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Preliminary safety and clinical activity of atezolizumab combined with cobimetinib and vemurafenib in BRAF V600-mutant metastatic melanoma

2016; Elsevier BV; Volume: 27; Linguagem: Inglês

10.1093/annonc/mdw379.05

1569-8041

Patrick Hwu, Omid Hamid, René González, Jeffrey R. Infante, Manish R. Patel, F. Stephen Hodi, Karl D. Lewis, Jeffrey J. Wallin, G. Mwawasi, Edward Cha, Nicole Richie, M. Ballinger, Ryan J. Sullivan,

Synthesis and biological activity

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