SAN FRANCISCO —
Findings from the CHECKMATE-8HW trial revealed that first-line nivolumab plus ipilimumab led to a significant improvement in progression-free survival (PFS) compared with chemotherapy among patients with metastatic CRC.
More specifically, at 2 years, PFS was 72% among patients with microsatellite instability–high (MSI-H) or deficient mismatch repair (dMMR) randomized to the immunotherapy combination compared with just 14% among those randomized to chemotherapy with or without targeted therapy.
The magnitude of the benefit was unexpected, especially considering patients received only four cycles of the immunotherapy combination in the trial. “It’s a good surprise,” said lead investigator Thierry Andre, MD, who presented the findings at the 2024 ASCO Gastrointestinal Cancers Symposium.
The findings indicate that nivolumab plus ipilimumab should really be “a new standard,” said Andre, a medical oncologist at Sorbonne University, Paris.
The combination as well as nivolumab alone has received US Food and Drug Administration’s (FDA’s) approval to treat MSI-H or dMMR metastatic CRC in the second line, following chemotherapy failure.
The FDA also approved pembrolizumab as first-line monotherapy for this CRC indication in 2020. The KEYNOTE-177 trial, which led to the pembrolizumab approval, reported a 2-year PFS of 48% among patients receiving the monotherapy. Andre was the lead investigator on KEYNOTE-177.
To compare PFS results for pembrolizumab and nivolumab alone, the CHECKMATE-8HW trial included a nivolumab monotherapy arm, but these results are pending, as are the overall survival findings, Andre said.
Overall, CHECKMATE-8HW must be taken into context with KEYNOTE-177, and “we need a little bit more trial data” for oncologists to decide between the two options, said Neil Newman, MD, a radiation oncologist at the University of Texas Health Science Center, San Antonio, Texas, who co-moderated Dr. Andre’s presentation.
Andre noted, however, that if the nivolumab and pembrolizumab monotherapy results are similar, most patients will likely receive the nivolumab/ipilimumab combination, given the improved PFS outcomes.
In CHECKMATE-8HW, patients were randomized to three regimens. The 202 patients in the combination arm received nivolumab 240 mg plus ipilimumab 1 mg/kg every 3 weeks for four doses, followed by nivolumab 480 mg every 4 weeks. The 101 patients in the chemotherapy group received investigator’s choice of mFOLFOX6 or FOLFIRI with or without bevacizumab or cetuximab. And the nivolumab monotherapy arm received nivolumab 240 mg every 2 weeks for six doses, followed by nivolumab 480 mg every 4 weeks.
Treatment continued until disease progression or unacceptable toxicity over a maximum of 2 years. The median duration of treatment was 13.5 months in the nivolumab/ipilimumab arm vs 4 months in the chemotherapy arm.
PFS curves started to separate between nivolumab/ipilimumab and chemotherapy at about 3 months.
Patients receiving the combination exhibited a 79% reduction in the risk for disease progression or death at 2 years (72% vs 14%; hazard ratio, 0.21; P < .0001). The median PFS was not reached with the combination vs 5.9 months with chemotherapy. The PFS benefit of nivolumab/ipilimumab held across various subgroups, including patients with KRAS or NRAS mutations and baseline lung, liver, or peritoneal metastases.
The incidence of grade 3/4 treatment-related adverse events was 23% with nivolumab/ipilimumab vs 48% in the chemotherapy arm. The most common grade 3/4 events with nivolumab/ipilimumab were diarrhea/colitis (5%), adrenal insufficiency (4%), hepatitis (3%), and inflammation of the pituitary gland (3%).
Two treatment-related deaths occurred in the combination arm — one from pneumonitis and the second from myocarditis — and none occurred in the chemotherapy arm.
Mark A. Lewis, MD, a gastrointestinal oncologist at Intermountain Healthcare in Murray, Utah, was impressed with the CHECKMATE-8HW findings. The data are shaping up to make nivolumab/ipilimumab “the next great step in metastatic CRC management beyond KEYNOTE-177,” Dr. Lewis said.
Dr. Lewis noted that the new trial makes it “imperative” to standardize testing for immunotherapy candidacy upfront. “It is completely unacceptable for any patient with metastatic CRC to not have their MMR/MSI status assessed,” he said. “Much as no oncologist would dare treat breast cancer without testing ER, PR, HER2 status, biomarkers cannot be a later-line afterthought in stage IV CRC.”
Drugmaker Bristol-Myers Squibb told this news organization that the company will be seeking a first-line indication for the combination, and anticipates approval early next year or possibly sooner, if the FDA grants a priority review.
The work was funded by Bristol-Myers Squibb and the ONO Pharmaceutical Company. Dr. Andre had numerous industry ties, including being a consultant for both BMS and Merck. He also reported honoraria from both companies. Dr. Newman and Dr. Lewis didn’t have any disclosures.
A version of this article appeared on Medscape.com.