Background ALK sequencing in tissue biopsies and circulating tumor DNA (ctDNA) assays at the time of disease progression can identify resistance mechanisms and guide next-line therapy in tyrosine kinase inhibitor (TKI)-treated patients with anaplastic lymphoma kinase (ALK)-driven lung adenocarcinoma. However, the clinical significance of other findings in these repeat biopsies remains unclear.

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. 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). 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.

Sequential administration of tyrosine kinase inhibitors (TKI) combined with local ablative treatments has considerably improved the prognosis of stage IV ALK+ NSCLC patients with a median overall survival (OS) currently exceeding 5 years after two ALK inhibitors.1 An unmet need is the identification of patients with worse outcome, who may benefit from different approaches.

Tyrosine kinase inhibitors (TKI) have improved prognosis in metastatic anaplastic lymphoma kinase (ALK)-driven lung adenocarcinoma, but patient outcomes vary widely. We retrospectively analyzed the clinical course of all cases with assessable baseline TP53 status and/or ALK fusion variant treated at our institutions (n = 102). TP53 mutations were present in 17/87 (20%) and the echinoderm microtubule-associated protein-like 4 (EML4)-ALK variant 3 (V3) in 41/92 (45%) patients. The number of metastatic sites at diagnosis was affected more by the presence of V3 than by TP53 mutations, and highest with both factors (mean 5.3, p < 0.001). Under treatment with ALK TKI, progression-free survival (PFS) was shorter with either TP53 mutations or V3, while double positive cases appeared to have an even higher risk (hazard ratio [HR] = 2.9, p = 0.015). The negative effect of V3 on PFS of TKI-treated patients was strong already in the first line (HR = 2.5, p = 0.037) and decreased subsequently, whereas a trend for PFS impairment under first-line TKI by TP53 mutations became stronger and statistically significant only when considering all treatment lines together. Overall survival was impaired more by TP53 mutations (HR = 4.9, p = 0.003) than by V3 (HR = 2.4, p = 0.018), while patients with TP53 mutated V3-driven tumors carried the highest risk of death (HR = 9.1, p = 0.02). Thus, TP53 mutations and V3 are independently associated with enhanced metastatic spread, shorter TKI responses and inferior overall survival in ALK(+) lung adenocarcinoma. Both markers could assist selection of cases for more aggressive management and guide development of novel therapeutic strategies. In combination, they define a patient subset with very poor outcome.