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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 = 487) or placebo (n = 489). 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.

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. Immune checkpoint inhibitors have led to unprecedented prolongation of overall survival (OS) for patients with advanced melanoma. Five-year follow-up of KEYNOTE-006 showed pembrolizumab prolonged survival versus ipilimumab. Efficacy results with 7-year follow-up are presented. At data cutoff (April 19, 2021), median follow-up was 85.3 months (range, 0.03-90.8 months). Median OS was 32.7 months for pembrolizumab versus 15.9 months for ipilimumab (hazard ratio [HR], 0.70; 95% CI, 0.58 to 0.83); 7-year OS was 37.8% and 25.3%, respectively. OS HRs favored pembrolizumab regardless of BRAF status or prior BRAF/MEK-inhibitor treatment and prognostic characteristics (elevated lactate dehydrogenase, large tumor size, and brain metastasis). Median modified progression-free survival (mPFS) was 9.4 months for pembrolizumab versus 3.8 months for ipilimumab; 7-year mPFS was 23.8% and 13.3%, respectively. In patients who completed ≥94 weeks of pembrolizumab, the 5-year OS was 92.9% and the 5-year mPFS was 70.1%. The objective response rate with second-course pembrolizumab (n = 16) was 56% (95% CI, 30 to 80) and the 2-year mPFS was 62.5%. These findings confirm that pembrolizumab provides long-term survival benefit in advanced melanoma.

Purpose: Ipilimumab and nivolumab have each shown treatment benefit for high-risk resected melanoma. The phase III CheckMate 915 trial evaluated adjuvant nivolumab plus ipilimumab versus nivolumab alone in patients with resected stage IIIB-D or IV melanoma., Patients and Methods: In this randomized, double-blind, phase III trial, 1,833 patients received nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks (916 patients) or nivolumab 480 mg once every 4 weeks (917 patients) for ≤ 1 year. After random assignment, patients were stratified by tumor programmed death ligand 1 (PD-L1) expression and stage. Dual primary end points were recurrence-free survival (RFS) in randomly assigned patients and in the tumor PD-L1 expression-level < 1% subgroup., Results: At a minimum follow-up of approximately 23.7 months, there was no significant difference between treatment groups for RFS in the all-randomly assigned patient population (hazard ratio, 0.92; 95% CI, 0.77 to 1.09; P = .269) or in patients with PD-L1 expression < 1% (hazard ratio, 0.91; 95% CI, 0.73 to 1.14). In all patients, 24-month RFS rates were 64.6% (combination) and 63.2% (nivolumab). Treatment-related grade 3 or 4 adverse events were reported in 32.6% of patients in the combination group and 12.8% in the nivolumab group. Treatment-related deaths were reported in 0.4% of patients in the combination group and in no nivolumab-treated patients., Conclusion: Nivolumab 240 mg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks did not improve RFS versus nivolumab 480 mg once every 4 weeks in patients with stage IIIB-D or stage IV melanoma. Nivolumab showed efficacy consistent with previous adjuvant studies in a population resembling current practice using American Joint Committee on Cancer eighth edition, reaffirming nivolumab as a standard of care for melanoma adjuvant treatment.

Purpose: Currently, there are no robust biomarkers that predict immunotherapy outcomes in metastatic melanoma. We sought to build multivariable predictive models for response and survival to anti-programmed cell death protein 1 (anti-PD-1) monotherapy or in combination with anticytotoxic T-cell lymphocyte-4 (ipilimumab [IPI]; anti-PD-1 ± IPI) by including routine clinical data available at the point of treatment initiation., Methods: One thousand six hundred forty-four patients with metastatic melanoma treated with anti-PD-1 ± IPI at 16 centers from Australia, the United States, and Europe were included. Demographics, disease characteristics, and baseline blood parameters were analyzed. The end points of this study were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The final predictive models for ORR, PFS, and OS were determined through penalized regression methodology (least absolute shrinkage and selection operator method) to select the most significant predictors for all three outcomes (discovery cohort, N = 633). Each model was validated internally and externally in two independent cohorts (validation-1 [N = 419] and validation-2 [N = 592]) and nomograms were created., Results: The final model for predicting ORR (area under the curve [AUC] = 0.71) in immunotherapy-treated patients included the following clinical parameters: Eastern Cooperative Oncology Group Performance Status, presence/absence