A phase Ib study of safety and clinical activity of atezolizumab (A) and cobimetinib (C) in patients (pts) with metastatic colorectal cancer (mCRC).

Abstract

560 Background: The majority of pts with mCRC have microsatellite stable (MSS) tumors with minimal response to PD-L1/PD-1 blockade. MEK inhibition upregulates tumor major histocompatibility complex-I expression, promotes intratumoral T-cell accumulation and improves anti–PD-L1 responses (Ebert, Immunity. 2016), supporting clinical evaluation of combined anti–PD-L1 (A) plus MEKi (C) in pts with mCRC. Methods: Pts with chemotherapy-refractory or locally advanced mCRC were evaluated. A was administered IV q2w at 800 mg. C was dosed PO daily at 20 to 60 mg during dose escalation and 60 mg during dose expansion (14/14 or 21/7 d on/off schedule). Primary endpoints were safety and tolerability. Investigator-assessed ORR and PFS by RECIST v1.1 and OS were secondary endpoints. Microsatellite instability (MSI) status was locally reported and centrally confirmed by NGS-based scoring. Results: As of May 10, 2017, 84 pts (57 KRASmt, 25 KRASwt, 2 unknown) were enrolled and evaluable. 66 pts had received 5+ prior therapies; 38 had known MSI status at baseline (MSS [n = 29], MSI-low [n = 8], MSI-H [n = 1]). A + C combination was tolerable. Treatment-related Gr 1-2 and Gr 3-4 AEs occurred at 60% and 37%, respectively. The most frequent related Gr 3-4 AEs were increased blood CPK, rash, diarrhea and fatigue (5% each). No treatment-related Gr 5 AEs occurred. 13% and 24% of pts experienced AEs leading to A and C withdrawal, respectively. Median follow-up was 14.3 mo (range, 0.5-29.8). Confirmed PR was observed in 7 pts (8%; locally reported MSS [n = 3], MSI-low [n = 1], MSI unknown [n = 3]). Median DOR was 14.8 mo (95% CI: 6.0, NE); DCR (PR + SD) was 31%. Median PFS was 1.9 mo (95% CI: 1.8, 2.3); median OS was 10.0 mo (95% CI: 6.2, 14.1). The 6-mo and 1-y OS rates were 65% (95% CI: 54, 76) and 46% (95% CI: 34, 58), respectively. Molecular determinants and immune biomarkers of response will be presented. Conclusions: A + C demonstrated a tolerable safety profile and improvements in OS vs those reported with SOC in heavily pretreated pts with mCRC. Objective responses observed in pts with MSS/MSI-low mCRC were durable, suggesting benefit of this novel combination in a pt population refractory to immune therapies. Clinical trial information: NCT01988896.