Background

The ALK inhibitor alectinib is a standard-of-care option for ALK+ NSCLC. However, most patients (pts) eventually develop disease progression on alectinib, often through the development of secondary ALK resistance mutations, such as G1202R. We present an exploratory integrated analysis of the impact of EML4-ALK fusion and secondary ALK mutations on efficacy with brigatinib from two phase 2 studies in alectinib-refractory ALK+ NSCLC.

Methods

ALTA-2 (NCT03535740) and J-ALTA (NCT03410108) enrolled 133 pts (ALTA-2, 86 pts; J-ALTA, 47 pts) with advanced ALK+ NSCLC that progressed on alectinib. ALK alteration analysis (Resolution Bioscience, Kirkland, WA) was conducted via next-generation sequencing of plasma circulating tumor DNA. Efficacy (confirmed objective response rate [ORR], duration of response [DoR], and progression-free survival [PFS]) was assessed by ALK mutation status.

Results

Of the 133 pts who progressed on alectinib, with or without prior crizotinib or chemotherapy, 131 had evaluable baseline plasma data. EML4-ALK fusion was detected in 77 pts at screening, of which 37.7% (29/77) had additional ALK secondary alterations. Pts with a baseline detectable EML4-ALK fusion, compared with pts without detectable EML4-ALK fusion (n=54), had lower ORR (26.0% vs 37.0%), DoR (5.3 months vs not achieved [NA]), and PFS (3.5 vs 9.3 months). The presence of secondary ALK mutations at baseline was associated with a similar ORR (34.5%) and median DoR (5.6 months) and shorter median PFS (3.7 months), with response/clinical benefit observed in pts with G1202R, L1196M, and I1171N ALK secondary mutations. Table: 1009P

Brigatinib efficacy parameters^a according to baseline ALK mutation status

Conclusions

Brigatinib showed clinically meaningful activity in pts with alectinib-resistant ALK+ NSCLC with or without a detectable ALK fusion and/or secondary mutations.

Clinical trial identification

NCT03535740; NCT03410108.

Editorial acknowledgement

Professional medical writing assistance was provided by Braden Roth, PhD, and Lauren Gallagher, RPh, PhD, of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, USA, and funded by Takeda Development Center Americas, Inc., Lexington, MA, USA.

Legal entity responsible for the study

Takeda Pharmaceutical Company Limited, Tokyo, Japan, and Takeda Development Center Americas, Inc., Lexington, MA, USA.

Funding

Takeda Pharmaceutical Company Limited, Tokyo, Japan, and Takeda Development Center Americas, Inc., Lexington, MA, USA.

