1353P - Effect of TP53 co-mutation in non-small cell lung cancer (NSCLC) with driver mutations

Background

TP53 variants 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 co-mutation in NSCLCs carrying rarer driver mutations with approved targeted treatments is unclear.

Methods

Records of 236 patients with rare driver mutation positive NSCLC at Princess Margaret Cancer Centre were reviewed. Associations between TP53 status, baseline demographics and outcomes (response [ORR], survival [OS], progression-free survival [PFS]), were investigated. ORR (to first-line targeted therapy only) was compared via Fisher’s exact test. OS and PFS were compared by Kaplan-Meier estimates, and Cox regression adjusted for stage at diagnosis with wildtype (WT) as reference.

Results

TP53 variants were found in 88/236 (37%; table) with two+ driver mutations in 22 (9%). There were no significant demographic differences between TP53-mutated (MUT) and WT except for smoking status (never smokers 58% TP53-MUT v 70% TP53-WT, p=0.002). ORR to first-line targeted treatment was 54% vs 71% in the TP53-MUT and WT cohorts, respectively (p=0.09). More patients with TP53-MUT cancer had progressive disease (PD) as best response (27% v 8%, p=0.005). Median PFS was 19.6 mos for TP53-MUT (95% CI 14.4-24.3) v 42.7 mos for WT (CI 31-72.9) (stage-adjusted hazard ratio (aHR) 2.35, CI 1.62-3.39; p<0.001). Median OS was significantly shorter in the TP53-MUT cohort at 20.9 mos (CI 17.3-30.7) compared to 66.4 mos (CI 54.8-not reached) (aHR 3.30, CI 2.20-4.95; p<0.001). In a subset with fusion mutations (ALK, ROS1, RET, NRG1), we saw similar trends in ORR (67% TP53-MUT v 88% WT, p=0.11), PFS (aHR 2.83, CI 1.52-5.27; p=0.001), and OS (aHR 5.00, CI 2.42-10.33; p<0.001). Table: 1353P

Conclusions

TP53 co-mutation with multiple rare driver mutations is predictive of poor response to targeted treatments and prognostic of shorter OS and PFS in NSCLC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

J. Feng: Financial Interests, Personal, Invited Speaker: AstraZeneca. N. Leighl: Financial Interests, Personal, Other, CME/independent lectures: MSD, BMS, Hoffmann LaRoche, EMD Serono; Financial Interests, Personal, Invited Speaker, independent lectures: Novartis, Takeda; Financial Interests, Personal, Advisory Board: Puma Biotechnology; Financial Interests, Institutional, Research Grant: Amgen, AstraZeneca, Array, Bayer, EMD Serono, Guardant Health, Lilly, MSD, Pfizer, Roche, Takeda, Janssen. G. Liu: Financial Interests, Personal, Advisory Board: Takeda, AstraZeneca, Pfizer, Lilly, Merck, Novartis, Jazz, Bristol Myers Squibb, EMD Serono; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Takeda, AstraZeneca, EMD Serono. P. Bradbury: Financial Interests, Personal, Advisory Role: Merck, AbbVie, Eli Lilly, Pfizer, Boehringer Ingelheim; Non-Financial Interests, Personal, Advisory Board: Mirati, AstraZeneca. A. Sacher: Financial Interests, Institutional, Coordinating PI: Genentech-Roche, BMS, AstraZeneca; Financial Interests, Institutional, Local PI: Amgen, Iovance, CRISPR Therapeutics, Merck, Pfizer, GSK, Spectrum, Lilly. F.A. Shepherd: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Local PI: AstraZeneca, Novartis. All other authors have declared no conflicts of interest.