Adjuvant Pembrolizumab Maintains Benefit-Risk Profile for High-Risk Stage II Melanoma in KEYNOTE-716 Analysis

This article was originally published on OncLive^®.

Adjuvant pembrolizumab (Keytruda; Merck) upheld its recurrence-free survival (RFS) advantage and was not associated with a higher incidence of new primary melanoma vs placebo in patients with completely resected stage IIB or IIC cutaneous melanoma, according to findings from a secondary analysis of the randomized phase 3 KEYNOTE-716 trial (NCT03553836).¹

The median RFS was not reached (NR) with pembrolizumab (n = 487) vs 59.2 months (95% CI, 53.9-NR) with placebo (n = 489; HR, 0.65; 95% CI, 0.52-0.80). The 48-month RFS rates were 68.7% and 56.5%, respectively.

For patients who did not develop any new skin cancer, the 48-month RFS rates were 71.3% and 59.7% in the pembrolizumab (n = 450) and placebo (n = 433) arms, respectively, vs 38.1% and 31.6%, respectively, in patients who developed new skin cancer in the investigational (n = 37) and placebo (n = 56) arms.

Among patients who developed new invasive primary melanoma or new primary melanoma in situ, the 48-month RFS were 66.0% and 50.0% in the pembrolizumab (n = 15) and placebo (n = 18) arms, respectively, vs 73.9% and 46.6%, respectively, in patients with basal cell carcinoma (BCC) and/or cutaneous squamous cell carcinoma (CSCC) in the investigational (n = 22) and placebo (n = 38) arms.

“The results of this secondary analysis of a randomized clinical trial suggest that patients with resected stage IIB or IIC melanoma are at risk of developing new skin cancers, regardless of adjuvant treatment received,” the authors wrote. “The incidence of new primary melanoma was similar between treatment groups, whereas nonmelanoma skin cancers were more common among the placebo group participants. These results provide important insights for [investigators], as limited data are available and no consensus exists on whether treatment with immunotherapy alters the risk of developing second cancers.”

What was the rationale for the secondary analysis?

Long-term survivors of melanoma are at risk of developing new melanomas or other cutaneous malignancies like BCC and CSCC, but the interplay between prior immunotherapy exposure and the likelihood of developing secondary cancer is not well understood.

The multicenter, double-blind KEYNOTE-716 trial was designed to evaluate adjuvant pembrolizumab vs placebo in patients with stage IIB or IIC cutaneous melanoma. Previously reported results highlighted significant improvements in RFS (HR, 0.62; 95% CI, 0.49-0.79) and distant metastasis-free survival (HR, 0.59; 95% CI, 0.44-0.79) with pembrolizumab vs placebo.²

The study enrolled 976 patients who were at least 12 years old with completely resected stage IIB or IIC cutaneous melanoma between September 23, 2018, and November 4, 2020.¹ Eligible patients were randomly assigned to receive intravenous pembrolizumab at 200 mg or 2 mg/kg for pediatric patients or placebo every 3 weeks for up to 17 cycles.

Given the long-term survival advantage afforded by pembrolizumab, secondary analyses were performed to better understand the incidence and time to diagnosis of new melanoma or other cutaneous malignant neoplasms, a sensitivity analysis of RFS with new primary melanoma counted as an event, and the occurrence of immune-mediated severe skin reactions.

What were the patient demographics?

A total of 976 patients were randomly assigned to receive either pembrolizumab or a placebo. The median age at diagnosis was 61 years (IQR, 52-69), and most patients were male (60.3%).

The median follow-up was 52.8 months (range, 39.4-64.8). In the pembrolizumab arm, 37 patients (7.6%) received a new skin cancer diagnosis, with a median time to diagnosis of 168.0 days (range, 1.0-1182.0). Of these, 12 (2.5%) were new invasive primary melanomas, 6 (1.2%) were new primary melanomas in situ, 19 (3.9%) were BCCs, and 9 (1.8%) were CSCCs. In the placebo arm, 56 patients (11.5%) received a new skin cancer diagnosis, with a median time to diagnosis of 177.0 days (range, 1.0-1043.0). Of these, 9 (1.8%) were new invasive primary melanoma, 9 (1.8%) were new primary melanoma in situ, 26 (5.3%) were BCC, and 17 (3.5%) were CSCC.

How did the safety profile compare between pembrolizumab and placebo?

With respect to safety, which was evaluated in patients who had received at least 1 dose of treatment, immune-mediated severe skin reactions occurred in 16 of 483 patients (3.3%) in the pembrolizumab arm vs 3 of 486 (0.6%) in the placebo arm. The rates of grade 3 or 4 events were 2.9% (n = 14) and 0.6% (n = 3), respectively. Such events in the pembrolizumab arm were bullous dermatitis (n = 1; 0.2%), erythema multiforme (n = 1; 0.2%), exfoliative rash (n = 1; 0.2%), pemphigoid (n = 1; 0.2%), pruritus (n = 3; 0.6%), rash (n = 7; 1.4%), maculopapular rash (n = 2; 0.4%), pruritic rash (n = 2; 0.4%), and pustular rash (n = 1; 0.2%).

Immune-mediated adverse effects or infusion reactions occurred in 185 of 483 patients (38.3%) in the pembrolizumab arm vs 46 of 486 (9.5%) in the placebo arm. Grade 3 or 4 events occurred in 53 (11.0%) and 6 (1.2%) patients, respectively.

Immune-mediated severe skin reactions led to treatment discontinuation in 3 patients (0.6%) in the pembrolizumab arm. Immune-mediated severe skin reactions requiring systemic corticosteroids occurred in 9 of 16 patients (56.3%) in the pembrolizumab arm vs 2 of 3 patients (66.7%) in the placebo arm. Immune-mediated severe skin reactions resolved in 14 of 16 cases (87.5%) in the pembrolizumab arm vs all 3 cases (100%) in the placebo arm.

What is the significance of these data?

“In this secondary analysis of a randomized clinical trial, the RFS benefit associated with pembrolizumab was sustained after accounting for new melanoma, and immune-mediated severe skin reactions occurred infrequently and were manageable,” the authors concluded. “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.”

References

1. Leachman SA, Luke JJ, Ascierto PA, et al. Adjuvant pembrolizumab for stage IIB or IIC melanoma: a secondary analysis of a randomized clinical trial. JAMA Netw Open. 2026;9(2):e2559603. doi:10.1001/jamanetworkopen.2025.59603
2. Luke JJ, Ascierto PA, Khattak MA, et al. Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma: final analysis of distant metastasis-free survival in the phase III KEYNOTE-716 study. J Clin Oncol. 2024;42(14):1619-1624. doi:10.1200/JCO.23.02355