Targeted therapy with MEK inhibitor cobimetinib (C) + BRAF inhibitor vemurafenib (V) in BRAFV600-mutant melanoma can result in anti-cancer immune activation and rapid clinical response. Inhibition of PD-L1 with atezolizumab (A; anti-PDL1) can also lead to anti-cancer immune activity and durable responses. Combining C + V with A, which may enhance and perpetuate antitumor immune activity, can potentially improve both clinical response and durability.
In a Phase 1b study, patients (pts) with untreated BRAFV600-mutant unresectable or metastatic melanoma received A + C + V after a 28 d run-in period with C + V. A was dosed IV q2w at 800 mg, C was PO QD at 60 mg for first 21 d of each 28 d cycle and V was PO BID at 960 mg during 1-21 d of run-in and 720 mg subsequently.
14 pts who received ≥ 1 dose of A were safety and efficacy evaluable. Median safety follow-up was 5.6 mo (range 1.5-12.8). All-grade (G) AEs that occurred in > 20% pts and reported as related to A and/or C and/or V were nausea, fatigue, flu-like symptoms, photosensitivity, maculopapular rash, elevated ALT/AST and bilirubin, mucosal inflammation and arthralgia. 6 pts had C- and/or V-related G3-4 AEs during run-in period, and 5 pts had A- and/or C- and/or V-related G3-4 AEs during the triple combination period; all were manageable and reversible. There were no unexpected AEs or G5 AEs. No A-related SAEs occurred. 1 pt discontinued all study treatment due to elevated ALT/AST. 13/14 pts (93%) showed responses (RECIST v1.1), including 1 CR and 12 PRs. 1 pt with PR had a 100% reduction in target lesions. Responses were unconfirmed, and median DOR and PFS were not estimable due to limited follow-up at the time of data cut (Feb 15, 2016). 11/13 pts continue in response. Updated data with functional biomarkers of T-cell activation will be presented.
A + C + V combination therapy results in a manageable safety profile and promising anti-tumor activity in pts with BRAFV600-mutant metastatic melanoma. These preliminary data show that anti-PDL1 therapy can be successfully combined with MEK and BRAF inhibitors and warrant further exploration. NCT01656642
Clinical trial identification
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd
F. Hoffmann-La Roche Ltd
O. Hamid: Consultant, speaker and receives funding from: AstraZeneca Bristol-Myers Squibb. Celldex Genentech/Roche Immunocore Incyte Merck Merck Serono MedImmune Novartis Pfizer Rinat. R. Gonzalez: Grants recieved from Roche/Genentech, BMS, Merck, Amgen. Consultant fees from Roche/Genentech and Novartis. J.R. Infante: I have no personal financial conflicts of interest but my institution receives research funding and consulting from Genentech. F.S. Hodi: Non-paid advisor to Genentech, BMS, Merck; member of the Amgen advisory board; compenstated advisor to Novartis; received clinical trials support from Genentech, BMS, Merck and Novartis. J. Wallin, G. Mwawasi, E. Cha, N. Richie, M. Ballinger: Employee of Genentech, Inc. R. Sullivan: Grants from Merck, personal fees from Novartis, outside the submitted work. All other authors have declared no conflicts of interest.