A combination of Bristol-Myers Squibb‘s Opdivo (nivolumab) and low-dose Yervoy (ipilimumab) induced promising and durable response rates in metastatic colorectal cancer patients with certain genetic abnormalities who had not received prior treatments, Phase 2 data shows.
These findings suggest the combination may become the next first-line therapy for metastatic colorectal cancer patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors.
The latest results from the open-label Phase 2 trial, called CheckMate-142 (NCT02060188), were recently revealed at the European Society of Medical Oncology (ESMO) 2018 Congress in Munich.
Heinz-Josef Lenz, MD, from the Norris Comprehensive Cancer Center in Los Angeles, presented the study, titled “Durable clinical benefit with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC).”
“The combination of low-dose ipilimumab and nivolumab has a durable clinical response and is well tolerated as first line treatment in patients with MSI-high metastatic colorectal cancer. The data suggest that nivolumab and ipilimumab may be a first line treatment option for these patients,” Lenz said in a press release.
Tumors with MSI-H and dMMR are those with mutations in genes that normally repair DNA. These patients are usually less responsive to chemotherapy and show shorter survival times.
However, the accumulation of mutations in tumor cells with these deficiencies sometimes generate structurally different proteins that the immune system identifies as malignant, making these tumors more responsive to immunotherapies.
Results from the CheckMate-142 study had already shown that a combination of Opdivo and low-dose Yervoy induced high and durable response rates in MSI-H metastatic colorectal cancer patients who had failed prior chemotherapy. The findings led to an accelerated approval from the U.S. Food and Drug Administration earlier this year.
Researchers are now reporting data from patients who had not yet received treatment for their MSI-H/dMMR metastatic colorectal cancers.
The study included 45 patients (51% men, median age of 66 years), who received Opdivo every two weeks and low-dose Yervoy every six weeks until their disease progressed or they experienced any signs of toxicity. Its main goal was overall response rate.
After a median follow-up of 13.8 months, the combination had partially shrunk the tumors of 53% patients and completely eliminated traces of tumor in 7%. Additionally, 23% of patients achieved disease stabilization with the treatment, amounting to a total disease control rate of 83%.
At the time of the analysis, more than half of patients were still responding to the combination. After one year, 83% of patients remained alive, and 77% were alive and disease-free.
While other trials had tested a combination of Opdivo and Yervoy, the use of low-dose Yervoy in the CheckMate-142 study resulted in fewer side effects. Severe or life-threatening adverse events were reported by 16% of patients, with only 7% of participants discontinuing treatment due to treatment-related adverse events.
“Nivolumab plus low-dose ipilimumab is effective in most patients with MSI-high metastatic colorectal cancer. Patients improve dramatically and some return to work,” said Thierry André, MD, head of medical oncology, Hôpital Saint-Antoine, Assistance Publique — Hôpitaux de Paris in France.
“It means healthcare systems can be confident that resources are being targeted effectively. This is in contrast to other metastatic cancers (melanoma, lung or kidney) where it is more difficult to select patients who benefit from immunotherapy,” he added.
These most recent findings from CheckMate-142 might lead to an accelerated approval from the FDA, based on response rates and duration of responses. However, a full FDA approval and an approval from the European Medicines Agency will likely require that a Phase 3 trial confirm the benefits of Opdivo plus low-dose Yervoy versus the standard of care.