The role of distinct co-mutation patterns with TP53 mutation in immunotherapy for NSCLC

TP53 mutations was reported to be correlated to the efficacy of program death-1 (PD-1) and program death ligand-1 (PD-L1). The role of co-mutations of TP53 with other recurrently mutated genes in outcome of anti-PD-(L)1 treatment for non-small cell lung cancer (NSCLC) is unknown. Here we mined a previously generated dataset to address the effect of co-mutations on the progression free survival (PFS) of NSCLC patients. Non-synonymous mutations and clinical data of 240 NSCLC patients with anti-PD-(L)1 based therapy was downloaded from cBioPortal. Totally 206 patients received monotherapy and 34 patients received combination therapy. In 240 NSCLC patients, TP53 mutation rate was 59.2%. For the monotherapy cohort, TP53 mutated NSCLC patients have a significantly longer PFS (4.3 vs. 2.5 months, P = 0.0019) compared with TP53 wild type NSCLC patients. The same tendency was also observed in the combination therapy cohort, but the difference in PFS (6.3 vs. 5.4 months, P = 0.12) was not significant. Ever-smoker had a longer PFS compared to never-smokers (4.0 vs. 2.7 months). For further co-mutation analysis with TP53 including KEAP1 mutation (53/240, 22.1%), KMT3C mutation (26/240, 10.8%), STK11 mutation (56/240, 23.3%), EGFR mutation (28/240, 11.7%) and KRAS mutation (86/240, 35.8%). Patients with both TP53 plus KEAP1 mutations in all 240 patients had a longer PFS compared with co-wild population (PFS 9.2 vs. 4.2 months, P = 0.012) when treated with PD-1/PD-L1 inhibitors. TP53 might be the dominating mutation correlating with longer PFS in PD-1/PD-L1 monotherapy. Different genes displayed distinct effect when co-mutated with TP53 in NSCLC patients.