Preselection of Lung Cancer Cases Using FGFR1 mRNA and Gene Copy Number for Treatment With Ponatinib

Clin Lung Cancer. 2019 Jan;20(1):e39-e51. doi: 10.1016/j.cllc.2018.09.001. Epub 2018 Sep 7.

Abstract

Introduction: Preclinically, high epidermal growth factor receptor 1 (FGFR1) messenger RNA (FGFR1-MRNA) and FGFR1 amplification (FGFR1-AMP) predicted sensitivity to fibroblast growth factor receptor inhibitors in non-small-cell lung cancer and small-cell lung cancer cell lines. KRAS mutations did not preclude sensitivity.

Patients and methods: Metastatic EGFR- and ALK-negative lung cancers were screened for FGFR1-MRNA by in-situ hybridization (ISH) and FGFR1-AMP by silver in-situ hybridization (SISH). Patients with positive findings were offered ponatinib, a multi-kinase inhibitor of FGFR1-4. Differences in overall survival (OS) between cohorts were assessed by the log-rank test. Association of FGFR1 positivity with clinicopathologic features were assessed by Fisher exact test and Kruskal-Wallis rank sum test.

Results: A total of 171 cases were prescreened: 9 (7.3%) of 123 SISH+; 53 (42.1%) of 126 ISH+; and 6 cases concordantly positive for SISH and ISH. SISH+ cases had fewer coincident KRAS mutations (P = .03) than SISH- cases, and ISH+ cases had worse OS (P = .020) than ISH- cases. Data distributions suggested a distinct higher positivity cut point for FGFR1 ISH (≥ 20%), occurring in 29 (23%) of 126 cases, was associated with small-cell lung cancer histology (P = .022), soft tissue metastases (P = .050) and shorter OS (P = .031). Four patients received ponatinib on study: All ISH+ by the initial cut point, 2 of 4 by higher cut point, 1 of 4 SISH+. Tolerability was poor. The best response for the 2 higher ISH cases was stable disease and progressive disease for the 2 lower ISH cases.

Conclusion: Elevated FGFR1-MRNA is more common than FGFR1-AMP and associated with worse OS. Higher FGFR1 mRNA expression may be associated with a specific phenotype and is worthy of further exploration. Ponatinib's poor tolerance suggests further fibroblast growth factor receptor exploration in ISH+ cases should utilize more selective FGFR1 inhibitors.

Keywords: Biomarker; FGFR1; Lung Cancer; Ponatinib.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Female
  • Gene Dosage / genetics*
  • Humans
  • Imidazoles / therapeutic use*
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / mortality
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Patient Selection
  • Pyridazines / therapeutic use*
  • RNA, Messenger / genetics*
  • Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics*
  • Survival Analysis

Substances

  • Antineoplastic Agents
  • Imidazoles
  • Pyridazines
  • RNA, Messenger
  • ponatinib
  • Receptor, Fibroblast Growth Factor, Type 1