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Soo Park, MD
Soo Park, MD
Posted: Wednesday, March 4, 2026
In patients with resected stage IIB or IIC melanoma, long-term survivorship brings a persistent risk of subsequent cutaneous malignancies, yet the influence of prior immunotherapy on this risk has remained uncertain. In a secondary analysis of the phase III KEYNOTE-716 trial reported in JAMA Network Open, Leachman et al evaluated the incidence of new primary melanomas and other cutaneous malignant neoplasms among patients treated with adjuvant pembrolizumab vs placebo.
Study Details
KEYNOTE-716 was a multicenter, double-blind, phase III trial that enrolled 976 patients aged 12 years or older with completely resected stage IIB or IIC cutaneous melanoma. Participants were randomly assigned between September 2018 and November 2020 to receive pembrolizumab at 200 mg or 2 mg/kg in pediatric patients (n = 487) or placebo (n = 489) every 3 weeks for up to 17 cycles (approximately 1 year). The current analysis, which was not prespecified in the original protocol, examined the incidence and timing of new invasive primary melanoma, melanoma in situ, basal cell carcinoma, and cutaneous squamous cell carcinoma. A sensitivity analysis of recurrence-free survival (RFS) was conducted in which new primary melanomas were counted as events. Immune-mediated severe skin reactions were also assessed among treated participants.
Key Results
At a median follow-up of 52.8 months, 37 patients in the pembrolizumab group (7.6%) and 56 in the placebo group (11.5%) were diagnosed with new skin cancers. In the pembrolizumab arm, 12 patients developed new invasive primary melanoma, 6 developed melanoma in situ, 19 developed basal cell carcinoma, and 9 developed cutaneous squamous cell carcinoma. In the placebo arm, 9 patients developed invasive melanoma, 9 developed melanoma in situ, 26 developed basal cell carcinoma, and 17 developed cutaneous squamous cell carcinoma.
The overall incidence of new skin cancers was lower in patients treated with pembrolizumab vs those treated with placebo, with a percent risk difference of −3.9% (95% confidence interval [CI] = −7.6% to −0.2%). The incidence of new primary melanoma was similar between study arms, whereas nonmelanoma skin cancers were more common in the placebo group.
In the RFS sensitivity analysis incorporating new primary melanoma as an event, 146 RFS events (30.0%) occurred in the pembrolizumab group vs 207 (42.3%) in the placebo group, corresponding to a hazard ratio of 0.65 (95% CI = 0.52–0.80). Median RFS was not reached in the pembrolizumab arm and was 59.2 months in the placebo arm; 48-month RFS rates were 68.7% and 56.5%, respectively. These findings indicate that the previously demonstrated RFS benefit of adjuvant pembrolizumab persists—even when new primary melanomas are considered events.
Immune-mediated severe skin reactions were uncommon but more frequent with pembrolizumab than with placebo. Any-grade severe skin reactions occurred in 3.3% of pembrolizumab-treated patients vs 0.6% treated with placebo, with grade 3 or 4 events reported in 2.9% and 0.6%, respectively. Most events resolved, and few led to treatment discontinuation.
The authors concluded: “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.”
DISCLOSURE: For full disclosures of all study authors, visit jamanetwork.com.
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