Elsevier

Annals of Oncology

Volume 29, Issue 10, October 2018, Pages 2068-2075
Annals of Oncology

Original articles
Thoracic tumors
Editor's Choice
Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer

https://doi.org/10.1093/annonc/mdy333Get rights and content
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open access

Abstract

Background

We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC).

Patients and methods

ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders.

Results

Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4–5.6) versus 10.3 months (95% CI: 8.6–12.0), P < 0.001; OS 15.0 months (95% CI: 5.0–24.9) versus 50.0 months (95% CI: 22.9–77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3–4.1) versus 6.2 months (95% CI: 1.8–10.5), P = 0.021; OS 2.0 months (95% CI: 0.0–4.6) versus 9.0 months (95% CI: 6.1–11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9–7.2) versus 14.0 months (95% CI: 8.0–20.1), P < 0.001; OS 17.0 months (95% CI: 6.7–27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1–10.7) versus 9.9 months (95% CI: 6.4–13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001).

Conclusions

In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.

Key words

ALK-rearranged NSCLC
sequential ALK-inhibitor therapy
TP53 mutation status

Cited by (0)

A. Kron and C. Alidousty authors contributed equally to this work.

A. M. Schultheis, R. Büttner and J. Wolf authors share senior authorship.

Data presented in part at the European Society of Medical Oncology Annual Meeting 2017, Madrid, Spain (abstract #3757) and the German Society of Hematology/Oncology Annual Meeting 2017, Stuttgart, Germany (abstract A-908-0026-00596).