First-line lorlatinib vs crizotinib in Asian patients with ALK+ non-small cell lung cancer (NSCLC): 5-year outcomes from the CROWN study

BackgroundLorlatinib provided unprecedented improvement in progression-free survival (PFS) and intracranial (IC) activity vs crizotinib in patients (pts) with previously untreated advanced ALK+ NSCLC (N=296) in the phase 3 CROWN study. Here, we report long-term outcomes in the Asian subgroup from this study after 5 years of follow-up.MethodsPts were randomized 1:1 to receive oral lorlatinib 100 mg once daily or crizotinib 250 mg twice daily and were stratified by ethnicity (Asian/non-Asian) and the presence of brain metastases (yes/no). The primary endpoint was PFS by blinded independent central review. Secondary endpoints included PFS, objective response (OR), IC OR, and IC time to progression (IC TTP), all by investigator assessment (IA), safety, and biomarker analysis. Endpoints were analyzed using unstratified analyses in the Asian subgroup.ResultsIn the Asian subgroup, 120 pts (41% of overall ITT population) were randomized to receive lorlatinib (n=59) or crizotinib (n=61). At the data cutoff of October 31, 2023, median PFS (months) by investigator assessment was not reached (NR; 95% CI, 64.3-NR) with lorlatinib and 9.2 (95% CI, 7.2-12.7) with crizotinib (HR 0.22; 95% CI, 0.13-0.37). Both OR and IC OR were clinically improved with lorlatinib (Table). The median IC TTP (months) was NR (95% CI, NR-NR) with lorlatinib and 14.6 (95% CI, 9.2-27.4) with crizotinib (HR 0.01; 95% CI, 0.01-0.11). No new safety signals emerged with longer follow-up. With lorlatinib, median PFS was NR regardless of EML4-ALK variant subtype v1 or v3 or TP53 mutation status.ConclusionsAfter 5 years of follow-up, lorlatinib efficacy and safety outcomes in the Asian subgroup were consistent with those in the overall population in the CROWN study and represent an unprecedented improvement for pts with ALK+ NSCLC. These data support the use of first-line lorlatinib in Asian pts with ALK+ NSCLC. Table: 1279P Efficacy by IA and safety in the CROWN Asian subgroup after 5 years of follow-up Pts in full analysis set Lorlatinibn=59 Crizotinibn=61 5-year PFS (95% CI), % 63 (49-74) 7 (2-17) ORR (95% CI), % 81.4 (69.1-90.3) 59.0 (45.7-71.4) Pts in full analysis set with baseline brain metastases Lorlatinibn=13 Crizotinibn=16 IC ORR (95% CI), % 69.2 (38.6-90.9) 6.3 (0.2-30.2) Pts in safety analysis set Lorlatinibn=59 Crizotinibn=60 Grade 3/4 all-causality AEs, n (%) 48 (81.4) 37 (61.7) Grade 3/4 TRAEs, n (%) 44 (74.6) 29 (48.3) TRAEs leading to permanent treatment discontinuation, n (%) 3 (5.1) 5 (8.3) AE, adverse event; ORR, objective response rate; TRAE, treatment-related adverse event. Clinical trial identificationNCT03052608.Editorial acknowledgementMedical writing support was provided by Arrianna Carey, PhD, of Nucleus Global and was funded by Pfizer.Legal entity responsible for the studyPfizer.FundingPfizer.DisclosureY. Wu: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, Boehringer Ingelheim, BeiGene, Hengrui, Merck, MSD, Pfizer, Roche, Sanofi; Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Takeda, Amgen, Daiichi Sankyo; Financial Interests, Coordinating PI: AstraZeneca, Boehringer Ingelheim, BMS, Hengrui, Merck, MSD, Pfizer, Roche, Eli Lilly; Financial Interests, Steering Committee Member: Sanofi, Yunhan; Non-Financial Interests, Leadership Role: Chinese Thoracic Oncology Group (CTONG); Non-Financial