Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01844505.

Conflict of interest statement

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.

Figures

FIG 1.

CONSORT diagram. AE, adverse event. aSince the 3-year analysis, patients were unmasked and seven patients discontinued from maintenance nivolumab placebo (six for “administrative reasons” and one for “other reasons”; this latter patient is included within the three patients in this group with a reason for treatment discontinuation as “other”).

FIG 2.

(A) PFS and (B) OS in patients who received nivolumab plus ipilimumab, nivolumab, or ipilimumab. Patients were followed for a minimum of 77 months. All rates are based on the current 6.5-year analysis; rates shown at earlier time points may differ slightly from those of previous reports. aDescriptive analysis. HR, hazard ratio; NR, not reached; OS, overall survival; PFS, progression-free survival.

FIG 3.

MSS in patients who received nivolumab plus ipilimumab, nivolumab, or ipilimumab. In this descriptive post hoc analysis, an event was defined as death as a result of melanoma; deaths as a result of any other causes were censored. HR, hazard ratio; MSS, melanoma-specific survival; NR, not reached.

FIG 4.

PFS in patients with (A) BRAF-mutant or (B) BRAF–wild-type tumors and OS in patients with (C) BRAF-mutant or (D) BRAF–wild-type tumors. Patients were followed for a minimum of 77 months. In the nivolumab plus ipilimumab, nivolumab, and ipilimumab groups, 314, 316, and 315 patients had BRAF mutational status results, respectively. aDescriptive analysis. HR, hazard ratio; NR, not reached; OS, overall survival; PFS, progression-free survival.

FIG 5.

PFS in patients (A) with or (B) without baseline liver metastases and OS in patients (C) with or (D) without baseline liver metastases. Patients were followed for a minimum of 77 months. aDescriptive analysis. HR, hazard ratio; NR, not reached; OS, overall survival; PFS, progression-free survival.

FIG 6.

OS by best overall response in patients in the (A) nivolumab plus ipilimumab, (B) nivolumab, or (C) ipilimumab groups. Patients with a best overall response of CR, PR, SD, or PD within 12 months of treatment initiation were followed for OS. To address guarantee-time bias, these landmark analyses excluded patients who had OS events (deaths) during the first 12 months; thus, OS remained at 100% for the first 12 months in this subpopulation. CR, complete response; OS, overall survival; PD, progressive disease; PR, partial response; SD, stable disease.

FIG 7.

Treatment-free interval and treatment status in patients alive at 6.5 years. (A) Median treatment-free interval in each treatment group following discontinuation of study treatment. Among 313 patients treated with nivolumab plus ipilimumab, 223 were included in the analysis and 90 were excluded (seven were still on study treatment; 54 had died, six were no longer in follow-up, and six withdrew consent, all without having received subsequent therapy; 17 were excluded for other reasons). Among 313 patients treated with nivolumab, 237 were included and 76 were excluded (eight were still on study treatment; 45 had died, two were no longer in follow-up, and three withdrew consent, all without having received subsequent therapy; 18 were excluded for other reasons). Among 311 patients treated with ipilimumab, 234 patients were included and 77 were excluded (57 had died, two were no longer in follow-up, and seven withdrew consent, all without having received subsequent therapy; 11 were excluded for other reasons). Median duration of treatment in these groups is also shown. (B) Treatment status in patients alive at 6.5 years. In the combination group, 145 patients were alive and still in follow-up at 6.5 years and were included in this analysis, and 168 patients were excluded (138 had died, six were lost to follow-up, seven withdrew consent, and 17 were excluded for other reasons). In the nivolumab group, 122 patients were included and 191 patients were excluded (164 had died, six were lost to follow-up, three withdrew consent, and 18 were excluded for other reasons). In the ipilimumab group, 63 patients were included and 248 patients were excluded (218 had died, six were lost to follow-up, 13 withdrew consent, and 11 were excluded for other reasons).