Nivolumab Approved for Patients with Chemotherapy-Resistant, Metastatic, MSI-H Colorectal Cancer

A subset of patients with metastatic colorectal cancer (mCRC) for which standard chemotherapy is ineffective can now receive the immunotherapy nivolumab (Opdivo®, Bristol-Myers Squibb).

The FDA’s approval of nivolumab, an anti-PD-1 checkpoint immunotherapy, applies to patients 12 years and older whose tumors are characterized by a specific biomarker—high microsatellite instability (MSI-H) or deficient DNA mismatch repair (dMMR). These MSI-dMMR tumors are unable to properly repair their DNA, and as a result, accumulate extraordinarily high levels of mutations. Some of these mutations can fuel tumor growth and survival, but they also provide—through the neoantigens they produce—targets for the immune system to attack.

“Patients with metastatic colorectal cancer who have dMMR or MSI-H tumors are less likely to respond to conventional chemotherapy,” said Heinz-Josef Lenz, MD, FACP, who serves as the J. Terrence Lanni Chair in Gastrointestinal Cancer Research at the University of Southern California. This has made immunotherapy a very promising option for these CRC patients, as well as patients with other types of MSI-H/dMMR tumors, as evidenced by the prior approval of pembrolizumab (Keytruda®, Merck).

The evidence that guided the FDA’s decision came from the phase II CheckMate-142 clinical trial, in which 32% (24/74) of patients with MSI-H/dMMR mCRC tumors responded to treatment with nivolumab. Of the 74 total patients, 53 had progressed after previous treatment with chemotherapy (fluoropyrimidine, oxaliplatin, and irinotecan). Of these 53 patients, 28% had either a partial or complete response after being treated with immunotherapy.

The median duration of response has not yet been reached, although durable responses have been seen in responders from each group. At least one patient’s response has lasted more than two years.

“As the third most common type of cancer in the United States, our view is that colorectal cancer—particularly for those with dMMR or MSI-H metastatic disease—has been in need of new research and treatments. The approval of Opdivo for appropriate patients with this disease gives the community more hope,” said Michael Sapienza, chief executive officer of the Colon Cancer Alliance.

In addition to MSI-H/dMMR, other biomarkers also have the potential to improve outcomes for CRC patients, by providing improved treatment approaches as well as diagnostic capabilities. Investigators funded by the Cancer Research Institute are at the forefront of these efforts.

Most recently, CRI partnered with Fight Colorectal Cancer to support Cynthia Sears, MD, (pictured) of the Johns Hopkins University School of Medicine, who is characterizing the relationship between bacteria, the immune system, and colorectal cancer. Yen-Chih Wang, PhD, of The Rockefeller University, and Lior Lobel, PhD, of Harvard, are also exploring how the gut microbiome influences disease in the colon. Additionally, Dan Liu, PhD, of the University of California, San Francisco, is defining the interactions of an immunosuppressive molecule in the context of colorectal cancer.