The phase 3, open-label, multicentre, randomised, three-arm IMblaze370 study investigated the combination of atezolizumab plus cobimetinib vs atezolizumab vs regorafenib in the third-line treatment setting of adult patients with unresectable locally advanced or metastatic colorectal cancer. Eligible patients had a baseline ECOG performance status of 0-1 and experienced disease progression or intolerance on at least two previous lines of systemic chemotherapy. The majority of patients had microsatellite stable disease, the recruitment of microsatellite instability (MSI)-high patients was capped at 5%. Finally, participants were stratified for the extended RAS status (wild-type vs mutant) and the time since diagnosis of first metastasis (<18 months vs ≥18 months).

The primary efficacy endpoint was overall survival (OS) in the intention-to-treat (ITT) population. Patients who received at least one dose of their assigned study drug were included in the safety assessment.

A total of 363 patients were randomised to receive atezolizumab 840 mg intravenously (IV) every 2 weeks (q2wk) plus cobimetinib 60 mg orally (p.o.) once daily (q.d.) on days 1-21 in 28-day cycles (N=183), single-agent atezolizumab 1200 mg IV q3wk (N=90), or regorafenib 160 mg p.o. q.d. on days 1-21 in 28-day cycles (N=90).

Results

At a median follow-up of 7.3 months (interquartile range [IQR], 3.7-13.6) the median OS measured 8.87 months (95% confidence interval [CI], 7.00-10.61) in the group of patients treated with atezolizumab plus cobimetinib. In the atezolizumab and regorafenib groups, the median OS measured 7.10 months (95% CI, 6.05-10.05) and 8.51 months (95% CI, 6.41-10.71), respectively. The hazard ratio (HR) for the anti-PD-L1 plus MEK inhibitor vs regorafenib monotherapy was 1.00 (95% CI, 0.73-1.38; P=0.99). When comparing single-agent atezolizumab with regorafenib the HR was 1.19 (95% CI, 0.83-1.71; P=0.34).

Safety

Grade 3-4 adverse events (AEs) occurred in 61% (109/179) of patients treated with atezolizumab plus cobimetinib. In the atezolizumab and regorafenib groups, grade 3-4 AEs were reported in 31% (28/90) and 58% (46/80) of patients, respectively. Common all-cause grade 3-4 AEs in the combination group included diarrhoea (11%), anaemia (6%), increased blood creatine phosphokinase (7%), and fatigue (4%). Serious AEs were reported in 40% (71/179) of patients receiving atezolizumab plus cobimetinib including two treatment-related deaths (sepsis), 17% (15/90) of patients receiving atezolizumab, and 23% (18/80) of patients receiving regorafenib including one treatment-related death (intestinal perforation).