Adjuvant Pembrolizumab versus IFNα2b or Ipilimumab in Resected High-Risk Melanoma

Several therapies have demonstrated an improvement in overall survival (OS) when used as initial treatment for patients with unresectable metastatic melanoma, including ipilimumab (1) and nivolumab alone or in combination (2), pembrolizumab (3), and combinations of BRAF and MEK inhibitors (4–7). In recent years, several of these approaches have been utilized in the adjuvant setting to prevent recurrence of melanoma after surgical excision (8). Adjuvant immunotherapy with high-dose IFNα2b, ipilimumab (CTLA4-blocking antibody, administered at 10 mg/kg of body weight every three weeks), or with nivolumab or pembrolizumab (PD-1–blocking antibodies), improved recurrence-free survival (RFS) in randomized clinical trials enrolling patients with completely resected melanoma at high risk of recurrence (9–13); and all are approved by the FDA for adjuvant use in melanoma. High-dose IFNα2b and ipilimumab have each been shown to improve OS compared with an observation or placebo control group in randomized adjuvant therapy trials (9, 10). These adjuvant immunotherapy trials enrolled patients with different but partially overlapping stages of melanoma. The European Organization for Research and Treatment of Cancer 1325 (KEYNOTE-054) clinical trial involved a high-risk patient population with stage III melanoma, and demonstrated 43% lower recurrence or death in patients receiving adjuvant pembrolizumab compared with placebo (12, 13). CheckMate 238 enrolled patients with resected higher-risk stage III and stage IV metastatic melanoma; nivolumab showed a 35% improvement in RFS compared with ipilimumab (11). The combination of nivolumab and ipilimumab (the latter given at 1 mg/kg every six weeks) was tested in a similar population and did not improve RFS over adjuvant nivolumab (14). It is currently unknown if the use of adjuvant anti–PD-1 therapy improves OS in patients with high-risk resected melanoma. In parallel to the testing of adjuvant immunotherapies for melanoma, adjuvant therapy with the BRAF inhibitor dabrafenib together with the MEK inhibitor trametinib for patients with resected stage III melanoma with a BRAF^V600E/K mutation demonstrated an improvement in RFS and distant metastasis-free survival compared with placebo (15). In this trial, OS was reported with the first interim analysis, but the protocol prespecified number of events had not been reached by year 5 (15).

We conducted a randomized phase III clinical trial in patients with completely resected melanoma at high risk of recurrence comparing adjuvant pembrolizumab with either of the two standard-of-care adjuvant immunotherapies at the time, which had previously been shown to improve OS over observation or placebo: the high-dose IFNα2b regimen (9) and ipilimumab at 10 mg/kg of body weight every three weeks (10). RFS and OS were both primary endpoints in order to determine if adjuvant pembrolizumab therapy would change the course of disease permanently, or if active therapies at the time of recurrence could attenuate differences between patients receiving adjuvant pembrolizumab or the prior standard-of-care adjuvant immunotherapies.

A total of 1,301 eligible patients were randomized from 211 sites in the United States, Canada, and Ireland: 647 patients were assigned to the pembrolizumab group and 654 to the standard-of-care group (Fig. 1). The characteristics of the patients at randomization were similar in the two groups (Table 1). When the trial first opened, standard-of-care adjuvant therapy consisted of high-dose IFNα2b (9). After the FDA approval of adjuvant ipilimumab (10), the protocol was amended to add ipilimumab as a treatment choice. Before the protocol amendment in April 2016, 74 patients had been randomized: 35 to IFNα2b and 40 to pembrolizumab. Among all eligible patients, 8 randomized to pembrolizumab and 89 randomized to standard of care did not receive the assigned regimen. Among the patients in the standard-of-care group who received the assigned treatment, 420 received ipilimumab and 145 received IFNα2b (Fig. 1).

