Brigatinib in Japanese patients with tyrosine kinase inhibitor-naive ALK-positive non-small cell lung cancer: first results from the phase 2 J-ALTA study

Abstract

Background: We evaluated the safety and efficacy of the anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) brigatinib in Japanese patients with TKI-naive ALK-positive non-small cell lung cancer (NSCLC) from the phase 2, open-label, single-arm, multicenter J-ALTA study.

Methods: In the TKI-naive cohort of J-ALTA, the primary end point was independent review committee (IRC)-assessed 12-month progression-free survival (PFS). Secondary end points included objective response rate (ORR), intracranial response, overall survival (OS), and safety.

Results: The data were cut approximately 12 months after last patient enrollment. Thirty-two patients with ALK TKI-naive ALK-positive NSCLC were enrolled (median age [range], 60.5 [29-85] years; median duration of follow-up, 14.2 [3.2-19.3] months; median treatment duration, 13.8 [0.4-19.3] months). IRC-assessed 12-month PFS was 93.0% (90% confidence interval (CI) 79.2-97.8%); ORR, 96.9% (95% CI 83.8-99.9%), 12-month OS, 96.9% (95% CI 79.8-99.6%), and median OS was not reached. Of five patients with measurable baseline CNS metastases, two had partial intracranial response. The most common treatment-emergent adverse events were increased blood creatine phosphokinase (81%), hypertension (59%), and diarrhea (47%). Grade ≥ 3 adverse events occurred in 91% of patients; pneumonitis was reported in 3 (9%) patients.

Conclusions: In the J-ALTA TKI-naive cohort, brigatinib demonstrated clinically meaningful efficacy consistent with the international phase 3 study. The safety profile in Japanese patients was consistent with previous studies. Brigatinib is an important first-line option for Japanese patients with ALK-positive NSCLC.

Clinical registration: NCT03410108.

Keywords: Anaplastic lymphoma kinase; Carcinoma; Non-small cell lung; Tyrosine kinase inhibitor.

