Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC).

3502 Background: Atezolizumab (atezo; MPDL3280A) is an engineered antibody that inhibits binding of PD-L1 to its receptors, PD-1 and B7.1. Atezo has demonstrated monotherapy activity in a multitude of human tumor types. However, response rates in microsatellite stable (MSS) CRCs have been lower than in other indications. In preclinical models, targeted inhibition of MEK leads to upregulation of MHC I on tumor cells, induces intratumoral T-cell infiltration and enhances anti-PDL1 activity. We therefore conducted a Phase Ib study combining cobi (MEK inhibitor) and atezo in patients (pts) with advanced solid tumors. Methods: Cobi was escalated from 20 to 60 mg daily (21 days on/7 days off) and combined with atezo 800 mg IV q2w. Tumor-specific expansion cohorts, including KRAS-mutant CRC, and serial biopsy cohorts in solid tumors were opened upon determination of the MTD. Safety, tolerability and confirmed ORR by RECIST v1.1 were evaluated. Results: As of October 12, 2015, 23 CRC (22 KRAS mutant, 1 WT) pts were enrolled during escalation and expansion. No dose-limiting toxicities were observed, and expansion occurred at atezo 800 mg q2w and cobi 60 mg. Median follow-up for safety in CRC pts was 3.78 mo (range, 1.1-11.7). The most common treatment-related AEs included diarrhea (69.6%), fatigue (52.2%), dermatitis acneiform (43.5%), rash (34.8%), maculopapular rash (26.1%), pruritus (26.1%) and nausea (26.1%). Incidence of treatment-related G3-4 AEs was 34.8%. The only treatment-related G3-4 AE in ≥ 2 pts was diarrhea (8.7%). No G5 AEs were reported. The ORR was 17% (4 PR, 5 SD). Three responses were ongoing (range, 4.0 to 7.7 mo at time of data cutoff). Three responders were mismatch repair-proficient, and 1 was unknown. Response was not associated with baseline PD-L1 expression. Results from the serial biopsy cohort showed enhanced PD-L1 upregulation, CD8 T-cell infiltration and MHC I expression on treatment, providing mechanistic rationale for the combination. Conclusions: The combination of cobi and atezo in CRC is well tolerated at the maximum administered doses. These results show that pts with MSS CRC can respond to the combination of cobi and atezo, and provide support for continued evaluation of the combination. Clinical trial information: NCT01988896.