Dr André on the Safety Profile of Nivolumab/Ipilimumab in MSI-H/dMMR Metastatic CRC

“The toxicity [with nivolumab plus ipilimumab] increased a little bit, but it’s not a surprise because it’s clear that CTLA-4 inhibitors [increase toxicity], especially immune-mediated and endocrine toxicities.”

Thierry André, MD, a professor of Medical Oncology at the Sorbonne Université and head of the Medical Oncology Department at the Saint Antoine Hospital, detailed the safety profile of nivolumab (Opdivo) plus ipilimumab (Yervoy) for the treatment of patients with microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC).

The combination was evaluated and compared with chemotherapy and nivolumab monotherapy in patients with MSI-H/dMMR mCRC in the phase 3 CheckMate 8HW trial (NCT04008030). Based on the study, the combination of nivolumab and ipilimumab demonstrated a slight increase in toxicity vs nivolumab alone, André began. However, he noted the slight increase was not a surprise, as CTLA-4 inhibitors commonly increase toxicity, which could particularly cause immune-mediated and endocrine toxicities. Of note, the most frequent grade 1 to 4 immune-mediated adverse effects (AEs) included hypothyroidism/thyroiditis, which led to some patients requiring hormone therapy for a longer duration. Nevertheless, these immune-mediated AEs were more common in patients treated with the combination compared with nivolumab monotherapy, André said.

In April 2025, the FDA approved nivolumab/ipilimumab for the treatment of adult and pediatric patients 12 years of age or older with MSI-H/dMMR unresectable or metastatic mCRC. Data from CheckMate 8HW supporting the approval showed that the combination improved progression-free survival (PFS) vs chemotherapy in patients being treated in the first line (HR, 0.21; 95% CI, 0.14-0.32; P < .0001)

Additional results from the study presented at the 2025 Gastrointestinal Cancers Symposium showed that the combination significantly improved PFS vs nivolumab monotherapy, regardless of the line of therapy (HR, 0.62; 95% CI, 0.48-0.81; P = .0003). Notably, the median PFS was not reached in the combination arm (95% CI, 53.8-not evaluable [NE]) compared with 39.3 months (95% CI, 22.1-NE) in the monotherapy arm. The 2- and 3-year PFS rates were 71% vs 56% and 68% vs 51% in the combination and monotherapy arms, respectively.

Patients on the study were randomly assigned 2:2:1 to receive nivolumab monotherapy (n = 353), nivolumab/ipilimumab (n = 354), or investigator’s choice of mFOLFOX6 (modified folinic acid plus fluorouracil and oxaliplatin) or FOLFIRI (folinic acid with fluorouracil and irinotecan) with or without bevacizumab (Avastin) or cetuximab (Erbitux; n = 132).