Updated Overall Survival in a Randomized Study Comparing Dacomitinib with Gefitinib as First-Line Treatment in Patients with Advanced Non-Small-Cell Lung Cancer and EGFR-Activating Mutations

Tony S Mok, Ying Cheng, Xiangdong Zhou, Ki Hyeong Lee, Kazuhiko Nakagawa, Seiji Niho, Alka Chawla, Rafael Rosell, Jesus Corral, Maria Rita Migliorino, Adam Pluzanski, Kay Noonan, Yiyun Tang, Malaika Pastel, Keith D Wilner, Yi-Long Wu, Tony S Mok, Ying Cheng, Xiangdong Zhou, Ki Hyeong Lee, Kazuhiko Nakagawa, Seiji Niho, Alka Chawla, Rafael Rosell, Jesus Corral, Maria Rita Migliorino, Adam Pluzanski, Kay Noonan, Yiyun Tang, Malaika Pastel, Keith D Wilner, Yi-Long Wu

Abstract

Background: ARCHER 1050, an ongoing, randomized, open-label, phase III trial of dacomitinib versus gefitinib in newly diagnosed patients with advanced non-small-cell lung cancer (NSCLC) and an EGFR-activating mutation, reported significant improvement in overall survival (OS) with dacomitinib.

Objective: This paper reports an updated OS analysis of ARCHER 1050 after an extended follow-up.

Patients and methods: In this multinational, multicenter trial, adults (aged ≥ 18 years or ≥ 20 years in Japan and Korea) with newly diagnosed NSCLC and EGFR mutation (exon 19 deletion or exon 21 L858R substitution), and no history of central nervous system metastases, were randomized 1:1 to receive dacomitinib 45 mg/day (n = 227) or gefitinib 250 mg/day (n = 225). Randomization was stratified by race and EGFR mutation type. An ad hoc updated analysis of OS was conducted at the protocol-defined cut-off of 48 months from first dosing of the last enrolled patient (13 May 2019).

Results: After a median follow-up of 47.9 months, 133 (58.6%) patients had died in the dacomitinib arm and 152 (67.6%) in the gefitinib arm. The hazard ratio (HR) for OS was 0.748 (95% CI 0.591-0.947; two-sided P = 0.0155); median OS was 34.1 months with dacomitinib versus 27.0 months with gefitinib. The HR for OS in patients with dose reduction(s) in the dacomitinib arm (n = 154) compared with all patients in the gefitinib arm was 0.554 (95% CI 0.420-0.730); median OS was 42.5 months for patients with dose reduction(s) in the dacomitinib arm. The most common adverse events were diarrhea (87.7%), paronychia (61.7%), dermatitis acneiform (49.3%), and stomatitis (43.6%) with dacomitinib, and diarrhea (55.8%) and alanine aminotransferase increased (40.2%) with gefitinib.

Conclusions: The OS benefit from first-line treatment with dacomitinib versus gefitinib was maintained after extended follow-up in patients with advanced NSCLC with EGFR-activating mutations. CLINICALTRIALS.GOV: NCT01774721 (registered 24 January 2013).

