Nivolumab Plus Ipilimumab Prolongs PFS vs Nivolumab Alone in MSI-H/dMMR mCRC

Treatment with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) led to early and sustained progression-free survival (PFS) benefits vs treatment with nivolumab alone across all lines of therapy in patients with mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H) metastatic colorectal cancer (mCRC), meeting one of the dual primary end points of the phase 3 CheckMate 8HW trial (NCT04008030).1

Findings, which were presented at the 2025 Gastrointestinal Cancers Symposium, showed thatamong patients with centrally confirmed MSI-H or dMMR status, data showed a median PFS that was not reached (NR; 95% CI, 53.8 months-not evaluable [NE]) with nivolumab plus ipilimumab vs 39.3 months (95% CI, 22.1-NE) with nivolumab monotherapy (HR, 0.62; 95% CI, 0.48-0.81; P = .0003). The PFS rates in each respective arm across this population were 76% vs 63% at 12 months, 71% vs 56% at 24 months, and 68% vs 51% at 36 months. Among all randomly assigned patients, the median PFS was 54.1 months vs 18.4 months, respectively (HR, 0.64; 95% CI, 0.52-0.79).

PFS outcomes generally favored the nivolumab/ipilimumab arm across all lines of therapy and prespecified patient subgroups based on factors including age, sex, ECOG performance status, and liver metastases.

In the MSI-H/dMMR tumor population, the objective response rate (ORR) was 71% (95% CI, 65%-76%) with nivolumab plus ipilimumab vs 58% (95% CI, 52%-64%) with nivolumab alone (P = .0011). Of note, complete responses (CRs) and partial responses (PRs), respectively, occurred in 30% and 40% of patients in the nivolumab/ipilimumab arm and 28% and 30% of those in the ipilimumab monotherapy arm. Additionally, the median time to response (TTR) in each respective arm was 2.8 months (range, 1.2-44.5) vs 2.8 months (range, 1.2-29.5), and the median duration of response (DOR) was NR (95% CI, NE-NE) vs NR (95% CI, NE-NE).

“Nivolumab plus ipilimumab demonstrated statistically significant and clinically meaningful improvement in PFS vs nivolumab in patients with centrally confirmed [MSI-H or dMMR mCRC] across all lines [of therapy]. [There were] early and sustained separation of PFS curves after the first scan,” Thierry André, MD, a professor of medical oncology at the Sorbonne Université in Paris and head of the Medical Oncology Department at the Saint Antoine Hospital, Assistance Publique Hôpitaux de Paris, France, stated in the presentation.1 “These results, combined with the previously reported superior PFS with nivolumab plus ipilimumab vs chemotherapy in the first-line setting,2 establish nivolumab plus ipilimumab as a new standard of care for patients with MSI-H/dMMR metastatic [CRC].”

In the multicenter, open-label phase 3 trial, patients were randomly assigned 2:2:1 to receive nivolumab monotherapy (n = 353), nivolumab plus ipilimumab (n = 354), or investigator’s choice of modified folinic acid plus fluorouracil and oxaliplatin (mFOLFOX6) or folinic acid plus fluorouracil and irinotecan (FOLFIRI) with or without bevacizumab (Avastin) or cetuximab (Erbitux; n = 132). In the monotherapy arm, patients received nivolumab at a dose of 240 mg once every 2 weeks for 6 doses followed by a dose of 480 mg once every 4 weeks. In the combination arm, patients received nivolumab at a dose of 240 mg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses followed by a dose of 480 mg every 4 weeks.

The trial’s primary end points were PFS per blinded independent central review for nivolumab plus ipilimumab vs chemotherapy in the first-line setting and PFS for nivolumab vs nivolumab plus ipilimumab across all lines of treatment. Secondary end points included ORR, health-related quality of life (HRQOL), and safety.

Patients with histologically confirmed unresectable or metastatic CRC, MSI-H or dMMR status per local testing, no prior treatment with immunotherapy, and an ECOG performance status of 0 or 1 were eligible for enrollment on the trial.

Of note, 352 patients in the nivolumab/ipilimumab arm and 351 in the nivolumab monotherapy arm received study treatment, with ongoing treatment at the time of analysis reported for 6% and 4% of patients, respectively. Additionally, 49% and 57% of patients discontinued treatment, mostly due to disease progression (23% vs 39%, respectively). The median duration of treatment in each respective arm was 20.5 months (range, 0-35.9) and 16.4 months (range, 0-36.0), with deaths reported in 29% and 42% of patients, respectively.

Data showed HRQOL improvements in the nivolumab/ipilimumab arm per EORTC QLQ-C30 Health Status subscale. The mean changes in HRQOL scores were typically positive in both arms, with outcomes in the nivolumab/ipilimumab arm reaching the trial’s prespecified threshold for meaningful change from baseline starting at week 21.

Any-grade treatment-related adverse effects (TRAEs) occurred in 81% and 71% of patients who received nivolumab/ipilimumab and nivolumab monotherapy, respectively. Common any-grade TRAEs in these respective arms included pruritus (26% vs 18%), diarrhea (20% vs 17%), and hypothyroidism (17% vs 9%). Additionally, the most common grade 3 or higher TRAE in each arm was adrenal insufficiency (2% vs < 1%).

Regarding immune-mediated AEs, the most common any-grade non-endocrine events in the combination and monotherapy arms, respectively, included rash (7% vs 6%), diarrhea or colitis (6% vs 4%), and hepatitis (4% vs 1%). Additionally, the most common endocrine events in each respective arm included hypothyroidism or thyroiditis (18% vs 9%), hyperthyroidism (12% vs 5%), and adrenal insufficiency (10% vs 3%).

References

1. Andre T, Elez E, Lenz H-J, et al. First results of nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) from CheckMate 8HW. J Clin Oncol. 2025;43(suppl 4):LBA143. doi:10.1200/JCO.2025.43.4_suppl.LBA143
2. Andre T, Elez E, Van Cutsem E, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): first results of the CheckMate 8HW study. J Clin Oncol. 2024;42(suppl 3):LBA768. doi:10.1200/JCO.2024.42.3_suppl.LBA768