Conflict of interest statement

Shunichi Sugawara: honoraria from Chugai Pharma, Pfizer, Kyowa Kirin, MSD KK, AstraZeneca, Lilly, Yakult Honsha, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Taiho Pharmaceutical, Novartis, and Ono Pharmaceutical. Masashi Kondo: honoraria from Chugai Pharma, Lilly, Pfizer, AstraZeneca, Ono Pharmaceutical, Bristol-Myers Squibb, and MSD KK; consulting/advisory role for Novartis, Takeda; speakers’ bureau for Chugai Pharma, Lilly, AstraZeneca, Ono Pharmaceutical, Bristol-Myers Squibb, and MSD; research funding (all to institution) from Chugai Pharma, Ono Pharmaceutical, AstraZeneca, MSD, and Takeda. Toshihide Yokoyama: honoraria from AstraZeneca KK, Bristol-Myers Squibb KK, Chugai Pharmaceutical, Nippon Boehringer Ingelheim, Novartis KK, Ono Pharmaceutical, Pfizer, and Nippon Kayaku; research funding (all to institution) from Eli Lilly Japan KK, Merck Sharp and Dohme KK, and Takeda. Toru Kumagai: consulting/advisory role for Takeda Pharmaceutical Company Limited and Nitto Denko Corporation; speakers’ bureau for Bristol-Myers Squibb KK, Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan KK, AstraZeneca KK, MSD KK, Taiho Pharmaceutical Co. Ltd., Nippon Boehringer lngelheim Co., Ltd., and Novartis Pharma KK; research funding (all to institution) from MSD KK, AstraZeneca KK, Ono Pharmaceutical, Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan KK, Novartis Pharma KK, Parexel International Corporation, Nippon Boehringer lngelheim Co., Ltd., Takeda Pharmaceutical Company Limited., Pfizer Japan Inc., Merck Biopharma Co., Ltd., Taiho Pharmaceutical Co. Ltd., Delta-Fly Pharma, Inc., IQVIA Services Japan KK, AbbVie GK, and Nippon Kayaku Co., Ltd.; other relationship: Pfizer Japan Inc. Makoto Nishio: speaker or member of the advisory boards of AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Merck Serono, Merck Sharp and Dohme, Novartis, Ono Pharmaceutical, Pfizer, Sankyo Healthcare, Taiho Pharmaceutical, Takeda, and Teijin Pharma; research support/grant support from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Merck Sharp and Dohme, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Takeda. Koichi Goto: grants and/or personal fees from Amgen Astellas BioPharma KK, AstraZeneca KK, Boehringer Ingelheim Japan, Bristol-Myers Squibb KK, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Eli Lilly Japan KK, Guardant Health, Ignyta, Janssen Pharmaceutical, Kyowa Kirin, Loxo Oncology, Medical and Biological Laboratories Co., Merck Serono, Merck Sharp and Dohme, Nippon Kayaku, Novartis KK, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, Sysmex Corporation, Taiho Pharmaceutical, Takeda, Thermo Fisher Scientific KK, and Xcoo. Kazuhiko Nakagawa: consulting/advisory role for Kyorin Pharmaceutical and Takeda; grants and/or personal fees from 3H Clinical Trial, AbbVie, Bayer Yakuhin, Care Net, Clinical Trial Co, CMIC Shift Zero, Eisai, EP-CRSU, EPS Corporation, EPS International, Gritstone Oncology, Icon Japan KK, inVentiv Health Japan, Kissei Pharmaceutical, Kyorin Pharmaceutical, Kyowa Kirin, Linical, Medical Mobile Communications, Medical Review Co, Medicus, Nanzando, Nichi-Iko Pharmaceutical, Nikkei Business Publications, Nippon Kayaku, Otsuka Pharmaceutical, Parexel, Pfizer R&D Japan KK, Reno Medical KK, Roche KK, Shuppan Publishers, Symbio Pharmaceutical, Syneos Health, Taiho Pharmaceutical, Takeda, Thermo Fisher Scientific, Yodosha, and Yomiuri Telecasting. Takashi Seto: grants and/or personal fees from AbbVie, Astellas Pharma, AstraZeneca, Bayer Yakuhin, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Kissei Pharmaceutical, Kyowa Kirin, Loxo Oncology, Merck Biopharma, Merck Sharp and Dohme, Nippon Boehringer Ingelheim, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Precision Medicine Asia, Taiho Pharmaceutical, Takeda, and Thermo Fisher Scientific. Nobuyuki Yamamoto: grants and/or personal fees from AbbVie GK, Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Eli Lilly Japan KK, Kyorin Pharmaceutical, Life Technologies Japan Ltd., Merck Biopharma, Merck Sharp and Dohme KK, Nippon Kayaku, Novartis, Ono Pharmaceutical, Pfizer, Shionogi, Taiho Pharmaceutical, Takeda, Terumo, Thermo Fisher Scientific, Toppan Printing, Tosoh, and Tsumura and Co. Kentarou Kudou: Mr. Kudou is an employee of Takeda Pharmaceutical Company Limited. Takayuki Asato: Mr. Asato is an employee of Takeda Pharmaceutical Company Limited. Pingkuan Zhang: Dr. Zhang is an employee of Takeda Development Center Americas, Inc. Yuichiro Ohe: grants and/or personal fees from AstraZeneca, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Celltrion, Chugai Pharmaceutical, Eli Lilly, Janssen, Kissei Pharmaceutical, Kyorin, Ignyta, Merck Sharp and Dohme, Nippon Kayaku, Novartis, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda, and Pfizer.

© 2022. The Author(s).