Of the 639 patients who received pembrolizumab, 108 (16.9%) discontinued the regimen due to an adverse event. Among the 565 patients who received standard-of-care therapy, 308 (53.6%) discontinued the regimen due to an adverse event. A total of 134 (21.0%) in the pembrolizumab group discontinued the regimen because of disease recurrence, as compared with 92 (16.3%) in the standard-of-care group. A total of 365 patients (57.1%) in the pembrolizumab group and 50 (8.8%) in the standard-of-care group completed the regimen as stipulated in the protocol (Fig. 1). The median duration of follow-up for the patients alive was 47.3 months among patients randomized to pembrolizumab and 43.3 months randomized to standard of care.

The protocol established that the final analysis for RFS and OS would occur after the planned number of events had happened, or at 3.5 years after the last patient was randomized if the anticipated number of events had not yet been reached. As 3.5 years had passed without reaching the planned number of events, the clinical trial was analyzed for the primary endpoints, at which point 98% of the anticipated RFS events and 57% of the anticipated OS events had occurred. In the intent-to-treat population, RFS was significantly longer in the pembrolizumab group than in the standard-of-care group; HR for recurrence or death 0.76 [99.62% confidence interval (CI), 0.59–0.99; log-rank P = 0.002; Fig. 2A]. The RFS was also longer favoring pembrolizumab in the subgroup of patients with PD-L1–positive melanoma, with an HR of 0.69 (95% CI, 0.58–0.84; Supplementary Fig. S1A). In the intent-to-treat population, the HR for OS was 0.82 (pembrolizumab: standard-of-care) with 96.3% CI, 0.61–1.09; log-rank P = 0.15 (Fig. 2B). In the subgroup of patients with PD-L1–positive melanoma, the HR for OS was 0.84 with 97.8% CI, 0.59–1.22; log-rank P = 0.29 (Supplementary Fig. S1B).

We performed an exploratory analysis of post-recurrence OS, which was not significantly different between the two arms: HR for death 1.20 (95% CI, 0.90–1.61). PD-1 blocking antibodies as a single drug were the most commonly used regimen after recurrence in the standard-of-care group (39% of patients); 14% of patients in the pembrolizumab group received single-agent PD-1 antibody therapy (Supplementary Table S1). Other post-recurrence therapies included anti–PD-1 in combination with anti-CTLA4 or other immune-modulating agents, anti-CTLA4 alone, intra-lesional oncolytic therapy, IL2, IFNα2b, BRAF, and MEK inhibitor targeted therapies, radiation, and surgery. Thirty percent of the patients in both groups did not have data available regarding post-recurrence treatment. The predominant site of first recurrence was distant (60% with pembrolizumab, 71% with standard of care). Proportions of local, in-transit, and regional recurrences in the pembrolizumab group were 16%, 12%, and 11%, respectively; proportions in the standard-of-care group were 9%, 8%, and 13%, respectively (Supplementary Table S1).

The between-group associations in RFS observed in the overall population were consistently observed across subgroups based on baseline characteristics, including according to sex, age, standard-of-care therapy received, and stage of disease, with the possible exception that the group with macroscopic lymph node involvement may derive more improvement from pembrolizumab compared with microscopic lymph node involvement (Fig. 3; RFS macroscopic/microscopic interaction P = 0.08, all other interactions P > 0.22). Patients with PD-L1–positive tumors in the standard-of-care group may derive improvement in postprogression OS compared with the pembrolizumab group (Supplementary Fig. S2; interaction P = 0.09). Otherwise, between-group associations for overall population OS and post-recurrence OS were similar across subgroups (overall population OS: Supplementary Fig. S3, all interaction P > 0.28; post-recurrence OS: Supplementary Fig. S2, all other interaction P > 0.54).

