LBA43 - Spartalizumab plus dabrafenib and trametinib (Sparta-DabTram) in patients (pts) with previously untreated BRAF V600–mutant unresectable or metastatic melanoma: Results from the randomized part 3 of the phase III COMBI-i trial

Background

Treatment (tx) with immune checkpoint inhibitors + targeted therapy may induce durable and deeper responses in a higher proportion of pts. Results from the safety run-in (part 1) and biomarker cohort (part 2) of COMBI-i (NCT02967692) have been previously reported. Part 3 is a global, placebo (PBO)-controlled, double-blind, Phase III study evaluating the anti -PD-1 antibody Sparta + Dab and Tram in pts with previously untreated BRAF V600 -mutant unresectable or metastatic melanoma. Here we report the primary analysis for part 3 of COMBI-i.

Methods

Pts were randomized 1:1 to receive Sparta 400 mg IV Q4W + Dab 150 mg orally BID + Tram 2 mg orally QD vs PBO-DabTram. The statistical plan ensured 80% power assuming a 5-month tx delay. The primary endpoint is investigator-assessed progression-free survival (PFS) using RECIST 1.1; significance threshold was P < .025 [equivalent HR < 0.801]. Overall survival (OS) is a key secondary endpoint.

Results

532 pts were randomized to receive Sparta-DabTram (n = 267) or PBO-DabTram (n = 265). At the data cutoff (July 1, 2020), median follow-up was 27.2 mo. Baseline characteristics were balanced across tx arms. Sparta-DabTram did not significantly improve PFS vs PBO (median PFS, 16.2 mo vs 12.0 mo; HR, 0.82 [95% CI, 0.655-1.027]; P = .042). Estimated 12- and 24-mo PFS rates with Sparta-DabTram vs PBO were 58% vs 50% and 44% vs 36%, respectively. While OS was not formally tested, median OS was not reached (NR) across tx arms (HR, 0.785). The objective response rate was 69% in the Sparta-DabTram arm (complete response rate [CRR], 20%) vs 64% in the PBO arm (CRR, 18%); median duration of response was NR vs 20.7 mo, respectively. Tx-related adverse events (TRAEs) grade ≥ 3 occurred in 55% vs 33% of pts treated with Sparta-DabTram vs PBO. TRAEs leading to discontinuation of all 3 study drugs occurred in 12% vs 8% of pts, respectively.

Conclusions

The primary endpoint was not met. Sparta-DabTram did not significantly improve PFS vs PBO-DabTram; analyses interrogating OS benefit are ongoing. AE management was challenging and resulted in frequent dose adaptations.

Clinical trial identification

NCT02967692; conducted in accordance with Study Protocol CPDR001F2301.

Editorial acknowledgement

Medical editorial assistance was provided by Michael Demars, PhD, and Allison Lytle, PhD, from ArticulateScience LLC and funded by Novartis Pharmaceuticals Corporation (East Hanover, NJ).

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation.

Funding

Novartis Pharmaceuticals Corporation.