of liver and lung metastases, serum lactate dehydrogenase, blood neutrophil-lymphocyte ratio, therapy (monotherapy/combination), and line of treatment. The final predictive models for PFS (AUC = 0.68) and OS (AUC = 0.77) included the same variables as those in the ORR model (except for presence/absence of lung metastases), and included presence/absence of brain metastases and blood hemoglobin. Nomogram calculators were developed from the clinical models to predict outcomes for patients with metastatic melanoma treated with anti-PD-1 ± IPI., Conclusion: Newly developed combinations of routinely collected baseline clinical factors predict the response and survival outcomes of patients with metastatic melanoma treated with immunotherapy and may serve as valuable tools for clinical decision making., Competing Interests: Inês Pires da SilvaConsulting or Advisory Role: MSDSpeakers' Bureau: Roche, Novartis, Bristol Myers SquibbTravel, Accommodations, Expenses: Roche, Bristol Myers Squibb Jennifer L. McQuadeHonoraria: Merck, Bristol Myers Squibb, RocheConsulting or Advisory Role: Bristol Myers Squibb, Roche Pharma AGTravel, Accommodations, Expenses: Merck Selma UgurelHonoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, Merck SeronoConsulting or Advisory Role: Bristol Myers Squibb, Roche, Merck SeronoResearch Funding: Bristol Myers Squibb (Inst), Merck Serono (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, Pierre Fabre Rudolf HerbstEmployment: Helios Kliniken Jochen UtikalStock and Other Ownership Interests: BioNTech, Moderna Therapeutics, Pfizer, Merck, SanofiHonoraria: Bristol Myers Squibb, Novartis, MSD Oncology, Roche, Pierre Fabre, SanofiConsulting or Advisory Role: Bristol Myers Squibb, Roche, MSD Oncology, Novartis, Pierre Fabre, Amgen, SanofiResearch Funding: Apogenix (Inst), Noxxon Pharma (Inst), Elsalys Biotech (Inst), TILT Biotherapeutics (Inst)Travel, Accommodations, Expenses: MSD Oncology, Roche, Novartis, Pierre Fabre, Bristol Myers Squibb, Amgen, Sanofi Claudia PföhlerHonoraria: Bristol Myers Squibb, Novartis, Roche, MSD, Merck Serono, Sun Pharma, Amgen, AbbVieConsulting or Advisory Role: Bristol Myers Squibb Foundation, Novartis, MSD, Roche, Sanofi, Allergy Therapeutics, Merck SeronoTravel, Accommodations, Expenses: Bristol Myers Squibb, Novartis, MSD, Roche, Pierre Fabre, Celgene, AbbVie, Merck Serono Patrick TerheydenHonoraria: Bristol Myers Squibb, Novartis, Roche, CureVac, Merck Serono, MSD OncologyConsulting or Advisory Role: Bristol Myers Squibb, Novartis, Pierre Fabre, Roche, Sanofi, Merck KGaA, 4SC, AlmirallTravel, Accommodations, Expenses: Bristol Myers Squibb, Pierre Fabre Michael WeichenthalHonoraria: Merck Sharp & Dohme, Roche, Novartis, Bristol Myers Squibb, SanofiConsulting or Advisory Role: Merck Sharp & Dohme, Roche, Novartis, Bristol Myers Squibb, Sun Pharma, Sanofi, Pierre FabreResearch Funding: Merck Sharp & Dohme (Inst), Millennium (Inst), Bristol Myers Squibb (Inst), Johnson & Johnson (Inst), Novartis (Inst) Ralf GutzmerHonoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, Novartis, Merck Serono, Almirall Hermal GmbH, Amgen, Sun Pharma, Pierre Fabre, Sanofi/Regeneron, ImmunocoreConsulting or Advisory Role: Bristol Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, Novartis, Almirall Hermal GmbH, 4SC, Amgen, Pierre Fabre, Merck Serono, Sun Pharma, Sanofi, ImmunocoreResearch Funding: Pfizer (Inst), Novartis (Inst), Johnson & Johnson (Inst), Amgen (Inst), Merck Serono (Inst), Sun Pharma (Inst), Sanofi (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Roche, Merck Serono, Pierre Fabre, Sun Pharma Peter MohrHonoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Roche/Genentech, Novartis, Amgen, Pierre Fabre, Merck, SanofiConsulting or Advisory Role: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Amgen, Roche, Merck, Pierre Fabre, SanofiSpeakers' Bureau: Novartis, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Amgen, SanofiResearch Funding: Merck Sharp & Dohme (Inst), Bristol Myers Squibb (Inst), Novartis (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Amgen, Roche, Sun Pharma, Sanofi Jessica L. SmithHonoraria: Pierre FabreTravel, Accommodations, Expenses: MSD Oncology Richard A. ScolyerEmployment: Royal Prince Alfred HospitalHonoraria: GlaxoSmithKline, Harvard Medical School, Wake Forest School of MedicineConsulting or Advisory Role: Bristol Myers Squibb GesmbH (Austria), Bristol Myers Squibb SA (Switzerland), GlaxoSmithKline, Merck Sharp & Dohme, NeraCare GmbH, Novartis Australia, Amgen, Myriad Genetics, MSD Sharp & Dohme (Australia) Pty Limited, Novartis, QBiotics, Provectus Biopharmaceuticals Australia, Evaxion BioTech A/S, Novartis Pharmaceuticals Australia Pty Limited, RocheResearch Funding: The Ainsworth Foundation (Inst), National