143P - Efficacy of immunotherapy in gastro-intestinal (GI) tumors with mismatch repair deficient (MMRd) unusual phenotype

Background

MMRd tumors classically display a loss of MLH1/PMS2 or MSH2/MSH6 on immunohistochemistry (IHC) with MSI-High on molecular testing. Nevertheless, up to 15% of MMRd tumors exhibit unusual phenotypes. Data on the efficacy of immunotherapy in this population remains scarce.

Methods

We conducted a retrospective study within the IMMUNODIG MSI cohort including patients with advanced GI MMRd tumors treated with immune checkpoint blockade (anti-PD1 or anti-PD-L1 +/- anti-CTLA-4) in the real-world setting. We selected patients with both IHC and molecular data available. Unusual MMRd tumors were classified into four distinct sub-groups: i) isolated loss of PMS2 or MSH6 (isolated), ii) classical loss of MLH1/PMS2 or MSH2/MSH6 without MSI (MMRd/MSS), iii) four MMR proteins retained with MSI (MMRp/MSI), and iv) complex loss of MMR proteins (complex) and were compared to classical phenotype.

Results

Out of 720 patients in IMMUNODIG MSI, 554 patients were eligible. Of these, 105 (19%) had an unusual phenotype (44 isolated, 38 complex, 15 MMRd/MSS and 8 MMRp/MSI). Compared to classical phenotypes, patients with unusual phenotypes had a younger age at treatment (59.6 yrs vs. 68.3 yrs, p= 0.001), a higher prevalence of non-colorectal cancers (p=0.003), increased RAS mutation rates (p=0.027), reduced BRAFV600E mutation rates (p<0.001), and a higher proportion of Lynch syndrome (p<0.001). After a median follow-up of 28.5 months (mo), there was a significant difference in PFS, with median values of 77 mo, 66.4 mo, 34.6 mo, not reached, and 7.5 mo for complex, isolated, classical, MMRp/MSI and MMRd/MSS subgroups, respectively (p=0.0062). Notably, objective response rates were of 59.5%, 55.3%, 60.8% for complex, isolated and classical contrasting with 37.5% and 28.6% for MMRp/MSI and MMRd/MSS, with no complete responses observed in the two latter.

Conclusions

This is to our knowledge the first study focusing on immunotherapy efficacy in MMRd unusual phenotypes. Our findings underscore the need for dual testing and advocate for the presence of both MMRd-IHC and MSI for optimal immunotherapy response. Of note, complex MMR aberrations and isolated PMS2/MSH6 losses may represent promising candidates for enhanced immunotherapy efficacy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

J. Selves.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.