Interests, Other, WCLC 2020 Conference Chair: IASLC; Non-Financial Interests, Leadership Role, Past President: Chinese Society of Clinical Oncology (CSCO); Non-Financial Interests, Other, Editorial Board member of Ann Oncology and ESMO Open: ESMO. H.R. Kim: Non-Financial Interests, Personal, Advisory Board: AstraZeneca, Yuhan, MSD Oncology, Takeda; Financial Interests, Personal, Advisory Role: ABL-BIO; Non-Financial Interests, Institutional, Local PI: Pfizer, AstraZeneca, Yuhan, GSK, BMS, Takeda, DAICHI; Non-Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Yuhan, MSD Oncology, Takeda; Non-Financial Interests, Personal, Steering Committee Member: AstraZeneca, BeiGene; Financial Interests, Personal, Stocks or ownership: Bridge Bio Therapeutics. R.A. Soo: Financial Interests, Advisory Board: Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi Sankyo, J INTS BIO, Janssen, Lily, Merck, Merck Serono, Novartis, Pfizer, Puma, Roche, Sanofi, Taiho, Takeda, Thermo Fisher, Yuhan; Financial Interests, Invited Speaker: Chugai; Financial Interests, Research Grant: AstraZeneca, Boehringer Ingelheim. Q. Zhou: Non-Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Lilly, Roche, Pfizer, Boehringer Ingelheim, MSD Oncology, Bristol Myers Squibb, Hengrui. H. Akamatsu: Financial Interests, Personal, Advisory Board: Amgen Inc., Janssen Pharmaceutical K.K., Sandoz; Financial Interests, Personal, Invited Speaker: AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol Myers Squibb, Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., MSD K.K., Nippon Kayaku. Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., Pfizer Inc., Takeda Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd.; Financial Interests, Institutional, Coordinating PI: Amgen Inc., Chugai Pharmaceutical Co. Ltd. G. Chang: Financial Interests, Personal, Other, Honoraria: F. Hoffmann-La Roche, Ltd., Eli Lilly and Company Oncology, AstraZeneca, Novartis, Pfizer, Boehringer-Ingelheim, Bristol Myers Squibb, Merck Sharp & Dohme. C.H. Chiu: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Roche, Merck KGaA; Financial Interests, Invited Speaker: Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Janssen, Merck KGaA, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche. H. Hayashi: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co. Ltd., Bristol Myers Squibb Co. Ltd., AstraZeneca K.K, Boehringer Ingelheim Japan Inc., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo K.K, Eli Lilly Japan K.K, Merck Biopharma Co. Ltd., MSD K.K., Novartis Pharmaceuticals K.K, Pfizer, Takeda Pharmaceutical Co. Ltd.; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb Co. Ltd., Eli Lilly Japan K.K, Pfizer, AstraZeneca K.K, Daiichi Sankyo Co., Ltd.; Financial Interests, Personal, Royalties, Currently no provided: Sysmex; Financial Interests, Personal, Steering Committee Member: Janssen Pharmaceutical K.K., GSK plc., Daiichi Sankyo, Inc.; Financial Interests, Institutional, Local PI: IQVIA Services Japan K.K, Syneos Health Clinical K.K., EPS Corporation, Nippon Kayaku Co., Ltd., Takeda Pharmaceutical Co., Ltd., MSD K.K., Amgen Inc., Taiho Pharmaceutical Co., Ltd., Bristol Myers Squibb Company, Janssen Pharmaceutical K.K., CMIC CO., Ltd., Pfizer R&D Japan G.K., Labcorp Development Japan K.K., Kobayashi Pharmaceutical Co., Ltd., Pfizer Japan Inc., AbbVie Inc., A2 Healthcare Corp., Eli Lilly Japan K.K., Medpace Japan KK, EPS International Co., Ltd,., Covance Japan Inc., EP-CRSU