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

Clinical Trial Updates 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 Jason J. Luke, MD, FACP 1 ; Paolo A. Ascierto, MD, PhD 2 ; Muhammad A. Khattak, MD, PhD 3 ; Luis de la Cruz Merino, MD, PhD 4,5 ; Michele Del Vecchio, MD, PhD 6 ; Piotr Rutkowski, MD, PhD 7 ; Francesco Spagnolo, MD 8 ; Jacek Mackiewicz, MD, PhD 9 ; Vanna Chiarion-Sileni, MD 10 ; John M. Kirkwood, MD 1 ; Caroline Robert, MD, PhD 11,12 ; Jean-Jacques Grob, MD, PhD 13 ; Federica de Galitiis, MD 14 ; Dirk Schadendorf, MD, PhD 15,16 ; Matteo S. Carlino, BMedSc, MBBS, FRACP 17,18 ; Xi Lawrence Wu, DrPH 19 ; Mizuho Fukunaga-Kalabis, MD 19 ; Clemens Krepler, MD 19 ; Alexander M.M. Eggermont, MD, PhD 20,21 ; and Georgina V. Long, PhD, MBBS (Hons), BSc (Hons1, UM), AO, FRACP 17,22 DOI https://doi.org/10.1200/JCO.23.02355 ABSTRACT Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Pembrolizumab adjuvant therapy was shown to significantly improve recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with resected stage IIB or IIC melanoma in earlier analyses of the randomized, double-blind, phase III KEYNOTE-716 study (ClinicalTrials.gov identifier: NCT03553836). We report results of the protocol-specified final analysis of DMFS for KEYNOTE-716. Overall, 976 patients were randomly allocated to pembrolizumab (n 5487) or placebo (n 5489). As of January 4, 2023, median follow-up was 39.4 months (range, 26.0-51.4 months). The median DMFS was not reached in either treatment group, and the estimated 36-month DMFS was 84.4% for pembrolizumab and 74.7% for placebo (hazard ratio [HR], 0.59 [95% CI, 0.44 to 0.79]). The median RFS was not reached in either treatment group, and the estimated 36-month RFS was 76.2% for pembrolizumab and 63.4% for placebo (HR, 0.62 [95% CI, 0.49 to 0.79]). DMFS and RFS results were consistent across most prespecified subgroups, including stage IIB and stage IIC melanoma. The safety profile of pembrolizumab was manageable and consistent with previous reports. These results continue to support the use of pembrolizumab adjuvant therapy in patients with resected stage IIB or IIC melanoma. INTRODUCTION In the randomized, double-blind, phase III KEYNOTE-716 study in patients with resected stage IIB or IIC melanoma, pembrolizumab as adjuvant therapy significantly improved recurrence-free survival (RFS) at the first interim analysis (hazard ratio [HR], 0.65 [95% CI, 0.46 to 0.92]; P5.0066) 1 and distant metastasis-free survival (DMFS) at the third interim analysis (HR, 0.64 [95% CI, 0.47 to 0.88]; P5.0029) 2 compared with placebo. These results led to the approval of pembrolizumab as adjuvant therapy in adult and pediatric patients with stage IIB or IIC melanoma by numerous regulatory authorities, including the US Food and Drug Administration and European Medicines Agency. 3,4 We report findings from the protocol-specified fourth interim analysis of KEYNOTE-716, including final DMFS and updated RFS results. METHODS Study Design and Patients The design of KEYNOTE-716 (ClinicalTrials.gov identifier: NCT03553836) has been described previously. 1 Eligible patients were age 12 years and older with newly diagnosed, resected, histologically confirmed, stage IIB (T3b or T4a) or IIC (T4b) cutaneous melanoma without regional lymph node involvement confirmed pathologically by sentinel lymph node biopsy, as defined by the American Joint Committee on Cancer 2017 classification, 8th edition. Patients were required to have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 and no previous treatment for melanoma beyond complete resection. Patients were randomly assigned in a 1:1 ratio to pembrolizumab 200 mg ACCOMPANYING CONTENT Appendix Protocol Accepted January 12, 2024 Published March 7, 2024 J Clin Oncol 42:1619-1624 © 2024 by American Society of Clinical Oncology View Online Article Creative Commons Attribution Non-Commercial No Derivatives 4.0 License ascopubs.org/journal/jco | Volume 42, Issue 14 | 1619 Downloaded from ascopubs.org by 150.214.182.238 on February 10, 2025 from 150.214.182.238 Copyright © 2025 American Society of Clinical Oncology. All rights reserved. (2mg/kgupto200mginpediatricpatients)orplacebointravenously once every 3 weeks for 17 cycles or until disease recurrence, unacceptable