JAMA Netw Open. 2026 Feb 2;9(2):e2559603. doi: 10.1001/jamanetworkopen.2025.59603.
ABSTRACT
IMPORTANCE: Patients with melanoma are at risk of developing subsequent cutaneous malignant neoplasms, and the effect of prior immunotherapy is unknown.
OBJECTIVE: To analyze new skin cancers in participants with high-risk stage II melanoma treated with adjuvant pembrolizumab or placebo.
DESIGN, SETTING, AND PARTICIPANTS: The multicenter double-blind, phase 3 KEYNOTE-716 randomized clinical trial enrolled 976 participants 12 years or older with completely resected stage IIB or IIC cutaneous melanoma between September 23, 2018, and November 4, 2020. Follow-up was completed on February 16, 2024. This analysis was not prespecified in the trial protocol.
INTERVENTIONS: Participants were randomly assigned to receive intravenous pembrolizumab, 200 mg (2 mg/kg for pediatric participants), or placebo, every 3 weeks for no more than 17 cycles.
MAIN OUTCOMES AND MEASURES: Secondary analyses of incidence and time to diagnosis of new melanoma or other cutaneous malignant neoplasm, sensitivity analysis of recurrence-free survival (RFS) with new primary melanoma counted as an event, and incidence of immune-mediated severe skin reactions.
RESULTS: A total of 976 participants were assigned to treatment (487 to pembrolizumab and 489 to placebo), of whom 589 (60.3%) were male (median age at diagnosis, 61 [IQR, 52-69] years). The median follow-up was 52.8 (range, 39.4-64.8) months. In the pembrolizumab group, 37 participants (7.6%) were diagnosed with new skin cancers (median time to diagnosis, 168.0 [range, 1.0-1182.0] days); 12 (2.5%) had new invasive primary melanoma, 6 (1.2%) had new primary melanoma in situ, 19 (3.9%) had basal cell carcinoma (BCC), and 9 (1.8%) had cutaneous squamous cell carcinoma (cSCC). In the placebo group, 56 participants (11.5%) were diagnosed with new skin cancers (median time to diagnosis, 177.0 [range, 1.0-1043.0] days); 9 (1.8%) had new invasive primary melanoma, 9 (1.8%) had new primary melanoma in situ, 26 (5.3%) had BCC, and 17 (3.5%) had cSCC. Median RFS with new primary melanoma counted as an event was not reached with pembrolizumab and was 59.2 months (95% CI, 53.9 months to not reached) with placebo (hazard ratio, 0.65; 95% CI, 0.52-0.80); 48-month RFS was 68.7% and 56.5%, respectively. Immune-mediated severe skin reactions occurred in 16 of 483 participants (3.3%) in the pembrolizumab group and 3 of 486 (0.6%) in the placebo group (grade 3 or 4: 14 [2.9%] vs 3 [0.6%]).
CONCLUSIONS AND RELEVANCE: In this secondary analysis of a randomized clinical trial, the incidence of new primary melanoma was not different between groups, whereas nonmelanoma skin cancers were more common with placebo. The RFS benefit of pembrolizumab remained after accounting for new primary melanomas. Immune-mediated severe skin reactions occurred infrequently and were manageable. These findings support the use of adjuvant pembrolizumab in high-risk stage II melanoma.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03553836.
PMID:41701495 | DOI:10.1001/jamanetworkopen.2025.59603