CO., LTD., GSK K.K., Sanofi K.K., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., PRA Health Sciences Inc., Astellas Pharma Inc., Ascent Development Services, AstraZeneca K.K., Daiichi Sankyo Co., Ltd., Novartis Pharma K.K., Merck Biopharma Co., Ltd., Mochida Pharmaceutical Co., Ltd., Japan Clinical Research Operations; Financial Interests, Institutional, Research Grant: Japanese Gastric Cancer Association, Clinical Research Support Center Kyushu, Japan Clinical Caner Research Organization, Ono Pharmaceutical Co., Ltd., Medical Research Support, Eisai Co., Ltd., Shionogi & Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Bayer Yakuhin, Ltd., Kyowa Kirin Co., Ltd.; Financial Interests, Institutional, Funding: SRL Medisearch Inc., Eisai Inc., Thoracic Oncology Research Group(TORG), West Japan Oncology Group (WJOG), Comprehensive Support Project for Oncological Research of Breast Cancer (CSPOR-BC), Mebix, Inc.; Non-Financial Interests, Member: West Japan Oncology Group, Japanese Society of Medical Oncology. S. Kim: Non-Financial Interests, Advisory Role: AstraZeneca, Janssen, Therapex; Financial Interests, Funding: Yuhan. Y. Goto: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Guardant Health Inc., Illumina, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Johnson and Johnson, D3bio; Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, MSD, Merck, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Thermo Fischer; Financial Interests, Personal, Other, Travel Grant: Daiichi Sankyo; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Preferred Network; Financial Interests, Personal and Institutional, Coordinating PI: Chugai, Novartis, Pfizer; Financial Interests, Institutional, Research Grant: Prefered Network; Financial Interests, Institutional, Coordinating PI: Guardant Health; Non-Financial Interests, Member of Board of Directors: Cancer Net Japan, JAMT. T. Kato: Financial Interests, Personal, Advisory Board, speaker: Pfizer; Financial Interests, Personal, Advisory Board, speaker, consultancy: Merck Biopharma, MSD, AstraZeneca; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Invited Speaker: Ono, Novartis, Eli Lilly, Bristol Myers Squibb, Boehringer Ingelheim, Amgen; Financial Interests, Personal, Other, consultancy: Takeda, Daiichi Sankyo; Financial Interests, Personal, Other, consultancy, speaker: Chugai; Financial Interests, Personal, Full or part-time Employment, Family member: Eli Lilly; Financial Interests, Institutional, Local PI: AbbVie, Amgen, Bayer, BeiGene, Blueprint Medicines, Chugai, Daiichi Sankyo, Eli Lilly, Gilead, GSK, Haihe Biopharma, Janssen, MSD, Merck Biophama, Novartis, Pfizer, Regeneron, Takeda, BMS, Arrivent; Financial Interests, Personal and Institutional, Steering Committee Member, Local PI: AstraZeneca; Financial Interests, Personal, Steering Committee Member: Roche. V.H.F. Lee: Financial Interests, Personal, Research Grant: AstraZeneca, Merck Sharp & Dohme; Financial Interests, Personal, Speaker, Consultant, Advisor: Pfizer, AstraZeneca, Boston Scientific, Amgen, Merck Sharp & Dohme, Eli Lilly, Eisai, Roche, Janssen; Financial Interests, Personal, Speaker’s Bureau: Pfizer, AstraZeneca, Boston Scientific, Amgen, Merck Sharp & Dohme, Eli Lilly, Eisai, Roche, Varian; Financial Interests, Institutional, Sponsor/Funding: AstraZeneca, Eisai, Roche, Merck Sharp & Dohme, Janssen. M. Nishio: Financial Interests, Personal, Speaker, Consultant, Advisor: Pfizer, Bristol Myers