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Big PFS Improvement in Highly Mutated CRC With Dual Immunotherapy
Apr. 17 2024

Frontline dual immunotherapy significantly improved progression-free survival (PFS) versus chemotherapy in microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) metastatic colorectal cancer (CRC), a randomized trial showed.

At a median follow-up of 24.3 months, median PFS had yet to be reached with nivolumab (Opdivo)/ipilimumab (Yervoy) compared with 5.8 months with chemotherapy. The difference translated into a 79% reduction in the hazard ratio (HR) for disease progression or death.

Nivolumab/ipilimumab also had a more favorable safety profile, with a 50% lower incidence of grade 3/4 treatment-related adverse events (TRAEs), reported Thierry Andre, MD, of Sorbonne University and Saint-Antoine Hospital in Paris, at the Gastrointestinal Cancers Symposiumopens in a new tab or window.

"The PFS benefit was observed across all prespecified subgroups, including patients with KRAS or NRAS mutations, and those with baseline liver, lung, or peritoneal metastases," said Andre. "This study is ongoing to assess the other dual primary endpoint of PFS of nivolumab plus ipilimumab versus nivolumab across all lines. These results support nivolumab plus ipilimumab as a standard-of-care first-line treatment option for patients with MSI metastatic colorectal cancer."

Overall, the results show a "powerful" effect of dual immunotherapy on PFS, but two deaths in that treatment group concerned Alan Venook, MD, of the University of California San Francisco. In response, Andre said one death resulted from cardiotoxicity and the other from acute myocarditis but occurred after the patient crossed over from chemotherapy to immunotherapy.

Continuing his questioning from the audience, Venook said, "I think perhaps the most important cohort are not the patients who benefited from the therapy but that small group of patients who appeared to get no benefit whatsoever from the immunotherapy."

"As opposed to KEYNOTE-177opens in a new tab or window, where we've never learned what might be unique about those patients and give us some insight as to why patients don't respond to this immunotherapy, I'm wondering what the plans are to analyze that subset because that could very well hold the key to the realm of understanding how we can get other patients to benefit from the same category of drugs," he added.

Andre noted that "it's difficult to answer that question and we don't know exactly."

Misclassification of MSI-H/dMMR status, pseudoprogression, and treatment resistance are among the potential explanations, he said.

KEYNOTE-177 established the role of immunotherapy in MSI-H/dMMR metastatic CRC and led to the approval of pembrolizumab (Keytruda) for that indication. However, a subgroup of patients did not benefit from immunotherapy. Additionally, fewer than half of the responding patients remained progression free at 2 years, and only a third at 5 years, underscoring the need for new therapeutic options, Andre said.

The phase II CheckMate 142opens in a new tab or window trial demonstrated efficacy for the nivolumab/ipilimumab combination and for single-agent nivolumab in previously treated MSI-H/dMMR metastatic CRC.

Andre reported initial results from the randomized phase III CheckMate-8HWopens in a new tab or window trial, which compared nivolumab/ipilimumab, single-agent nivolumab, or investigator's choice of chemotherapy with or without bevacizumab (Avastin) among patients with untreated or previously treated disease.

The analysis comprised 202 patients allocated to nivolumab/ipilimumab and 101 patients assigned to chemotherapy. The patients were evenly distributed with respect to stage IV disease (42% and 49%), right-sided tumors (68% and 67%), sites of metastases (liver: 38% and 42%, lung: 22% and 25%, and peritoneum: 42% and 43%), PD-L1 expression <1% (72% and 79%), BRAF mutation (26% and 24%), KRAS/NRAS mutation (21% for both), and prior surgery (86% and 83%).

The results showed a dramatic difference in median PFS in favor of nivolumab/ipilimumab (95% CI 0.13-0.35, P<0.0001). Similar large differences emerged in favor of combination immunotherapy for landmark PFS analyses at 12 months (79% vs 21%) and 24 months (72% vs 14%).

Grade 3/4 TRAEs occurred in 23% of the nivolumab/ipilimumab arm and 48% of patients randomized to chemotherapy. Grade 3/4 non-endocrine immune-mediated adverse events (IMAEs) in the immunotherapy group included diarrhea/colitis (5%), hepatitis (3%), and rash and pneumonitis (2% each). Endocrine IMAEs included adrenal insufficiency (4%), hypothyroidism/thyroiditis (2%), and hypophysitis (3%).

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