medwireNews: Among patients with metastatic colorectal cancer (CRC) and DNA repair deficiency, first-line treatment with nivolumab plus ipilimumab significantly improves progression-free survival (PFS) versus chemotherapy, show phase 3 trial data.
The study investigators explain that “DNA repair defects, which can be defined as microsatellite-instability–high (MSI-H) by polymerase-chain-reaction assays or next-generation sequencing or as mismatch-repair–deficient (dMMR) by immunohistochemical assays, are reported in approximately 4 to 7% of metastatic colorectal cancer cases.”
And historically such patients “have poor outcomes when treated with standard chemotherapy with or without targeted therapies,” they continue in The New England Journal of Medicine.
They therefore investigated the immune checkpoint inhibitors nivolumab and ipilimumab in the open-label CheckMate 8HW trial, which enrolled 303 patients who had not received systemic therapy for metastatic CRC and had MSI-H or dMMR disease according to local testing. The participants were randomly assigned to receive either:
nivolumab 240 mg plus ipilimumab 1 mg/kg every 3 weeks for 12 weeks followed by nivolumab 480 mg every 4 weeks for up to 2 years until they had disease progression or unacceptable toxicity; orinvestigator’s choice of chemotherapy, with or without targeted therapy (bevacizumab or cetuximab).
At a median follow-up of 31.5 months, treatment with nivolumab plus ipilimumab was associated with a significant PFS benefit in the primary efficacy population comprising 255 patients who had their MSI-H or dMMR status confirmed by central testing.
The 12-month PFS rates were 79% and 21% for nivolumab–ipilimumab and chemotherapy, respectively, while the corresponding 24-month rates were 72% and 14%.
The respective median PFS durations were not reached and 5.9 months. But as the proportional hazards assumption was violated, the researchers performed restricted mean survival time analysis at 24 months, which estimated times in the nivolumab–ipilimumab and chemotherapy groups of 19.2 and 8.6 months (between-group difference 10.6 months).
The findings were similar when all randomized patients were considered, with the median PFS duration unreached with nivolumab plus ipilimumab and 6.2 months with chemotherapy. However, the Kaplan–Meier curves crossed initially, which the study authors speculate could be because 13% of the patients in the nivolumab-ipilimumab arm were found to have “microsatellite-stable or mismatch repair–proficient tumors according to central testing, a percentage that may have driven the initial detriment observed in the population of all patients who underwent randomization.”
Turning to the safety data, Thierry Andre, from Sorbonne Université in Paris, France, and associates report that “[t]he toxic effects of nivolumab plus ipilimumab were consistent with the known profiles of each individual component,” and “no new safety concerns were identified.”
Treatment-related adverse events (TRAEs) of grade 3 or 4 occurred in 23% in the dual immunotherapy group and 48% of those in the chemotherapy group. The respective rates of discontinuation of any study drug due to TRAEs were 16% and 32%.
There were two treatment-related deaths in the nivolumab–ipilimumab arm, one case each of myocarditis and pneumonitis, and none in the chemotherapy arm.
Andre and colleagues say that these findings support the first-line use of nivolumab plus ipilimumab in MSI-H or dMMR metastatic CRC.
And they conclude: “The CheckMate 8HW trial is ongoing to assess the other primary end point of progression-free survival with nivolumab plus ipilimumab as compared with nivolumab among patients regardless of previous systemic treatment for metastatic disease.”
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