Abstract 638P
Background
Dacomitinib is an approved 2nd generation EGFR tyrosine kinase inhibitor. In the phase III ARCHER1050 trial, both progression-free survival (PFS) and overall survival (OS) were improved with first line dacomitinib compared to gefitinib. Dacomitinib had substantial toxicity, however post-hoc analysis revealed efficacy (PFS, OS) was similar in both dose-reduced patients (pts) and overall study population. ATORG-003 evaluated a dose titration strategy, to improve tolerability but maintain efficacy, and is the first prospective study of dacomitinib intracranial efficacy and resistance (tissue/plasma NGS, Guardant360).
Methods
ATORG-003 (Asian Thoracic Oncology Research Group; 5 Asian countries) enrolled treatment naïve stage IIIB-IV EGFR mutated NSCLC. Pts received dacomitinib 30 mg daily for 4 wks, with shared clinician/pt decision for titration to 45 mg in pts with grade ≤1 toxicity. Primary endpoint was 12 month (mth) PFS rate (in pts without CNS metastases only). Secondary endpoints were time to treatment failure (TTF), objective response rate (ORR), OS, intracranial ORR (iORR) and PFS (iPFS), and safety.
Results
From Sep 2019 to Oct 2022, 118 pts (54% female, median age 65 yrs [range 33-84], 57%/42%/1% ex19del/L858R/both, 20% CNS mets). 18% dose titrated to 45 mg at Cycle 2, and 70% tolerated 30 or 45 mg without dose reduction. The primary endpoint was met, with a 12 mth PFS rate of 60% in the primary analysis cohort. Median PFS was 16.1 mths (95%CI, 12.1-19.2) and median TTF was 19.3 mths (95%CI, 16.1-22.1). In all pts, ORR was 77% and median OS was not reached. In the CNS mets cohort, iORR was 54% and median iPFS was 17.6 mths (95%CI, 7.2-23.1). In the overall study, all pts had treatment-related adverse events (TRAEs), with grade 3/4 TRAEs in 25%. Most common G3/4 TRAEs were rash (7%), paronychia (4%) and hypokalemia (3%). EGFR T790M resistance was detected in 29/96 (30%) via plasma and 15/29 (52%) pts via tissue NGS.
Conclusions
ATORG-003 prospectively showed dacomitinib with dose titration is a viable strategy in advanced EGFR mutated NSCLC, to maintain efficacy but improve tolerability. Dacomitinib has substantial intracranial activity and high rates of T790M resistance for sequential treatment approaches.
Clinical trial identification
NCT04027647.
Editorial acknowledgement
Legal entity responsible for the study
Asian Thoracic Oncology Research Group (ATORG).
Funding
Pfizer.
Disclosure
A.C. Tan: Financial Interests, Personal, Advisory Board: Amgen, Pfizer, Bayer; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Guardant Health, Merck, Amgen, Takeda; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Takeda. T.M. Kim: Financial Interests, Personal, Other, Consultancy: AstraZeneca, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Janssen, Novartis, Takeda, Samsung Bioepis, Regeneron, Boryng; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca/MedImmune, Boryung, Hanmi, Janssen, Boehringer-Ingelheim, Novartis, Takeda, Sanofi, Roche/Genentech, Merck Sharp & Dohme Corp, Merck Serono, Regeneron, Genmab, Bayer, RAPT Therapeutics, Blueprint Medicines Corporation, Black Diamond Therapeutics, AbbVie, Amgen, BEYONDBIO Inc, Fore Biotherapeutics, Dizal Pharmaceutical, Incyte Corporation, BeiGene. L. Yueh Ni: Financial Interests, Personal, Advisory Board: AstraZeneca, Pfizer; Financial Interests, Personal, Invited Speaker: Novartis, Eisai, Roche. G.F. Ho: Financial Interests, Personal, Advisory Board: Merck & Co., Inc., Novartis, AstraZeneca, Boehringer Ingelheim, Pfizer; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Pfizer, Merck & Co., Inc., Novartis, Roche, Boehringer Ingelheim, MSD, F. Hoffmann-La Roche AG, Eisai, Tadeka; Financial Interests, Personal, Other, Chairperson: Bristol Myers Squibb; Financial Interests, Institutional, Local PI: EliLily, Regeneron Pharmaceuticals, Merck & Co., Inc., AB Science, Astellas, Tessa Therapeutics, Roche, Arcus Bioscience, AstraZeneca, Pfizer, Janssen Research & Development, Mirati Therapeutics, Novartis, Amgen, Boehringer Ingelheim; Non-Financial Interests, Institutional, Product Samples: Eli Lilly, Janssen Pharmaceuticals, Novartis, Pfizer, Taiho; Non-Financial Interests, Personal, Training: MSD, IPSEN, AstraZeneca, Bristol Myers Squibb, Regeneron Pharmaceuticals, Dr Reddy’s, Roche. T. Reungwetwattana: Financial Interests, Personal, Advisory Board: AstraZeneca, Pfizer, Roche, Yuhan, MSD, Novartis, BMS, Amgen; Financial Interests, Personal, Local PI: AstraZeneca, Roche, Novartis, MSD; Financial Interests, Personal, Steering Committee Member: Yuhan. N. Prasongsook: Financial Interests, Personal, Advisory Board: Roche (Thailand); Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Bristol Myers Squibb, Pfizer; Financial Interests, Institutional, Advisory Board: Amgen. D. Kim: Financial Interests, Personal, Invited Speaker: Korean Cancer Association, Korean Society of Medical Oncology, Korean Association for Lung Cancer, Japan Cancer Association; Financial Interests, Personal, Other, Scientific Advisor: Health Insurance Review & Assessment Service, Korea; Financial Interests, Personal, Writing Engagement, Medical writing assistance: Amgen, AstraZeneca, Boehringer-Ingelheim, BMS, Chong Keun Dang, Daiichi Sankyo, GSK, Pfizer, MSD, Merck, Novartis, Roche, Takeda, Yuhan; Financial Interests, Institutional, Local PI, Clinical Trial Funding: Alpha Biopharma, Amgen, AstraZeneca/Medimmune, Boehringer-Ingelheim, Daiichi Sankyo, Janssen, Merus, MIrati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Bridge BioTherapeutics, GSK; Financial Interests, Institutional, Coordinating PI, Clinical Trial Funding: Hanmi, Chong Keun Dang; Financial Interests, Institutional, Research Grant, Laboratory research funding to my institution: InnoN, IMBDx; Non-Financial Interests, Personal, Advisory Role: Amgen, BMS/Ono Pharmaceuticals, Daiichi Sankyo, Janssen, GSK, Pfizer, AstraZeneca, SK Biopharm, Takeda, Yuhan; Non-Financial Interests, Personal, Member of Board of Directors: Korean Society of Medical Oncology, Korean Association for Lung Cancer, Asian Thoracic Oncology Research Group; Non-Financial Interests, Personal, Advisory Role, Member of Scientific Advisory Board: NoveltyNobility; Other, Personal, Other, Clinical trial research funding to my institution: Asian Thoracic Oncology Research Group. T.S.K. Mok: Financial Interests, Personal, Invited Speaker: ACEA Pharma, AbbVie, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Daz Group, Eli Lilly, Fishawack Facilitate, InMed Medical Communication, Janssen Pharmaceutical NV, Jiahui Holdings Co., LiangYiHui Healthcare, Lucence Health Inc., Lunit USA, Inc., MD Health, MSD, Medscape/WebMD, Merck Pharmaceuticals HK Ltd, Merck Serono, MiRXES, Novartis, OrigiMed Co. Ltd., PER, PeerVoice, Permanyer SL, Pfizer, Prime Oncology, Research to Practice, Roche, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting Co., Ltd., Shanghai Promedican Pharmaceuticals Co., Ltd, Taiho Pharmaceutical Co., Ltd, Takeda, Touch Medical Media; Financial Interests, Personal, Advisory Board: ACEA Pharma, AbbVie, Alpha Biopharma, Amgen, Amoy Diagnostics, Bayer Healthcare Pharmaceuticals Ltd., BeiGene, BerGenBio ASA, Berry Oncology, Berry Oncology, Blueprint Medicines, Boehringer