Disclosure

S.I. Ou: Financial Interests, Personal, Invited Speaker: Pfizer, Roche; Financial Interests, Personal, Advisory Board: JNJ/Janssen, Elevation Oncology; Financial Interests, Personal, Stocks/Shares: Turning Point Therapeutics, Elevation Oncology; Financial Interests, Institutional, Invited Speaker: Pfizer, Mirati, JNJ/jassen, Merus. M. Nishio: Financial Interests, Personal, Other, grants and personal fees: Ono Pharmaceutical, Bristol Myers Squibb, Pfizer, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, MSD, Novartis, Daiichi Sankyo, Takeda Pharmaceutical Company Limited; Financial Interests, Personal, Other, personal fees: Boehringer Ingelheim, Merck Biopharma, Teijin Pharma Limited, AbbVie. T. Yoshida: Financial Interests, Personal, Other, Honoraria: AstraZeneca, MSD Oncology, Ono Pharmaceutical, Chugai/Roche, Lilly Japan, Nippon Boehringer Ingelheim, Bristol Myers Squibb Japan, Novartis, Archer DX, Takeda, Pfizer; Financial Interests, Personal, Other, consulting or advisory role: Lilly Japan, Chugai/Roche, Novartis, Boehringer Ingelheim, AstraZeneca; Financial Interests, Institutional, Funding: Chugai/Roche, AstraZeneca, AbbVie, Amgen, MSD, Bristol Myers Squibb, Ono Pharmaceutical, Takeda, Daiichi Sankyo, Novartis. M. Ahn: Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Takeda, MSD, Yuhan, Amgen, Alpha Pharmaceutical, Janssen, BMS, Roche, Daichi Sankyo. T.S.K. Mok: Financial Interests, Personal, Invited Speaker: AbbVie, Acea Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Daiichi Sankyo, Fishawack Facilitate, InMed Medical Communication, Lunit USA, Inc., Merck Serono, MSD, Roche, MD Health, Medscape/WebMD, PeerVoice, Permanyer SL, Prime Oncology, Research to Practice, Touch Medical Media, Sanofi-Aventis, Takeda, PER, AstraZeneca, Hutchison Chi-Med; Financial Interests, Personal, Advisory Board: AbbVie, Acea Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Blueprint Medicines, Berry Oncology, CStone Pharma, Daiichi Sankyo, Fishawack Facilitate, Eisai, Gritstone Oncology, Guardant Health, G1 Therapeutics, Hengrui, Ignyta, IQVIA, Incyte Corporation, Inivata, Janssen, Loxo Oncology, Qiming Dev., Lunit USA, Inc., Merck Serono, MSD, Roche, Mirati Therapeutics, MoreHealth, Novartis, OrigiMed, Puma Tech., Sanofi-Aventis, Takeda, Virtus Medical, Yuhan, Curio Science; Financial Interests, Personal, Stocks/Shares: Sanomics Ltd., Hutchison Chi-Med, Biolidics Ltd., Loxo Oncology, OrigiMed Co., Virtus Medical Group, Lunit USA, Inc., Aurora Tele-Oncology; Financial Interests, Institutional, Funding, For clinical trials performed at CUHK: AstraZeneca, BMS, Merck Serono, MSD, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, XCovery, Takeda, G1 Therapeutics, Clovis Oncology; Non-Financial Interests, Advisory Role: geneDecode, AstraZeneca; Non-Financial Interests, Other, Invited Speaker: AstraZeneca; Non-Financial Interests, Invited Speaker: Aurora Tele-Oncology, Lunit USA, Inc., Sanomics Ltd.; Non-Financial Interests, Leadership Role: American Society of Clinical Oncology (ASCO), Asian Thoracic Oncology Research Group (ATORG), Chinese Lung Cancer Research Foundation Limited (CLCRF), Chinese Society of Clinical Oncology (CSCO), Hong Kong Cancer Fund (HKCF), Hong Kong Cancer Therapy Society (HKCTS), St. Stephen’s College & Prep. School (Hong Kong); Non-Financial Interests, Leadership Role, Term ended on 30 April 2019: International Association for the Study of Lung Cancer (IASLC). K. Kudou, T. Asato, H. Yang, X. Tong, P. Zhang: Financial Interests, Personal, Full or part-time Employment: Takeda. N. Yamamoto: Financial Interests, Personal, Invited Speaker: MSD K.K, AstraZeneca, Ono Pharmaceutical Co., Ltd., Thermo Fisher Scientific, Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Boehringer Ingelheim, Novartis, Pfizer Inc., Bristol-Myers Squibb, Nippon Kayaku, GlaxoSmithKline K.K., Sanofi K.K., Hisamitsu Pharmaceutical Co., Inc., Merck Biopharma; Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Boehringer Ingelheim, Novartis, Bristol-Myers Squibb, Nippon Kayaku, Life Technologies Japan Ltd., Amgen Inc., Guardant Health Japan, Janssen Pharmaceutical K.K.; Financial Interests, Institutional, Research Grant: MSD K.K; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Pfizer Inc., Amgen Inc., Janssen Pharmaceutical K.K.; Financial Interests, Institutional, Funding: Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Toppan Printing, Terumo. E.S. Kim: Financial Interests, Personal, Other, Consulting and research: AstraZeneca, Roche/Genentech, Mirati.