Conflict of interest statement

Tony Mok: grant/research funding (paid to institution): AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, G1 Therapeutics, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Roche, SFJ, Takeda, and XCovery; speaker’s fees: ACEA Pharma, Alpha Biopharma Co., Ltd., Amgen, Amoy Diagnostics Co., LTD., AstraZeneca (before Jan 2019), Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, InMed Medical Communication, Merck Sharp & Dohme, Novartis, Pfizer, PrIME Oncology, Roche/Genentech, Taiho, and Takeda Oncology; honoraria for consultation services: Abbvie Inc., ACEA Pharma (since Aug 2018), Alpha Biopharma Co., Ltd., Amgen, Amoy Diagnostics Co., Ltd., AstraZeneca (before Jan 2019), Bayer, Boehringer Ingelheim, Blueprint Medicines Corporation, Bristol-Myers Squibb, Celgene, CStone Pharmaceuticals, Daiichi Sankyo, Eli Lilly, Fishawack Facilitate Ltd., Hengrui Therapeutics Inc., Ignyta, Inc., Incyte Corporation, InMed Medical Communication, IQVIA, Janssen, Loxo-Oncology, Merck Serono, Merck Sharp & Dohme, MoreHealth, Novartis, OncoGenex Pharmaceuticals, Inc., OrigiMed, PeerVoice, Pfizer, PrIME Oncology, Roche/Genentech, Sanofi-Aventis R&D, SFJ Pharmaceutical Ltd., Takeda Pharmaceuticals HK Ltd., Vertex Pharmaceuticals, Yuhan Corporation, Medscape/WebMD (medical education/CME activities), PeerVoice (independent medical education), Prime Oncology (medical education); stock shareholder/option: Clearbridge Biomedics (now Biolidics Ltd.), Hutchison Chi-Med, Loxo-Oncology, OrigiMed Co. Ltd., Sanomics Ltd., and Virtus Medical Group; advisory board: Abbvie Inc., ACEA Pharma, Amgen, AstraZeneca, Bayer, Blueprint Medicines Corporation, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Cirina, CStone Pharmaceuticals, Daiichi Sankyo, Eli Lilly, Fishawack Facilitate Ltd., G1 Therapeutics, Inc., geneDecode Co., Ltd. (uncompensated), Hengrui Therapeutics Inc., Hutchison Chi-Med, Ignyta, Inc., Incyte Corporation, IQVIA, Janssen, Loxo-Oncology, Lunit, Inc., Merck Serono, Merck Sharp & Dohme, Novartis, OncoGenex Technologies Inc., OrigiMed, Pfizer, Roche/Genentech, Sanofi-Aventis R&D, SFJ Pharmaceutical, Takeda Oncology, Vertex Pharmaceuticals, Virtus Medical Group, and Yuhan Corporation; board of directors/leadership (remunerated): AstraZeneca and Hutchison Chi-Med; board of directors/leadership (non-remunerated): 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), International Association for the Study of Lung Cancer (IASLC; term ended Apr 2019), and St. Stephen’s College & Prep. School. Kazuhiko Nakagawa: grants: MSD K.K., A2 Healthcare Corp., inVentiv Health Japan Astellas Pharm Inc., Daiichi Sankyo Co., Ltd., Novarits Pharma K.K., AbbVie Inc., Quintiles Inc., IQVIA Services JAPAN K.K., ICON Japan K.K., Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., EP-CRSU CO., LTD., GRITSONE ONCOLOGY.INC, Linical Co., Ltd., Eli Lilly Japan K.K., Eisai Co., Ltd., Bristol-Myers Squibb, Nippon Boehringer Ingelheim Co., Ltd., Taiho Pharmaceutical Co., Ltd., Pfizer Japan Onc., PAREXEL International Corp., SymBio Pharmaceuticals Limited, Ono Pharmacuetical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., EPS Corporation, Bayer Yakuhin Ltd., Syneos Health, EPS International Co., Ltd., Pfizer R&D Japan G.K., Otsuka Pharmaceutical Co., Ltd.; honoraria: AstraZeneca K.K., Nichi-Iko Pharmaceutical Co., Ltd., Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd., MSD K.K., Taiho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb, Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly Japan K.K., Novartis Pharma K.K., SymBio Pharmaceuticals Limited, Pfizer Japan Inc., Chugai Pharmaceutical Co., Ltd., Clinical Trial Co., Ltd., NANZANDO Co., Ltd., MEDICUS SHUPPAN Publishers Co., Ltd., YODOSHA CO., LTD., Care Net Inc., Nikkei Business Publications Inc., Reno Medical K.K., Daiichi Sankyo Co., Ltd., KYORIN Pharmaceutical Co., Ltd., Thermo Fisher Scientific K.K., Medical Review Co., Ltd., YOMIURI TELECASTING CORPORATION, Roche Diagnostics K.K., Nippon Kayaku Co., Ltd., Bayer Yakuhin Ltd., Merck Biopharma Co., Ltd., Medical Mobile Communications Co., Ltd., AbbVie Inc., 3H Clinical Trial Inc. Seiji Niho: grants: AstraZeneca, Pfizer, Merck Biopharma, Eli Lilly, MSD, and Chugai; honoraria: AstraZeneca, Pfizer, Eli Lilly, Chugai, Taiho, MSD, Bristol-Myers Squibb, Novartis, Boehringer Ingelheim, Taiho, Ono, and Shionogi. Alka Chawla: former employee of SFJ Pharmaceuticals. Jesus Corral: Education grants, provided consultation, attended advisory boards and/or provided lectures for Pfizer, AstraZeneca, Roche, Eli Lilly, MSD, and Bristol-Myers Squibb. Adam Pluzanski: lecture fees and travel grants: Pfizer. Kay Noonan, Yiyun Tang, Malaika Pastel, and Keith Wilner: Pfizer employees and stockholders. Yi-Long Wu: grants (to institute): AstraZeneca, BMS, Boehringer Ingelheim, Pfizer, and Roche; honoraria: AstraZeneca, Boehringer Ingelheim, MSD, and Roche; lectures/speakers bureaus: AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Pfizer, and Roche. Ying Cheng, Xiangdong Zhou, Ki Hyeong Lee, Rafael Rosell, and Maria Rita Migliorino: no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
Updated overall survival (ITT). CI confidence interval, HR hazard ratio, ITT intent-to-treat, OS overall survival, OS42 overall survival probability at 42 months
Fig. 2
Fig. 2
Subgroup analyses for overall survival (ITT). aTest for interaction (Wald Chi-Square test, two-sided). CI confidence interval, ECOG Eastern Cooperative Oncology Group, EGFR epidermal growth factor receptor, HR hazard ratio, ITT intent-to-treat, OS overall survival, PS performance status
Fig. 3
Fig. 3
Overall survival for (a) dose-reduced patients treated with dacomitinib and all dacomitinib-treated patients and (b) by lowest dose level of dacomitinib (ITT). ITT intent-to-treat, OS overall survival

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