Brigatinib Versus Alectinib in ALK-Positive NSCLC After Disease Progression on Crizotinib: Results of Phase 3 ALTA-3 Trial

James Chih Hsin Yang; Geoffrey Liu; Shun Lu; Jianxing He; Mauricio Burotto; Myung Ju Ahn; Dong Wan Kim; Xiao Qing Liu; Yanqiu Zhao; Sylvie Vincent; Jiani Yin; Xin Ma; Huamao M. Lin; Sanjay Popat

doi:10.1016/j.jtho.2023.08.010

Brigatinib Versus Alectinib in ALK-Positive NSCLC After Disease Progression on Crizotinib: Results of Phase 3 ALTA-3 Trial

James Chih Hsin Yang, Geoffrey Liu, Shun Lu, Jianxing He, Mauricio Burotto, Myung Ju Ahn, Dong Wan Kim, Xiao Qing Liu, Yanqiu Zhao, Sylvie Vincent, Jiani Yin, Xin Ma, Huamao M. Lin, Sanjay Popat^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Introduction: This open-label, phase 3 trial (ALTA-3; NCT03596866) compared efficacy and safety of brigatinib versus alectinib for ALK+ NSCLC after disease progression on crizotinib. Methods: Patients with advanced ALK+ NSCLC that progressed on crizotinib were randomized 1:1 to brigatinib 180 mg once daily (7-d lead-in, 90 mg) or alectinib 600 mg twice daily, aiming to test superiority. The primary end point was blinded independent review committee–assessed progression-free survival (PFS). Interim analysis for efficacy and futility was planned at approximately 70% of 164 expected PFS events. Results: The population (N = 248; brigatinib, n = 125; alectinib, n = 123) was notable for long median duration of prior crizotinib (16.0–16.8 mo) and low rate of ALK fusion in baseline circulating tumor DNA (ctDNA; 78 of 232 [34%]). Median blinded independent review committee–assessed PFS was 19.3 months with brigatinib and 19.2 months with alectinib (hazard ratio = 0.97 [95% confidence interval: 0.66–1.42], p = 0.8672]). The study met futility criterion. Overall survival was immature (41 events [17%]). Exploratory analyses pooled across the treatment groups revealed median PFS of 11.1 versus 22.5 months in patients with versus without ctDNA-detectable ALK fusion at baseline (hazard ratio: 0.48 [95% confidence interval: 0.32–0.71]). Treatment-related adverse events in more than 30% of patients (brigatinib, alectinib) were elevated levels of blood creatine phosphokinase (70%, 29%), aspartate aminotransferase (53%, 38%), and alanine aminotransferase (40%, 36%). Conclusions: Brigatinib was not superior to alectinib for PFS in crizotinib-pretreated ALK+ NSCLC. Safety was consistent with the well-established and unique profiles of each drug. The low proportion of patients with ctDNA-detectable ALK fusion may account for prolonged PFS with both drugs in ALTA-3.

Original language	English
Journal	Journal of Thoracic Oncology
DOIs	https://doi.org/10.1016/j.jtho.2023.08.010
State	Accepted/In press - 2023
Externally published	Yes

Bibliographical note

Funding Information:
The authors thank the patients, their families, and their caregivers; the ALTA-3 investigators and their team members at each study site; and colleagues from Takeda Pharmaceutical Company Limited. Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Lauren Gallagher, RPh, PhD, and Lela Creutz, PhD, of Peloton Advantage, LLC, an OPEN Health company, and funded by Takeda Development Center Americas, Inc. , Lexington, Massachusetts, and complied with the Good Publication Practice guidelines (DeTora LM, et al. Ann Intern Med. 2022;175:1298-1304). This study was sponsored by Takeda Development Center Americas, Inc., Lexington, Massachusetts.

Publisher Copyright:
© 2023 International Association for the Study of Lung Cancer

Keywords

Alectinib
Anaplastic lymphoma kinase
Brigatinib
Non–small cell lung cancer
Tyrosine kinase inhibitor

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jtho.2023.08.010

Cite this

Yang, J. C. H., Liu, G., Lu, S., He, J., Burotto, M., Ahn, M. J., Kim, D. W., Liu, X. Q., Zhao, Y., Vincent, S., Yin, J., Ma, X., Lin, H. M., & Popat, S. (Accepted/In press). Brigatinib Versus Alectinib in ALK-Positive NSCLC After Disease Progression on Crizotinib: Results of Phase 3 ALTA-3 Trial. Journal of Thoracic Oncology. https://doi.org/10.1016/j.jtho.2023.08.010