Figures

Fig. 1

J-ALTA study design. aAlthough the protocol allowed both TKI-refractory and TKI-naive patients to enroll in the safety evaluation lead-in, all enrolled patients had a history of prior ALK TKI therapy. Thus, the nine patients enrolled in Part 1 were included in the efficacy evaluation of refractory patients (Part 2). ALK, anaplastic lymphoma kinase; ALK + , anaplastic lymphoma kinase-positive; DLT, dose-limiting toxicity; IDMC, independent data monitoring committee; NSCLC, non-small cell lung cancer; PFS, progression-free survival; PK, pharmacokinetics; TKI, tyrosine kinase inhibitor

Fig. 2

Disposition of patients in the J-ALTA ALK TKI-naive cohort. ALK, anaplastic lymphoma kinase; TKI, tyrosine kinase inhibitor

Fig. 3

Efficacy of brigatinib in Japanese patients with ALK-positive NSCLC not previously treated with ALK TKIs. a Kaplan–Meier estimates of IRC-assessed PFS. Of the 32 patients in the cohort, 3 (9.4%) had an event. b Objective response per IRC assessments by time on treatment in all patients (n = 32). c Best percentage change from baseline in the sum of the longest diameters of target lesions per IRC assessment for patients who had a measurable lesion at baseline and at least one postbaseline assessment (n = 31). The line at − 30% indicates the threshold for partial response according to RECIST, version 1.1. One patient had investigator-assessed baseline measurable disease and therefore satisfied entry criteria. However, the tumor was located in a nontarget region. Since the IRC review found no measurable lesion in the target region at baseline, the patient was necessarily excluded from the plot. The best overall response in this patient was CR by the IRC and PR by the investigator. SD for ≥ 6 weeks from the first dose could be evaluated as an IRC-assessed SD case. However, one of the 31 responders discontinued treatment due to disease progression (by investigator assessment) prior to being evaluated as IRC-assessed SD, and therefore was not evaluable. d Kaplan–Meier estimates of OS. Of the 32 patients in the TKI-naive cohort, one patient died. e Intracranial PFS in all patients, regardless of presence of CNS metastases at baseline. Of the 32 patients, 3 (9.4%) had an intracranial event or died. For the analysis of iPFS, systemic disease progression followed by withdrawal from study without intracranial disease progression was censored. Tick marks in Kaplan–Meier plots indicate censored data. ALK, anaplastic lymphoma kinase; CNS, central nervous system; iPFS, intracranial progression-free survival; IRC, independent review committee; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; TKI, tyrosine kinase inhibitor

Fig. 3

Efficacy of brigatinib in Japanese patients with ALK-positive NSCLC not previously treated with ALK TKIs. a Kaplan–Meier estimates of IRC-assessed PFS. Of the 32 patients in the cohort, 3 (9.4%) had an event. b Objective response per IRC assessments by time on treatment in all patients (n = 32). c Best percentage change from baseline in the sum of the longest diameters of target lesions per IRC assessment for patients who had a measurable lesion at baseline and at least one postbaseline assessment (n = 31). The line at − 30% indicates the threshold for partial response according to RECIST, version 1.1. One patient had investigator-assessed baseline measurable disease and therefore satisfied entry criteria. However, the tumor was located in a nontarget region. Since the IRC review found no measurable lesion in the target region at baseline, the patient was necessarily excluded from the plot. The best overall response in this patient was CR by the IRC and PR by the investigator. SD for ≥ 6 weeks from the first dose could be evaluated as an IRC-assessed SD case. However, one of the 31 responders discontinued treatment due to disease progression (by investigator assessment) prior to being evaluated as IRC-assessed SD, and therefore was not evaluable. d Kaplan–Meier estimates of OS. Of the 32 patients in the TKI-naive cohort, one patient died. e Intracranial PFS in all patients, regardless of presence of CNS metastases at baseline. Of the 32 patients, 3 (9.4%) had an intracranial event or died. For the analysis of iPFS, systemic disease progression followed by withdrawal from study without intracranial disease progression was censored. Tick marks in Kaplan–Meier plots indicate censored data. ALK, anaplastic lymphoma kinase; CNS, central nervous system; iPFS, intracranial progression-free survival; IRC, independent review committee; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; TKI, tyrosine kinase inhibitor