Atezolizumab, Cobimetinib Combo Active in mCRC

Johanna C. Bendell, MD

Atezolizumab (Tecentriq) in combination with cobimetinib (Cotellic) induced a 31% disease control rate (DCR) in patients with heavily-pretreated metastatic colorectal cancer (mCRC).

In results from a 2-stage phase Ib study presented at the 2018 Gastrointestinal Cancers Symposium, the overall response rate (ORR) was 8% (n = 7). All responses were partial responses (PRs).

Nineteen patients (23%) had stable disease (SD) as best response. DCR, defined as PR + SD ≥6 weeks, was 31%. Fifty-one patients (61%) had progressive disease.

The atezolizumab and cobimetinib combination of an anti—PD-L1 inhibitor with a MEK 1/2 inhibitor represents the first potential immune-modifying combination for patients with microsatellite stable (MSS) mCRC, according to the investigators.

“We all know that patients with refractory colorectal cancer certainly need more treatment options and, to this point, for the 95% of patients with microsatellite stable disease, we’ve not seen very much activity with single-agent checkpoint inhibitors,” said Johanna C. Bendell, MD.

“We saw preclinical evidence that suggests that adding atezolizumab, which is a PD-L1 inhibitor, and cobimetinib, a MEK1/2 inhibitor, potentially would have a synergistic effect,” added Bendell, chief development officer, Sarah Cannon Research Institute.

Eighty-four patients had enrolled in the study as of May 17, 2017; 57 were KRAS mutant-type, 25 were KRAS wild-type, and the status of 2 patients was unknown. Sixty-six (79%) had received ≥5 previous systemic therapies.

At baseline, 42 patients (50%) were MSS, 9 (11%) were microsatellite instability (MSI)-low, and 1 (1%) was MSI-high. MSI status was unknown for 32 patients (38%).

The median patient age was 56.5 years (range, 23-81) and 44% of patients were female. For PD-L1 expression, 57% were immune cell (IC) 0/1 and 8% were IC2/3. PD-L1 expression was unknown for 29 patients (35%).

Stage 1 established 60 mg of cobimetinib as the treatment dose for patients with chemotherapy-refractory or locally advanced mCRC in stage 2. In stage 2, patients were assigned to a cobimetinib regimen of 21 days on/7 days off (n = 59) or 14 days on/14 days off (n = 21). Patients in both groups received 800 mg of atezolizumab every 2 weeks.

At the September 4, 2017, data cutoff, ORR was 8% (95% CI, 1-26) in KRAS wild-type patients, with a DCR of 32%. In KRAS-positive patients, ORR was 9% (95 CI, 3-19) with a DCR of 30%.

The median duration of response was 14.3 months (95% CI, 6.0-not evaluable). Among the 7 patients who responded to treatment, 4 had MSS and 1 had MSI-low disease. MSI status was unknown in the remaining 2 patients.

The median overall progression-free survival (PFS) was 1.9 months (95% CI, 1.8-2.3). The median PFS was 2.5 months (95% CI, 1.8-3.7) in MSS patients, 2.0 months (95% CI, 1.8-2.3) in KRAS-mutant patients, and 1.8 months (95% CI, 1.8-2.6) in KRAS wild-type patients. The 6-month PFS rate was 18% overall, 27% in MSS patients, 22% in KRAS-mutant patients, and 9% in KRAS wild-type patients.

The median overall survival (OS) was 9.8 months (95% CI, 6.2-14.1), with a 6-month OS rate of 65% and a 12-month OS rate of 43%. For MSS patients, the median OS was 13.0 months (95% CI, 6.0-25.8), with a 6-month OS rate of 71% and a 12-month OS rate of 51%.

The median OS was 9.5 months (95% CI, 6.0-17.6) in KRAS mutant patients, with a 6-month OS rate of 67%. The median OS was 10.0 months (95% CI, 4.9-17.1) in KRAS wild-type patients, with a 6-month OS rate of 65% and a 12-month OS rate of 43%.

“Importantly, the 12-month overall survival was 43%, which compares very favorably to historical data for regorafenib [Stivarga] of a 12-month overall survival of 24%,” Bendell said.

Investigators concluded that the combination was generally well tolerated and the majority of adverse events (AEs) were manageable.

Overall, 98% of the cohort experienced any-grade, any-cause AEs, and 96% experienced treatment-related(TR) AEs. There were no grade 5 AEs recorded, but 32 patients (38%) experienced grade 3/4 AEs.

Rash, diarrhea, fatigue, and increased blood creatine phosphokinase were the most common grade 3/4 TRAEs (5% each).

Thirty-eight patients (45%) experienced serious AEs, and 10 (12%) had serious TRAEs. Twenty patients (24%) withdrew due to AEs. Eleven (13%) withdrew due to AEs associated with atezolizumab and 20 (24%) due to AEs associated with cobimetinib.

Bendell added that this combination is currently under evaluation in the randomized, phase III IMblaze370 (NCT02788279) trial. The 3-arm trial is comparing the cobimetinib/atezolizumab combination with atezolizumab monotherapy or single-agent regorafenib in patients with previously treated, unresectable locally advanced or metastatic colorectal adenocarcinoma. Investigators completed accrual about a year ago and data are scheduled to be released later this year.

Bendell JC, Bang YJ, Chee CE, et al. A phase Ib study of safety and clinical activity of atezolizumab (A) and cobimetinib (C) in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol. 2018;36, (suppl 4S; abstr 560).