toxicity, or withdrawal of consent. Randomization was stratified by T category (T3b, T4a, or T4b) for adults, with a separate stratum for patients age 12-17 years. The protocol and all amendments were approved by the appropriate institutional review board or ethics committee at each institution. All patients provided written informed consent. End Points and Statistical Analysis This fourth interim analysis was based on a target of 195 DMFS events. The primary end point was investigatorassessed RFS. Secondary end points included investigatorassessed DMFS and safety and tolerability. Efficacy was assessed in all randomly allocated patients (intention-to- treat [ITT] population). Safety was assessed in all patients who received ≥1 dose of study treatment. RFS and DMFS were estimated using the Kaplan-Meier method. A stratified Cox proportional hazards model with the Efron method of handling ties was used to assess the magnitude of treatment difference between groups, with HRs and 95% CIs with treatment as a covariate. There was no formal hypothesis testing because statistical significance criteria for RFS and DMFS were met at previous analyses. Prespecified subgroups included T category (T3b vT4a vT4b), age (<65 v≥65 years), sex (male vfemale), race (White vnon-White), ECOG PS (0 v1), and geographic region (United States vnon– United States). Post hoc analysis of RFS and DMFS by disease stage was also conducted. HRs and 95% CIs for subgroups were estimated using an unstratified Cox proportional hazards model. TABLE 1. Baseline Demographics and Clinical Characteristics of the Intention-to-Treat Population Characteristic Pembrolizumab (n 5487) Placebo (n 5489) Age, years, median (range) 60 (16-84) 61 (17-87) <65 303 (62.2) 295 (60.3) ≥65 184 (37.8) 194 (39.7) Sex Male 300 (61.6) 289 (59.1) Female 187 (38.4) 200 (40.9) Race White 435 (89.3) 439 (89.8) Other 10 (2.1) 5 (1.0) Missing 42 (8.6) 45 (9.2) ECOG status 0 454 (93.2) 452 (92.4) 1 32 (6.6) 35 (7.2) 2 0 1 (0.2) Missing 1 (0.2) 1 (0.2) Geographic region United States 95 (19.5) 80 (16.4) Not United States 392 (80.5) 409 (83.6) T stage a T3a 2 (0.4) 0 T3b 200 (41.1) 201 (41.1) T4a 113 (23.2) 116 (23.7) T4b 172 (35.3) 172 (35.2) Disease stage a IIA 1 (0.2) 0 IIB 309 (63.4) 316 (64.6) IIC 171 (35.1) 169 (34.6) IIIC 4 (0.8) 1 (0.2) IV 0 2 (0.4) Missing 2 (0.4) 1 (0.2) NOTE. Data are No. (%) unless otherwise specified. Abbreviations: ECOG, Eastern Cooperative Oncology Group; T, tumor. a Patients not meeting inclusion criteria after random assignment were recorded as protocol deviations; however, these patients were still included in the intention-to-treat population. 1620 | © 2024 by American Society of Clinical Oncology Luke et al Downloaded from ascopubs.org by 150.214.182.238 on February 10, 2025 from 150.214.182.238 Copyright © 2025 American Society of Clinical Oncology. All rights reserved. RESULTS Patients A total of 976 patients were randomly allocated to pembrolizumab (n 5487) or placebo (n 5489). Baseline characteristics were generally balanced between treatment groups (Table 1). The median time from random assignment to data cutoff (January 4, 2023) was 39.4 months (range, 26.0-51.4). Efficacy The median DMFS in the ITT population was not reached (NR) in either group (HR, 0.59 [95% CI, 0.44 to 0.79]; Fig 1A). The estimated 36-month DMFS rate was 84.4% for pembrolizumab and 74.7% for placebo. In patients with stage IIB disease, the median DMFS was NR in both groups and the 36-month DMFS rate was 86.7% for pembrolizumab and 78.9% for placebo (HR, 0.62 [95% CI, 0.42 to 0.92]; Fig 1B). In patients with stage IIC disease, the median DMFS was NR in both groups and the 36-month DMFS rate was 80.9% for pembrolizumab and 68.1% for placebo groups, respectively (HR, 0.57 [95% CI, 0.36 to 0.88]; Fig 1C). DMFS across prespecified subgroups is shown in Figure 1D. The median RFS in the ITT population was NR in both groups (Fig 2A). The estimated 36-month RFS rate was 76.2% for pembrolizumab and 63.4% for placebo (HR, 0.62 [95% CI, 0.49 to 0.79]). In patients with stage IIB disease, the median A Pembrolizumab Placebo 74 (15.2) 119 (24.3) NR (NR-NR) NR (NR-NR) 0.59 (0.44-0.79) Events, No. (%) Median DMFS, Months (95% CI) HR (95% CI) 36-month rate 84.4% 74.7% 487 489 Pembrolizumab Placebo 480 482 469 