Adjuvant Pembrolizumab Continues to Provide Survival Benefit in Stage IIB/C Melanoma

Pembrolizumab led to sustained improvements in recurrence-free survival and distant metastasis–free survival vs placebo as adjuvant therapy in patients with resected stage IIB or IIC melanoma


Jason Luke, MD, FACP

Pembrolizumab (Keytruda) led to sustained improvements in recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) vs placebo as adjuvant therapy in patients with resected stage IIB or IIC melanoma, according to updated data from the phase 3 KEYNOTE-716 trial (NCT03553836) presented at the 2023 ASCO Annual Meeting.1

At a median follow up of 39.4 months, 117 RFS events were seen with pembrolizumab and 174 events with placebo. Patients had a 36-month RFS rate of 76.2% with pembrolizumab vs 63.4% with placebo (HR, 0.62; 95% CI, 0.49-0.78).

At the time of median follow-up, there were 193 DMFS events in the overall population (n = 976). This consisted of 74 events with pembrolizumab, and 199 events with placebo (HR, 0.59; 95% CI, 0.44-0.79). The 36-month DMFS rate was 84.4% with pembrolizumab vs 74.7% with placebo. Median DMFS was not reached in either arm.

“Results of this protocol-specified final DMFS analysis of KEYNOTE-716 clearly support the use of pembrolizumab as the standard of care adjuvant therapy in patients [with] resected stage IIB and IIC melanoma,” said lead study author Jason Luke, MD, FACP, in a presentation of the data.

Luke is an associate professor of medicine in the Division of Hematology/Oncology, and director of the Cancer Immunotherapeutic Center as part of the Immunology and Immunotherapy Program at UPMC Hillman Cancer Center.

Previously reported data from KEYNOTE-716 showed that adjuvant pembrolizumab led to a statistically significant improvement in RFS and DMFS vs placebo in prior landmark analyses. Findings from the first planned analysis showed that the 12-month RFS rate with pembrolizumab was 90.5% vs 83.1% with placebo (HR, 0.65; 95% CI, 0.46-0.92; P = 0.0066). Second interim analysis revealed an 18-month RFS rate of 85.8% with pembrolizumab vs 77.0% with placebo (HR, 0.61; 95% CI, 0.45-0.82). In the third interim analysis, the 24-month RFS rate was 81.2% with pembrolizumab vs 72.8% with placebo (HR, 0.64; 95% CI, 0.50-0.84). The 24-month DMFS rate was 88.1% with pembrolizumab vs 82.2% with placebo (HR, 0.64; 95% CI, 0.47-0.88; P = 0.0029).1,2

The randomized, double-blind, placebo-controlled trial recruited participants from 160 academic medical centers across 16 countries.2Patients enrolled in KEYNOTE-716 were 12 years of age or older with newly diagnosed, completely resected, stage IIB or IIC melanoma. Other inclusion criteria were a negative sentinel lymph node biopsy, no evidence of regional or distant metastases, no previous treatment other than resection, and an ECOG performance score of 0 or 1. Eligible patients were stratified according to the size and extent of the primary tumor (T3b, T4a, or T4b), as well as pediatric status (age 12-17 years vs ≥18 years).

In part 1, patients were randomized 1:1 to 200 mg (2 mg/kg in pediatric participants) of intravenous (IV) pembrolizumab or IV placebo, both of which were administered every 3 weeks for 17 cycles until disease recurrence or unacceptable toxicity.1,3 In part 2 of the study, patients who completed all 17 cycles of pembrolizumab or placebo and experienced disease recurrence were allowed to be rechallenged with or cross over to receive pembrolizumab at the same dose and schedule, respectively. Treatment was continued for up to 2 years, or until disease progression or recurrence. Notably, data from this portion of the study are immature and have yet to be presented.

The primary end point was investigator-assessed RFS in the intention-to-treat population. Key secondary end points included safety, overall survival (OS), and investigator-assessed DMFS.3 Notably, investigators did not formally assess either RFS or DMFS, as prior interim analysis showed that these measures were statistically significant.

At the data cutoff of January 4, 2023, 976 patients had been assigned to treatment. A total of 487 patients were assigned to the pembrolizumab arm, and 489 were randomized to the placebo arm.

The median age in the pembrolizumab arm was 60 years (range, 16-84), with 184 patients 65 years of age or older. Three-hundred patients identified as male, and 454 patients had an ECOG performance score of 0. Regarding T category, 200 patients were T3b, 113 were T4a, and 172 were T4b. Most patients (n = 309) had stage IIB disease; 171 patients had stage IIC tumors.

In the placebo arm, the median age was 61 years (range, 17-87), with 194 patients 65 years of age or older. The number of male patients was 289, and ECOG performance score was 0 in 452 patients. In terms of T category, 201 patients were T3b, 116 were T4a, and 172 were T4b.

Assessment of patients’ cancer stage revealed that 316 had stage IIB disease and 169 had stage IIC disease.

Of the 483 patients treated in the pembrolizumab arm, 320 completed treatment. The majority of patients who discontinued treatment in the pembrolizumab arm did so due to AEs (n = 85). Other reasons for discontinuation in this group included patient withdrawal (n = 40), relapse/recurrence (n = 24), physician decision (n = 10), and a protocol violation or other issue (n = 4).

Conversely, 367 of the 486 patients treated in the placebo arm completed treatment.

However, the main reason for discontinuation in the placebo arm was relapse/recurrence (n = 61), with AEs contributing to 24 discontinuations. Discontinuation also occurred due to patient withdrawal (n = 27), physician decision (n = 4), and a protocol violation or other issue (n = 3).No patients are currently being treated on the study in either arm.

