Immune checkpoint inhibitors have substantially improved prognosis of patients with metastatic colorectal cancer (mCRC) characterized by microsatellite instability-high (MSI-H) status or mismatch repair deficiency (dMMR). At an industry-sponsored meeting organized by the Hong Kong Society of Digestive Oncology, Professor Heinz-Josef Lenz of the USC Norris Comprehensive Cancer Center in Los Angeles, California, US, discussed updated results of the phase III CheckMate 8HW trial, which support the paradigm shift in favour of first-line dual immunotherapy (IO) with nivolumab plus ipilimumab vs monotherapy and chemotherapy for patients with MSI-H/dMMR mCRC.
Why dual IO?
Patients with MSI-H/dMMR mCRC have historically had poor outcomes with standard chemotherapy, prompting exploration of IO in this subgroup. Previously, pembrolizumab, a PD-1 inhibitor, gained global approval in the first-line setting. However, subgroup analysis of its registrational trial showed limited benefit in patients with liver metastases and specific gene mutations, such as KRAS or NRAS, highlighting an unmet need. [NCCN Clinical Practice Guidelines in Oncology, Colon Cancer, version 4.2025; N Engl J Med 2020;383:2207-2218; Shiu KK, et al, ESMO 2023, abstract LBA32; JAMA Netw Open 2023;6:e230400; Lancet Oncol 2022;23:659-670]
Survival data from the phase II CheckMate 142 study have brought forward dual checkpoint blockade with nivolumab, a PD-1 inhibitor, plus ipilimumab, a cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor, as a promising approach. [J Clin Oncol 2022;40:161-170]
CheckMate 8HW: First-line nivolumab plus ipilimumab as standard of care
CheckMate 8HW is the first randomized trial to compare dual vs single-agent IO in patients with MSI-H/dMMR mCRC. Patients were randomized in a 2:2:1 ratio to receive either nivolumab plus ipilimumab (nivolumab 240 mg plus ipilimumab 1 mg/kg Q3W for four doses, then nivolumab monotherapy 480 mg Q4W), nivolumab alone (240 mg Q2W for six doses, then 480 mg Q4W), or chemotherapy with or without targeted therapies. Dual primary endpoints were progression-free survival (PFS) with nivolumab plus ipilimumab vs chemotherapy as first-line therapy and PFS with nivolumab plus ipilimumab vs nivolumab alone in patients across all lines of therapy. [Andre T, et al, ASCO GI 2025, abstract LBA143; Lancet 2025; 405:383-395]
First-line dual IO vs chemotherapy
Among all randomized patients with centrally confirmed MSI-H/dMMR mCRC, first-line nivolumab plus ipilimumab achieved a median PFS of 54.1 months vs 5.9 months for chemotherapy (hazard ratio [HR], 0.21; 95 percent confidence interval [CI], 0.14–0.31; p<0.0001). “Longer follow-up confirmed plateauing of survival curves, suggesting potential for cures,” commented Lenz. (Figure) [Lenz HJ, et al, ASCO 2025, abstract 3501]
First-line dual IO was consistently superior to chemotherapy across all prespecified patient subgroups, with all HRs favouring the combination group. [N Engl J Med 2024;391:2014-2026; Andre T, et al, ASCO GI 2024, abstract LBA768]
“Notably, patients with liver metastases treated with dual IO [HR, 0.11; 95 percent CI, 0.05–0.25] had even better responses than those without [HR, 0.28; 95 percent CI, 0.17–0.46],” highlighted Lenz.
Dual IO vs nivolumab monotherapy
Nivolumab plus ipilimumab also showed significant and clinically meaningful PFS improvement vs nivolumab alone across all lines of therapy (median PFS, not reached [NR] vs 39.3 months; HR, 0.62; 95 percent CI, 0.48–0.81; p=0.0003). The respective PFS rates at 36 months were 68 and 51 percent. PFS results favoured nivolumab plus ipilimumab across all prespecified subgroups. [Lancet 2025;405:383-395; Andre T, et al, ASCO GI 2025, abstract LBA143]
“Early PFS decline was more pronounced with nivolumab monotherapy, suggesting that double blockade helps obtain better immune antitumour activity,” noted Lenz. “The difference in PFS rates of 10–15 percent between dual IO and monotherapy became apparent as early as 3 months.”
PFS2: Additional rationale for upfront dual IO
“For oncologists considering when to start with dual IO, the PFS2 [time from randomization to progression after subsequent systemic therapy, start of second subsequent systemic therapy or death] analysis in CheckMate 8HW provides convincing results,” he stressed. “Compared with chemotherapy, early exposure to nivolumab plus ipilimumab conferred a durable benefit not fully recaptured by delayed use of dual IO after chemotherapy.” [Lenz HJ, et al, ASCO 2025, abstract 3501]
Despite a high rate (71 percent) of subsequent IO in the chemotherapy group, PFS2 was still longer in those who received first-line nivolumab plus ipilimumab (NR vs 30.3 months; HR, 0.28; 95 percent CI, 0.18–0.44). Similarly, when considering whether to start with dual or single-agent IO, compared with nivolumab monotherapy, PFS2 results favoured nivolumab plus ipilimumab across all lines of therapy (HR, 0.57; 95 percent CI, 0.42–0.78).
“When dual IO is given first, it completely remodels the tumour microenvironment and increases the efficacy of cytotoxic and targeted agents in the subsequent line,” explained Lenz.
Toxicity management
In CheckMate 8HW, nivolumab plus ipilimumab was associated with fewer grade 3–4 adverse events (AEs) vs chemotherapy (23 vs 48 percent). [Andre T, et al, ASCO GI 2024, abstract LBA768] Patients treated with dual IO had more frequent grade 3–4 treatment-related AEs vs nivolumab alone (22 vs 14 percent), most of which occurred within the first 3 months of treatment. This timing predictability supports proactive monitoring and anticipation of early management. The most common events associated with nivolumab plus ipilimumab included pruritus, diarrhoea and hypothyroidism, which were generally manageable. (Table) [Lenz HJ, et al, ASCO 2025, abstract 3501; Lancet 2025;405:383-395]
Summary
“In patients with MSI-H/dMMR mCRC, do not wait for an effective treatment in later lines,” stressed Lenz. “CheckMate 8HW showed that first-line nivolumab plus ipilimumab is associated with statistically significant and clinically meaningful improvements in PFS and PFS2 vs upfront chemotherapy and nivolumab monotherapy across all lines of therapy, with early and sustained separation of the PFS and PFS2 curves.”
“The durability of response and consistent benefit across all subgroups solidly position dual IO as a first-line standard treatment for patients with MSI-H/dMMR mCRC. Nivolumab plus ipilimumab is not only feasible but preferable, with a manageable safety profile and a robust body of evidence favouring its early use,” concluded Lenz.