@article{8889a85296ca4377892d5a32f154c92d,

title = "Brigatinib Versus Alectinib in ALK-Positive NSCLC After Disease Progression on Crizotinib: Results of Phase 3 ALTA-3 Trial",

abstract = "Introduction: This open-label, phase 3 trial (ALTA-3; NCT03596866) compared efficacy and safety of brigatinib versus alectinib for ALK+ NSCLC after disease progression on crizotinib. Methods: Patients with advanced ALK+ NSCLC that progressed on crizotinib were randomized 1:1 to brigatinib 180 mg once daily (7-d lead-in, 90 mg) or alectinib 600 mg twice daily, aiming to test superiority. The primary end point was blinded independent review committee–assessed progression-free survival (PFS). Interim analysis for efficacy and futility was planned at approximately 70% of 164 expected PFS events. Results: The population (N = 248; brigatinib, n = 125; alectinib, n = 123) was notable for long median duration of prior crizotinib (16.0–16.8 mo) and low rate of ALK fusion in baseline circulating tumor DNA (ctDNA; 78 of 232 [34%]). Median blinded independent review committee–assessed PFS was 19.3 months with brigatinib and 19.2 months with alectinib (hazard ratio = 0.97 [95% confidence interval: 0.66–1.42], p = 0.8672]). The study met futility criterion. Overall survival was immature (41 events [17%]). Exploratory analyses pooled across the treatment groups revealed median PFS of 11.1 versus 22.5 months in patients with versus without ctDNA-detectable ALK fusion at baseline (hazard ratio: 0.48 [95% confidence interval: 0.32–0.71]). Treatment-related adverse events in more than 30% of patients (brigatinib, alectinib) were elevated levels of blood creatine phosphokinase (70%, 29%), aspartate aminotransferase (53%, 38%), and alanine aminotransferase (40%, 36%). Conclusions: Brigatinib was not superior to alectinib for PFS in crizotinib-pretreated ALK+ NSCLC. Safety was consistent with the well-established and unique profiles of each drug. The low proportion of patients with ctDNA-detectable ALK fusion may account for prolonged PFS with both drugs in ALTA-3.",

keywords = "Alectinib, Anaplastic lymphoma kinase, Brigatinib, Non–small cell lung cancer, Tyrosine kinase inhibitor",

author = "Yang, {James Chih Hsin} and Geoffrey Liu and Shun Lu and Jianxing He and Mauricio Burotto and Ahn, {Myung Ju} and Kim, {Dong Wan} and Liu, {Xiao Qing} and Yanqiu Zhao and Sylvie Vincent and Jiani Yin and Xin Ma and Lin, {Huamao M.} and Sanjay Popat",

note = "Funding Information: The authors thank the patients, their families, and their caregivers; the ALTA-3 investigators and their team members at each study site; and colleagues from Takeda Pharmaceutical Company Limited. Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Lauren Gallagher, RPh, PhD, and Lela Creutz, PhD, of Peloton Advantage, LLC, an OPEN Health company, and funded by Takeda Development Center Americas, Inc. , Lexington, Massachusetts, and complied with the Good Publication Practice guidelines (DeTora LM, et al. Ann Intern Med. 2022;175:1298-1304). This study was sponsored by Takeda Development Center Americas, Inc., Lexington, Massachusetts. Publisher Copyright: {\textcopyright} 2023 International Association for the Study of Lung Cancer",

year = "2023",

doi = "10.1016/j.jtho.2023.08.010",

language = "English",

journal = "Journal of Thoracic Oncology",

issn = "1556-0864",

publisher = "International Association for the Study of Lung Cancer",

}

TY - JOUR

T1 - Brigatinib Versus Alectinib in ALK-Positive NSCLC After Disease Progression on Crizotinib

T2 - Results of Phase 3 ALTA-3 Trial

AU - Yang, James Chih Hsin

AU - Liu, Geoffrey

AU - Lu, Shun

AU - He, Jianxing

AU - Burotto, Mauricio

AU - Ahn, Myung Ju

AU - Kim, Dong Wan

AU - Liu, Xiao Qing

AU - Zhao, Yanqiu

AU - Vincent, Sylvie

AU - Yin, Jiani

AU - Ma, Xin

AU - Lin, Huamao M.

