MSS colorectal cancers, which comprise the vast majority of mCRC patients (pts), appear essentially resistant to PD-L1/PD-1 blockade vs many other tumors. Since inhibition of MEK promotes T cell accumulation intratumorally and combines with anti-PDL1 pre-clinically (Ebert, Immunity 2016), the combination of cobi (MEK inhibitor) and atezo (anti-PDL1) was evaluated in pts with mCRC.
44 mCRC pts were enrolled with 23 evaluable pts for efficacy, including 22 KRASmt and 1 KRASwt, who failed prior lines of therapy and were not selected by PD-L1 expression. Of these 23 pts, 3 were treated with cobi during escalation (2 at 20 mg; 1 at 60 mg) and 20 were treated during expansion (60 mg). Cobi was dosed PO for 21 d on/7 d off and atezo at 800 mg IV q2w. Primary endpoints were safety and tolerability. Secondary endpoints included investigator-assessed efficacy by RECIST v1.1. MSS status was confirmed centrally by mutation load profiling.
As of Feb 12, 2016, the 23 efficacy evaluable mCRC pts had a median safety follow-up of 3.78 mo (range, 1.1-15.1). None were identified as MSI-H and the majority expressed low levels of PD-L1 at baseline. The 6 mo survival rate was 72% (95% CI: 52, 93). Confirmed responses were seen in 4 pts (17%) with duration ranging from 5.4 to 11.1 mo and were ongoing in 2 pts. Activity did not correlate with PD-L1 expression. All grade treatment-related AEs occurring in > 20% pts included diarrhea, fatigue, dermatitis acneiform, rash, maculopapular rash, pruritus, nausea, creatine phosphokinase increase and AST elevation, consistent with that seen for the single agents. G3-4 AEs related to either drug were seen in 8 pts (34.8%). The most common individual, related G3-4 AEs (diarrhea and rash) occurred in ≤ 2 pts (8.7%). No G5 AEs occurred. Four AEs led to discontinuation of cobi. No AEs led to atezo withdrawal. Updated biomarker data including anti-tumor immune markers will be presented.
In chemotherapy-refractory MSS mCRC where single-agent cobi and atezo have shown minimal activity, encouraging early results with the combination are observed for ORR, DOR, and 6 mo survival. Further trial follow-up is ongoing. NCT01988896
Clinical trial identification
Legal entity responsible for the study
F. Hoffmann La-Roche Ltd.
F. Hoffmann La-Roche Ltd.
J.R. Infante: I have no personal financial conflicts of interest but my institution receives research funding and consulting from Genentech. J. Wallin, M. Das Thakur, G. Mwawasi, P. Foster, E. Cha: Genentech employee. All other authors have declared no conflicts of interest.