LBA-01Safety and efficacy of cobimetinib (cobi) and atezolizumab (atezo) in a Phase 1b study of metastatic colorectal cancer (mCRC)

Background: Microsatellite instability-high (MSI-H) colorectal cancers are associated with high mutation burden and are responsive to PD-L1/PD-1 blockade. However, the majority of mCRC pts are MSS and have lower response rates to PD-L1/PD-1 blockade. Although MEK inhibition has minimal activity in mCRC, preclinical models demonstrate intratumoral T cell accumulation with MEK inhibition and durable tumor regression when combined with anti-PDL1. Therefore, we evaluated the combination of cobi (MEK inhibitor) and atezo (anti-PDL1) in patients (pts) with mCRC. Methods: A Phase 1b dose escalation and expansion study treated advanced solid tumor pts with 20, 40, and 60mg cobi daily (21d on / 7d off) in combination with a fixed dose of 800mg atezo IV q2w. The expansion dose was 60mg cobi and 800mg atezo. Safety and preliminary investigator-assessed efficacy by RECIST v1.1 were assessed. As of Oct 12, 2015, the study enrolled 23 previously treated mCRC pts, including 22 KRASmt and 1 KRASwt, without selection for MSI-H status or PD-L1 expression. Results: No DLTs, treatment-related G4, or any G5 AEs were identified. G3 AEs related to study treatment were reported in 8 pts (35%). The most common AEs of any grade were rash, diarrhea, and fatigue. The median safety follow-up was 3.78 mo (range, 1.1-11.7). There were 4 confirmed PRs (17%) and 5 SDs. Duration of response ranged from 4.0 to 7.7 mo and responses were ongoing in 3 of 4 pts at time of data cutoff. Baseline PD-L1 expression did not correlate with activity. No MSI-H pts were identified among the responders. 3 PRs were MSS or MSI-low by local testing. The MSI status of 1 PR was unknown. Biomarker data suggest enhanced immune response with the combination. Conclusions: These early results show that anti-PDL1 immunotherapy can be active in the broader MSS mCRC population when combined with MEK inhibition. Cobi and atezo is a rational and tolerated regimen to investigate further in MSS mCRC. NCT01988896.