There are 20 Phase II and III trials in the US investigating PD-1/L1 inhibitors in colorectal cancer, of which 13 are open to patients with microsatellite stable (MSS) disease. Merck’s PD-1 inhibitor Keytruda (pembrolizumab), and Bristol-Myers Squibb’s PD-1 inhibitor Opdivo (nivolumab) in combination with its CTLA-4 inhibitor Yervoy (ipilimumab), have demonstrated impressive results in colorectal cancer patients with tumors with high microsatellite instability (H-MSI) or with mutations in DNA mismatch repair (dMMR). However, patients with MSS disease are currently ineligible for immunotherapies. Positive results from any of these late-stage trials could significantly increase the use of immunotherapy in this indication, and may pave the way for immunotherapy in other non-immunogenic tumor types.

For patients with MSI-H or dMMR colorectal cancer, Keytruda is currently approved for first-line therapy and Opdivo + Yervoy is approved in the second line. However, early trials with checkpoint inhibitors in colorectal cancer demonstrated limited responses in MSS patients. Immunotherapies have also experienced several failures in MSS patients, such as Roche’s IMblaze-370 study, which compared the company’s PD-L1 inhibitor Tecentriq (atezolizumab) in combination with Genentech’s Cotellic (cobimetinib) to Bayer’s Stivarga (regorafenib) and did not meet its primary endpoint of improved survival.

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The tumor microenvironment in MSI-H and dMMR patients is much more immunogenic compared with that of MSS patients. However, the majority of colorectal cancer patients are classified as having MSS. For these patients, a different strategy is needed to enhance immune cell recruitment and prime MSS tumors to immunotherapy agents. Phase II and III trials are investigating PD-1/L1 inhibitors in combination with either the current standard of care or novel agents in MSS colorectal cancer patients, with the hope of enhancing the immune response. The addition of novel therapies to PD-1 inhibitors appears to hold promise. For example, the KEYNOTE-016 trial of Keytruda monotherapy resulted in no responses in MSS patients, but the addition of Eisai/Merck’s vascular endothelial growth factor receptor inhibitor, Lenvima (lenvatinib), led to an overall response rate of 22% in the LEAP-005 trial.

Immunotherapy has transformed the treatment landscape in several indications, resulting in increases in both overall survival and quality of life. However, so-called “cold” tumors such as those of MSS colorectal cancer patients have proven difficult to treat due to the lack of inflammation and infiltrated T-cells. GlobalData anticipates that the identification of novel therapeutic targets and combinations with checkpoint inhibitors could lead to progress in the treatment of MSS colorectal cancer in the next 10 years.