ESMO World GI Congress 2018: IMblaze370 study Did Not Meet Its Primary Endpoint

Studying combination of atezolizumab with cobimetinib in patients with MSS/MSI-L metastatic CRC

IMblaze370 study did not meet its primary endpoint; atezolizumab plus cobimetinib and atezolizumab monotherapy did not demonstrate statistically significant prolonged overall survival (OS) benefit vs. regorafenib in the intention-to-treat (ITT) population of patients with previously treated, unresectable locally advanced or metastatic colorectal cancer (CRC). In the study, 91.7% of included patients had tumour with microsatellite stable (MSS) / microsatellite instability-low (MSI-L) status. The primary analysis results (LBA-004) were presented at the 20th anniversary ESMO World Congress on Gastrointestinal Cancer (20-23 June 2018, Barcelona, Spain). 

The study team explained in background that patients with chemotherapy-refractory MSS metastatic CRC are a population with limited treatment options and relatively short survival. 

An anti–PD-L1 monoclonal antibody, atezolizumab inhibits the binding of PD-L1 to its receptors PD-1 and B7.1, leading to the re-invigoration of tumour-specific T-cell immunity. Cobimetinib inhibits MEK1/MEK2 in the MAPK pathway, and blocking the MAPK pathway has been shown to favourably alter the tumour, tumour microenvironment and T-cell responses to promote anti-tumour immune activity. 

The investigators hypothesized that combining atezolizumab with cobimetinib may allow better immune recognition and generate greater anti-tumour effects than either agent alone in MSS / MSI-L metastatic CRC. 

IMblaze370 (NCT02788279) is a global, multicentre, open-label, randomised phase III trial that compared atezolizumab plus cobimetinib and atezolizumab monotherapy with standard-of-care regorafenib in patients with previously treated, unresectable locally advanced or metastatic CRC. 

Patients were randomised 2:1:1 to receive atezolizumab plus cobimetinib, atezolizumab monotherapy or regorafenib, respectively. Atezolizumab was administered intravenously at 840 mg Q2W in the combination arm or at 1200 mg Q3W in the monotherapy arm. Cobimetinib was administered orally at 60 mg on a 21-days-on/7-days-off schedule and regorafenib was administered orally at 160 mg on a 21-days-on/7-days-off schedule. 

The primary endpoint was OS in ITT patients; secondary endpoints included investigator-assessed progression-free survival (PFS), overall response rate (ORR) and duration of response (DoR) per RECIST v1.1. 

As of 9 March 2018, 363 patients were evaluated for efficacy and safety. The median age was 58 years; 26% of patients had received > 3 lines of prior treatment in the metastatic setting. Only 1.7% of enrolled patients were identified as having MSI-High metastatic CRC, while 91.7% had MSS or MSI-L and 6.6% had missing MSI status; 54.3% had RAS-mutant metastatic CRC. 

Median OS was 8.9 month with atezolizumab plus cobimetinib vs. 8.5 month with regorafenib, hazard ratio (HR) 1.00, 95% CI: 0.73, 1.38 (p = 0.987). Median OS was 7.1 month with atezolizumab monotherapy (HR vs. regorafenib, 1.19 [95% CI: 0.83, 1.71]). 

The PFS HR for atezolizumab plus cobimetinib vs. regorafenib was 1.25 (95% CI: 0.94, 1.65) and for atezolizumab monotherapy vs. regorafenib was 1.39 (95% CI: 1.00, 1.94). 

The ORRs were 2.7%, 2.2% and 2.2% with atezolizumab plus cobimetinib, atezolizumab monotherapy and regorafenib, respectively. 

Treatment-related grade 3-4 adverse events (AEs) were reported in 45% of patients who received atezolizumab plus cobimetinib, 10% who received atezolizumab monotherapy and 49% who received regorafenib. Treatment-related AEs of any grade with >30% occurrence were diarrhoea (56%), rash (42%) and nausea (32%) with atezolizumab plus cobimetinib, none with atezolizumab monotherapy, and palmar-plantar erythrodyaesthesia (51%), fatigue (43%), diarrhoea (35%) and decreased appetite (34%) with regorafenib. 

The study team concluded that the IMblaze370 did not meet its primary endpoint. Atezolizumab plus cobimetinib and atezolizumab monotherapy did not demonstrate statistically significant prolonged OS benefit vs. regorafenib in the ITT population. The PFS and ORR were similar across treatment arms. No new safety signals were observed and the safety profiles of atezolizumab plus cobimetinib combination and atezolizumab monotherapy were consistent with previous findings. 

Reference 

Bendell J, Ciardiello F, Tabernero J, et al. Efficacy and safety results from IMblaze370, a randomised Phase III study comparing atezolizumab+cobimetinib and atezolizumab monotherapy vs regorafenib in chemotherapy-refractory metastatic colorectal cancer. Annals of Oncology 2018; Volume 29, Issue suppl_5. mdy208.003, https://doi.org/10.1093/annonc/mdy208.003