Adjuvant Pembrolizumab Maintains Survival Benefit Without Raising New Melanoma Risk in Stage II Disease
Secondary analysis of KEYNOTE-716 trial finds adjuvant pembrolizumab improves recurrence-free survival in stage IIB/IIC melanoma without increasing new primary melanoma risk, while reducing non-melanoma skin cancers.
A secondary analysis of the phase 3 KEYNOTE-716 trial finds that adjuvant pembrolizumab improves recurrence-free survival in patients with high-risk stage IIB or IIC melanoma without increasing the risk of new primary melanoma. The analysis, published in JAMA Network Open, examined data from 976 patients aged 12 years or older with completely resected stage IIB or IIC cutaneous melanoma.
Participants were randomly assigned to receive intravenous pembrolizumab or placebo every three weeks for up to one year. Median follow-up was 52.8 months. The post hoc analysis evaluated the incidence of new skin cancer diagnoses, recurrence-free survival with new primary melanoma counted as an event, and the incidence of immune-mediated adverse events and infusion reactions.
Overall, 7.6% of patients in the pembrolizumab group developed a new skin cancer compared with 11.5% in the placebo group, a risk difference of -3.9%. New invasive primary melanoma occurred in 2.5% of patients receiving pembrolizumab versus 1.8% receiving placebo. The incidence of melanoma in situ was similar between groups: 1.2% with pembrolizumab versus 1.8% with placebo.
Non-melanoma skin cancers were more common in the placebo group. Basal cell carcinoma was diagnosed in 3.9% of patients treated with pembrolizumab versus 5.3% of those who received placebo. Cutaneous squamous cell carcinoma occurred in 1.8% versus 3.5%, respectively. The median time to diagnosis of any new skin cancer was 168 days in the pembrolizumab arm and 177 days in the placebo arm.
The recurrence-free survival benefit previously reported with pembrolizumab persisted even when new primary melanomas were counted as events. At 48 months, recurrence-free survival was 68.7% in the pembrolizumab group versus 56.5% in the placebo group (hazard ratio 0.65; 95% CI, 0.52-0.80). Median recurrence-free survival was not reached in the pembrolizumab arm and was 59.2 months in the placebo arm.
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% of patients in the pembrolizumab arm and 0.6% of those in the placebo arm. Immune-mediated severe skin reactions were resolved in 87.5% of patients in the pembrolizumab arm and in all patients in the placebo arm.
The researchers noted that patients with resected stage IIB or IIC melanoma remain at risk of developing new skin cancers regardless of adjuvant treatment received. The incidence of new primary melanoma was similar between treatment groups, whereas non-melanoma skin cancers were more common among the placebo group participants. The findings 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.
The study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co Inc.