Squibb Japan, Ono Pharmaceutical, AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Lilly, Nippon Kayaku, Takeda, Merck, Janssen, Amgen, Eisai, Daiichi Sankyo/UCB Japan. D. Kim: Non-Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, BMS/ONO Pharmaceuticals, Daiichi Sankyo, GSK, Janssen, Merck, MSD, Oncobix, Pfizer, SK Biopharm, Takeda, Novelty Nobility; Non-Financial Interests, Personal, Coordinating PI: Hanmi; Financial Interests, Personal, Invited Speaker: Korean Association for Lung Cancer, Korean Cancer Association, Korean Society of Medical Oncology, Taiwan Lung Cancer Society, Asian Thoracic Oncology Research Group; Non-Financial Interests, Personal, Member of Board of Directors: Asian Thoracic Oncology Research Group, Korean Association for Lung Cancer, Korean Cancer Association, Korean Society of Medical Oncology, Korea Cancer Research Foundation, National Cancer Control Planning Board; Financial Interests, Institutional, Research Funding: Alpha Biopharma, AstraZeneca/Medimmune, Boehringer-Ingelheim, Bridge BioTherapeutics, Chong Keun Dang, Daiichi Sankyo, GSK, Hanmi, IMBDx, InnoN, IQVIA, Janssen, Merck, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Amgen; Non-Financial Interests, Personal, Steering Committee Member: AstraZeneca, Daiichi Sankyo, Pfizer; Financial Interests, Personal, Writing Engagement: Amgen, AstraZeneca, Boehringer-Ingelheim, Bridge BioTherapeutics, Chong Keun Dang, Daiichi Sankyo, GSK, IMBDx, Janssen, Merus, Mirati Therapeutics, MSD, Merck, Novartis, Pfizer, Roche, Takeda, Yuhan. S. Lu: Financial Interests, Personal, Advisory Role: AstraZeneca, Pfizer, Hutchison MediPharma, ZaiLab, GenomiCare, Novartis, Yuhan Corporation, Menarini, Mirati Therapeutics Inc., Daiichi Sankyo, Inc., D3 Bio Limited, Simcere, Takeda, Roche; Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, Hansoh; Non-Financial Interests, Personal, Member of Board of Directors: Innovent Biologics, Inc.; Financial Interests, Personal, Research Grant: AstraZeneca, Hutchison, BMS, Heng Rui BeiGene, Roche, Hansoh; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Roche, Hansoh. A. Polli: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks or ownership: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. J. Martini: Financial Interests, Personal, Full or part-time Employment: Pfizer Inc.; Financial Interests, Personal, Stocks or ownership: Pfizer Inc.; Financial Interests, Personal, Stocks/Shares: Pfizer Inc. T.S.K. Mok: Financial Interests, Personal, Advisory Board: AbbVie Inc., ACEA Pharma, Amgen, AstraZeneca, Alentis Therapeutics AG, BerGenBio ASA, Berry Oncology, Blueprint Medicines Corporation, Boehringer Ingelheim, Bowtie Life Insurance Co Ltd., Bristol Myers Squibb, C4 Therapeutics Inc., Covidien LP, CStone Pharmaceuticals, Curio Science, D3 Bio Ltd., Daiichi Sankyo Inc., Eisai, Fishawack Facilitate Ltd., G1 Therapeutics Inc., Gilead Sciences Inc., Gritstone Oncology, Inc., Guardant Health, Hengrui Therapeutics Inc., HutchMed, Ignyta Inc., Incyte Corporation, Imagene AI Ltd., Inivata, IQVIA, Janssen, Lakeshore Biotech, Lily, Loxo-Oncology Inc., Lunit, Inc., Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics Inc., MiRXES Group, Novartis, OrigiMed, Pfizer, Puma Biotechnology Inc., Roche/Genentech, Regeneron Pharmaceuticals Inc., Sanofi-Aventis R&D, SFJ Pharmaceutical, Simcere of America Inc., Simcere Zaiming, Inc., Takeda, Vertex Pharmaceuticals, Virtus Medical Group, Yuhan Corporation; Non-Financial