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

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.

• Authors: 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 Kris, Julien Mazieres, Justin F Gainor, Oliver Gautschi
• Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (J Thorac Oncol) Vol. 13 Issue 10 Pg. 1595-1601 (10 2018) ISSN: 1556-1380 [Electronic] United States
• PMID: 30017832 (Publication Type: Journal Article, Multicenter Study)
• Copyright: Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Chemical References

• MAS1 protein, human
• Protein Kinase Inhibitors
• Proto-Oncogene Mas

Topics

• Adult
• Aged
• Aged, 80 and over
• Brain Neoplasms (genetics, secondary)
• Female
• Humans
• Lung Neoplasms (genetics, pathology)
• Male
• Middle Aged
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Proto-Oncogene Mas
• Treatment Outcome