Ingelheim, Bowtie Life Insurance Co Ltd, Bristol Myers Squibb, C4 Therapeutics, CStone Pharma, Cirina Ltd., Covidien LP, Curio Science, D3 Bio Ltd., Da Volterrra, Daiichi Sankyo, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd / Genentech, Fishawack Facilitate, G1 Therapeutics, Gilead Sciences, Gritstone Oncology, Guardant Health, Hengrui, IQVIA, Ignyta, Imagene AI Ltd, Incyte Corporation, Inivata, Janssen, Lakeshore Biotech, Loxo Oncology, Lucence Health Inc., Lunit USA, Inc., MSD, Medscape LLC / WebMD, Merck Serono, MiRXES, Mirati Therapeutics, MoreHealth, Novartis, OSE Immunotherapeutics, OrigiMed, Pfizer, Prenetics Global Limited, Puma Tech., Qiming Dev., Regeneron Pharmaceuticals Inc., Roche, SFJ Pharmaceutical Ltd., Sanofi-Aventis, Simcere Zaiming, Inc, Simcere of America Inc, Synergy Research, Takeda, Tigermed, Vertex Pharmaceuticals, Virtus Medical, Yuhan Corporation; Financial Interests, Personal, Other, consultation services: AVEO Pharmaceuticals, Inc, Alentis Therapeutics AG, BerGenBio ASA, Bridge Biotherapeutics Inc, Elevation Oncology, GLG’s Healthcare, Genentech, Illumina, Inc., Novocure GmbH, Phanes Therapeutics, geneDecode Co., Ltd; Financial Interests, Personal, Other, Consultation services: Adagene, XENCOR, Inc; Financial Interests, Personal, Other, Consultation Services: HiberCell, Inc., Seagen International GmbH, AnHeart Therapeutics Inc, Ningbo NewBay Technology Development Co., Ltd., InxMed (Hong Kong) Limited; Financial Interests, Personal, Other, Consultant Services: Schrödinger, Inc; Financial Interests, Personal, Member of Board of Directors: AstraZeneca, Aurora, Insighta; Financial Interests, Personal, Member of Board of Directors, Former known as Hutchison Chi-Med: HutchMed; Financial Interests, Personal, Stocks/Shares, Former known as Hutchison Chi-Med: HutchMed; Financial Interests, Personal, Stocks/Shares: Biolidics Ltd., Aurora Tele-Oncology, AstraZeneca, D3 Bio, Lunit Inc., Precentics, Alentis Therapeutics AG; 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, Personal, Advisory Role: geneDecode; Non-Financial Interests, Personal, Other, Invited Speaker: AstraZeneca, Aurora Tele-Oncology, Lunit USA, Inc.; Non-Financial Interests, Personal, Leadership Role, Term ended: Chinese Society of Clinical Oncology (CSCO); Non-Financial Interests, Personal, Leadership Role, Term ended on 30 June 2022: American Society of Clinical Oncology (ASCO); Non-Financial Interests, Personal, Leadership Role: Asian Thoracic Oncology Research Group (ATORG), Chinese Lung Cancer Research Foundation Limited (CLCRF), Hong Kong Cancer Fund (HKCF), Hong Kong Cancer Therapy Society (HKCTS), St. Stephen’s College & Prep. School (Hong Kong); Non-Financial Interests, Personal, Leadership Role, Term ended on 30 April 2019: International Association for the Study of Lung Cancer (IASLC); Non-Financial Interests, Personal, Leadership Role, Honorary Secretary, from Dec 2022 - Present: Hong Kong Academy of Sciences. D.S.W. Tan: Financial Interests, Personal, Advisory Board: Amgen, Novartis, Boehringer Ingelheim, C4 Therapeutics, AstraZeneca, GSK, Takeda, Eisai, Guardant, Merck, Pfizer, Roche, Regeneron, Genmab; Financial Interests, Institutional, Research Grant: AstraZeneca, Amgen, Pfizer, ACM Biolabs; Financial Interests, Personal, Steering Committee Member: Novartis. H.H.F. Loong: Financial Interests, Institutional, Invited Speaker: Boehringer-Ingelheim, MSD; Financial Interests, Personal, Invited Speaker: Eli Lilly, Illumina, Bayer, Guardant Health; Financial Interests, Personal, Advisory Board: Novartis, Takeda. All other authors have declared no conflicts of interest.