Health and Medical Research Council, Melanoma Research Alliance (MRA) GrantTravel, Accommodations, Expenses: Bristol Myers Squibb, Novartis AustraliaUncompensated Relationships: Melanoma Institute Australia Ana M. AranceConsulting or Advisory Role: BMS, Roche, Novartis, Pierre Fabre, MSD, Merck, SanofiSpeakers' Bureau: Pierre Fabre, Novartis, MSD, BMS, Roche, Merck, SanofiResearch Funding: Pierre Fabre, Novartis, Roche, BMS, MSD, Merck, Sanofi, AmgenTravel, Accommodations, Expenses: BMS, MSD, Novartis, Pierre Fabre, Roche, Merck, Sanofi Lisa PickeringConsulting or Advisory Role: Pfizer, Ipsen, BMS, Eisai, MSD Oncology, NovartisSpeakers' Bureau: Pfizer, BMSResearch Funding: NIHR (Inst), Rosetrees Trust (Inst), Kidney and melanoma cancer fund of RMH charity (Inst) James LarkinHonoraria: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Roche/Genentech, Incyte, iOnctura, Merck Serono, Eisai, Dynavax Technologies, Cancer Research UK, touchIME, touchEXPERTSConsulting or Advisory Role: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Boston Biomedical, Incyte, iOnctura, Iovance Biotherapeutics, Immunocore, YKT Corporation, Apple Tree PartnersResearch Funding: Pfizer (Inst), Novartis (Inst), MSD (Inst), Bristol Myers Squibb (Inst), Achilles Therapeutics (Inst), Roche (Inst), Nektar (Inst), Covance (Inst), Immunocore (Inst), AVEO (Inst), Pharmacyclics (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Incyte, GlaxoSmithKline, Pierre Fabre, Merck Serono, iOnctura, British Uro-Oncology Group (BUG), ESMO, National Cancer Research Institute (NCRI), EUSA Pharma, Syneos Health, Kidney Cancer Association, Bioevents, MedConcept, RV Mais Paul LoriganHonoraria: Novartis, Pierre Fabre, Merck, BMS, MSD, NeraCare GmbH, Amgen, Roche, Oncology Education, NektarConsulting or Advisory Role: Merck Sharp & Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Novartis, NektarSpeakers' Bureau: Merck Sharp & Dohme, Novartis, Bristol Myers Squibb, Pierre FabreResearch Funding: BMS, Pierre FabreTravel, Accommodations, Expenses: Merck Sharp & Dohme, Bristol Myers Squibb Christian U. BlankStock and Other Ownership Interests: Uniti Cars, ImmageneConsulting or Advisory Role: Roche/Genentech (Inst), MSD Oncology (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), GlaxoSmithKline (Inst), Pfizer (Inst), AstraZeneca (Inst), Lilly (Inst), Pierre Fabre (Inst), GenMab (Inst), Third Rock VenturesResearch Funding: Bristol Myers Squibb (Inst), Novartis (Inst), NanoString Technologies (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb Dirk SchadendorfHonoraria: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Immunocore, Merck Serono, Array BioPharma, Pfizer, Pierre Fabre, Philogen, Regeneron, 4SC, Sanofi/Regeneron, NeraCare GmbH, Sun Pharma, InflarxGmbH, Ultimovacs, SandozConsulting or Advisory Role: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi/Regeneron, NektarSpeakers' Bureau: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi/Regeneron, Merck KGaAResearch Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Roche (Inst), MSD Oncology (Inst), Array BioPharma/Pfizer (Inst)Travel, Accommodations, Expenses: Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, Merck Sharp & Dohme, Pierre Fabre, Sanofi/Regeneron Michael A. DaviesConsulting or Advisory Role: Genentech/Roche, Novartis, Bristol Myers Squibb, NanoString Technologies, Array BioPharma, Apexigen, ABM Therapeutics, Pfizer, EisaiResearch Funding: GlaxoSmithKline (Inst), Genentech/Roche (Inst), AstraZeneca (Inst), Merck (Inst), Oncothyreon (Inst), Myriad Genetics (Inst), Sanofi (Inst), Pfizer (Inst) Matteo S. CarlinoHonoraria: Bristol Myers Squibb, MSD, NovartisConsulting or Advisory Role: Bristol Myers Squibb, MSD, Amgen, Novartis, Pierre Fabre, Roche, IDEAYA Biosciences, Sanofi, Merck Serono, Regeneron, QBiotics, Nektar, Eisai, OncoSec Douglas B. JohnsonConsulting or Advisory Role: Bristol Myers Squibb, Merck, Novartis, Janssen, Iovance Biotherapeutics, Catalyst Pharmaceuticals, Oncosec, Pfizer, Mosaic ImmunoEngineering, TargovaxResearch Funding: Incyte, Bristol Myers SquibbPatents, Royalties, Other Intellectual Property: Intellectual property and patents pending surrounding use of MHC-II and response to immune therapy Georgina V. LongHonoraria: BMS, Pierre FabreConsulting or Advisory Role: Aduro Biotech, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Hexal, Highlight Therapeutics, Merck Sharpe & Dohme, Novartis, OncoSec, Pierre Fabre, QBiotics, Regeneron, SkylineDx, Specialised Therapeutics, Array BioPharma, Evaxion Biotech A/S, Evaxion Biotech A/S, SkylineDX B.V Alexander M. MenziesConsulting or Advisory Role: MSD Oncology, Novartis, Pierre Fabre, Bristol Myers Squibb, Roche, QBioticsNo other potential conflicts of interest were reported.