Among the 97 patients who did not receive therapy as assigned by the study randomization, 52 (54%) withdrew consent for further follow-up or were lost to follow-up within 30 days of randomization, and RFS and OS were censored at this time. There was no evidence of a difference in RFS or OS comparing patients who received therapy per protocol (n = 1,204) versus the patients who did not (n = 97); HR for recurrence or death (not treated:treated) 1.44 with 95% CI, 0.89–2.13 and HR for OS 1.41 with 96.3% CI, 0.66–3.02. RFS and OS results in the subset of patients who received therapy per protocol (n = 1,204, safety population) were similar to results in the intent-to-treat population (n = 1,301); HR for recurrence or death 0.75 with 99.62% CI, 0.58–0.97 and HR for OS 0.78 with 96.3% CI, 0.58–1.04. In a final exploratory analysis, we analyzed the RFS data according to the two treatment options in the standard-of-care group: high-dose IFN or ipilimumab (Supplementary Fig. S4). In a Cox regression model for RFS, the interaction between randomized group with pre-randomization standard-of-care choice is P = 0.49, indicating no strong evidence of heterogeneity in treatment arm association with RFS by pre-randomization standard-of-care treatment choice.

Adverse events of any grade related to the trial regimen occurred in more than 90% of patients: 583 patients (91%) treated with pembrolizumab, 401 (95%) treated with ipilimumab, and 143 (99%) treated with IFNα2b (Table 2). Proportions of grade 3 and higher adverse events related to treatment were 17%, 43%, and 65% among patients treated with pembrolizumab, ipilimumab, and IFNα2b, respectively. Fatigue (59%) and maculopapular rash (29%) were the most common events among patients treated with pembrolizumab, whereas fatigue (51%) and diarrhea (48%) were most common among patients treated with ipilimumab; and fatigue (88%) and nausea (72%) were most common among patients treated with IFNα2b (Table 2). Pneumonitis was an uncommon event in all of the treatment arms, and as its frequency was less than 10%, it is not included in Table 2. Among patients treated with pembrolizumab, pneumonitis of any grade was observed in 4.1% of patients and grade 3 pneumonitis in 0.6%. Among patients treated with ipilimumab, the proportions of pneumonitis were 5.0% (all grades) and 1.4% (grade 3), and among patients treated with IFNα2b, they were 2.0% (all grades) and 0% (grade 3). Supplementary Table S2 provides information on any-causality adverse events in 10% or more of patients with any of the three treatment regimens. There was one death due to myocarditis in the pembrolizumab group attributed by the investigators to the treatment, and two among patients receiving ipilimumab, one due to colitis and one due to pneumonitis.

In this randomized phase III trial comparing pembrolizumab to either ipilimumab or IFNα2b for the treatment of patients with resected, high-risk stage III and IV melanoma, pembrolizumab was associated with a statistically significant 23% improvement in RFS. For OS, the HR of 0.82 was not statistically significant. An HR of 0.84 without statistical significance was also seen in the subgroup of patients with tumor PD-L1 expression. The RFS benefit observed in this trial is in the range of what has been shown with nivolumab compared with ipilimumab in a similar population of patients with resected stage III or IV melanoma in the CheckMate 238 trial (11). The KEYNOTE-054 study compared pembrolizumab with placebo in patients with resected stage III cutaneous melanoma and also demonstrated an improvement in RFS (12, 13). Therefore, three large adjuvant clinical trials have shown consistent improvement in RFS with the adjuvant administration of an anti–PD-1 therapy. The consequent question of whether adjuvant anti–PD-1 therapy improves OS has not been reported as final results in the KEYNOTE-054 trial (12, 13) and showed a nonsignificant 2% difference at four years in the CheckMate 238 trial, analyzed at 73% of the survival events needed for significance (16). In the current trial, pembrolizumab improved OS by 18%, which also did not meet the prespecified level of significance when analyzed at 57% of the originally planned survival events. The difference in RFS and OS benefit in our trial may reflect the use of other widely available effective therapies for patients with melanoma recurrence (2–7), or may in part reflect the assessment of OS at a fixed time per protocol, leading to a smaller number of events than would have been necessary for a fully powered event-driven analysis. However, because OS is highly dependent on the availability of post-recurrence therapies, which tend to improve over time, it is unlikely that this result would change with later evaluations.

