Analysis reinforces benefit and safety of adjuvant Keytruda for stage 2 melanoma

For people with high-risk stage 2B or 2C melanoma, surviving surgery is only part of the battle. Even after surgical removal, the risk of recurrence remains. Many patients go on to receive adjuvant therapy, i.e., treatment given after surgery to eliminate remaining cancer cells and lower the risk of recurrence.

Some reassurance is offered by a secondary analysis of the pivotal KEYNOTE-716 trial, published February 2026 in JAMA Network Open. Investigators, led by Sancy A. Leachman, M.D., Ph.D., adjunct professor of dermatology at Oregon Health & Science University in Portland, Oregon, report that adjuvant treatment with Keytruda (pembrolizumab) not only extends recurrence-free survival, but does not increase the risk of new primary melanoma and may even lower the incidence of certain other skin cancers.

Melanoma survivors face a heightened lifetime risk of additional cutaneous malignancies, including basal cell carcinoma and cutaneous squamous cell carcinoma. At the same time, immune checkpoint inhibitors, such as Keytruda, have transformed melanoma care, raising questions about whether stimulating the immune system might influence the development of new primary cancers. Earlier data have been mixed, leaving clinicians uncertain about the long-term dermatologic safety profile of adjuvant immunotherapy.

For the new analysis, Leachman and colleagues examined data from 976 patients aged 12 years or older with completely resected stage 2B or 2C cutaneous melanoma who were enrolled in the randomized, double-blind, phase 3 KEYNOTE-716 trial. Participants were assigned to receive intravenous Keytruda or placebo every three weeks for up to one year. Median follow-up was 52.8 months.

Overall, 7.6% of people in the Keytruda 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 Keytruda versus 1.8% receiving placebo. The incidence of melanoma in situ was similar between groups: 1.2% with Keytruda versus 1.8% with placebo However, non-melanoma skin cancers were more common in the placebo group, including basal cell carcinoma (5.3% vs 3.9%) and cutaneous squamous cell carcinoma (3.5% vs 1.8%).

Importantly, the recurrence-free survival benefit previously reported with Keytruda persisted even when new primary melanomas were counted as events. At 48 months, recurrence-free survival was 68.7% in the Keytruda 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 Keytruda arm and was 59.2 months in the placebo arm.

Immune-mediated severe skin reactions were infrequent. Among treated patients, 3.3% in the Keytruda group experienced severe immune-mediated skin reactions compared with 0.6% in the placebo group. Most cases were resolved, with few leading to treatment discontinuation.

In their paper, the authors emphasize a practical reality: patients with resected stage 2B or 2C melanoma remain at risk for new skin cancers regardless of whether they receive adjuvant therapy. Rates of new primary melanoma were similar between groups, while non-melanoma skin cancers were more common in the placebo arm. In a field where clinicians have had limited data and no clear consensus about how immune checkpoint inhibitors affect second cancer risk, those findings offer needed clarity.

“Surviving your first melanoma doesn’t mean you’re out of the woods. Patients with Stage 2B or 2C disease continue to develop new skin cancers at a rate that demands ongoing vigilance,” says Leachman, lead author and chief medical officer at SkinBit.

Prior research on immune checkpoint inhibitors and second primary cancers has produced mixed results, with some studies suggesting increased risk and others showing no clear signal. In that context, the continued recurrence-free survival benefit seen in KEYNOTE-716 is reassuring.

“We can now reassure patients and clinicians: adjuvant pembrolizumab delivers meaningful survival benefit without raising the risk of a new primary melanoma,” Leachman says.

“Perhaps the most surprising finding was that immunotherapy did not just avoid harm,” she says. “Patients on pembrolizumab actually developed fewer nonmelanoma skin cancers than those on placebo.”

The analysis was post hoc and not powered specifically to detect differences in second primary cancers. Still, the findings may ease concerns for patients and clinicians weighing the benefit-risk profile of adjuvant Keytruda in high-risk stage 2 melanoma.