Journal
JOURNAL OF THORACIC ONCOLOGY
Volume 13, Issue 10, Pages 1595-1601Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jtho.2018.07.004
Keywords
RET fusion; RET rearrangement; brain metastases; lung cancer cabozantinib; vandetanib multikinase inhibitor
Categories
Funding
- Foundation Medicine
- Ignyta
- Loxo
- TP Therapeutics
- Astra Zeneca
- Pfizer
- Blueprint Medicine
- Genentech Roche
- Takeda
- Genentech/Roche
- ThermoFisher Scientific
- Guardant Health
- AbbVie
- Bristol-Myers Squibb
- Boehringer Ingelheim
- Chugai
- Lilly
- MSD
- Novartis
- Roche
- Merck Sharp
- Dohme
- Millenium
- GlaxoSmithKline
- Infinity Pharmaceuticals
- Ariad
- Merck
- Amgen
- Array Biopharma
- Theravance
- Ariad/Takeda
- NIH by NCI Cancer Support Grant [P30 CA008748]
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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. (C) 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
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