One of the study findings was that the first recurrence at distant sites was 11% higher in the standard-of-care treatment group. This was due to an apparent increase in local and in-transit recurrences in the pembrolizumab arm (12% higher), whereas both groups had a similar proportion of recurrence events in regional lymph nodes. These are exploratory findings, and their significance is hard to determine with this data set. We also note here that the early relapse rate at the first scan visit was very high in our study, as has been observed in previous adjuvant therapy melanoma trials (11, 13), and was consistent between both arms. This finding suggests that the ability to detect distant disease at baseline is limited using current imaging scans and physical exam alone. We are hopeful highly sensitive blood-based markers for minimal residual disease will improve our confirmation of baseline disease-free status.

Efforts testing neoadjuvant therapy with immune-checkpoint inhibitors in melanoma are currently under way. Multiple regimens have been tested in small feasibility studies, including a single dose of pembrolizumab, varying strengths and doses of nivolumab plus ipilimumab, and monotherapy versus combination of immune-checkpoint blockade (17–20). However, it is currently not known whether it is superior to give systemic therapy before or after surgery of resectable melanoma. A large, randomized trial powered to detect differences in event-free survival known as S1801 is currently enrolling in the U.S. cooperative groups, and compares adjuvant pembrolizumab given as described in the current study versus three doses of neoadjuvant pembrolizumab followed by 15 doses of adjuvant pembrolizumab given every three weeks.

In conclusion, pembrolizumab as adjuvant therapy for patients with high-risk resected stage III and IV melanoma improves RFS in comparison with the prior standard-of-care adjuvant immunotherapies, but a similar association with OS was not observed among all patients or in the subset of patients with PD-L1–positive tumors. The safety profile of pembrolizumab is consistent with the toxicity spectrum that has already been defined for this agent. Single-agent anti–PD-1 antibody treatment should be considered the standard-of-care for adjuvant immunotherapy in high-risk melanoma.

The SWOG clinical trial S1404 enrolled patients from December 2015 to October 2017 who were 18 years of age or older with histologically confirmed cutaneous, acral, or mucosal melanoma, and were within 98 days from definitive surgery. Patients had resectable stage IIIA (N2a), IIIB, IIIC, or IV disease defined by the American Joint Committee on Cancer 2009 classification, 7th edition (21). A complete regional lymphadenectomy was required for all patients with stage III disease. Imaging studies to document melanoma-free status at enrollment included either a total body PET combined with CT of diagnostic quality or a CT of the chest, abdomen, and pelvis with contrast, and an MRI or CT scan of the brain with intravenous contrast. Main exclusion criteria included prior immunotherapy in any setting for melanoma, active autoimmune disease that had required systemic treatment within two years of study entry, uveal melanoma, and a history of brain metastasis. For full information on eligibility criteria, see the protocol in the Supplementary Information. Tumor tissue was required for central pathologic evaluation for PD-L1 expression by IHC using the 22C3 antibody as previously described (22), and was scored on a scale of 0 to 5 (with higher numbers reflecting a higher level of PD-L1 expression); a score of 2 or higher (staining on greater than 1% of cells) was considered to indicate PD-L1 positivity. The clinical trial was registered as ClinicalTrials.gov number NCT02506153.

This was an open-label randomized phase III study. Patients were randomized to receive either intravenous infusion of 200 mg of pembrolizumab every three weeks for a total of 18 doses, or an approved standard-of-care adjuvant immunotherapy. When the trial was first opened, the standard of care consisted of high-dose IFNα2b, given intravenously at 20 million units/m² of body surface area per day, five days per week for four weeks followed by 10 million units/m² of body surface given subcutaneously three times per week for 11 months (9). After the FDA approval of adjuvant ipilimumab in October 2015, the protocol was amended in April 2016 to add the choice of ipilimumab dosed at 10 mg/kg of body weight intravenously every three weeks for four doses followed by the same dose as maintenance every 12 weeks for up to 11 doses (10). Block randomization (1:1 ratio; block sizes varied: 6, 8, 10; sequence prespecified by SWOG) was performed centrally using the NCI web-based OPEN platform and stratified according to stage, PD-L1 melanoma staining, and the planned standard-of-care regimen.

