Nivolumab/Ipilimumab Combo Elicits Further PFS Benefit in Frontline MSI-H/dMMR mCRC

Updated efficacy findings from the phase 3 CheckMate-8HW trial also showed fewer grade 3/4 adverse events with nivolumab/ipilimumab vs chemotherapy.

Nivolumab (Opdivo) plus ipilimumab (Yervoy) elicited longer progression-free survival (PFS) vs chemotherapy in patients who had not previously received systemic therapy with microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) metastatic colorectal cancer (mCRC), according to results from the phase 3 CheckMate-8HW trial (NCT04008030), published in The New England Journal of Medicine.¹

The combination therapy was associated with a statistically significant improvement in PFS per blinded independent review vs chemotherapy (P < .001), meeting the trial’s primary end point. Additionally, estimated 12- and 24-month PFS were 79% (95% CI, 72%-84%) and 72% (95% CI, 64%-79%) with nivolumab/ipilimumab vs 21% (95% CI, 11%-32%) and 14% (95% CI, 6%-25%), respectively, in the control arm.

“In this trial, progression-free survival outcomes with nivolumab plus ipilimumab were superior to those with chemotherapy in the first-line treatment of MSI-H or dMMR metastatic colorectal cancer,” Thierry Andre, MD, professor of medical oncology at Sorbonne Université and head of the Medical Oncology Department at Saint Antoine Hospital, in Paris, France, and coinvestigators wrote in the study.¹ “Grade 3/4 treatment-related toxic effects were consistent with the established profiles of each individual drug, and no new safety concerns were identified.”

The phase 3 CheckMate-8HW trial randomly assigned patients 2:2:1 to receive either nivolumab plus ipilimumab (n = 202), nivolumab monotherapy, or chemotherapy (n =101) with or without targeted therapies, stratified by tumor location and number of previous systemic treatments. In the combination arm, nivolumab was administered at 240 mg and intravenous ipilimumab at 1 mg/kg every 3 weeks for 12 weeks, followed by 480 mg of nivolumab every 4 weeks.

Patients in the chemotherapy arm received investigator’s choice of chemotherapy with or without targeted therapies with the option to cross over to the combination arm upon disease progression. Dosing in the crossover group included 240 mg nivolumab every 2 weeks plus 1 mg/kg ipilimumab every 6 weeks, both for 12 weeks, followed by 480 mg nivolumab and the same 1 mg/kg dose of ipilimumab every 6 weeks. Dosing in all cohorts continued for 2 years or until disease progression, unacceptable toxicity, or withdrawal of consent.

The median age in the combination and chemotherapy arms, respectively, was 62 years (range, 21-86) and 65 years (range, 26-97), 53% and 55% were female, and predominantly White (87% vs 84%). In each respective arm, 55% vs 51% had an ECOG performance status score of 0, 40% vs 43% had stage IVA disease at enrollment, and 85% vs 83% had centrally confirmed MSI-H or dMMR status.

The dual primary end points of the study were PFS as determined by blinded review in nivolumab plus ipilimumab vs chemotherapy and nivolumab plus ipilimumab vs nivolumab monotherapy. Key secondary end points included overall survival, investigator-assessed PFS, PFS by blinded independent review in all randomized patients, and objective response determined by blinded review.

Any-grade adverse events (AEs) occurred in 99% of the combination arm and 98% of the chemotherapy arm, with grade 3/4 AEs occurring in 48% and 67% of respective arms. Grade 3/4 treatment-related AEs (TRAEs) occurred in 23% and 48%, respectively.

TRAEs leading to drug discontinuation occurred in 16% of the combination group and 32% of the chemotherapy group. In total, 22% of the combination group who received at least 1 therapy dose and 42% of the chemotherapy group had died.

Nivolumab plus ipilimumab earned a CHMP recommendation for colorectal cancer in November 2024.²

References

1. Andre T, Elez E, Cutsem EV, et al. Nivolumab plus ipilimumab in microsatellite-instability–high metastatic colorectal cancer. N Engl J Med. 2024;391(21):2014-2025. doi:10.1056/NEJMoa2402141
2. Bristol Myers Squibb receives positive CHMP opinion for Opdivo® (nivolumab) plus Yervoy® (ipilimumab) for the first-line treatment of adult patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer. News release. Bristol Myers Squibb. November 15, 2024. Accessed December 19, 2024. https://tinyurl.com/434jvfcu