Further analysis of RFS according to tumor stage showed that patients with stage IIB RFS had a 36-month landmark rate of 79.7% with pembrolizumab vs 66.5% with placebo (HR, 0.58; 95% CI, 0.43-0.79). RFS rates were 71.4% with pembrolizumab and 58.0% with placebo at 36 months in patients with stage IIC disease (HR, 0.65; 0.45-0.94). In the stage IIB population, RFS events were seen in 64 patients with pembrolizumab and 32.6 patients with placebo. These numbers were 49 and 40.8, respectively, in the stage IIC population.

DMFS according to tumor stage showed that patients with stage IIB melanoma had a 36-month DMFS rate of 86.7% with pembrolizumab vs 78.9% with placebo. This equated to 41 DMFS events with pembrolizumab, and 65 events with placebo (HR, 0.62; 95% CI, 0.42-0.92). In patients with stage IIC disease, 36-month DMFS rates were 80.9% and 68.1%, respectively. Thirty-one patients had a DMFS event with pembrolizumab vs 51 with placebo (HR, 0.57; 95% CI, 0.36-0.88).

“Notably, this was a population where early in the study…it seemed like the benefit [with pembrolizumab] was less. As the [RFS] data have matured, we’ve seen that [this] has essentially resolved itself,” Luke noted.

Assessment of DMFS and RFS favored pembrolizumab across key subgroups, including T subcategory, age, sex, race, ECOG status, and geographic location (US vs non-US).

Overall, 95.4% of patients in the pembrolizumab arm and 91.8% of those in the placebo arm experienced an adverse effect (AE) of any severity or cause. Of these, 82.6% and 63.6% of AEs experienced in these respective arms were treatment related. Grade 3 or 4 treatment-related AEs (TRAEs) occurred in 17.2% of patients given pembrolizumab and 5.1% of patients given placebo. TRAEs leading to discontinuation occurred in 15.9% and 2.5% of patients in experimental and control arms, respectively.

The remaining AEs in each arm were immune mediated or caused by infusion reactions. Grade 3/4 immune-mediated AEs occurred in 11% of patients given pembrolizumab and 1.2% of those given placebo.

“In terms of [the] safety summary, there are no new safety signals from the clinical trial dating back to our initial reports,” Luke stated. “Breakdown of these specific toxicities is very similar to the analyses that we have provided previously...”

Analysis of OS, as well as the crossover/re-challenge portion of the study, will occur once the data mature. Biomarker analyses are also planned for this study.

“It’s important that all patients are offered this treatment…patients can decide it might not be the best treatment for them, but it’s an FDA-approved therapy, and it should be offered,” Luke concluded.

Disclosures: Dr Luke reported serving as a consultant or in an advisory role for 7 Hills Pharma, AbbVie, Alnylam, Alphamab, Bayer, Bright Peak Therapeutics, Bristol-Myers Squibb, Checkmate Pharmaceuticals, Codiak Biosciences, Crown Bioscience, CStone Pharmaceuticals, Day One Therapeutics, EMD Serono, Endeavor BioMedicines, Flame Biosciences, Genentech, Gilead Sciences, Hotspot Therapeutics, Immunocore, Incyte, Inzen Therapeutics, Janssen, Kadmon, KSQ Therapeutics, Merck, Nektar, Novartis, Onc.AI, Partner Therapeutics, Pfizer, Reflexion Medical, Regeneron, Ribon Therapeutics, Rubius Therapeutics, SERVIER, Silicon Therapeutics, STINGthera, STipe Therapeutics, Synlogic, Synthekine, Tempest Therapeutics, Tesaro, TRex Bio, Werewolf Therapeutics, Xencor, and Xilio Therapeutics; he received institutional research funding from Abbvie, Agios, Array BioPharma, Astellas Pharma, BioNTech, Bristol-Myers Squibb, Corvus Pharmaceuticals, EMD Serono, Fstar, Genmab, Ikena Oncology, Immatics, Incyte, Kadmon, KAHR Medical, Macrogenics, Merck, Moderna Therapeutics, Nektar, NextCure, Numab, Replimune, Rubius Therapeutics, Scholar Rock, Spring bank, Synlogic, Takeda, Tizona Therapeutics, Inc., Trishula Therapeutics, and Xencor; he has stock and other ownership interests with Actym Therapeutics, Alphamab, Arch Oncology, Kanaph Therapeutics, Mavu Pharmaceutical, NeoTX, NeoTX, Onc.AI, Pyxis, STipe Therapeutics, Tempest Therapeutics, he reports travel expenses paid for byArray BioPharma, Bristol-Myers Squibb, EMD Serono, Janssen, Merck, Mersana, Novartis, Pyxis, Reflexion Medical, and Xilio Therapeutics.


  1. Luke JJ, Ascierto PA, Khattak MA, et al. Pembrolizumab versus placebo as adjuvant therapy in stage IIB or IIC melanoma: final analysis of distant metastasis-free survival in the phase 3 KEYNOTE-716 study. J Clin Oncol. 2023;41(suppl 17):LBA9505. doi:10.1200/JCO.2023.41.17_suppl.LBA9505
  2. Luke JJ, Rutkowski P, Queirolo P, et al. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet. 2022;399(10336):1718-1729. doi:10.1016/S0140-6736(22)00562-1
  3. Safety and efficacy of pembrolizumab compared to placebo in resected high-risk stage II melanoma (MK-3475-716/KEYNOTE-716). Updated November 2, 2022. Accessed June 12, 2023.
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