2929 - TP53 mutations impair overall survival of TKI-treated patients with oncogene-driven NSCLC

Background

Tyrosine kinase inhibitors (TKI) have considerably improved survival of patients with oncogene-driven non-small cell lung cancer (NSCLC). However, prognosis varies widely, and identification of molecular factors with a critical role for adverse outcome could facilitate further advances in management.

Methods

We retrospectively studied the clinical course of patients with metastatic epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)-driven NSCLC and known baseline TP53 status that received TKI at our institutions. Overall survival (OS) from the start of treatment for metastatic disease was analyzed according to Kaplan-Meier or by Cox regression.

Results

A total of n = 149 EGFR⁺ and n = 76 ALK⁺ patients were included with a median age of 62 years (interquartile range [IQR] 19), a median ECOG performance status of 0.5 (IQR 1) and a predominance of female (136/225=60%) never-/light-smokers (median number of pack-years 9, IQR 16). Median OS was 36 months for EGFR⁺ and 44 months for ALK⁺ NSCLC patients. TP53 mutations were present at diagnosis in 34% (51/149) of EGFR⁺ and 19% (15/76) of ALK⁺ patients, and they were associated with inferior OS in both EGFR⁺ (24 vs. 40 months in median, p = 0.027) and ALK⁺ NSCLC (24 vs. 53 months, p = 0.001). Their adverse effect was comparable to that of a worse initial clinical condition as reflected by an ECOG performance status of 1 compared to 0 (HR = 1.8 for ECOG vs. 1.8 for TP53 mutations in EGFR⁺ patients, and HR = 4.1 for ECOG vs. 3.7 for TP53 mutations in ALK⁺ patients, all p < 0.05 in bivariable analyses), and it was independent from that of the oncogene variant in both patient groups (HR = 1.9 for other EGFR alterations vs. exon 19 indels, and HR = 1.8 for TP53 mutations vs. wild-type in EGFR⁺ patients; HR = 2.3 for EML4-ALK V3 vs. V1/V2, and HR = 4.7 for TP53 mutations vs. wild-type in ALK⁺ patients, all p < 0.05 in bivariable analyses).

Conclusions

TP53 mutations impair overall survival of TKI-treated patients with EGFR- and ALK-driven NCSLC independent of baseline clinical status and oncogene variant. Their detection could assist selection of cases for more aggressive management. Preclinical exploration of their role in acquired TKI resistance could guide novel therapeutic strategies.

Clinical trial identification

Legal entity responsible for the study

Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, and Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Funding

German Center for Lung Research (DZL) and German Cancer Consortium (DKTK).

Editorial Acknowledgement

none

Disclosure

F. Bozorgmehr: Research funding: BMS; Honorarium: MSD, Novartis. V. Endris: Advisory board and lecture fees: AstraZeneca, ThermoFisher. F.J.F. Herth: Advisory board fees and honoraria: Lilly, Roche, AstraZeneca, Novartis, Boehringer Ingelheim, Chiesi, Teva, Pulmonx BTG, Olympus; Research funding: Lilly, Roche, AstraZeneca, Novartis, Boehringer Ingelheim, Chiesi, Teva. C.P. Heussel: Consultation, lecture and other fees: Novartis, Basilea, Bayer, Grifols, Boehringer Ingelheim, Pierre Fabre, Covidien, Siemens, Chiesi, Intermune, MEDA Pharma, Bracco, Pfizer, MSD, Roche, Lilly, AstraZeneca, Schering-Plough, Essex, Gilead, MeVis, Fresenius, Astellas; Stocks ownership: GSK. T. Muley: Research funding, Patents: Roche. J.R. Fischer: Advisory board honoraria: Boehringer Ingelheim, Roche, Celgene, AstraZeneca. F. Lasitschka: Advisory Board honoraria: BMS, MSD, Roche; Speaker's honorary: Novartis; Travel grants: BMS. P. Schirmacher: Advisory board honoraria: Pfizer, Roche, Novartis, AstraZeneca; Speaker's honoraria, Research funding: Roche, AstraZeneca, Novartis. M. Thomas: Advisory board honoraria: Novartis, Lilly, BMS, MSD, Roche, Celgene, Takeda, AbbVie, Boehringer Ingelheim; Speaker's honoraria: Lilly, MSD, Takeda; Research funding: AstraZeneca, BMS, Celgene, Novartis, Roche; Travel grants: BMS, MSD, Novartis, Boehringer Ingelheim. A. Stenzinger: Advisory board honoraria: BMS, AstraZeneca, ThermoFisher, BMS; Speaker's honoraria: BMS, Illumina, AstraZeneca, Novartis, ThermoFisher; Travel grants: Illumina, AstraZeneca, ThermoFisher; Research funding: Chugai. All other authors have declared no conflicts of interest.