Prognostic and predictive role of HLA supertypes in pMMR mCRC patients receiving FOLFOXIRI/bev ± atezolizumab in the AtezoTRIBE study.

3547 Background: The HLA system plays a crucial role in the development of the adaptive immune response, influencing antigen presentation and T-cell-mediated tumour recognition. Emerging evidence suggests that specific HLA allele groups named supertypes may influence the efficacy of immune-checkpoint inhibitors (ICIs). We investigated the impact of HLA supertypes in the pMMR cohort of mCRC patients (pts) treated with FOLFOXIRI/bev ± atezolizumab in the AtezoTRIBE study. Methods: Genomic DNA from blood samples was genotyped using Oncoarray, a custom array manufactured by Illumina including approximately 530K SNP markers. HLA class I and II alleles were characterized with minimac3 algorithm using the Four-digit Multi-ethnic HLA v2 (2022) reference panel. The presence of 22 HLA supertypes were assigned based on the imputed dosages across relevant alleles. The effects of HLA supertypes on survival were evaluated with Cox proportional hazard models. Given the exploratory nature of the analysis, no adjustments for multiple comparisons were applied. Results: Among 153 assessed pts (102 and 51 treated with FOLFOXIRI/bev/atezo and FOLFOXIRI/bev, respectively), B44 and DR9 supertypes were associated with worse prognosis in terms of both PFS (mPFS 11.4 months (mos) for B44 pos vs 13.9 mos for B44 neg; HR 1.74; 95% CI 1.19–2.52; p = 0.004, and mPFS 11.4 mos for DR9 pos vs 13.2 mos for DR9 neg; HR 2.37; 95% CI 1.01–5.60; p = 0.04, respectively) and OS (mOS 29.6 mos for B44 pos vs 36.6 mos for B44 neg; HR 1.59; 95% CI 1.03–2.45; p = 0.038, and mOS 26.6 for DR9 pos vs 33.9 mos for DR9 neg; HR 3.22; 95% CI 1.24–8.38; p = 0.017, respectively) in multivariable analysis. As summarized in the Table, PFS and OS benefit from the addition of atezolizumab to FOLFOXIRI/bev was reported among A3 neg but not A3 pos patients, and B8 pos patients derived higher benefit than B8 neg. Conclusions: Our exploratory findings suggest that HLA supertypes could influence prognosis and ICIs-based treatment efficacy in pMMR mCRC pts. In particular, B8 and A3 supertypes could identify patients more likely to benefit from the addition of ICIs to FOLFOXIRI/bev. These findings highlight the potential of HLA profiling to optimize the use of immunotherapy in pMMR mCRC pts. Median PFS Median OS FOLFOXIRI/bev/ atezo (months) FOLFOXIRI/bev (months) HR 95%CI P for interaction FOLFOXIRI/bev/ atezo (months) FOLFOXIRI/bev (months) HR 95%CI P for interaction A3 0.048 0.064 Pos 12.5 11.6 0.89 (0.53-1.51) 27.0 31.7 0.96 (0.53-1.73) Neg 15.0 10.1 0.43 (0.26-0.71) NR 27.3 0.44 (0.24-0.81) B8 0.014 0.040 Pos 13.7 5.6 0.16 (0.05-0.60) 35.9 16.7 0.21 (0.06-0.76) Neg 13.3 11.6 0.63 (0.43-0.93) 36.1 31.4 0.70 (0.44-1.11)