<scp> <i>TP53</i> </scp> mutation is associated with improved disease control in patients with advanced <scp> <i>RAS</i> </scp> wild‐type colorectal adenocarcinoma treated with cetuximab and pembrolizumab

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 (RAS^wt) CRC. In this post hoc secondary analysis, we show that the cetuximab and pembrolizumab-treated patients with TP53 mutant (p53^mt) tumors had significantly higher progression-free survival (PFS) and a decrease in tumor burden compared to patients with TP53 wild-type (p53^wt) tumors but no difference in overall survival compared to patients with p53^wt tumors. The gene set enrichment analysis showed a uniform upregulation of multiple metabolic and immune gene sets, including NK-mediated immunity and IL-12 pathway, while the IL6 pathway was downregulated. There were no overlapping transcriptional alterations between the p53^mt and p53^wt groups with treatment that remain constant despite the therapeutic intervention. Functional overlap with treatment in both groups in the proliferative, immune, and metabolic pathways were identified. In the baseline tumor samples, the number of PD-L1⁺ tumor cells was significantly higher in p53^mt tumors while the number of OX40^-/AE1_AE3^-/PD-L1^- non-tumor cells, positive for either LAG3, CTLA4 or TIM3, was significantly higher in p53^wt tumors. In conclusion, TP53 status was prognostic of improved PFS with cetuximab plus pembrolizumab in RAS^wt CRC. Future studies evaluating immune-oncology agents in patients with MSS, RAS^wt CRC should include TP53 as an integrated biomarker and evaluate its performance as a positive predictive biomarker (ClinicalTrials.gov NCT02713373).