2804 - Combination treatment with cobimetinib (C) and atezolizumab (A) vs pembrolizumab (P) in previously untreated patients (pts) with BRAFV600 wild type (wt) advanced melanoma: primary analysis from the phase 3 IMspire170 trial

Background

Treatment for pts with advanced BRAF^V600 wt melanoma includes immune checkpoint inhibitors, such as P, an anti–PD-1 antibody. MAPK activation is implicated in BRAF^V600 wt melanoma, and emerging data suggest that MAPK inhibition may enhance antitumor immune response to checkpoint inhibitors. In a phase I study, the combination of C, a MEK inhibitor, plus A, an anti–PD-L1 antibody, showed promising antitumor activity. In a phase III randomized study we evaluated whether C+A would improve efficacy compared with P monotherapy in pts with BRAF^V600 wt advanced melanoma.

Methods

Pts had previously untreated unresectable stage III or IV BRAF ^V600 wt melanoma. Pts were stratified by PD-L1 expression, LDH level, and geographic location, and were randomized 1:1 to receive C (60 mg, days 1-21) plus A (840 mg, every 2 wk) in 28-day cycles or P (200 mg, every 3 wk) until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. Primary endpoint was PFS, assessed by independent review committee (IRC). Key secondary endpoints were confirmed objective response rate (ORR), disease control rate (DCR), OS, and safety.

Results

446 pts were randomized to C+A (n = 222) or P (n = 224); 68% of pts had PD-L1–positive tumors and 25% had LDH >ULN. Median follow-up was 7 mo (range 0-15). C+A did not significantly improve IRC-assessed PFS vs P (median 5.5 vs 5.7 mo; HR 1.15; 95% CI 0.88-1.50; P = 0.295). Results were consistent across pt subgroups. Confirmed IRC-assessed ORR was 26% vs 32% with C+A vs P; DCR was 46% vs 44%. Median OS was not reached in either arm (HR 1.06; 95% CI 0.69-1.61). AEs were consistent with known safety profiles of the individual agents. Grade ≥3 AEs occurred in 67% vs 33% of pts receiving C+A vs P; AEs leading to discontinuation of all treatments occurred in 12% vs 6%.

Conclusions

IMspire170 did not meet its primary endpoint. The combination of C+A did not demonstrate an improvement in PFS vs P monotherapy in pts with BRAF^V600 wt advanced melanoma. The safety profile of C+A was consistent with that observed in previous studies of this combination.

Clinical trial identification

NCT03273153.

Editorial acknowledgement

ApotheCom, Yardley, PA, USA.

Legal entity responsible for the study

Roche.

Funding

Roche.

Disclosure

A.M. Arance: Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Sharp and Dohme; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck. H. Gogas: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (institution), Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Research grant / Funding (institution): Roche. B. Dreno: Advisory / Consultancy: Roche. K.T. Flaherty: Advisory / Consultancy, Shareholder / Stockholder / Stock options, BMS: advisory/consultancy: X4 Pharmaceuticals; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Merck: advisory/consultancy; research grant (institution): PIC Therapeutics; Advisory / Consultancy, Research grant / Funding (institution), Takeda: advisory/consultancy: Sanofi; Advisory / Consultancy, Verastem: advisory/consultancy: Amgen; Advisory / Consultancy, Boston Biomedical: advisory/consultancy: Asana; Advisory / Consultancy, Pierre Fabre: advisory/consultancy: Adaptimmune; Advisory / Consultancy, Cell Medica: advisory/consultancy: Fount; Advisory / Consultancy, Debiopharm: advisory/consultancy; research grant (institution): Aeglea; Advisory / Consultancy, Research grant / Funding (institution), Clovis Oncology: shareholder/stock: Array BioPharma; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Strata Oncology: shareholder/stock: Shattuck Labs; Advisory / Consultancy, Vivid Biosciences: shareholder/stock: Tolero; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Checkmate Pharmaceuticals: shareholder/stock: Apricity; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Oncoceutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Fog Pharma; Advisory / Consultancy: Neon; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Tvardi; Advisory / Consultancy, Shareholder / Stockholder / Stock options: xCures; Advisory / Consultancy: Monopteros; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Genentech. L. Demidov: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: BIOCAD; Research grant / Funding (self): Amgen. D. Stroyakovskiy: Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Novartis. Z. Eroglu: Advisory / Consultancy: Array; Advisory / Consultancy: Regeneron; Research grant / Funding (institution): Novartis. P.F. Ferrucci: Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Novartis. J. Pigozzo: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD. P. Rutkowski: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self): Eli Lilly; Travel / Accommodation / Expenses: Orphan Drugs. J. Mackiewicz: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche. I. Rooney: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. A. Voulgari: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. S. Troutman: Full / Part-time employment: Genentech. B. Pitcher: Full / Part-time employment: Roche. Y. Yan: Shareholder / Stockholder / Stock options: Roche; Full / Part-time employment: Genentech. J.M.G. Larkin: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Vitaccess: honoraria (self)/advisory/consultancy/travel: Achilles; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Covance: research grant (institution): AZ; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Immunocore: research grant (institution): Boston Biomedical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Pharmacyclics: research grant (institution): BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Aveo: research grant (institution): Eisai; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: EUSA Pharma; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: GSK; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Imugene; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Incyte; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: iOnctura; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Kymab; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Nektar; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Secarna.