Brigatinib in Crizotinib-Refractory ALK+ NSCLC: 2-Year Follow-up on Systemic and Intracranial Outcomes in the Phase 2 ALTA Trial.

Abstract

INTRODUCTION:

We report updated data from a phase 2 randomized study evaluating brigatinib in crizotinib-refractory anaplastic lymphoma kinase-positive NSCLC.

METHODS:

Patients were randomized 1:1 to take either oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (arm B), stratified by central nervous system (CNS) metastases and best response to crizotinib. The primary end point was investigator-assessed confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included independent review committee (IRC)-assessed progression-free survival (PFS), intracranial PFS (iPFS), and overall survival (OS). Exploratory analyses included CNS versus ex-CNS target lesion response and correlation of depth of response with PFS and OS.

RESULTS:

Among 222 randomized patients (112 and 110 in arms A and B, respectively), 59 (27%) remained on brigatinib at analysis (median follow-up: 19.6 versus 24.3 months). At baseline, 71% and 67% had brain lesions among A and B arms, respectively. Investigator-assessed confirmed objective response rate was 46% versus 56%. Median IRC-assessed PFS was 9.2 months (95% confidence interval: 7.4-12.8) versus 16.7 months (11.6-21.4). Median OS was 29.5 months (18.2-not reached) versus 34.1 months (27.7-not reached). IRC-confirmed intracranial objective response rate in patients with measurable baseline brain lesions was 50% (13 of 26) versus 67% (12 of 18); median duration of intracranial response was 9.4 versus 16.6 months. IRC-assessed iPFS was 12.8 versus 18.4 months. Across arms, median IRC-assessed PFS was 1.9, 5.5, 11.1, 16.7, and 15.6 months for patients with no, 1%-25%, 26%-50%, 51%-75%, and 76%-100% target lesion shrinkage, respectively. No new safety findings were observed with longer follow-up.

CONCLUSIONS:

Brigatinib (180 mg once daily with lead-in) continues to demonstrate robust PFS, long iPFS and duration of intracranial response, and high intracranial objective response rate in crizotinib-refractory patients. Depth of response may be an important end point to capture in future targeted therapy trials.

• Authors: Rudolf M Huber, Karin H Hansen, Luis Paz-Ares Rodríguez, Howard L West, Karen L Reckamp, Natasha B Leighl, Marcello Tiseo, Egbert F Smit, Dong-Wan Kim, Scott N Gettinger, Maximilian J Hochmair, Sang-We Kim, Corey J Langer, Myung-Ju Ahn, Edward S Kim, David Kerstein, Harry J M Groen, D Ross Camidge
• Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (J Thorac Oncol) Vol. 15 Issue 3 Pg. 404-415 (03 2020) ISSN: 1556-1380 [Electronic] United States
• PMID: 31756496 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Chemical References

• Organophosphorus Compounds
• Protein Kinase Inhibitors
• Pyrimidines
• Crizotinib
• Anaplastic Lymphoma Kinase
• brigatinib

Topics

• Anaplastic Lymphoma Kinase (genetics)
• Crizotinib (therapeutic use)
• Follow-Up Studies
• Humans
• Lung Neoplasms (drug therapy)
• Organophosphorus Compounds
• Protein Kinase Inhibitors (therapeutic use)
• Pyrimidines