TP53 Mutation is a Prognostic Biomarker for Patients with Advanced RAS Wild-Type Colorectal Adenocarcinoma Treated with Cetuximab and Pembrolizumab [dataset 1]

Immunotherapy with checkpoint inhibitors targeting the PD1/PD-L1 and CTLA4 pathways has limited activity in patients with microsatellite stable (MSS) colorectal adenocarcinoma (CRC). In a prior study, the combination of cetuximab and pembrolizumab failed to improve outcomes for patients with advanced RAS wild-type (RASwt) CRC. In this post hoc secondary analysis, we show that patients with TP53 mutant (p53mt) tumors had significantly higher progression-free survival (PFS) and decrease in tumor burden compared to patients with TP53 wild-type (p53wt) tumors. The gene set enrichment analysis showed uniform upregulation in several metabolic gene sets and most immune gene sets including NK-mediated immunity and IL-12 pathway while the IL6 pathway was downregulated. While there were no overlapping transcriptional alterations between the p53mt and p53wt groups with treatment that remain constant despite the therapeutic intervention, we did identify functional overlap with treatment in both groups in proliferative, immune, and metabolic pathways. In the pre-treatment tumor samples, the number of PD-L1+ tumor cells was significantly higher in p53mt tumors while the number of exhausted-1 immune cells (defined as OX40-/AE1_AE3-/PD-L1- cells, positive for 1/3 exhaustion markers, LAG3 or CTLA4 or TIM3) was significantly higher in p53wt tumors. In conclusion, TP53 status was prognostic of improved disease control with cetuximab plus pembrolizumab in RASwt CRC. Future studies evaluating immune-oncology agents in patients with MSS, RASwt CRC should include TP53 as an integrated biomarker and evaluate its performance as a positive predictive biomarker (ClinicalTrials.gov NCT02713373).