage IIB or IIC melanoma remain at risk of developing new skin cancers, regardless of adjuvant treatment. The similar incidence of new primary melanoma between groups and the higher frequency of nonmelanoma skin cancers in the placebo group provide context for clinicians counseling patients on long-term surveillance. The sustained RFS benefit after accounting for new melanomas, along with infrequent and manageable severe skin reactions, does not suggest a need to change the previously established benefit-risk profile of adjuvant pembrolizumab.

Expert Commentary

“In this secondary analysis of a randomized clinical trial, the RFS benefit associated with pembrolizumab was sustained after accounting for new melanoma, and immune-mediated severe skin reactions occurred infrequently and were manageable. These findings do not suggest a need for change to the previously published benefit-risk profile of adjuvant pembrolizumab for high-risk stage II melanoma,” the researchers concluded.

Reference
Leachman SA, Luke JJ, Ascierto PA, et al. Adjuvant pembrolizumab for stage IIB or IIC melanoma: a secondary analysis of a randomized clinical trial. JAMA Netw Open. 2026;9(2):e2559603. doi:10.1001/jamanetworkopen.2025.59603