Disclosure

P. Nathan: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Ipsen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Immunocore; Honoraria (self), Advisory/Consultancy: 4SC. R. Dummer: Advisory/Consultancy: Novartis; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Roche; Advisory/Consultancy: Amgen; Advisory/Consultancy: Takeda; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Sun Pharma; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Catalym; Advisory/Consultancy: Second Genome; Advisory/Consultancy: Regeneron; Advisory/Consultancy: Alligator. G.V. Long: Advisory/Consultancy: Aduro; Advisory/Consultancy: Amgen; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Mass-Array; Advisory/Consultancy: Merck; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Novartis; Advisory/Consultancy: OncoSec Medical; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Roche; Advisory/Consultancy: Sandoz. P.A. Ascierto: Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Roche-Genentech; Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Sharp & Dohme; Advisory/Consultancy: Novartis; Advisory/Consultancy, Research grant/Funding (institution): Array; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Incyte; Advisory/Consultancy: NewLink Genetics; Advisory/Consultancy: Genmad; Advisory/Consultancy: Medimmune; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Syndax; Advisory/Consultancy: Sun Pharma; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Idera; Advisory/Consultancy: Ultimovacs; Advisory/Consultancy: Sandoz; Advisory/Consultancy: Immunocore; Advisory/Consultancy: 4SC; Shareholder/Stockholder/Stock options: PrimeVax; Advisory/Consultancy: Alkermes; Advisory/Consultancy: Italfarmaco; Advisory/Consultancy: Nektar; Advisory/Consultancy: Boehringer-Ingelheim; Leadership role: Fondazione Melanoma; Leadership role: Campania Society of ImmunoTherapy of Cancer; Leadership role: Society of Melanoma Research; Leadership role: Cancer Development Drug Forum; Leadership role: Society of Immuno Therapy of Cancer. H.A. Tawbi: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck; Honoraria (self), Advisory/Consultancy: Array; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): GlaxoSmithKline. C. Robert: Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Pierre Fabre; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Sanofi; Honoraria (self), Advisory/Consultancy: Biothera. P. Rutkowski: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self): Roche; Honoraria (self), Speaker Bureau/Expert testimony: Pierre Fabre; Honoraria (self): Amgen; Honoraria (self): Blueprint Medicines; Honoraria (self): Eli Lilly; Speaker Bureau/Expert testimony: Pfizer. C. Dutriaux: Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Sharp & Dohme; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Pierre Fabre; Advisory/Consultancy, Travel/Accommodation/Expenses: Merck. M. Mandala': Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Sanofi. P. Lorigan: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Merck Sharp & Dohme; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Pierre Fabre; Advisory/Consultancy: Amgen; Non-remunerated activity/ies: Roche; Advisory/Consultancy: NeraCare GmbH. P.F. Ferrucci: Advisory/Consultancy: Roche; Advisory/Consultancy: Novartis; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Pierre Fabre. K.T. Flaherty: Officer/Board of Directors: Clovis Oncology; Officer/Board of Directors: Strata Oncology; Officer/Board of Directors: Vivid Biosciences; Officer/Board of Directors: Checkmate Pharmaceuticals; Advisory/Consultancy: X4 Pharmaceuticials; Advisory/Consultancy: PIC Therapeautics; Advisory/Consultancy, Research grant/Funding (institution): Sanofi; Advisory/Consultancy: Amgen; Advisory/Consultancy: Asana BioSciences; Advisory/Consultancy: Adaptimmune; Advisory/Consultancy: Fount Therapeutics; Advisory/Consultancy: Aeglea BioTherapeutics; Advisory/Consultancy: Shattuck Labs; Advisory/Consultancy: Tolero Pharmaceuticals; Advisory/Consultancy: Apricity Therapeutics; Advisory/Consultancy: Oncoceutics; Advisory/Consultancy: FogPharma; Advisory/Consultancy: Neon Therapeutics; Advisory/Consultancy: Tvardi Therapeutics; Advisory/Consultancy: xCures; Advisory/Consultancy: Monopteros Therapeutics; Advisory/Consultancy: Vibliome Therapeutics; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Genentech; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Merck; Advisory/Consultancy: Takeda; Advisory/Consultancy: Verastem Oncology; Advisory/Consultancy: Boston Biomedical; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Debiopharm. J.C. Brase: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. S. Green: Full/Part-time employment: Novartis. T. Haas: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. A. Masood: Full/Part-time employment: Novartis. E. Gasal: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. A. Ribas: Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: Chugai; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Sanofi; Honoraria (self), Advisory/Consultancy: Compugen; Honoraria (self), Advisory/Consultancy: CytomX Therapeutics; Honoraria (self), Advisory/Consultancy: Highlight Therapeutics; Honoraria (self), Advisory/Consultancy: ImaginAb; Honoraria (self), Advisory/Consultancy: Isoplexis; Honoraria (self), Advisory/Consultancy: Merus; Honoraria (self), Advisory/Consultancy: RAPT Therapeutics; Honoraria (self), Advisory/Consultancy: Rgenix; Honoraria (self), Advisory/Consultancy: Tango Therapeutics; Honoraria (self), Advisory/Consultancy, Officer/Board of Directors: Arcus Biosciences; Honoraria (self), Advisory/Consultancy, Officer/Board of Directors: Lutris Pharma; Honoraria (self), Advisory/Consultancy, Officer/Board of Directors: PACT Pharma. D. Schadendorf: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Sharp & Dohme ; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Regeneron; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Pierre Fabre; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Array; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Merck EMR; Advisory/Consultancy: Immunocore; Honoraria (institution), Advisory/Consultancy: Nektar; Honoraria (self), Advisory/Consultancy: 4SC. All other authors have declared no conflicts of interest.