463 456 449 444 427 434 412 427 402 417 389 396 372 376 350 322 287 276 243 185 176 130 131 71 62 22 32 5 7 0 0 100 0 10 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 No. at risk: 20 30 40 50 DMFS (%) 60 70 80 90 Time (months) B Pembrolizumab Placebo 41 (13.3) 65 (20.6) NR (NR-NR) NR (NR-NR) 0.62 (0.42-0.92) Events, No. (%) Median DMFS, Months (95% CI) HR (95% CI) 36-month rate 86.7% 78.9% 309 316 Pembrolizumab Placebo 304 315 298 306 290 297 284 285 280 274 277 269 273 262 263 252 252 240 213 196 179 161 120 113 83 79 47 38 13 19 2 5 0 0 100 0 10 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 No. at risk: 20 30 40 50 DMFS (%) 60 70 80 90 Time (months) C Pembrolizumab Placebo 31 (18.1) 51 (30.2) NR (NR-NR) NR (NR-NR) 0.57 (0.36-0.88) Events, No. (%) Median DMFS, Months (95% CI) HR (95% CI) 36-month rate 80.9% 68.1% 171 169 Pembrolizumab Placebo 169 166 166 156 162 151 156 142 150 138 146 133 140 127 129 120 120 110 105 91 93 82 61 63 44 52 24 24 9 13 3 2 0 0 100 0 10 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 No. at risk: 20 30 40 50 DMFS (%) 60 70 80 90 Time (months) D Favors Pembrolizumab 0.1 0.5 1.0 Events/ No. of Patients Favors Placebo HR (95% CI) 0.59 (0.45-0.80) 0.75 (0.47-1.19) 0.38 (0.18-0.82) 0.57 (0.36-0.88) 0.68 (0.46-1.00) 0.50 (0.32-0.79) 0.57 (0.40-0.81) 0.62 (0.37-1.04) 0.59 (0.44-0.81) 0.61 (0.45-0.82) 0.63 (0.29-1.34) 0.60 (0.44-0.82) 193/976 73/400 33/225 82/340 106/598 87/378 131/589 62/387 171/874 177/906 271/175 166/801 Overall T-stage T3b T4a T4b Age, years <65 t65 Sex Male Female Race White ECOG status 0 Geographic region United States Non–United States FIG 1. Kaplan-Meier estimates of DMFS (A) in the ITT population, (B) in patients with stage IIB melanoma, and (C) in patients with stage IIC melanoma. (D) Forest plot of key subgroups. DMFS, distant metastasis-free survival; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; ITT, intention-to-treat; NR, not reached; T, tumor. Journal of Clinical Oncology ascopubs.org/journal/jco | Volume 42, Issue 14 | 1621 Phase III KEYNOTE-716 Study: Final Analysis of DMFS Downloaded from ascopubs.org by 150.214.182.238 on February 10, 2025 from 150.214.182.238 Copyright © 2025 American Society of Clinical Oncology. All rights reserved. RFS was NR in both groups and the 36-month RFS rate was 79.7% for pembrolizumab and 66.5% for placebo (HR, 0.58 [95% CI, 0.43 to 0.79]; Fig 2B). In patients with stage IIC disease, the median RFS was NR in both groups and the 36-month RFS rate was 71.4% for pembrolizumab and 58.0% for placebo (HR, 0.65 [95% CI, 0.45 to 0.94]; Fig 2C). RFS across prespecified subgroups is shown in Figure 2D. Safety Overall, 483 patients in the pembrolizumab group and 486 in the placebo group received ≥1 dose of study treatment. Treatment-related adverse events (TRAEs) occurred in 82.6% of patients in the pembrolizumab group (grade 3/4, 17.2%) and 63.6% in the placebo group (grade 3/4, 5.1%; Appendix Table A1, online only). TRAEs led to treatment discontinuation in 15.9% and 2.5% of patients in the pembrolizumab and placebo groups, respectively. No patients died because of TRAEs. Immune-mediated AEs and infusion reactions occurred in 37.9% of patients in the pembrolizumab group (grade 3/4, 11.0%) and 9.5% in the placebo group (grade 3/4, 1.2%; Appendix Table A2). DISCUSSION In this protocol-specified fourth interim and final DMFS analysis of KEYNOTE-716, pembrolizumab adjuvant therapy continued to demonstrate a DMFS and an RFS benefit A Pembrolizumab Placebo 117 (24.0) 174 (35.6) NR (NR-NR) NR (NR-NR) 0.62 (0.49-0.79) Events, No. (%) Median RFS, Months (95% CI) HR (95% CI) 36-month rate 76.2% 63.4% 487 489 Pembrolizumab Placebo 472 477 457 452 441 430 426 395 413 378 400 363 390 350 371 331 353 311 300 252 254 210 173 149 117 113 62 51 18 30 4 7 0 0 100 0 10 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 No. at risk: 20 30 40 50 RFS (%) 60 70 80 90 Time (months) B Pembrolizumab Placebo 64 (20.7) 103 (32.6) NR (NR-NR) NR (NR-NR) 0.58 (0.43-0.79) Events, No. (%) Median RFS, Months (95% CI) HR (95% CI) 36-month rate 79.7% 66.5% 309 316 Pembrolizumab Placebo 301 310 293 297 285 283 276 264 272 252 266 244 263 236 255 226 242 214 204 172 169 140 115 96 77 70 43 31 12 18 2 5 0 0 100 0 10 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 