Atezolizumab, Cobimetinib Combo Falls Short in Phase III mCRC Trial

Sandra Horning, MD

Combination therapy with the PD-L1 inhibitor atezolizumab (Tecentriq) and the MEK inhibitor cobimetinib (Cotellic) failed to improve overall survival (OS) versus regorafenib (Stivarga) in previous treated patients with locally advanced or metastatic colorectal cancer (CRC), according to topline findings from the phase III IMblaze370 study.

Single-agent atezolizumab also did not demonstrate a clinically significant benefit versus regorafenib in the study, according to Genentech (Roche), the manufacturer of atezolizumab and cobimetinib. Patients on the study had progressive disease or were intolerant to treatment following 2 or more lines of chemotherapy.

Among the IMblaze370 population, 95% of patients had tumors that were microsatellite stable (MSS). Genentech reported that the data from the trial will be presented at an upcoming medical conference.

“While these results are not what we hoped for, we remain committed to applying our deep experience to develop medicines that will improve outcomes for people living with gastrointestinal cancers,” Sandra Horning, MD, chief medical officer and head of Global Product Development, Genentech, said in a statement.

The IMblaze370 study (NCT02788279) randomized 363 previously treated patients with advanced or metastatic CRC in a 2:1:1 ratio to atezolizumab/cobimetinib, atezolizumab alone, or single-agent regorafenib. The primary endpoint was OS, with progression-free survival (PFS), overall response rate (ORR) and duration of response as secondary endpoints. In its statement on the results, Genentech reported that there were no new safety signals with the combination.

Results from a 2-stage phase Ib study presented at the 2018 Gastrointestinal Cancers Symposium showed that the atezolizumab/cobimetinib combination induced a 31% disease control rate (DCR) in patients with heavily-pretreated metastatic CRC (mCRC). The 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.

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 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 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%.

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 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).

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.