Nivolumab+ipilimumab (PD-1+CTLA-4) PFS benefit holds with single MSI PCR or MMR IHC CDx in MSI-H/dMMR mCRC

Nivolumab (PD-1 inhibitor) plus ipilimumab (CTLA-4 inhibitor) was evaluated in a post hoc CheckMate-8HW (Phase 3; NCT04008030) analysis asking whether central companion diagnostics (Idylla MSI PCR and/or Dako MMR IHC) change the observed first-line PFS benefit versus chemotherapy in locally called MSI-H/dMMR unresectable/metastatic CRC. In the CTA+ population (local MSI-H/dMMR; n=301 of 303 randomized to nivo+ipi [n=202] vs chemo [n=101]), PFS was NR vs 6.2 months (HR 0.32, 95% CI 0.22–0.45); among central single-assay positives, the HRs were similar or slightly lower (MSI+ HR 0.20; dMMR HR 0.22) and matched central dual-positive pts (HR 0.20; n=208 dual-positive), with PFS NR in the nivo+ipi arms and ~6 months with chemo across these subsets. The “discordant” centrally MSS or pMMR groups were small (e.g., MSS n=45 total; pMMR n=39 total) and showed no benefit (HRs ~1.4–1.5), but tissue-missingness and low discordant counts limit inference; importantly, this does not alter the current clinical bottom line that immunotherapy (not chemo) is the SOC in true MSI-H/dMMR mCRC, consistent with the centrally confirmed CheckMate-8HW primary analysis (nivo+ipi PFS NR vs chemo 5.8 months; HR 0.21).