Purpose: In the phase III CheckMate 067 trial, durable clinical benefit was demonstrated previously with nivolumab plus ipilimumab and nivolumab alone versus ipilimumab. Here, we report 6.5-year efficacy and safety outcomes., Patients and Methods: Patients with previously untreated unresectable stage III or stage IV melanoma were randomly assigned 1:1:1 to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks (n = 314), nivolumab 3 mg/kg once every 2 weeks (n = 316), or ipilimumab 3 mg/kg once every 3 weeks (four doses; n = 315). Coprimary end points were progression-free survival and overall survival (OS) with nivolumab plus ipilimumab or nivolumab versus ipilimumab. Secondary end points included objective response rate, descriptive efficacy assessments of nivolumab plus ipilimumab versus nivolumab alone, and safety. Melanoma-specific survival (MSS; descriptive analysis), which excludes deaths unrelated to melanoma, was also evaluated., Results: Median OS (minimum follow-up, 6.5 years) was 72.1, 36.9, and 19.9 months in the combination, nivolumab, and ipilimumab groups, respectively. Median MSS was not reached, 58.7, and 21.9 months, respectively; 6.5-year OS rates were 57%, 43%, and 25% in patients with BRAF -mutant tumors and 46%, 42%, and 22% in those with BRAF -wild-type tumors, respectively. In patients who discontinued treatment, the median treatment-free interval was 27.6, 2.3, and 1.9 months, respectively. Since the 5-year analysis, no new safety signals were observed., Conclusion: These 6.5-year CheckMate 067 results, which include the longest median OS in a phase III melanoma trial reported to date and the first report of MSS, showed durable, improved clinical outcomes with nivolumab plus ipilimumab or nivolumab versus ipilimumab in patients with advanced melanoma and, in descriptive analyses, with the combination over nivolumab monotherapy., Competing Interests: Jedd D. WolchokStock and Other Ownership Interests: Tizona Therapeutics Inc, Adaptive Biotechnologies, Imvaq Therapeutics, Beigene, Linnaeus Therapeutics, Arsenal IO, Georgiamune, LLC, Apricity Therapeutics, Maverick Therapeutics, Trieza TherapeuticsConsulting or Advisory Role: Bristol Myers Squibb, Merck, Sellas Life Sciences, Lilly, Tizona Therapeutics, Inc, Amgen, Chugai Pharma, Adaptive Biotechnologies, Ascentage Pharma, PsiOxus Therapeutics, F-Star Biotechnology, Surface Oncology, Apricity Therapeutics, Astellas Pharma, Recepta Biopharma, Arsenal IO, Boehringer Ingelheim, AstraZeneca, Daiichi Sankyo, IncDragonfly Therapeutics, Georgiamune, Kyowa Kirin Pharmaceutical, Maverick Therapeutics, Werewolf Therapeutics, Trishula Therapeutics, Idera, Imvaq Therapeutics, Bicara TherapeuticsResearch Funding: Bristol Myers Squibb (Inst), Genentech/Roche (Inst), Merck Sharp & Dohme (Inst)Patents, Royalties, Other Intellectual Property: I am a coinventor on an issued patent for DNA vaccines for treatment of cancer in companion animals. I am a coinventor on a patent for use of oncolytic Newcastle Disease virus. I am a coinventor and receive royalties for a blood test for monitoring myeloid derived suppressor cells. I am coinventor and receive royalties for a patent for immune modulating antibodies. I am a coinventor on a patent for CAR+ T cells targeting differentiation antigens as means to treat cancer. I am a coinventor on a patent for Anti-CD40 agonist mAb fused to Monophosphoryl Lipid A (MPL) for cancer therapy. Alphavirus replicon particles expressing TRP2. Engineered Vaccinia Viruses for Cancer Immunotherapy. Recombinant poxviruses for cancer immunotherapy Vanna Chiarion-SileniConsulting or Advisory Role: MSD Oncology, Merck Serono, Bristol Myers Squibb, Novartis, Pierre Fabre, RocheSpeakers' Bureau: Bristol Myers Squibb, Novartis, Merck Serono, Pierre FabreTravel, Accommodations, Expenses: Bristol Myers Squibb, Pierre Fabre Rene GonzalezStock and Other Ownership Interests: AstraZeneca, GlaxoSmithKline, Lilly, Johnson & Johnson, Merck, Novartis, Pfizer, Procter & Gamble, SanofiConsulting or Advisory Role: AmgenResearch Funding: Millenium Pharamceuticals (Inst), Takeda (Inst), Boston Biomedical (Inst), Bristol Myers Squibb (Inst), Checkmate Pharmaceuticals (Inst), Incyte (Inst), Syndax (Inst), Roche/Genentech (Inst), Tesaro (Inst), Amgen (Inst), Morphotek (Inst), Checkmate Pharmaceuticals (Inst), Regeneron (Inst), Iovance Biotherapeutics (Inst), Nektar (Inst), Kartos Therapeutics (Inst), Taiga (Inst), Incyte (Inst), Exicure (Inst), Replimune (Inst), Alkermes (Inst), Ultimovacs (Inst), Moderna Therapeutics (Inst), OncoSec¸ Synlogic (Inst), Merck (Inst), Array BioPharma (Inst), Senhwa Biosciences (Inst), Immunocore (Inst), EMD Serono (Inst) Jean-Jacques GrobConsulting or Advisory Role: BMS, MSD Oncology, Roche/Genentech, Novartis, Amgen, Pierre Fabre, Sun Pharma, Merck KGaA, Sanofi, Pfizer, RocheSpeakers' Bureau: NovartisTravel, Accommodations, Expenses: BMS, MSD Oncology, Novartis, Pierre Fabre Piotr RutkowskiHonoraria: Bristol Myers Squibb, MSD, Novartis, Roche, Lilly, Pfizer, Pierre Fabre, Sanofi, MerckConsulting or Advisory Role: Novartis, Blueprint Medicines, Bristol Myers Squibb, Pierre Fabre, MSD, AmgenSpeakers' Bureau: Pfizer, Novartis, LillyResearch Funding: Novartis (Inst), Roche (Inst), Bristol Myers Squibb (Inst)Travel, Accommodations, Expenses: Orphan Europe, Pierre Fabre Christopher D. LaoConsulting or Advisory Role: Immunocore, BMSResearch Funding: Bristol Myers Squibb, Dynavax Technologies, GenentechTravel, Accommodations, Expenses: Immunocore, BMS C. Lance CoweyEmployment: Texas Oncology, US OncologyLeadership: US OncologyHonoraria: MerckConsulting or Advisory Role: Merck, Novartis, Pfizer¸ Iovance BiotherapeuticsResearch Funding: Bristol Myers Squibb (Inst), Genentech/Roche (Inst), Novartis (Inst), EMD Serono (Inst), Merck (Inst), Array BioPharma (Inst), Amgen (Inst), Regeneron (Inst), Celldex (Inst), Seattle Genetics (Inst) Dirk SchadendorfHonoraria: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Immunocore, Merck Serono, Array BioPharma, Pfizer, Pierre Fabre, Philogen, Regeneron, 4SC, Sanofi/Regeneron, NeraCare GmbH, Sun Pharma, InflarxGmbH, Ultimovacs, SandozConsulting or Advisory Role: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi/Regeneron, NektarSpeakers' Bureau: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi/Regeneron, Merck KGaAResearch Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Roche (Inst), MSD Oncology (Inst), Array BioPharma/Pfizer (Inst)Travel, Accommodations, Expenses: Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, Merck Sharp & Dohme, Pierre Fabre, Sanofi/Regeneron John WagstaffHonoraria: Bristol Myers Squibb, Roche, Pierre Fabre, Novartis, GlaxoSmithKline UK Ltd, PfizerConsulting or Advisory Role: Bristol Myers Squibb, Roche, Pfizer, Novartis, Pierre FabreSpeakers' Bureau: Bristol Myers Squibb Reinhard DummerHonoraria: Roche, Novartis, Bristol Myers Squibb, MSD, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator Bioscience, MaxiVax, touchIME, T3 Pharmaceuticals, PfizerConsulting or Advisory Role: Roche, Bristol Myers Squibb, MSD, Novartis, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Alligator Bioscience, touchIME, MaxiVax, Regeneron, Pfizer, T3 PharmaceuticalsResearch Funding: Roche (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), MSD (Inst), Amgen (Inst) Pier Francesco FerrucciConsulting or Advisory Role: Bristol Myers Squibb, Roche, Novartis, MSD Oncology, Pierre FabreResearch Funding: BMSTravel, Accommodations, Expenses: MSD Oncology, Bristol Myers Squibb Michael SmylieHonoraria: Bristol Myers Squibb, Novartis Canada Pharmaceuticals Inc, Merck, Roche Canada, Sanofi/RegeneronConsulting or Advisory Role: Merck Marcus O. ButlerHonoraria: Merck, Roche, Bristol Myers Squibb, NovartisConsulting or Advisory Role: Merck, Bristol Myers Squibb, Novartis, Immunovaccine, Immunocore, Adaptimmune, EMD Serono, GlaxoSmithKline, Genzyme, Sanofi, LaRoche Posay, Sun Pharma, Instil Bio, Iovance Biotherapeutics, Pfizer, AdaptimmuneResearch Funding: Merck, Takara BioExpert Testimony: Merck Andrew HillEmployment: Tasman OncologyStock and Other Ownership Interests: Tasman Oncology Ivan Márquez-RodasConsulting or Advisory Role: Bristol Myers Squibb, MSD¸ Novartis, Roche, Amgen, Sanofi, AstraZeneca, Merck Serono, Incyte, Bioncotech, Pierre Fabre, RegeneronTravel, Accommodations, Expenses: Bristol Myers Squibb, MSD¸ Roche, Bioncotech John B. A. G. HaanenStock and Other Ownership Interests: Neogene TherapeuticsConsulting or Advisory Role: MSD Oncology (Inst), Pfizer (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Roche/Genentech (Inst), Ipsen (Inst), Achilles Therapeutics (Inst), Immunocore (Inst), Sanofi (Inst), Third Rock Ventures (Inst), Neogene Therapeutics (Inst), Molecular Partners (Inst), bioNTech (Inst), T-Knife (Inst), PokeAcel (Inst), Instil Bio (Inst), Iovance Biotherapeutics (Inst)Research Funding: MSD (Inst), Bristol-Myers Squibb (Inst), Novartis (Inst), Neon Therapeutics (Inst), Amgen (Inst), BioNTech (Inst), Asher Biotherapeutics (Inst) Massimo GuidoboniConsulting or Advisory Role: BMS, Novartis, Pierre FabreSpeakers' Bureau: BMS, Novartis, Pierre FabreResearch Funding: MSD Michele MaioStock and Other Ownership Interests: