Prognostic and predictive effects of TP53 co-mutation in patients with non-small cell lung cancer with rare treatable driver mutations.

Background: TP53 mutations (TP53-MUT) are common in NSCLC and have been reported as predictive of response and prognostic of poor outcome in EGFR-mutant NSCLC. The impact of TP53-MUT in NSCLCs with rarer driver mutations and approved targeted treatments is unclear.

Methods: Records of 436 patients were reviewed and associations between TP53 status, demographics, and outcomes (overall response [ORR], survival [OS] and progression-free survival [PFS], and incidence of brain metastases [BM]), were investigated.

Results: TP53-MUTs were found in 184/436 (42.4 %) with a significant demographic difference noted in stage distribution (p = 0.044). Median (m)OS was significantly shorter in TP53-MUT at 23.3 m (95 %CI 19.6-30.7) v 66.4 m (CI 55.0-not reached [NR]) (stage adjusted harzard ratio [aHR] 2.62, CI 1.98-3.46, p < 0.001). mRFS in early stage trended towards worse outcomes in TP53-MUT (p = 0.142). mPFS on first line treatment was shorter in TP53-MUT 5.0 m (CI 3.4-7.6) v 10.0 m (CI 6.1-13.5) (aHR 1.64, CI 1.23-2.19, p < 0.001). ORR to first instance of targeted treatment was 62 % v 70 % (TP53-MUT v WT) with more progressive disease as best response 24 % v 11 % (p = 0.0177). TP53-MT had a non-significant trend towards more BM at any point (46 % v 34 % p = 0.063) and a higher cumulative incidence of BM in stage I-III patients (Gray's test p < 0.001). When comparing disruptive versus non-disruptive TP53 mutations, there were no significant differences in demographics or survival outcomes.

Conclusions: Co-occurring TP53 variants with rare driver mutations are predictive of a poor response to targeted treatments and associated with shorter OS and PFS in NSCLC.