Adjuvant Pembrolizumab Shows Efficacy in High-Risk Stage II Melanoma in Adults and Children Older Than 12

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Adjuvant pembrolizumab reduced the risk of recurrence in adults and children older than age 12 with high-risk stage II (AJCC 8th edition, stage IIB/IIC) melanoma vs placebo, according to a late-breaking interim analysis of the phase III KEYNOTE-716 trial, presented during the European Society for Medical Oncology (ESMO) Congress 2021.1 At a median follow-up of 14.4 months, pembrolizumab significantly reduced the risk of recurrence by 35% (P = .00658). The incidence of distant metastasis was also reduced with adjuvant pembrolizumab vs placebo.

The current standard of care for completely resected stage II melanoma is observation, even though patients with stage IIB and IIC melanoma have a deep or ulcerated primary tumor and are at the same risk of recurrence and death as those with stage IIIA and IIIB melanoma, where adjuvant immunotherapy with PD-1 antibodies is standard. The interim results of KEYNOTE-716 are poised to upend the current approach and suggest that adjuvant immunotherapy may become a new standard of care for high-risk stage II melanoma.

These results are set to substantially change the population of patients with melanoma who would receive treatment in the adjuvant setting.
— Jason J. Luke, MD

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“These results are set to substantially change the population of patients with melanoma who would receive treatment in the adjuvant setting,” stated lead author Jason J. Luke, MD, Director, Cancer Immunotherapeutics Center, UPMC Hillman Cancer Center, Pittsburgh. “Historically, we have defined high-risk patients after surgery as those with lymph node–positive disease. This trial suggests that the depth of the primary tumor and the ulceration status provide substantial information about the risk of recurrence and metastases and whether or not to pursue adjuvant therapy. In the future, we will need to reconsider how we incorporate sentinel lymph node biopsy into our risk stratification.”

Study Details

The international, double-blind, placebo-controlled KEYNOTE-716 trial was conducted at 150 centers in 16 countries. It is the first randomized phase III trial of an anti–PD-1 therapy in resected stage II melanoma, according to Dr. Luke. The study randomly assigned 976 patients with completely resected cutaneous stage IIB or IIC melanoma to receive immunotherapy with pembrolizumab vs placebo in a blinded fashion; treatment was continued for up to 1 year. The study had two parts: part 1 explored the use of pembrolizumab as adjuvant therapy, and part 2 is open-label and includes patients who had disease recurrence after treatment with pembrolizumab or placebo and are slated to receive up to 35 additional cycles (2 years) of pembrolizumab. Part 2 data are not yet mature.

Eligibility criteria included patient age older than 12; newly diagnosed, completely resected, high-risk stage II melanoma; and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Only small amounts of tissue were available, so PD-L1 status or BRAF status was not prespecified at baseline. Patients received pembrolizumab at 200 mg intravenously every 3 weeks (or the pediatric dose of 2 mg/kg every 3 weeks) or placebo. Stratification factors were T category (3b, 4a, 4b) and pediatric status. The primary endpoint was recurrence-free survival; secondary endpoints were distant metastasis–free survival, overall survival, and safety. Health-related quality of life (assessed by the EORTC QLQ-C30 Global Health Status Quality-of-Life scale) was an exploratory endpoint.

Efficacy was assessed in an intent-to-treat analysis of all randomly assigned patients, and safety was assessed in all patients who received at least one dose of study treatment.

Study medication was discontinued by 144 patients in the pembrolizumab group and 205 in the placebo group. At baseline, the median age was 60 years, and there was one pediatric patient (aged 12–17) in each study arm.

“The study met its primary endpoint quite early,” Dr. Luke said. At the interim analysis of part 1, 54 patients (11.1%) given pembrolizumab experienced recurrence vs 82 (16.8%) of those randomly assigned to receive placebo. Looking at patients who developed new primary melanomas, the benefit of pembrolizumab was similar: 62 patients in the pembrolizumab arm vs 96 in the placebo arm. Subgroup analysis showed that all prespecified subgroups benefited from pembrolizumab: T category, sex, age, ECOG status, and geographic distribution.

Distant recurrences were numerically lower with immunotherapy as well: 23 events (4.7%) vs 38 events (7.8%), respectively. The 12-month recurrence-free survival rate was 90.5% with pembrolizumab vs 83.1% with placebo. Median recurrence-free survival was not reached in either group at this relatively early time point.

“There has been a belief that early-stage melanoma does not recur very fast and that these patients do not develop metastatic disease. These data clearly disprove those beliefs and show that patients with high-risk stage II melanoma recur quickly and distantly, just like patients with stage IIIA and IIIB. Treatment with pembrolizumab reduced recurrence rates in a meaningful and statistically significant way, indicating that patients with stage II melanoma should be offered adjuvant therapy,” Dr. Luke stated.