No. at risk: 20 30 40 50 RFS (%) 60 70 80 90 Time (months) C Pembrolizumab Placebo 49 (28.7) 69 (40.8) NR (NR-NR) NR (33.3-NR) 0.65 (0.45-0.94) Events, No. (%) Median RFS, Months (95% CI) HR (95% CI) 36-month rate 71.4% 58.0% 171 169 Pembrolizumab Placebo 166 164 161 152 154 145 148 130 139 125 132 118 125 114 114 105 109 97 94 80 83 70 56 53 38 43 19 20 6 12 2 2 0 0 100 0 10 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 No. at risk: 20 30 40 50 RFS (%) 60 70 80 90 Time (months) D Favors Pembrolizumab 0.1 0.5 1.0 Events/ No. of Patients Favors Placebo HR (95% CI) 0.63 (0.50-0.79) 0.60 (0.41-0.89) 0.55 (0.32-0.92) 0.65 (0.45-0.94) 0.67 (0.49-0.92) 0.58 (0.41-0.82) 0.60 (0.45-0.80) 0.65 (0.43-0.98) 0.64 (0.50-0.82) 0.63 (0.49-0.81) 0.93 (0.53-1.63) 0.57 (0.44-0.74) 291/976 106/400 61/225 118/340 156/598 135/378 195/589 96/387 265/874 259/906 50/175 241/801 Overall T-stage T3b T4a T4b Age, years <65 t65 Sex Male Female Race White ECOG status 0 Geographic region United States Non–United States FIG 2. Kaplan-Meier estimates of RFS (A) in the ITT population, (B) in patients with stage IIB melanoma, and (C) in patients with stage IIC melanoma, and (D) RFS in key subgroups. ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; ITT, intention-to-treat; NR, not reached; RFS, recurrence-free survival; T, tumor. 1622 | © 2024 by American Society of Clinical Oncology Luke et al Downloaded from ascopubs.org by 150.214.182.238 on February 10, 2025 from 150.214.182.238 Copyright © 2025 American Society of Clinical Oncology. All rights reserved. compared with placebo in patients with resected stage IIB or IIC melanoma. After an additional 12 months of follow-up, the DMFS benefit previously reported at the third interim analysis was sustained, 2 with pembrolizumab providing a reduction in the risk of distant metastasis compared with placebo. The DMFS benefit was also consistent across prespecified subgroups, including stage IIB and IIC melanoma. The RFS benefit previously observed with pembrolizumab was also sustained, with pembrolizumab reducing the risk of recurrence or death in the ITTpopulation, in patientswith stage IIB or stage IIC melanoma, and in most subgroups. 1,2 The HRs for DMFS and RFS in the current analysis were also consistent with previous reports, indicating that the benefitobserved with pembrolizumab is durable. 1,2 For both DMFS and RFS, a continued separation of the Kaplan-Meier curves was observed over time and appeared to be widening for DMFS. The safety results also support previous studies showing pembrolizumab has a manageable safety profile. 1,2,5 Overall survival results will be reported at the fifth interim analysis. Patients with stage IIB and IIC melanoma have a similar prognosis as that for patients with stage III melanoma and have a similar or greater risk of recurrence than patients with stage IIIA and stage IIIB melanoma. 6-8 Pembrolizumab is the first systemic adjuvant therapy to be approved for use in patients with stage II melanoma, and, to our knowledge, KEYNOTE-716 is the only study with long-term follow-up data available. Other studies investigating adjuvant treatments include the phase III CheckMate-76K study. In a prespecified interim analysis of patients with resected stage IIB or IIC melanoma enrolled in CheckMate-76K, adjuvant nivolumab improved RFS (HR, 0.42 [95% CI, 0.30 to 0.59]; P< .0001) and DMFS (HR, 0.47 [95% CI, 0.30 to 0.72]) compared with placebo, which confirmed the benefitofadjuvant therapy with an anti–PD-1 agent in the population. 9 Additional studies underway include the phase III COLOMBUS-AD study, which is being conducted to investigate adjuvant encorafenib plus binimetinib versus placebo in resected stage IIB or IIC BRAF V600 -mutated melanoma. 