Immunotherapy for Colorectal Cancer

A Review of Current and Novel Therapeutic Approaches

Aaron J. Franke; William Paul Skelton IV; Jason S. Starr; Hiral Parekh; James J. Lee; Michael J. Overman; Carmen Allegra; Thomas J. George


J Natl Cancer Inst. 2019;111(11):1131-1141. 

In This Article

Role of Immunotherapy in MSS:pMMR mCRC

Although the available evidence clearly supports the use of immunotherapy for the small subset (3%–5%) of patients with dMMR:MSI-H stage IV CRC, unfortunately, analyses of MSS:pMMR mCRC cohorts in the checkpoint inhibitor trials have failed to demonstrate any clinically meaningful response or survival benefit with either PD-1 monotherapy or dual checkpoint blockade.[35] To enhance the activity of these agents in MSS:pMMR tumors, investigators have evaluated the potential synergistic approach of checkpoint inhibitor and tumor signal transduction pathways. Preclinical models demonstrated targeting the mitogen-activated protein kinase pathway through the inhibition of MEK (mitogen-activated protein kinase kinase) increases tumor cell expression of MHC-I, thereby stimulating clonal expansion of peritumoral T cells and enhancing anti–PD-L1 activity.[60] This biologic synergy was further investigated combining immunotherapy (anti–PD-L1) and cobimetinib, an oral, highly selective, and reversible small molecule inhibitor of MEK1/2, and central components of the RAS/RAF/MEK/ERK signaling pathway.

Unfortunately, the highly anticipated results of the randomized phase III IMblaze370 study reported that the combination (cobimetinib and atezolizumab) failed to meet its primary OS endpoint. In an analysis of 363 patients with refractory mCRC (92% MSS:pMMR), the immunotherapy combination and atezolizumab monotherapy did not demonstrate a statistically significant OS benefit vs regorafenib in the intention-to-treat population.[61] The median OS in the atezolizumab + cobimetinib and regorafenib arms was 8.9 vs 8.5 months (HR = 1.00, 95% CI = 0.73 to 1.38, P = .99), and 7.1 months with atezolizumab monotherapy (HR vs regorafenib = 1.19, 95% CI = 0.83 to 1.71). In addition, PFS and ORR were similar across treatment groups. While we await the final peer-reviewed manuscript as well as correlative and subset analyses, it is important to note the incredibly rapid speed at which this study enrolled, a reflection of the desire for and still unmet need in the mCRC patient population.