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Dual versus single-agent immune checkpoint inhibitor therapy in microsatellite instability-high metastatic colorectal
A Zaidi1, J P Solar Vasconcelos1, T do Amaral Miranda1
1Department of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada.
Background:
Immune checkpoint inhibitors (ICIs) improve outcomes in microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) metastatic colorectal cancer (mCRC). Pembrolizumab is a first-line option (KEYNOTE-177), but new data from CheckMate 8HW support nivolumab-ipilimumab. In the absence of head-to-head trials, indirect comparisons using reconstructed individual patient data (IPD) provides an approach for inferring relative efficacy and safety.
Methods:
Progression-free survival (PFS) curves from KEYNOTE-177 and CheckMate 8HW were reconstructed using IPDfromKM. Phase II curves assessed cross-phase consistency. Cox models estimated hazard ratios (HRs), and grade 3/4 immune-mediated adverse events (IMAEs) contextualized efficacy.
Results:
Trial arms were comparable overall but varied in follow-up and treatment-line inclusion. Compared with pembrolizumab, nivolumab-ipilimumab showed longer estimated PFS [HR 0.64, 95% confidence interval (CI) 0.49-0.83]. Single-agent nivolumab and pembrolizumab demonstrated similar outcomes (HR 0.96, 95% CI 0.75-1.23), while reconstructed estimates for nivolumab-ipilimumab versus nivolumab were consistent with published CheckMate 8HW data (HR 0.66, 95% CI 0.53-0.82). Grade 3/4 IMAEs were more frequent with dual ICI versus nivolumab (odds ratio 2.2, P = 0.004) but not pembrolizumab (P = 0.25).
Conclusions:
Indirect IPD analysis suggests nivolumab-ipilimumab may prolong PFS versus pembrolizumab in MSI-H/dMMR mCRC, although with increased toxicity. Survival estimates for single-agent nivolumab and pembrolizumab appeared comparable. These findings highlight the utility of IPD reconstruction for indirect comparisons where head-to-head evidence is unlikely.