Theravance, Epigen TherapeuticsHonoraria: Bristol Myers Squibb, AstraZeneca, Roche, MSD, Merck, Amgen, Pierre Fabre¸ Alfasigma, Sanofi, LillyConsulting or Advisory Role: Bristol Myers Squibb, Roche, AstraZeneca, MSD, Merck, Pierre Fabre, AlfasigmaPatents, Royalties, Other Intellectual Property: DNA Hypomethylating agents for cancer therapyTravel, Accommodations, Expenses: Bristol Myers Squibb, AstraZeneca, Roche, MSD, Merck, Amgen, Pierre Fabre, Alfasigma Patrick SchöffskiHonoraria: Deciphera, Blueprint Medicines, Boehringer IngelheimConsulting or Advisory Role: Blueprint Medicines, Ellipses Pharma, Adaptimmune, Intellisphere, Transgene, Deciphera, Exelixis, Boehringer Ingelheim, Medscape, Guided Clarity, Ysios Capital, Studiecentrum voor Kernenergie, Modus Outcomes, Advance Medical/Teladoc Health (Inst), Curio Science, SQZ Biotechnology, CRT Pioneer Fund LP, AdcendoResearch Funding: CoBioRes NV (Inst), Eisai (Inst), G1 Therapeutics (Inst), Novartis (Inst), PharmaMar (Inst)Travel, Accommodations, Expenses: MSD (Inst), Ipsen (Inst), Boehringer Ingelheim (Inst) Matteo S. CarlinoHonoraria: Bristol Myers Squibb, MSD, NovartisConsulting or Advisory Role: Bristol Myers Squibb, MSD, Amgen, Novartis, Pierre Fabre, Roche, IDEAYA Biosciences, Sanofi, Merck Serono, Regeneron, QBiotics, Nektar, Eisai, OncoSec Céleste LebbéHonoraria: Roche, Bristol Myers Squibb, Novartis, Amgen, MSD, Pierre Fabre, Pfizer, IncyteConsulting or Advisory Role: Bristol Myers Squibb, MSD, Novartis, Amgen, Roche, Merck Serono, Sanofi, Pierre FabreSpeakers' Bureau: Roche, Bristol Myers Squibb, Novartis, Amgen, MSDResearch Funding: Roche (Inst), Bristol Myers Squibb (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, MSD, Novartis, Sanofi, Pierre FabreOther Relationship: Avantis Medical Systems Grant McArthurResearch Funding: Genentech/Roche (Inst), MSD (Inst), Roche (Inst) Paolo A. AsciertoStock and Other Ownership Interests: PrimeVaxConsulting or Advisory Role: Bristol Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca¸ Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Takis Biotech, Lunaphore Technologies, Seattle Genetics, ITeos Therapeutics,Research Funding: Bristol Myers Squibb (Inst), Roche/Genentech (Inst), Array BioPharma (Inst), Sanofi (Inst)Travel, Accommodations, Expenses: Merck Sharp & Dohme Gregory A. DanielsHonoraria: Sanofi/RegeneronConsulting or Advisory Role: Sanofi/RegeneronSpeakers' Bureau: Regeneron, Array BioPharma, Sanofi/Regeneron,Research Funding: Bristol Myers Squibb (Inst), Amgen (Inst), Viralytics (Inst), Nektar (Inst), Merck (Inst) Georgina V. LongHonoraria: BMS, Pierre FabreConsulting or Advisory Role: Aduro Biotech, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Hexal, Highlight Therapeutics, Merck Sharpe & Dohme, Novartis, OncoSec, Pierre Fabre, QBiotics, Regeneron, SkylineDx, Specialised Therapeutics, Array BioPharma, Evaxion Biotech A/S Tuba BasEmployment: Bristol Myers Squibb (I), Merck, Fiore Healthcare Advisors (I)Stock and Other Ownership Interests: Merck Sharp & Dohme, Bristol Myers Squibb (I)Consulting or Advisory Role: Fiore Healthcare Advisors (I)Travel, Accommodations, Expenses: Merck Sharp & Dohme, Fiore Healthcare Advisors (I) Corey RitchingsEmployment: Bristol Myers SquibbStock and Other Ownership Interests: Bristol Myers Squibb James LarkinHonoraria: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Roche/Genentech, Incyte, iOnctura, Merck Serono, Eisai, Dynavax Technologies, Cancer Research UK, touchIME, touchEXPERTSConsulting or Advisory Role: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Boston Biomedical, Incyte, iOnctura, Iovance Biotherapeutics, Immunocore, YKT Corporation, Apple Tree PartnersResearch Funding: Pfizer (Inst), Novartis (Inst), MSD (Inst), Bristol Myers Squibb (Inst), Achilles Therapeutics (Inst), Roche (Inst), Nektar (Inst), Covance (Inst), Immunocore (Inst), AVEO (Inst), Pharmacyclics (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Incyte, GlaxoSmithKline, Pierre Fabre, Merck Serono, iOnctura, British Uro-Oncology Group (BUG), ESMO, National Cancer Research Institute (NCRI), EUSA Pharma, Syneos Health, Kidney Cancer Association, Bioevents, MedConcept, RV Mais F. Stephen HodiEmployment: Dana-Farber Cancer InstituteLeadership: Bicara TherapeuticsStock and Other Ownership Interests: Apricity Health, Torque, Pionyr, Bicara TherapeuticsConsulting or Advisory Role: Merck Sharp & Dohme, Novartis, Genentech/Roche, EMD Serono, Sanofi, Bristol Myers Squibb, Surface Oncology, Compass Therapeutics, Partners Therapeutics, Pionyr, Torque, Rheos Medicines, Boston Pharmaceuticals, Checkpoint Therapeutics, Eisai, Bioentre, Gossamer Bio, Iovance Biotherapeutics, Trillium Therapeutics, Catalym¸ Amgen, Immunocore,Research Funding: Bristol Myers Squibb (Inst), Merck Sharp & Dohme, Genentech/Roche, Novartis,Patents, Royalties, Other Intellectual Property: Patent pending as per institutional policy. Patent pending royalties received on MICA-related disorders application to institution per institutional IP policy. Angiopoietin-2 Biomarkers Predictive of Anti-immune checkpoint response. Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms. Methods of Using Pembrolizumab and TrebananibTravel, Accommodations, Expenses: Novartis, Bristol Myers SquibbOther Relationship: Bristol Myers Squibb, Genentech/RocheNo other potential conflicts of interest were reported.

Purpose: We conducted the phase III double-blind European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial to evaluate pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. On the basis of 351 recurrence-free survival (RFS) events at a 1.25-year median follow-up, pembrolizumab prolonged RFS (hazard ratio [HR], 0.57; P < .0001) compared with placebo. This led to the approval of pembrolizumab adjuvant treatment by the European Medicines Agency and US Food and Drug Administration. Here, we report an updated RFS analysis at the 3.05-year median follow-up., Patients and Methods: A total of 1,019 patients with complete lymph node dissection of American Joint Committee on Cancer Staging Manual (seventh edition; AJCC-7), stage IIIA (at least one lymph node metastasis > 1 mm), IIIB, or IIIC (without in-transit metastasis) cutaneous melanoma were randomly assigned to receive pembrolizumab at a flat dose of 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 1 year or until disease recurrence or unacceptable toxicity. The two coprimary end points were RFS in the overall population and in those with programmed death-ligand 1 (PD-L1)-positive tumors., Results: Pembrolizumab (190 RFS events) compared with placebo (283 RFS events) resulted in prolonged RFS in the overall population (3-year RFS rate, 63.7% v 44.1% for pembrolizumab v placebo, respectively; HR, 0.56; 95% CI, 0.47 to 0.68) and in the PD-L1-positive tumor subgroup (HR, 0.57; 99% CI, 0.43 to 0.74). The impact of pembrolizumab on RFS was similar in subgroups, in particular according to AJCC-7 and AJCC-8 staging, and BRAF mutation status (HR, 0.51 [99% CI, 0.36 to 0.73] v 0.66 [99% CI, 0.46 to 0.95] for V600 E/K v wild type)., Conclusion: In resected high-risk stage III melanoma, pembrolizumab adjuvant therapy provided a sustained and clinically meaningful improvement in RFS at 3-year median follow-up. This improvement was consistent across subgroups.

Purpose: Improved understanding of the incidence, risk factors, and timing of CNS metastasis is needed to inform surveillance strategies for patients with melanoma., Patients and Methods: Clinical data were extracted from the databases of 2 major melanoma centers in the United States and Australia for 1,918 patients with American Joint Committee on Cancer (AJCC) 8th edition stage III melanoma, diagnosed from 1998-2014, who had (negative) baseline CNS imaging within 4 months of diagnosis. The cumulative incidence of CNS metastasis was calculated in the presence of the competing risk of death, from stage III presentation and at benchmark time points 1, 2, and 5 years postdiagnosis., Results: At a median follow-up of 70.2 months, distant recurrence occurred in 711 patients (37.1%). The first site of distant metastasis was CNS only for 3.9% of patients, CNS and extracranial (EC) for 1.8%, and EC only for 31.4%. Overall, 16.7% of patients were diagnosed with CNS metastasis during follow-up. The cumulative incidence of CNS metastasis was 3.6% (95% CI, 2.9% to 4.6%) at 1 year, 9.6% (95% CI, 8.3% to 11.0%) at 2 years, and 15.8% (95% CI, 14.1% to 17.6%) at 5 years. The risk of CNS metastasis was significantly influenced by patient sex, age, AJCC stage, primary tumor site, and primary tumor mitotic rate in multivariable and conditional analyses. High primary tumor mitotic rate was significantly associated with increased risk of CNS metastasis at diagnosis and all subsequent time points examined., Conclusion: Similar rates of CNS metastasis were observed in 2 large, geographically distinct cohorts of patients with stage III melanoma. The results highlight the importance of primary tumor mitotic rate. Furthermore, they provide a framework for developing evidence-based surveillance strategies and evaluating the impact of contemporary adjuvant therapies on the risk of CNS metastasis development.

