The incidence of new primary melanoma was similar among patients with completely resected stage IIB or IIC cutaneous melanoma who did vs did not receive adjuvant pembrolizumab, while nonmelanoma skin cancers were more common with placebo, according to a secondary analysis of the multicenter phase III KEYNOTE-716 trial published in JAMA Network Open. Leachman et al reported that pembrolizumab also maintained a recurrence-free survival benefit after accounting for new primary melanomas and was associated with “infrequent” and “manageable” immune-mediated severe skin reactions.

“The results…suggest that patients with resected stage IIB or IIC melanoma are at risk of developing new skin cancers, regardless of adjuvant treatment received,” the investigators wrote. “These results provide important insights for clinicians, as limited data are available and no consensus exists on whether treatment with immunotherapy alters the risk of developing second cancers.”

Furthermore, they stated, “These findings support the use of adjuvant pembrolizumab in high-risk stage II melanoma.”

Study Details

A total of 976 patients aged 12 years or older with completely resected stage IIB or IIC cutaneous melanoma were randomly assigned to receive 200 mg (2 mg/kg for pediatric patients) of intravenous pembrolizumab (n = 487) or placebo (n = 489) every 3 weeks for up to 17 cycles. Follow-up data were provided for a median of 52.8 months.

This post hoc analysis evaluated the incidence and time to diagnosis of new invasive primary melanoma, new melanoma in situ, basal cell carcinoma, and cutaneous squamous cell carcinoma. It also included a sensitivity analysis of recurrence-free survival, counting new primary melanoma as an event, as well as an evaluation of the incidence of immune-mediated severe skin reactions.

Incidence of New Skin Cancers

Overall, new skin cancers were diagnosed in 7.6% of patients treated with pembrolizumab compared with 11.5% of those who received placebo. New invasive primary melanoma occurred in 2.5% and 1.8% of patients, respectively, and new primary melanoma in situ was reported in 1.2% and 1.8%. Nonmelanoma skin cancers were seen more frequently in the placebo arm: basal cell carcinoma was diagnosed in 3.9% of patients treated with pembrolizumab vs 5.3% of those who received placebo, and cutaneous squamous cell carcinoma in 1.8% vs 3.5%, respectively. The median time to diagnosis of any new skin cancer was 168 days with pembrolizumab and 177 days with placebo.  

Recurrence-Free Survival

The median recurrence-free survival with new primary melanoma counted as an event was not reached in the pembrolizumab arm and was 59.2 months (95% confidence interval [CI] = 53.9 months to not reached) in the placebo arm (hazard ratio [HR] = 0.65, 95% CI = 0.52–0.80). At 48 months, the recurrence-free survival rate was 68.7% with pembrolizumab and 56.5% with placebo. 

Safety Findings

Immune-mediated adverse events or infusion reactions of any grade were reported in 38.3% of patients treated with pembrolizumab and 9.5% of those who received placebo; grade 3 or 4 events occurred in 11.0% and 1.2%, respectively. Immune-mediated severe skin reactions were documented in 3.3% (grade 3/4: 2.9%) of patients in the pembrolizumab arm and 0.6% (grade 3/4: 0.6%) of those in the placebo arm.

The investigators concluded, “In this secondary analysis of a randomized clinical trial, the recurrence-free survival 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.”

Sancy A. Leachman, MD, PhD, of Oregon Health & Science University, Portland, is the corresponding author of the JAMA Network Open article.

Disclosure: The study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co Inc. For full disclosures of the authors, visit jamanetwork.com.