10 Adjuvant pembrolizumab treatment for patients with resected high-risk stage IIB-IV melanoma is also being investigated as coformulationwithvibostolimabinthephaseIIIKEYVIBE-010 study 11 and in combination with the individualized neoantigen therapy V940 in the phase III V940-001 study. In the final DMFS analysis of KEYNOTE-716, pembrolizumab continued to demonstrate manageable safety and a clinically meaningful DMFS and RFS benefit compared with placebo, supporting the use of pembrolizumab adjuvant therapy in patients with resected stage IIB or IIC melanoma. AFFILIATIONS 1 UPMC Hillman Cancer Center and University of Pittsburgh, Pittsburgh, PA 2 Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy 3 Fiona Stanley Hospital and Edith Cowan University, Perth, WA, Australia 4 Instituto de Biomedicina de Sevilla (IBiS)/Hospital Universitario Virgen Macarena/CSIC/Universidad de Sevilla, Seville, Spain 5 Department of Clinical Oncology, Hospital University Virgen Macarena, Seville, Spain 6 Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 7 Maria Sklodowska–Curie National Research Institute of Oncology, Warsaw, Poland 8 IRCCS Ospedale Policlinico San Martino, Genoa, Italy 9 Poznan University of Medical Sciences and Greater Poland Cancer Center, Poznan, Poland 10 Istituto Oncologico Veneto (IOV) IRCCS, Padova, Italy 11 Gustave Roussy, Villejuif, France 12 Paris-Saclay University, Paris, France 13 Assistance Publique-Hopitaux de Marseille, Aix-Marseille University, Marseille, France 14 Dermopathic Institute of the Immaculate (IDI) IRCCS, Rome, Italy 15 University Hospital Essen and German Cancer Consortium Partner Site, Essen, Germany 16 National Center for Tumor Diseases (NCT)-West, Campus Essen, Research Alliance Ruhr, Research Center One Health, and University Duisburg-Essen, Essen, Germany 17 Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia 18 Westmead and Blacktown Hospitals, Sydney, NSW, Australia 19 Merck & Co, Inc, Rahway, NJ 20 University Medical Center Utrecht and Princess M´ axima Center, Utrecht, the Netherlands 21 Comprehensive Cancer Center Munich of the Technical University Munich and the Ludwig Maximilian University, Munich, Germany 22 Royal North Shore Hospital and Mater Hospital, Sydney, NSW, Australia CORRESPONDING AUTHOR Jason J. Luke, MD, FACP; e-mail: [email protected]. PRIOR PRESENTATION Presented at the 2023 ASCO Annual Meeting, Chicago, IL, June 2-6, 2023. SUPPORT Supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ. CLINICAL TRIAL INFORMATION NCT03553836 (KEYNOTE-716) AUTHORS’DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the authors are available with this article at DOI https://doi.org/10.1200/JCO.23.02355. DATA SHARING STATEMENT Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ (MSD), is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company’s clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial Journal of Clinical Oncology ascopubs.org/journal/jco | Volume 42, Issue 14 | 1623 Phase III KEYNOTE-716 Study: Final Analysis of DMFS Downloaded from ascopubs.org by 150.214.182.238 on February 10, 2025 from 150.214.182.238 Copyright © 2025 American Society of Clinical Oncology. All rights reserved. participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data sharing website (available at: http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data-sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the United States and European Union or after product development is discontinued. There are circumstances that may prevent MSD from sharing requested data, including country- or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts; after approval of the statistical analysis plan and execution of a data-sharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker covariates and add them to a file with clinical data that is uploaded to an analysis portal so that the requestor can perform the proposed analyses. AUTHOR CONTRIBUTIONS Conception and design: Jason J. Luke, John M. Kirkwood, Matteo S. Carlino, Muhammad A. Khattak, Alexander M.M. Eggermont Provision of study materials or patients: All authors Collection and assembly of data: Jason J. Luke, Muhammad A. Khattak, Luis de la Cruz Merino, Michele Del Vecchio, Piotr Rutkowski, Francesco Spagnolo, Jacek Mackiewicz, Vanna Chiarion-Sileni, John M. Kirkwood, Caroline Robert, Jean-Jacques Grob, Federica de Galitiis, Dirk Schadendorf, Matteo S. Carlino, Mizuho Fukunaga-Kalabis, Clemens Krepler, Georgina V. Long Data analysis and interpretation: Jason J. Luke, Alexander M.M. Eggermont, Caroline Robert, Dirk Schadendorf, Georgina V. Long, Luis de la Cruz Merino, Matteo S. Carlino, Michele Del Vecchio, Paolo A. Ascierto, Xi Lawrence Wu, Muhammad A. Khattak, Mizuho Fukunaga- Kalabis, Clemens Krepler, Jean-Jacques Grob, Vanna Chiarion-Sileni, John