Combination of Atezolizumab and Cobimetinib Active in mCRC

March 22, 2018
Jason Harris

The combinations of atezolizumab and cobimetinib induced a 31% disease control rate in patients with heavily-pretreated metastatic colorectal cancer. Results from a 2-stage phase Ib study presented at the 2018 Gastrointestinal Cancers Symposium demonstrated an overall response rate of 8% (n = 7). All responses were partial responses. 

Johanna C. Bendell, MD

The combinations of atezolizumab (Tecentriq) and cobimetinib (Cotellic) induced a 31% disease control rate (DCR) in patients with heavily-pretreated metastatic colorectal cancer (mCRC).

Results from a 2-stage phase Ib study presented at the 2018 Gastrointestinal Cancers Symposium demonstrated an overall response rate (ORR) of 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%. 51 patients (61%) had progressive disease.

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

“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.

84 patients enrolled in the study as of May 17, 2017; 57 were KRAS mutant-type, 25 wereKRASwild-type, and the status of 2 patients was unknown. 66 (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 of the patients (38%).

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%).

60 mg of cobimetinib was established in Stage 1 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). Both groups of patients received 800 mg of atezolizumab every 2 weeks.

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

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

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

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%.

Median OS was 9.5 months (95% CI, 6.0-17.6) in KRAS mutant patients, with a 6-month OS rate of 67%. 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.

In conclusion, the combination was generally well tolerated and the majority of adverse events (AEs) were manageable, according to investigators.

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).

38 patients (45%) experienced serious AEs, and 10 (12%) had serious TRAEs. 20 patients (24%) withdrew due to AEs. 11 (13%) withdrew due to AEs associated with atezolizumab and 20 (24%) due to AEs associated with cobimetinib.

Bendell explained 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.

Reference:

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).