FDA Approves Immunotherapy Combination for Metastatic Colorectal Cancer

The Food and Drug Administration (FDA) approved the combination use of intravenous Opdivo (nivolumab) plus Yervoy (ipilimumab) for patients with previously treated microsatellite instability-high (MSI-H) or DNA mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC), according to Bristol-Myers Squibb, the manufacturer of the drugs.

The approval is based on findings from the phase 2 CheckMate-142 trial, designed to evaluate the combination therapy compared with Opdivo monotherapy in 119 patients with metastatic CRC who previously progressed on fluoropyrimidine, oxaliplatin and irinotecan regimens.

The 82 patients assigned to the combination who previously were treated with fluoropyrimidine, oxaliplatin and irinotecan experienced an overall response rate of 46 percent, including three patients who experienced a complete response.

Among all enrolled 119 patients, nearly half (49 percent) responded to Opdivo plus Yervoy treatment. Five experienced a complete response, and 53 a partial response. While the targeted average duration of response was not reached, 83 percent of patients had responses that lasted six weeks or longer, and 19 percent had responses that lasted a year or longer.

“For patients with dMMR/MSI-H (metastatic) CRC, the FDA approval of combination ipilimumab and nivolumab provides a novel therapeutic option with a higher response rate than that from monotherapy immunotherapy. It is encouraging that durable disease control and promising survival is also seen,” Aaron Franke, M.D., MSc, hematology/oncology fellow at the Moffitt Cancer Center, said in an interview with CURE.

This is not the first immunotherapy regimen approved in this space. In fact, in August 2017, single-agent Opdivo was approved for patients with MSI-H or dMMR metastatic CRC whose disease had progressed on fluropyrimidine, oxaliplatin and irinotecan.

Researchers are finding that MSI-H and dMMR tumors often respond particularly well to immunotherapy. Damage in the DNA mismatch repair proteins, which fix errors when cells replicate, can lead to a tumor testing positive for MSI-H status. This happens in about 4 to 5 percent of patients with metastatic CRC.

The Opdivo/Yervoy combination is associated with the following side effects: immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion reactions; and embryo-fetal toxicity.

The most frequent serious adverse reactions reported in at least 2 percent of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia and dehydration.

The most common adverse reactions (reported in at least 20 percent of patients) were fatigue (49 percent), diarrhea (45 percent), pyrexia (36 percent), musculoskeletal pain (36 percent), abdominal pain (30 percent), pruritus (28 percent), nausea (26 percent), rash (25 percent), decreased appetite (20 percent), and vomiting (20 percent).

“Unfortunately, more significant toxicity is noted with the combination, and diligence is needed to monitor these immune-mediated side effects,” Franke said.

While the approval provides a new effective treatment option for eligible patients, there are still unanswered questions and next steps to be investigated, such as the ideal duration and the optimal sequencing of these treatments. Researchers and clinicians alike also need better risk factor determination for toxicity and biomarkers to better predict who is likely to respond to single versus combination immunotherapy, according to Franke.

“Although these agents have shown tremendous promise, leading to their FDA-approved indication in 2017, the (gastrointestinal) oncology community recognizes that many patients, even those with dMMR/MSI-H CRC, do not respond to a single-agent immunotherapy approach,” Franke said.