M. Kirkwood Manuscript writing: All authors Final approval of manuscript: All authors Accountable for all aspects of the work: All authors ACKNOWLEDGMENT The authors thank the patients and their families and caregivers for participating in the study, along with all investigators and site personnel. The authors thank Scot Ebbinghaus (Merck & Co, Inc, Rahway, NJ), Nageatte Ibrahim (Merck & Co, Inc, Rahway, NJ), and James Anderson for critical review of the manuscript. Medical writing and/or editorial assistance was provided by Jemimah Walker, PhD, and Rob Steger, PhD, of ApotheCom (Yardley, PA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ. REFERENCES 1. 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 399:1718-1729, 2022 2. Long GV, Luke JJ, Khattak MA, et al: Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma (KEYNOTE-716): Distant metastasis-free survival results of a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncol 23:1378-1388, 2022 3. KEYTRUDA (Pembrolizumab) Injection, for Intravenous Use [Package Insert]. Rahway, NJ, Merck & Co, 2023 4. KEYTRUDA 25 mg/mL Concentrate for Solution for Infusion (Summary of Product Characteristics). Haarlem, the Netherlands, Merck Sharp & Dohme B.V., 2023 5. Robert C, Hwu WJ, Hamid O, et al: Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: A landmark analysis in patients with advanced melanoma. Eur J Cancer 144:182-191, 2021 6. Gershenwald JE, Scolyer RA, Hess KR, et al: Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 67: 472-492, 2017 7. Garbe C, Keim U, Amaral T, et al: Prognosis of patients with primary melanoma stage I and II according to American Joint Committee on Cancer version 8 validated in two independent cohorts: Implications for adjuvant treatment. J Clin Oncol 40:3741-3749, 2022 8. Garbe C, Keim U, Suciu S, et al: Prognosis of patients with stage III melanoma according to American Joint Committee on Cancer version 8: A reassessment on the basis of 3 independent stage III melanoma cohorts. J Clin Oncol 38:2543-2551, 2020 9. Long GV, Del Vecchio M, Weber J, et al: Adjuvant therapy with nivolumab versus placebo in patients with resected stage IIB/C melanoma (CheckMate 76K). SKIN J Cutan Med 7:s163, 2023 10. van Akkooi ACJ, Hauschild A, Long GV, et al: 464TiP Phase III study of adjuvant encorafenib plus binimetinib vs placebo in fully resected stage IIB/C BRAFV600-mutated melanoma: COLUMBUS-AD study design. Ann Oncol 33:S1617-S1618, 2022 11. Long GV, Eggermont AM, Gershenwald JE, et al: KEYVIBE-010: Adjuvant coformulated vibostolimab with pembrolizumab versus adjuvant pembrolizumab in patients with high-risk stage II-IV melanoma. J Clin Oncol 41, 2023 (suppl 16; abstr TPS9611) 1624 | © 2024 by American Society of Clinical Oncology Luke et al Downloaded from ascopubs.org by 150.214.182.238 on February 10, 2025 from 150.214.182.238 Copyright © 2025 American Society of Clinical Oncology. All rights reserved. AUTHORS’DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST 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 The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I 5Immediate Family Member, Inst 5My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Jason J. Luke Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, STipe Therapeutics, NeoTX Consulting or Advisory Role: Bristol Myers Squibb, MSD, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab, Abbvie, Bayer, Incyte, Partner Therapeutics, Synlogic, Werewolf Therapeutics, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius Therapeutics, Tesaro, Xilio Therapeutics, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen Therapeutics, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak Therapeutics, Onc.AI, STipe Therapeutics, Codiak Biosciences, Day One Therapeutics, Endeavor BioMedicines, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine Research Funding: MSD (Inst), Bristol Myers Squibb (Inst), Incyte (Inst), Corvus Pharmaceuticals (Inst), Abbvie (Inst), Macrogenics (Inst), Xencor (Inst), Array BioPharma (Inst), Agios (Inst), Astellas Pharma (Inst), EMD Serono (Inst), Immatics (Inst), Kadmon (Inst), Moderna Therapeutics (Inst), Nektar (Inst), Spring bank (Inst), Trishula Therapeutics (Inst), KAHR Medical (Inst), Fstar (Inst), Genmab (Inst), Ikena Oncology (Inst), Numab (Inst), Replimune (Inst), Rubius Therapeutics (Inst), Synlogic (Inst), Takeda (Inst), Tizona Therapeutics, Inc (Inst), BioNTech (Inst), Scholar Rock (Inst), NextCure (Inst) Patents, Royalties, Other Intellectual Property: Serial No. 15/612,657 (Cancer Immunotherapy), Serial No. PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof) Travel, Accommodations, Expenses: Bristol Myers Squibb, Array BioPharma, EMD Serono, Janssen, MSD, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio Therapeutics Paolo A. Ascierto Consulting or Advisory Role: Bristol Myers Squibb, Roche/Genentech, MSD, Novartis, Merck Serono, Pierre Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Lunaphore Technologies, Seagen, ITeos Therapeutics, Medicenna, Bio-AI Health, ValoTx, Replimune, Bayer, Erasca, Inc, Philogen, BioNTech SE, Anaveon Research Funding: Bristol Myers Squibb (Inst), Roche/Genentech (Inst), Sanofi(Inst), Pfizer (Inst) Travel, Accommodations, Expenses: Pfizer, Bio-AI Health, Replimune, MSD Oncology, Pierre Fabre Muhammad A. Khattak Travel, Accommodations, Expenses: Pierre Fabre Luis de la Cruz Merino Consulting or Advisory Role: Roche (Inst), MSD Oncology, Bristol Myers Squibb, Gilead Sciences, AstraZeneca, Incyte Research Funding: Roche (Inst), Celgene (Inst) Travel, Accommodations, Expenses: Roche Michele Del Vecchio Consulting or Advisory Role: Novartis, Bristol Myers Squibb, MSD, Pierre Fabre, Immunocore Piotr Rutkowski Honoraria: Bristol Myers Squibb, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi, MSD Consulting or Advisory Role: Novartis, Blueprint Medicines, Bristol Myers Squibb, Pierre Fabre, MSD, Amgen, Philogen, AstraZeneca Speakers’Bureau: Pfizer, Novartis, Pierre Fabre Research Funding: Novartis (Inst), Roche (Inst), Bristol Myers Squibb (Inst), Pierre Fabre (Inst) Travel, Accommodations, Expenses: Orphan Europe, Pierre Fabre Francesco Spagnolo Honoraria: Bristol Myers Squibb, Novartis, MSD, Pierre Fabre, Sanofi, Merck Serono, Sun Pharma Consulting or Advisory Role: Novartis, MSD, Philogen, Sun Pharma, Pierre Fabre Travel, Accommodations, Expenses: Bristol Myers Squibb Jacek Mackiewicz Consulting or Advisory Role: Bristol Myers Squibb, MSD Travel, Accommodations, Expenses: Bristol Myers Squibb, MSD, Pierre Fabre Other Relationship: Bristol Myers Squibb, MSD, Novartis Vanna Chiarion-Sileni Consulting or Advisory Role: Pierre Fabre, MSD Travel, Accommodations, Expenses: Pierre Fabre John M. Kirkwood Honoraria: Bristol Myers Squibb Consulting or Advisory Role: Harbor BioMed, Scopus BioPharma, Pfizer, AXIO Research, Immunocore, Natera, DermTech, Ankyra Therapeutics, Becker Pharmaceutical Consulting, Fenix Group International, IQVIA, MSD, Replimune, SR One Capital Management, Iovance Biotherapeutics, Checkmate Pharmaceuticals, OncoSec, OncoCyte, Cancer Network, Takeda, Applied Clinical Intelligence, PATHAI, Magnolia Innovation, iOnctura, Jazz Pharmaceuticals, Regeneron, Cancer Study Group, Istari Oncology, CytomX Therapeutics, Lytix Biopharma, PyrOjas Corporation, Bristol Myers Squibb, Amgen, Valar Labs Research Funding: Amgen (Inst), Bristol Myers Squibb (Inst), Checkmate Pharmaceuticals (Inst), Immunocore (Inst), Iovance Journal of Clinical Oncology ascopubs.org/journal/jco | Volume 42, Issue 14 Phase III KEYNOTE-716 Study: Final Analysis of DMFS Downloaded from ascopubs.org by 150.214.182.238 on February 10, 2025 from 150.214.182.238 Copyright © 2025 American Society of Clinical Oncology. All rights reserved. Biotherapeutics (Inst), Novartis (Inst), Immvira (Inst), Harbor BioMed (Inst), Takeda (Inst), Verastem (Inst), Lion Biotechnologies (Inst) Travel, Accommodations, Expenses: Checkmate Pharmaceuticals, Bristol Myers Squibb, Regeneron, Ankyra Therapeutics, Iovance Biotherapeutics Caroline Robert Stock and Other Ownership Interests: RiboNexus Consulting or Advisory Role: Bristol Myers Squibb, Roche, Novartis, Pierre Fabre, MSD, Sanofi, AstraZeneca, Pfizer, Sun Pharma Research Funding: Novartis (Inst), Phio Pharmaceuticals (Inst) Jean-Jacques Grob Consulting or Advisory Role: BMS, MSD Oncology, Roche/Genentech, Novartis, Amgen, Pierre Fabre, Sun Pharma, Merck KGaA, Sanofi, Roche, Philogen, Ultimovacs Speakers’Bureau: Novartis, Pierre Fabre Travel, Accommodations, Expenses: BMS, MSD Oncology, Novartis, Pierre Fabre