Immunotherapy for microsatellite stable colorectal cancer holds promise

During Colorectal Cancer Awareness month, it is important to highlight that precision medicine approaches are gaining traction in this indication. Positive results from any of the ongoing late-stage trials in microsatellite stable (MSS) colorectal cancer patients could see immunotherapy gaining a foothold in this indication, says GlobalData, a leading data and analytics company.

Jessica McCormack, Oncology and Hematology Analyst at GlobalData, comments: “The programmed cell death protein 1 (PD-1) inhibitors Opdivo and Keytruda have demonstrated impressive results in colorectal cancer patients with tumors with high microsatellite instability (MSI-H) and mutations in DNA mismatch repair (dMMR), but there are currently no approved immune checkpoint inhibitors for patients with MSS disease.”

There are a total of 20 ongoing Phase II–III clinical trials in the US for colorectal cancer that include a PD-1/programmed death-ligand 1 (PD-L1) inhibitor. Of these, 13 trials are open to patients with MSS disease, for which there are currently no approved immune checkpoint inhibitors.

McCormack continues: “The tumor microenvironment in MSI-H and dMMR patients is very different compared to that in MSS patients. MSI-H and dMMR tumors are more immunogenic, which means these tumors are responsive to immunotherapy. However, the majority of colorectal cancer patients are classified as having MSS. For these patients, a different strategy will be needed in order to enhance the recruitment of immune cells and prime MSS tumors to receive a benefit from immunotherapy agents.”

There are now 13 ongoing Phase II and III trials investigating PD-1/PD-L1 inhibitors in combination with either the current standard of care (typically a targeted therapy in combination with chemotherapy) or novel agents in MSS colorectal cancer patients.

McCormack adds: “It is hoped that by combining immune checkpoint inhibitors with the standard of care therapies, a greater immune response will be elicited. There are also a number of novel therapeutic agents being investigated with some potentially promising results. For example, the LEAP-005 trial of Keytruda + Lenvima has reported a 22% overall response rate in third-line patients. Considering that Keytruda monotherapy resulted in no responses in the KEYNOTE-016 study, that is an impressive improvement.”

The success of immunotherapies in MSS colorectal cancer would signal hope that the use of immunotherapies can be extended to other non-immunogenic (or “cold”) tumors, which have so far not responded well to these therapies. This would represent a significant commercial opportunity, and would also be an advancement in available therapies for cancer patients.

McCormack concludes: “Immune checkpoint inhibitors have really transformed the treatment landscape in other indications and have resulted in huge increases in both survival and quality of life. It is hoped that by identifying novel therapeutic targets and combining these with checkpoint inhibitors, similar progress can be seen in MSS colorectal cancer in the future.”

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