Purpose: BRAF/MEK inhibition is a standard of care for patients with BRAF V600E/K-mutated metastatic melanoma. For patients with less frequent BRAF mutations, however, efficacy data are limited., Methods: In the current study, 103 patients with metastatic melanoma with rare, activating non-V600E/K BRAF mutations that were treated with either a BRAF inhibitor (BRAFi), MEK inhibitor (MEKi), or the combination were included. BRAF mutation, patient and disease characteristics, response, and survival data were analyzed., Results: Fifty-eight patient tumors (56%) harbored a non-E/K V600 mutation, 38 (37%) a non-V600 mutation, and seven had both V600E and a rare BRAF mutation (7%). The most frequent mutations were V600R (43%; 44 of 103), L597P/Q/R/S (15%; 15 of 103), and K601E (11%; 11 of 103). Most patients had stage IV disease and 42% had elevated lactate dehydrogenase at BRAFi/MEKi initiation. Most patients received combined BRAFi/MEKi (58%) or BRAFi monotherapy (37%). Of the 58 patients with V600 mutations, overall response rate to BRAFi monotherapy and combination BRAFi/MEKi was 27% (six of 22) and 56% (20 of 36), respectively, whereas median progression-free survival (PFS) was 3.7 months and 8.0 months, respectively ( P = .002). Of the 38 patients with non-V600 mutations, overall response rate was 0% (zero of 15) to BRAFi, 40% (two of five) to MEKi, and 28% (five of 18) to combination treatment, with a median PFS of 1.8 months versus 3.7 months versus 3.3 months, respectively. Multivariable analyses revealed superior survival (PFS and overall survival) with combination over monotherapy in rare V600 and non-V600 mutated melanoma., Conclusion: Patients with rare BRAF mutations can respond to targeted therapy, however, efficacy seems to be lower compared with V600E mutated melanoma. Combination BRAFi/MEKi seems to be the best regimen for both V600 and non-V600 mutations. Yet interpretation should be done with care because of the heterogeneity of patients with small sample sizes for some of the reported mutations.

Purpose Pneumonitis is an uncommon but potentially fatal toxicity of anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) monoclonal antibodies (mAbs). Clinical, radiologic, and pathologic features are poorly described. Methods Patients who received anti-PD-1/PD-L1 monotherapy or in combination with anti-cytotoxic T-cell lymphocyte-4 mAb were identified at two institutions (Memorial Sloan Kettering Cancer Center: advanced solid cancers, 2009 to 2014, and Melanoma Institute of Australia: melanomas only, 2013 to 2015). Pneumonitis was diagnosed by the treating investigator; cases with confirmed malignant lung infiltration or infection were excluded. Clinical, radiologic, and pathologic features of pneumonitis were collected. Associations among pneumonitis incidence, therapy received, and underlying malignancy were examined with Fisher's exact test as were associations between pneumonitis features and outcomes. Results Of 915 patients who received anti-PD-1/PD-L1 mAbs, pneumonitis developed in 43 (5%; 95% CI, 3% to 6%; Memorial Sloan Kettering Cancer Center, 27 of 578 [5%]; Melanoma Institute of Australia, 16 of 337 [5%]). Time to onset of pneumonitis ranged from 9 days to 19.2 months. The incidence of pneumonitis was higher with combination immunotherapy versus monotherapy (19 of 199 [10%] v 24 of 716 [3%]; P < .01). Incidence was similar in patients with melanoma and non-small-cell lung cancer (overall, 26 of 532 [5%] v nine of 209 [4%]; monotherapy, 15 of 417 v five of 152 [ P = 1.0]; combination, 11 of 115 v four of 57 [ P = .78]). Seventy-two percent (31 of 43) of cases were grade 1 to 2, and 86% (37 of 43) improved/resolved with drug holding/immunosuppression. Five patients worsened clinically and died during the course of pneumonitis treatment; proximal cause of death was pneumonitis (n = 1), infection related to immunosuppression (n = 3), or progressive cancer (n = 1). Radiologic and pathologic features of pneumonitis were diverse. Conclusion Pneumonitis associated with anti-PD-1/PD-L1 mAbs is a toxicity of variable onset and clinical, radiologic, and pathologic appearances. It is more common when anti-PD-1/PD-L1 mAbs are combined with anti-cytotoxic T-cell lymphocyte-4 mAb. Most events are low grade and improve/resolve with drug holding/immunosuppression. Rarely, pneumonitis worsens despite immunosuppression, and may result in infection and/or death.