Nivolumab-ipilimumab improves PFS in MSI-H/dMMR metastatic CRC

In the first-line treatment of patients with microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (CRC), dual immunotherapy using a combination of nivolumab and ipilimumab delivers a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with chemotherapy, according to the CheckMate 8HW trial presented at ASCO GI 2024.

In the initial analysis of this phase III trial, there was a 79-percent reduction in the risk of disease progression or death with the nivolumab-ipilimumab combination compared with standard chemotherapy in this patient population. [ASCO GI 2024, abstract LBA768]

“The trial met its primary endpoint,” said lead author Dr Thierry Andre from Sorbonne Université and Hôpital Saint Antoine in Paris, France.

CheckMate 8HW trial included 303 patients with MSI-H/dMMR mCRC. Participants were randomized to receive nivolumab 240 mg plus ipilimumab 1 mg/kg Q3W for four doses, followed by NIVO 480 mg Q4W (n=202), or the investigator’s choice of chemotherapy (mFOLFOX6 or FOLFIRI, with or without bevacizumab or cetuximab; n=101). Over 80 percent of participants (85 percent and 83 percent, respectively) had centrally confirmed MSI-H/dMMR status at baseline.

After a median follow-up of 24.3 months, median PFS was not reached in the combination arm and was 5.9 months in the chemotherapy arm (hazard ratio, 0.21; p<0.0001).

Patients who were treated with the combination therapy had a higher PFS rate at 12 months compared with those who were receiving chemotherapy (79 percent vs 21 percent). This effect was maintained through month 24 (72 percent vs 14 percent).

The PFS benefit observed with the combination regimen was consistent across all prespecified subgroups, including KRAS or NRAS mutation status and baseline liver, lung, or peritoneal metastases.

With regard to safety, those who received nivolumab-ipilimumab combination regimen had fewer grade ≥3 treatment-related adverse events compared with those who were receiving chemotherapy (23 percent vs 48 percent).

The safety profile of the combination regimen was consistent with the established profiles of each drug, and no new safety signals were identified, Andre noted.

“Overall, nivolumab plus ipilimumab demonstrated superior PFS over chemotherapy in patients with centrally confirmed MSI-H/dMMR metastatic CRC,” said Andre. “Results support [the combination] as a standard-of-care first-line treatment option for patients with MSI-H/dMMR metastatic CRC.”

“These exciting results from the CheckMate 8HW study have potentially practice-changing implications for previously untreated patients with MSI-H/dMMR metastatic CRC,” Andre said in a press release. “Additional data may help define the further benefit of the combination of nivolumab and ipilimumab compared with nivolumab alone and [this may] help oncologists determine the best treatment options for their patients.”