Immunotherapy with antibodies targeting programmed death receptor 1 (PD-1) and its ligand (PD-L1) has changed the standard of care for many tumor types, including metastatic colorectal cancer (mCRC) with high levels of microsatellite instabilities (MSI-H). Unfortunately, only around 5% of patients with mCRC have an MSI-H genotype, while the remaining 95% are microsatellite stable (MSS). In contrast to MSI-H, the MSS genotype is associated with a lower tumor mutation burden, resulting in fewer neoantigens and less overall immune stimulation. Single-agent immunotherapy has shown minimal activity in MSS tumors. However, preclinical evidence suggests that inhibition of MEK with cobimetinib leads to upregulation of MHC1 on tumor cells, induces intratumoral T-cell activation, and enhances anti-PD-L1 activity. This synergistic combination was evaluated in a phase Ib trial in several solid tumor types, including heavily pretreated, advanced CRC.
At the 2018 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, Johanna Bendell, MD (Sarah Cannon Research Institute, Nashville, Tennessee, United States), presented results from a phase Ib dose-escalation and dose-expansion study evaluating the combination of atezolizumab and cobimetinib in 84 patients with previously treated mCRC. The combination was associated with an overall response rate (ORR) of 8% and a disease-control rate (DCR) of 31%. Of the 7 responding patients, 4 had MSS and 1 had MSI-low mCRC, while the remaining 2 had unknown MSI status. Responses were durable, with a median duration of response of 14.3 months. In all treated patients, atezolizumab plus cobimetinib resulted in a 6-month progression-free survival (PFS) rate of 18% and a 12-month overall survival (OS) rate of 43%. Of note, however, in the subset of patients with MSS disease, 6-month PFS was 27% and 12-month OS was 51%. The 12-month OS rates compare favorably with the 12-month OS of 24% with regorafenib, a standard treatment option in this setting.
The adverse event (AE) profile associated with the combination was manageable, with most AEs related to cobimetinib. The most frequent treatment-related grade 3/4 AEs, occurring in 5% of patients each, were rash, diarrhea, fatigue, and increased blood creatine phosphokinase.
Dr Bendall concluded that this combination represents the first potential immune-modifying therapy for patients with MSS mCRC. The phase III IMblaze 370 (COTEZO) trial, which is comparing the combination of cobimetninib and atezolizumab with atezolizumab and with regorafenib in pretreated patients with mCRC (95% MSS and 5% MSI-H), has completed accrual and results are eagerly awaited.
For further insights on this study and the latest advances in immunotherapy for mCRC, please see the prIME Oncology Clinical Spotlight featuring an expert discussion between Dr Axel Grothey, Dr Johanna Bendell, and Dr Ian Chau.