Nivolumab New Standard for Previously Treated MSI-H Metastatic CRC

January 24, 2017

The immune checkpoint inhibitor nivolumab showed durable responses and disease control in a group of heavily pretreated patients with DNA mismatch repair deficient/microsatellite instability high (MSI-H) metastatic colorectal cancer.

The immune checkpoint inhibitor nivolumab showed durable responses and disease control in a group of heavily pretreated patients with DNA mismatch repair deficient/microsatellite instability high (MSI-H) metastatic colorectal cancer, according to updated results from the CheckMate 142 study (abstract 519) presented at the 2017 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, held January 19–21 in San Francisco.

“Nivolumab monotherapy provided durable responses, disease control, and long-term survival in patients with MSI-H metastatic CRC,” said Michael J. Overman, MD, of the University of Texas MD Anderson Cancer Center. “Responses were observed regardless of tumor or immune cell PD-L1 expression, regardless of BRAF or KRAS mutation status, and regardless of clinical history of Lynch syndrome.”

According to Overman, about 4% of patients with metastatic colorectal cancer have a high degree of microsatellite instability due to a deficiency in the DNA mismatch repair system. These patients may be less responsive to conventional chemotherapy than patients who are mismatch repair proficient, and their disease is associated with elevated levels of tumor neoantigens, and tumor-infiltrating lymphocytes, and have upregulated expression of checkpoint regulators in immune cells.

Patients enrolled on the study had DNA mismatch repair deficient/MSI-H metastatic disease and had progressed on or were intolerant to one or more prior lines of therapy. Among the 74 patients enrolled, 84% had received two or more prior lines of therapy.

Patients were assigned to receive nivolumab 3 mg/kg every 2 weeks. The primary endpoint was overall response rate per investigator assessment. Secondary endpoints included overall response rate by blinded independent review.

With a median follow up of 7.4 months, the overall response rate was 31.1% per investigator and 27% by review committee. According to investigators, there were no complete responses, 23 partial responses, and 29 patients had stable disease, for a disease control rate for 12 or more weeks of 68.9%. According to the blinded independent review, there were two complete responses, 18 patients with partial response, and 29 patients with stable disease for a disease control rate for 12 or more weeks of 62.2%.

The median time to response was about 2.7 months. The median progression-free survival was 9.6 months with a 12-month rate of 48.4% per investigator review. The 12-month progression-free survival rate was 45.6% per review committee. The median overall survival has not been reached.

Grade 3/4 treatment-related adverse events occurred in 20.3% of patients and there were no deaths related to drug toxicity. The researchers evaluated several patient-reported outcomes and found clinically meaningful improvements in quality of life, functioning, and symptoms as early as week 13 of the study. In addition, using a generic health quality of life-related scale, patients who continued treatment for 19 weeks achieve a level of health that would be regarded as equal to or exceeding the general health of many populations.

“These results suggest that nivolumab should be considered a new standard of care for patients with previously treated MSI-H advanced CRC,” Overman said. “This is in line with the recent amendment to NCCN guidelines which recommend all metastatic colorectal cancer patients have testing for MSI-H and also patients with MSI-H colorectal cancer after initial therapy be considered for either pembrolizumab or nivolumab monotherapy.”