AU - Popat, Sanjay

N1 - Funding Information: The authors thank the patients, their families, and their caregivers; the ALTA-3 investigators and their team members at each study site; and colleagues from Takeda Pharmaceutical Company Limited. Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Lauren Gallagher, RPh, PhD, and Lela Creutz, PhD, of Peloton Advantage, LLC, an OPEN Health company, and funded by Takeda Development Center Americas, Inc. , Lexington, Massachusetts, and complied with the Good Publication Practice guidelines (DeTora LM, et al. Ann Intern Med. 2022;175:1298-1304). This study was sponsored by Takeda Development Center Americas, Inc., Lexington, Massachusetts. Publisher Copyright: © 2023 International Association for the Study of Lung Cancer

PY - 2023

Y1 - 2023

N2 - Introduction: This open-label, phase 3 trial (ALTA-3; NCT03596866) compared efficacy and safety of brigatinib versus alectinib for ALK+ NSCLC after disease progression on crizotinib. Methods: Patients with advanced ALK+ NSCLC that progressed on crizotinib were randomized 1:1 to brigatinib 180 mg once daily (7-d lead-in, 90 mg) or alectinib 600 mg twice daily, aiming to test superiority. The primary end point was blinded independent review committee–assessed progression-free survival (PFS). Interim analysis for efficacy and futility was planned at approximately 70% of 164 expected PFS events. Results: The population (N = 248; brigatinib, n = 125; alectinib, n = 123) was notable for long median duration of prior crizotinib (16.0–16.8 mo) and low rate of ALK fusion in baseline circulating tumor DNA (ctDNA; 78 of 232 [34%]). Median blinded independent review committee–assessed PFS was 19.3 months with brigatinib and 19.2 months with alectinib (hazard ratio = 0.97 [95% confidence interval: 0.66–1.42], p = 0.8672]). The study met futility criterion. Overall survival was immature (41 events [17%]). Exploratory analyses pooled across the treatment groups revealed median PFS of 11.1 versus 22.5 months in patients with versus without ctDNA-detectable ALK fusion at baseline (hazard ratio: 0.48 [95% confidence interval: 0.32–0.71]). Treatment-related adverse events in more than 30% of patients (brigatinib, alectinib) were elevated levels of blood creatine phosphokinase (70%, 29%), aspartate aminotransferase (53%, 38%), and alanine aminotransferase (40%, 36%). Conclusions: Brigatinib was not superior to alectinib for PFS in crizotinib-pretreated ALK+ NSCLC. Safety was consistent with the well-established and unique profiles of each drug. The low proportion of patients with ctDNA-detectable ALK fusion may account for prolonged PFS with both drugs in ALTA-3.

AB - Introduction: This open-label, phase 3 trial (ALTA-3; NCT03596866) compared efficacy and safety of brigatinib versus alectinib for ALK+ NSCLC after disease progression on crizotinib. Methods: Patients with advanced ALK+ NSCLC that progressed on crizotinib were randomized 1:1 to brigatinib 180 mg once daily (7-d lead-in, 90 mg) or alectinib 600 mg twice daily, aiming to test superiority. The primary end point was blinded independent review committee–assessed progression-free survival (PFS). Interim analysis for efficacy and futility was planned at approximately 70% of 164 expected PFS events. Results: The population (N = 248; brigatinib, n = 125; alectinib, n = 123) was notable for long median duration of prior crizotinib (16.0–16.8 mo) and low rate of ALK fusion in baseline circulating tumor DNA (ctDNA; 78 of 232 [34%]). Median blinded independent review committee–assessed PFS was 19.3 months with brigatinib and 19.2 months with alectinib (hazard ratio = 0.97 [95% confidence interval: 0.66–1.42], p = 0.8672]). The study met futility criterion. Overall survival was immature (41 events [17%]). Exploratory analyses pooled across the treatment groups revealed median PFS of 11.1 versus 22.5 months in patients with versus without ctDNA-detectable ALK fusion at baseline (hazard ratio: 0.48 [95% confidence interval: 0.32–0.71]). Treatment-related adverse events in more than 30% of patients (brigatinib, alectinib) were elevated levels of blood creatine phosphokinase (70%, 29%), aspartate aminotransferase (53%, 38%), and alanine aminotransferase (40%, 36%). Conclusions: Brigatinib was not superior to alectinib for PFS in crizotinib-pretreated ALK+ NSCLC. Safety was consistent with the well-established and unique profiles of each drug. The low proportion of patients with ctDNA-detectable ALK fusion may account for prolonged PFS with both drugs in ALTA-3.

KW - Alectinib

KW - Anaplastic lymphoma kinase

KW - Brigatinib

KW - Non–small cell lung cancer

KW - Tyrosine kinase inhibitor

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U2 - 10.1016/j.jtho.2023.08.010

DO - 10.1016/j.jtho.2023.08.010

M3 - Article

C2 - 37574132

AN - SCOPUS:85171148033

SN - 1556-0864

JO - Journal of Thoracic Oncology

JF - Journal of Thoracic Oncology

ER -

Brigatinib Versus Alectinib in ALK-Positive NSCLC After Disease Progression on Crizotinib: Results of Phase 3 ALTA-3 Trial

Abstract

Bibliographical note

Keywords

UN SDGs

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