Dirk Schadendorf Honoraria: Roche/Genentech, Novartis, Bristol Myers Squibb, MSD, Immunocore, Merck Serono, Pfizer, Pierre Fabre, Philogen, Regeneron, 4SC, Sanofi/Regeneron, NeraCare GmbH, Sun Pharma, InflarxGmbH, Ultimovacs, Daiichi Sankyo Japan, LabCorp, Replimune, Agenus, AstraZeneca, Erasca, Inc, immatics, Novigenix, Pamgene, Seagen Consulting or Advisory Role: Roche/Genentech, Novartis, Bristol Myers Squibb, MSD, Pierre Fabre, Sanofi/Regeneron, Agenus, AstraZeneca, Daiichi Sankyo, Erasca, Inc, immatics, Immunocore, NeraCare GmbH, Replimune Speakers’Bureau: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Sanofi/Regeneron, Merck KGaA Research Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Roche (Inst), MSD Oncology (Inst), Array BioPharma/Pfizer (Inst), Amgen (Inst) Travel, Accommodations, Expenses: Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, MSD, Pierre Fabre, Sanofi/Regeneron Matteo S. Carlino Honoraria: Bristol Myers Squibb, MSD, Novartis Consulting or Advisory Role: Bristol Myers Squibb, MSD, Amgen, Novartis, Pierre Fabre, Roche, IDEAYA Biosciences, Sanofi, Merck Serono, Regeneron, QBiotics, Nektar, Eisai, OncoSec Xi Lawrence Xu Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc Stock and Other Ownership Interests: Merck & Co, Inc Mizuho Fukunaga-Kalabis Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc Stock and Other Ownership Interests: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc Clemens Krepler Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc Stock and Other Ownership Interests: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc Alexander M.M. Eggermont Stock and Other Ownership Interests: Skyline Diagnostics, IO Biotech, Sairopa Honoraria: Ellipses Pharma, MSD, Pfizer, Sellas Life Sciences, Skyline Diagnostics, BIOINVENT, IO Biotech, BioNTech, Agenus, MSD, Sairopa, Brenus Pharma, IQVIA, TigaTx, Trained Therapeutix Discovery, CatalYm, Scorpion Therapeutics, ISA Pharmaceuticals, GenOway, Pierre Fabre, BioNTech, GlaxoSmithKline Consulting or Advisory Role: Ellipses Pharma, ISA Pharmaceuticals, MSD, Pfizer, Sellas Life Sciences, Skyline Diagnostics, BIOINVENT, CatalYm, Agenus, IO Biotech, MSD, Sairopa, TigaTx, Trained Therapeutix Discovery, IQVIA, Brenus Pharma, Scorpion Therapeutics, Pierre Fabre, GenOway, BioNTech, BioNTech, GlaxoSmithKline Speakers’Bureau: MSD, Bristol Myers Squibb Georgina V. Long This author is a member of the Journal of Clinical Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript. Honoraria: BMS, Pierre Fabre Consulting or Advisory Role: Agenus, Amgen, Array BioPharma, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion Biotech, Hexal, Highlight Therapeutics, Innovent Biologics, MSD, Novartis, OncoSec, PHMR, Pierre Fabre, Provectus, QBiotics, Regeneron, AstraZeneca No other potential conflicts of interest were reported. © 2024 by American Society of Clinical Oncology Luke et al Downloaded from ascopubs.org by 150.214.182.238 on February 10, 2025 from 150.214.182.238 Copyright © 2025 American Society of Clinical Oncology. All rights reserved. APPENDIX TABLE A1. TRAEs in the As-Treated Population TRAE With Incidence ≥5% Pembrolizumab (n 5483) Placebo (n 5486) Any Grade, No. (%) Grade 3-4, a No. (%) Any Grade, No. (%) Grade 3-4, a No. (%) Any 399 (82.6) 83 (17.2) 309 (63.6) 25 (5.1) Pruritus 119 (24.6) 3 (0.6) 52 (10.7) 0 (0.0) Fatigue 104 (21.5) 1 (0.2) 93 (19.1) 1 (0.2) Diarrhea 90 (18.6) 5 (1.0) 56 (11.5) 1 (0.2) Arthralgia 79 (16.4) 1 (0.2) 39 (8.0) 0 (0.0) Rash 78 (16.1) 7 (1.4) 34 (7.0) 1 (0.2) Hypothyroidism 77 (15.9) 0 (0.0) 13 (2.7) 0 (0.0) Hyperthyroidism 49 (10.1) 1 (0.2) 3 (0.6) 0 (0.0) Asthenia 47 (9.7) 1 (0.2) 40 (8.2) 0 (0.0) ALT level increased 39 (8.1) 4 (0.8) 22 (4.5) 1 (0.2) Nausea 37 (7.7) 0 (0.0) 33 (6.8) 0 (0.0) Rash maculopapular 36 (7.5) 2 (0.4) 9 (1.9) 0 (0.0) Myalgia 32 (6.6) 2 (0.4) 16 (3.3) 0 (0.0) AST level increased 31 (6.4) 1 (0.2) 11 (2.3) 1 (0.2) Abbreviation: TRAE, treatment-related adverse event. a There were no grade 5 TRAEs. Journal of Clinical Oncology ascopubs.org/journal/jco | Volume 42, Issue 14 Phase III KEYNOTE-716 Study: Final Analysis of DMFS Downloaded from ascopubs.org by 150.214.182.238 on February 10, 2025 from 150.214.182.238 Copyright © 2025 American Society of Clinical Oncology. All rights reserved.