Frequency of Brain Metastases and Multikinase Inhibitor Outcomes in Patients With RET–Rearranged Lung Cancers

Alexander Drilon, Jessica J. Lin, Thomas Filleron, Ai Ni, Julie Milia, Isabella Bergagnini, Vaios Hatzoglou, Vamsidhar Velcheti, Michael Offin, Bob Li, David P. Carbone, Benjamin Besse, Tony Mok, Mark M. Awad, Jurgen Wolf, Dwight Owen, D. Ross Camidge, Gregory J. Riely, Nir Peled, Mark G. KrisJulien Mazieres, Justin F. Gainor, Oliver Gautschi

Research output: Contribution to journalArticlepeer-review

160 Scopus citations

Abstract

Introduction: In ret proto-oncogene (RET)–rearranged lung cancers, data on the frequency of brain metastases and, in particular, the outcomes of multikinase inhibitor therapy in patients with intracranial disease are not well characterized. Methods: A global, multi-institutional registry (cohort A, n = 114) and a bi-institutional data set (cohort B, n = 71) of RET-rearranged lung cancer patients were analyzed. Patients were eligible if they had stage IV lung cancers harboring a RET rearrangement by local testing. The incidence of brain metastases and outcomes with multikinase inhibitor therapy were determined. Results: The frequency of brain metastases at the time of diagnosis of stage IV disease was 25% (95% confidence interval [CI]: 18%–32%) in all patients from both cohorts. The lifetime prevalence of brain metastasis in stage IV disease was 46% (95% CI: 34%–58%) in patients for whom longitudinal data was available. The cumulative incidence of brain metastases was significantly different (p = 0.0039) between RET-, ROS1-, and ALK receptor tyrosine kinase (ALK)–rearranged lung cancers, with RET intermediate between the other two groups. Although intracranial response data was not available in cohort A, the median progression-free survival of multikinase inhibitor therapy (cabozantinib, vandetanib, or sunitinib) in patients with brain metastases was 2.1 months (95% CI: 1.3–2.9 months, n = 10). In cohort B, an intracranial response was observed in 2 of 11 patients (18%) treated with cabozantinib, vandetanib (± everolimus), ponatinib, or alectinib; the median overall progression-free survival (intracranial and extracranial) was 3.9 months (95% CI: 2.0–4.9 months). Conclusions: Brain metastases occur frequently in RET-rearranged lung cancers, and outcomes with multikinase inhibitor therapy in general are suboptimal. Novel RET-directed targeted therapy strategies are needed.

Original languageEnglish
Pages (from-to)1595-1601
Number of pages7
JournalJournal of Thoracic Oncology
Volume13
Issue number10
DOIs
StatePublished - 1 Oct 2018
Externally publishedYes

Keywords

  • RET fusion
  • RET rearrangement
  • brain metastases
  • lung cancer cabozantinib
  • vandetanib multikinase inhibitor

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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