Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for BRAF V600-Mutant Unresectable or Metastatic Melanoma

Reinhard Dummer, Georgina V Long, Caroline Robert, Hussein A Tawbi, Keith T Flaherty, Paolo A Ascierto, Paul D Nathan, Piotr Rutkowski, Oleg Leonov, Caroline Dutriaux, Mario Mandalà, Paul Lorigan, Pier Francesco Ferrucci, Jean Jacques Grob, Nicolas Meyer, Helen Gogas, Daniil Stroyakovskiy, Ana Arance, Jan C Brase, Steven Green, Tomas Haas, Aisha Masood, Eduard Gasal, Antoni Ribas, Dirk Schadendorf, Reinhard Dummer, Georgina V Long, Caroline Robert, Hussein A Tawbi, Keith T Flaherty, Paolo A Ascierto, Paul D Nathan, Piotr Rutkowski, Oleg Leonov, Caroline Dutriaux, Mario Mandalà, Paul Lorigan, Pier Francesco Ferrucci, Jean Jacques Grob, Nicolas Meyer, Helen Gogas, Daniil Stroyakovskiy, Ana Arance, Jan C Brase, Steven Green, Tomas Haas, Aisha Masood, Eduard Gasal, Antoni Ribas, Dirk Schadendorf

Abstract

Purpose: Preclinical data suggest the combination of an anti-programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with BRAF V600-mutant metastatic melanoma. COMBI-i is a phase III trial evaluating spartalizumab, an anti-programmed death receptor 1 antibody, in combination with dabrafenib and trametinib (sparta-DabTram), versus placebo plus dabrafenib and trametinib (placebo-DabTram) in patients with BRAF V600-mutant unresectable or metastatic melanoma.

Methods: Patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age ≥ 18 years with unresectable or metastatic BRAF V600-mutant melanoma. The primary end point was investigator-assessed progression-free survival. Overall survival was a key secondary end point (ClinicalTrials.gov identifier: NCT02967692).

Results: At data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placebo-DabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03]; P = .042 [one-sided; nonsignificant]). The objective response rates were 69% (183 of 267 patients) versus 64% (170 of 265 patients), respectively. Grade ≥ 3 treatment-related adverse events occurred in 55% (146 of 267) of patients in the sparta-DabTram arm and 33% (88 of 264) in the placebo-DabTram arm.

Conclusion: The study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.