Dr. Luke noted that other drugs used for adjuvant therapy for melanoma (ie, high-dose interferon and ipilimumab) led to severe adverse events in more than 50% of patients. These other agents have been withheld from use in patients with early-stage disease due to tolerability issues. “Anti–PD-1 therapy is more attractive from a risk/benefit point of view. Given the results of this trial, I think we should be offering it to our patients (with high-risk stage II disease),” said Dr. Luke.


  • KEYNOTE-716 is the first phase III trial to address immunotherapy vs placebo in high-risk stage II melanoma.
  • Adjuvant pembrolizumab achieved a clinically meaningful and statistically significant improvement in recurrence-free survival vs placebo, as well as an improvement in distant metastasis–free survival.
  • Adjuvant pembrolizumab may prove to be a new standard of care for high-risk stage II melanoma.


Safety and Quality of Life

“There were obviously more treatment-related adverse events in the pembrolizumab arm,” noted Dr. Luke. Grade 3 or 4 any-cause events occurred in 125 patients (25.9%) in the pembrolizumab group vs 83 (17.1%) in the placebo group. Grade 3 or 4 drug-related adverse events were reported in 78 patients (16.1%) given pembrolizumab and 83 patients (17.1%) given placebo. Treatment discontinuation due to drug-related adverse events was reported in 74 pembrolizumab-treated patients (15.3%) vs 12 placebo-treated patients (2.5%).

No deaths due to any cause or a drug-related cause were attributed to pembrolizumab, whereas four any-cause deaths occurred with placebo. Immune-mediated events attributable to pembrolizumab were mostly grade 1 or 2, with hypothyroidism (15.7% vs 3.5%, respectively) and hyperthyroidism (10.4% vs 0.6%, respectively) being the most common.

Hormonal therapy was necessary for the management of adverse events of interest (ie, endocrine toxicities) in 18.6% of patients given pembrolizumab.

“Health status and quality of life over time showed only minimal changes with pembrolizumab, and the confidence intervals overlap. This suggests that global health status and quality of life were similar between groups at all time points,” Dr. Luke noted.


DISCLOSURE: Dr. Luke holds stock or other ownership interests in Actym Therapeutics, Alphamab Oncology, Arch Oncology, Kanaph Therapeutics, Mavu Pharmaceutical, Onc.AI, Pyxis, and Tempest Therapeutics; has served as a consultant or advisor to 7 Hills Pharma, AbbVie, Alnylam, Alphamab Oncology, Astellas Pharma, Bayer, Bristol Myers Squibb, C-Stone Pharmaceuticals, Checkmate Pharmaceuticals, Crown Bioscience, Eisai, EMD Serono, Flame Biosciences, Genentech, Immunocore, Incyte, Inzen, Janssen, Kadmon, KSQ Therapeutics, Merck, Mersana, Nektar, Novartis, Partner Therapeutics, Pfizer, Reflexion Medical, Regeneron, Ribon Therapeutics, Rubius, Silicon Therapeutics, Spring Bank, Synlogic, Tempest Therapeutics, Tesaro, TRex Bio, Werewolf, Xencor, and Xilio; has received research funding from Agios, Array BioPharma, Astellas Pharma, BioNTech AG, EMD Serono, FStar, Genmab, Ikena Oncology, Immatics, Kadmon, KAHR Medical, Moderna Therapeutics, Nektar, Numab, Replimmune, Rubius Therapeutics, Scholar Rock, Spring Bank, Synlogic, Takeda, Tizona Therapeutics, and Trishula Therapeutics; has received institutional research funding from AbbVie, Bristol Myers Squibb, Corvus Pharmaceuticals, Incyte, MacroGenics, Merck, and Xencor; holds intellectual property in “Serial #15/612,657 (cancer immunotherapy)” and “Serial #PCT/US18/36052 (microbiome biomarkers for anti–PD-1/PD-L1 responsiveness: diagnostics, prognostic and therapeutic uses thereof)”; and has been reimbursed for travel, accommodations, or other expenses by Array BioPharma, Bristol Myers Squibb, EMD Serono, Janssen, Merck, Mersana, Novartis, Pyxis, Reflexion Medical, and Xilio.


1. Luke JJ, Rutkowski P, Queirolo P, et al: Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: Efficacy and safety results from the KEYNOTE-716 double-blind phase III trial. ESMO Congress 2021. Abstract LBA3_PR. Presented September 18, 2021.

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