Investigator-assessed recurrence was based on imaging or physical exam, with biopsy confirmation whenever possible. Clinical assessment and whole-body imaging occurred every three months for the first two years beyond randomization, and then every six months. Brain imaging was performed annually. Beyond year 5, no study-specific imaging was required, but RFS and OS status were to be monitored up to 10 years. Adverse events were scored using NCI Common Terminology Criteria for Adverse Events, version 5.0.

The trial was sponsored by SWOG, the NCI, and Merck Sharp & Dohme Corp. The initial protocol and all amendments were reviewed and approved by SWOG, the NCI, the NCI Central Institutional Review Board, and at each institution. Each study subject provided voluntary, written, informed consent as approved by the human subject protection committee of each institution. The work was conducted in compliance with all ethical guidelines including good clinical practice standards and the Declaration of Helsinki. The data were collected by staff at each site and monitored by SWOG. The data were analyzed and interpreted by the authors. All authors had access to the full data used in the manuscript and attest that the study as reported here follows the protocol.

The three primary endpoints were RFS, OS, and OS in the subgroup with PD-L1–positive tumors. RFS was measured from date of randomization to date of first of recurrence or death from any cause; patients last known to be alive without recurrence were censored at date of last contact. OS was measured from date of randomization to date of death from any cause; patients last known to be alive were censored at the date of last contact. Models for power and sample size calculations are detailed in the protocol. Full information was 536 RFS and 374 OS events in the overall population. Per protocol, the final analysis would occur at 3.5 years after the last patient was randomized if the anticipated number of events had not yet been reached. Alpha allocation to control the study-wise error to <0.05 is detailed in the Supplementary Materials. The alpha levels for these analyses are 0.0038 for RFS, 0.037 for OS in the overall population, and 0.023 for OS in the PD-L1–positive subgroup (the alpha in the PD-L1–positive subgroup accounts for the correlation between the subgroup and overall population, and maintains the study-wise alpha <0.05 with calculations per Speissens and DuBois; ref. 23). Baseline characteristics were compared between groups with Wilcoxon rank sum tests and Fisher exact tests. All three primary analyses were based on stratified log-rank tests in the intent-to-treat population. RFS and OS were estimated using the Kaplan–Meier method, and Cox regression models were fit. A nonrandomized comparison of survival from recurrence by randomized treatment was also performed. For primary endpoint analyses, CIs are reported to match the alpha level of the test. For other analyses, 95% CIs are reported. Two-sided P values are reported. Toxicity was summarized among patients who received at least one dose of protocol therapy. All analyses were performed in R (version 4.0.2) and SAS (version 9.4).

All data (to replicate every analysis in the manuscript and any Supplementary Information) will be posted to the NCI NCTN Data Archive per NCTN policy (https://nctn-data-archive.nci.nih.gov). Patient-level data, including a data dictionary, will be available within six months of publication through the United States NCTN/NCORP Data Sharing Archive (https://nctn-data-archive.nci.nih.gov) following the Data Sharing Archive policies. Deidentified patient-level data, including the numbers, tables, and figures in the paper, will be made available. The protocol (including the statistical analysis plan in section 11 of the protocol) and the informed consent form are available in the Supplementary Information.