Conflict of interest statement

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) 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 Caroline RobertConsulting or Advisory Role: Bristol Myers Squibb, Roche, Novartis, Pierre Fabre, MSD, Sanofi, AstraZeneca, Pfizer Hussein A. TawbiConsulting or Advisory Role: Novartis, Bristol Myers Squibb, Genetech/Roche, Merck, Array BioPharma, Eisai, Iovance Biotherapeutics, Karyopharm Therapeutics, Boxer CapitalResearch Funding: Bristol Myers Squibb (Inst), Novartis (Inst), Merck (Inst), GlaxoSmithKline (Inst), Genentech/Roche (Inst), Celgene (Inst) Keith T. FlahertyStock and Other Ownership Interests: Clovis Oncology, Loxo, X4 Pharma, Strata Oncology, PIC Therapeutics, Shattuck Labs, Apricity Health, Oncoceutics, FOGPharma, Tvardi Therapeutics, Checkmate Pharmaceuticals, Kinnate Biopharma, Scorpion Therapeutics, ALX Oncology, xCures, Monopteros Therapeutics, Vibliome Therapeutics, Transcode Therapeutics, Soley Therapeutics,Consulting or Advisory Role: Novartis, Lilly, Oncoceutics, Tvardi Therapeutics, Takeda, Boston Biomedical, Debiopharm Group, FOGPharma 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 TherapeuticsResearch Funding: Bristol Myers Squibb (Inst), Roche/Genentech (Inst), Array BioPharma (Inst), Sanofi (Inst)Travel Accommodations, Expenses: Merck Sharp & Dohme Paul D. NathanConsulting or Advisory Role: AstraZeneca, Bristol Myers Squibb, MSD, Immunocore, Pfizer, Pierre Fabre, Novartis, GlaxoSmithKline, Ipsen, 4SC, MerckSpeaker's Bureau: Bristol Myers Squibb, Novartis, MSD, Merck,Travel Accommodations, Expenses: Bristol Myers Squibb, MSD Piotr RutkowskiHonoraria: Bristol Myers Squibb, MSD, Novartis, Roche, Pfizer, Pierre Fabre, Sanofi, MerckConsulting or Advisory Role: Novartis, Blueprint Medicines, Bristol Myers Squibb, Pierre Fabre, MSD, AmgenSpeaker's Bureau: Pfizer, Novartis, Pierre FabreResearch Funding: Novartis (Inst), Roche (Inst), Bristol Myers Squibb (Inst)Travel Accommodations, Expenses: Orphan Europe, Pierre Fabre Caroline DutriauxHonoraria: Bristol Myers Squibb, MSD, Novartis, Pierre FabreConsulting or Advisory Role: Bristol Myers Squibb, MSD, Novartis, Pierre FabreTravel Accommodations, Expenses: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre Mario MandalàHonoraria: MSD Oncology, Novartis, Pierre FabreConsulting or Advisory Role: Bristol Myers Squibb, MSD Oncology, Novartis, Pierre FabreResearch Funding: Novartis (Inst) 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, NektarSpeaker's Bureau: Merck Sharp & Dohme, Novartis, Bristol Myers Squibb, Pierre Fabre, BMSTravel Accommodations, Expenses: Merck Sharp & Dohme, Bristol Myers Squibb Pier Francesco FerrucciConsulting or Advisory Role: Bristol Myers Squibb, Roche, Novartis, MSD Oncology, Pierre FabreResearch Funding: BMS (Inst)Travel Accommodations, Expenses: MSD Oncology, Bristol Myers Squibb Jean Jacques GrobConsulting or Advisory Role: BMS, MSD Oncology, Roche/Genentech, Novartis, Amgen, Pierre Fabre, Sun Pharma, Merck KGaA, Sanofi, Pfizer, RocheSpeaker's Bureau: NovartisTravel Accommodations, Expenses: BMS, MSD Oncology, Novartis, Pierre Fabre Nicolas MeyerConsulting or Advisory Role: Bristol Myers Squibb, MSD Oncology, Roche/Genentech, Novartis, Pierre Fabre, AbbVie, Sun Pharma, Merckle GmbHResearch Funding: Bristol Myers Squibb (Inst), MSD Oncology (Inst) Helen GogasHonoraria: Bristol Myers Squibb, MSD Oncology, Pierre Fabre, Sanofi/RegeneronConsulting or Advisory Role: Bristol Myers Squibb, MSD Oncology, Amgen, Pierre Fabre, Sanofi/RegeneronResearch Funding: Bristol Myers Squibb, Roche, MSD Oncology, Amgen (Inst), Novartis (Inst)Travel Accommodations, Expenses: Bristol Myers Squibb, MSD, Amgen, Pfizer Daniil StroyakovskiySpeaker's Bureau: Roche/Genentech, Bristol Myers Squibb, BioCad, AstraZenecaTravel Accommodations, Expenses: AstraZeneca, Novartis, Roche Ana AranceConsulting or Advisory Role: BMS, Roche, Novartis, Pierre Fabre, MSD, Merck, SanofiSpeaker's 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 Jan C. BraseEmployment: NovartisStock and Other Ownership Interests: NovartisPatents, Royalties, Other Intellectual Property: Coinventor on patent application Steven GreenEmployment: NovartisStock and Other Ownership Interests: Novartis Tomas HaasEmployment: NovartisStock and Other Ownership Interests: Novartis Aisha MasoodEmployment: NovartisStock and Other Ownership Interests: NovartisOther Relationship: Novartis Eduard GasalEmployment: Novartis, Innovent BiologicsLeadership: Innovent BiologicsStock and Other Ownership Interests: Novartis, Innovent Biologics, Revolution Medicines, Amgen, NateraTravel Accommodations, Expenses: Novartis, Innovent Biologics Antoni RibasLeadership: PACT Pharma, Arcus Biosciences, LutrisStock and Other Ownership Interests: Compugen, CytomX Therapeutics, Advaxis, Tango Therapeutics, PACT Pharma, Merus, ImaginAb, Lutris, Highlight Therapeutics, MapKure, 4c Biomed, Kite/Gilead, Isoplexis, Appia, Synthekine, Pluto, Inspirna, RAPT Therapeutics, ImmPACT-BioHonoraria: Merck Sharp & Dohme, Novartis, Amgen, Chugai/Roche, Genentech/Roche, Sanofi, Vedanta Biosciences, AstraZenecaConsulting or Advisory Role: Merck, Amgen, Novartis, Chugai Pharma, SanofiResearch Funding: Agilent (Inst), Bristol Myers Squibb (Inst)Patents, Royalties, Other Intellectual Property: Nonviral gene editing to Arsenal Bio Dirk SchadendorfHonoraria: Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Immunocore, Merck Serono, Array BioPharna, 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, NektarSpeaker's 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/RegeneronNo other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
COMBI-i part 3 CONSORT diagram. AE, adverse event; PD, progressive disease.
FIG 2.
FIG 2.
(A) Kaplan-Meier estimates of investigator-assessed PFS in the intention-to-treat population and (B) analysis of PFS in predetermined prognostic subgroups. (A) The log-rank P value of .042 is one-sided and thus not significant. (B) P values are two-sided for treatment by subgroup interaction. aBRAF V600 mutation as determined by local testing. AJCC 7, American Joint Committee on Cancer's Cancer Staging Manual, 7th edition; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; LDH, lactate dehydrogenase; mut/Mb, mutations per megabase; PD-L1, programmed death ligand 1; PFS, progression-free survival; placebo-DabTram, placebo plus dabrafenib and trametinib; sparta-DabTram, spartalizumab plus dabrafenib and trametinib; TMB, tumor mutational burden; ULN, upper limit of normal.
FIG 3.
FIG 3.
Kaplan-Meier estimates of investigator-assessed PFS in predefined (A) PD-L1 (

FIG 4.

Kaplan-Meier estimates of DOR in…

FIG 4.

Kaplan-Meier estimates of DOR in the intention-to-treat population. DOR, duration of response; NE,…

FIG 4.
Kaplan-Meier estimates of DOR in the intention-to-treat population. DOR, duration of response; NE, not estimable; placebo-DabTram, placebo plus dabrafenib and trametinib; sparta-DabTram, spartalizumab plus dabrafenib and trametinib.
FIG 4.
FIG 4.
Kaplan-Meier estimates of DOR in the intention-to-treat population. DOR, duration of response; NE, not estimable; placebo-DabTram, placebo plus dabrafenib and trametinib; sparta-DabTram, spartalizumab plus dabrafenib and trametinib.

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