K.F. Grossmann reports grants from NIH/NCI during the conduct of the study; planned future employment with Merck; and has received consulting fees from and served as a consultant or adviser for Bristol Myers Squibb, Novartis, Iovance, and Array. M. Othus reports grants from CA180819 during the conduct of the study, as well as personal fees from Merck, Daiichi Sankyo, BioSiight, Celgene, and Glycomimetics outside the submitted work. S.P. Patel reports personal fees from Merck during the conduct of the study, as well as other support from Bristol Myers Squibb, TriSalus Life Sciences, Reata Pharmaceuticals, Novartis, Deciphera, Provectus Biopharmaceuticals, Foghorn Therapeutics, Seattle Genetics, CastleBiosciences, and Immunocore outside the submitted work. A.A. Tarhini reports grants and personal fees from Bristol Myers Squibb, Genentech-Roche, Sanofi Genzyme, Regeneron, and Pfizer, personal fees from Merck, OncoSec, Novartis, Partner Therapeutics, Immunocore, BioNTech, and Array Biopharma, and grants from Clinigen, Checkmate, and Acrotech outside the submitted work. V.K. Sondak reports personal fees from Alkermes, Bristol Myers Squibb, Merck, Novartis, Regeneron, and Replimune, and grants from Neogene Therapeutics and Turnstone outside the submitted work. T.M. Petrella reports personal fees from Merck, Bristol Myers Squibb, Novartis, Sanofi, and Pfizer outside the submitted work. N.I. Khushalani reports grants from SWOG during the conduct of the study, as well as grants, personal fees, and other support from Bristol Myers Squibb and Regeneron, grants and personal fees from Merck, Novartis, and HUYA Bioscience, grants from Replimmune, Celgene, GlaxoSmithKline, and Amgen, personal fees from Array Biopharma, Immunocore, Jounce Therapeutics, Iovance Biotherapeutics, Sanofi Genzyme, and National Comprehensive Cancer Network (through Pfizer), and other support from AstraZeneca, Incyte, Nektar, Bellicum Pharmaceuticals, Asensus Surgical, Mazor Robotics, and Amarin Corporation outside the submitted work. J.V. Cohen reports personal fees from Regeneron and Sanofi Genzyme outside the submitted work. E.I. Buchbinder reports personal fees from Bristol Myers Squibb outside the submitted work. P. Funchain reports grants from Pfizer and Bristol Myers Squibb and personal fees from Eisai outside the submitted work. K.D. Lewis reports grants from SWOG during the conduct of the study, as well as grants and personal fees from Merck, Bristol Myers Squibb, Regeneron, Sanofi, Genentech, and Iovance, personal fees from Pfizer, and grants from Nektar, OncoSec, Ultimavacs, Alkermes, and SeaGen outside the submitted work. B. Chmielowski reports grants from SWOG during the conduct of the study, as well as personal fees from Nektar, Novartis, Genentech, IDEAYA Biosciences, OncoSec, Iovance, Sanofi Genzyme, Deciphera, Epizyme, Biothera, and Regeneron outside the submitted work. R.R. Kudchadkar reports grants and personal fees from Merck, Regeneron, and Pfizer and personal fees from Bristol Myers Squibb and Novartis outside the submitted work. D.B. Johnson reports grants from SWOG/NCI during the conduct of the study, as well as other support from Bristol Myers Squibb, Catalyst, Iovance, Janssen, Merck, Mosaic ImmunoEngineering, Novartis, Pfizer, OncoSec, and Targovax, and grants from Bristol Myers Squibb and Incyte outside the submitted work. Z. Eroglu reports grants from Pfizer and Novartis, and personal fees from Genetech, Pfizer, Eisai, OncoSec, Natera and Regeneron outside the submitted work. S.W. Ebbinghaus reports personal fees from Merck during the conduct of the study. S. Ahsan reports personal fees from Merck during the conduct of the study, as well as other support from Merck outside the submitted work. N. Ibrahim is an employee of Merck. J.M. Kirkwood reports grants and personal fees from Amgen, Bristol Myers Squibb, Checkmate Pharmaceuticals, Immunocore, Iovance Biotherapeutics, Merck, and Novartis Pharmaceuticals, personal fees from Ankyra Therapeutics, Axio Research/Instil Bio, Becker Pharmaceutical, DermTech, Elsevier, Fenix Group International, Harbour BioMed, Intellisphere, LLC/Cancer Network, IQVIA, Istari Oncology, Millennium Pharmaceuticals/Takeda, Natera Inc., OncoCyte Corporation, OncoSec Medical Inc., Pfizer, Replimune, Scopus BioPharma, and SR One, and grants from Castle Biosciences, Immvira Pharma, Lion Biotechnologies, and Schering-Plough outside the submitted work. A. Ribas reports other support from SWOG, NCI, and Merck during the conduct of the study, as well as personal fees from Amgen, Chugai, Genentech, Merck, Novartis, Roche, Sanofi, Vedanta, 4C Biomed, Appia, Apricity, Arcus, Highlight, Compugen, ImaginAb, Kalthera-Immpact Bio, MapKure, Merus, Rgenix, Lutris, PACT Pharma, Synthekine, Tango, Advaxis, CytomX, Five Prime, RAPT, Isoplexis, and Kite-Gilead and grants from Agilent and Bristol Myers Squibb outside the submitted work. No disclosures were reported by the other authors.

K.F. Grossmann: Conceptualization, supervision, investigation, writing–original draft, project administration, writing–review and editing. M. Othus: Conceptualization, data curation, formal analysis, supervision, validation, investigation, visualization, methodology, writing–original draft, project administration, writing–review and editing. S.P. Patel: Conceptualization, supervision, investigation, writing–review and editing. A.A. Tarhini: Conceptualization, investigation, writing–review and editing. V.K. Sondak: Conceptualization, investigation, writing–review and editing. M.V. Knopp: Investigation, writing–review and editing. T.M. Petrella: Investigation, writing–review and editing. T. Truong: Investigation, writing–review and editing. N.I. Khushalani: Investigation, writing–review and editing. J.V. Cohen: Investigation, writing–review and editing. E.I. Buchbinder: Investigation, writing–review and editing. K. Kendra: Investigation, writing–review and editing. P. Funchain: Investigation, writing–review and editing. K.D. Lewis: Investigation, writing–review and editing. R.M. Conry: Investigation, writing–review and editing. B. Chmielowski: Investigation, writing–review and editing. R.R. Kudchadkar: Investigation, writing–review and editing. D.B. Johnson: Investigation, writing–review and editing. H. Li: Data curation, formal analysis, methodology, writing–review and editing. J. Moon: Data curation, formal analysis, methodology, writing–review and editing. Z. Eroglu: Investigation, writing–review and editing. B. Gastman: Investigation, writing–review and editing. M. Kovacsovics-Bankowski: Data curation, validation, writing–review and editing. K.S. Gunturu: Investigation, writing–review and editing. S.W. Ebbinghaus: Conceptualization, funding acquisition, investigation, project administration, writing–review and editing. S. Ahsan: Funding acquisition, investigation, project administration, writing–review and editing. N. Ibrahim: Conceptualization, funding acquisition, project administration, writing–review and editing. E. Sharon: Conceptualization, funding acquisition, project administration, writing–review and editing. L.A. Korde: Funding acquisition, project administration, writing–review and editing. J.M. Kirkwood: Conceptualization, supervision, investigation, writing–review and editing. A. Ribas: Conceptualization, formal analysis, supervision, investigation, writing–original draft, writing–review and editing.

The authors extend their deepest gratitude to the patients, their families, and supportive friends/caregivers for participating in the study. We thank Dr. Lawrence Flaherty (Barbara Ann Karmanos Cancer Institute, Detroit, MI) for serving as chair of the SWOG data monitoring committee for oversight of this trial. We thank Danae Campos and Catrina Mireles for logistical and administrative support. The authors wish to thank SWOG Melanoma Committee Patient Advocates, Valerie Guild (deceased) and Samantha Guild, for their invaluable contributions in support of this study. This sudy was supported by NIH/NCI NCTN grants CA180888, CA180819, CA180820, CA180863, UG1CA233178, UG1CA233329, UG1CA189821, UG1CA233331, UG1CA233324, and in part by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.. A. Ribas is supported by NIH/NCI grants R35 CA197633 and P01 CA244118.

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