Interests, Personal, Advisory Board, (uncompensated): geneDecode Co. Ltd.; Financial Interests, Personal, Advisory Role: AbbVie Inc., ACEA Pharma, Adagene, Alpha Biopharma Co., Ltd., Alentis Therapeutics AG, Amgen, Amoy Diagnostics Co., Ltd., AnHeart Therapeutics Inc., AstraZeneca, AVEO Pharmaceuticals, Inc., Bayer Healthcare Pharmaceuticals Ltd., BeiGene, BerGenBio ASA, Berry Oncology, BI, Blueprint Medicines Corporation, BMS, Bowtie Life Insurance Company Limited, Bridge Biotherapeutics Inc., Covidien LP, C4 Therapeutics Inc., Cirina Ltd., CStone Pharmaceuticals, Curio Science, D3 Bio Ltd., Da Volterra, Daiichi Sankyo, Eisai, Elevation Oncology, F. Hoffmann-La Roche Ltd., Genentech, GLG’s Healthcare, Fishawack Facilitate Ltd., G1 Therapeutics Inc., geneDecode Co., Ltd., Gilead Sciences, Inc., Gritstone Oncology, Inc., Guardant Health, Hengrui Therapeutics Inc., HiberCell, Inc., HutchMed, Ignyta, Inc., Illumina, Inc., Incyte Corporation, Inivata, IQVIA, Janssen, Lakeshore Biotech Ltd., Lilly, Lunit USA, Inc., Loxo-Oncology, Lucence Health Inc., Medscape LLC/ WebMD, Medtronic, Merck Serono, MSD, Mirati Therapeutics Inc., MiRXES, MoreHealth, Novartis, Novocure GmbH, Omega Therapeutics Inc., OrigiMed, OSE Immunotherapeutics, PeerVoice, Phanes Therapeutics, Pfizer, PrIME Oncology, Prenetics Global Limited, Puma Biotechnology Inc., Qiming Development (HK) Ltd., Regeneron Pharmaceuticals Inc., Roche Pharmaceuticals/ Diagnostics/ Foundation One, Sanofi-Aventis, Schrödinger, Inc., Seagen International GmbH, SFJ Pharmaceutical Ltd., Simcere of America Inc., Summit Therapeutics Sub, Inc., Synergy Research, Takeda Pharmaceuticals HK Ltd., Tigermed, Vertex Pharmaceuticals, Virtus Medical Group, XENCOR, Inc., Yuhan Corporation, Zai Lab; Financial Interests, Personal, Full or part-time Employment: The Chinese University of Hong Kong; Financial Interests, Personal, Invited Speaker: ACEA Pharma, Alpha Biopharma Co., Ltd., Amgen, Amoy Diagnostics Co., Ltd., AstraZeneca, BeiGene, BI, BMS, Daiichi Sankyo, Daz Group, Fishawack Facilitate Ltd., InMed Medical Communication, Janssen Pharmaceutica NV, Jiahui Holdings Co. Limited, LiangYiHui Healthcare, Lilly, Lucence Health Inc., MD Health Brazil, Medscape LLC, Merck Pharmaceuticals HK Ltd., Merck Sharp & Dohme, MiRXES, Novartis, OrigiMed Co. Ltd., P. Permanyer SL, PeerVoice, Physicians’ Education Resource (PER), Pfizer, prIME Oncology, Research to Practice, Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting Co., Ltd., Shanghai Promedican Pharmaceuticals Co., Ltd., Taiho Pharmaceutical Co. Ltd., Takeda Oncology, Touch Independent Medical Education Ltd.; Financial Interests, Personal, Member of Board of Directors: AstraZeneca PLC, HutchMed, Aurora, Insighta; Non-Financial Interests, Personal, Other, Travel support: AstraZeneca, MiRXES, Daiichi Sankyo, Novartis, Roche, AbbVie, Pfizer, Liangyihui, Zai Lab, MSD; Other, Personal, Non remunerated activity, (2018 – 2022): American Society of Clinical Oncology (ASCO); Other, Personal, Non remunerated activity, (2016 – Present): Asian Thoracic Oncology Research Group (ATORG); Other, Personal, Non remunerated activity, (2005 – 2012): Chinese Lung Cancer Research Foundation Limited (CLCRF); Other, Personal, Non remunerated activity, (2009 – 2020): Chinese Society of Clinical Oncology (CSCO); Other, Personal, Non remunerated activity, (2011 - Present): Hong Kong Cancer Fund (HKCF); Other, Personal, Non remunerated activity, (2004 – Present): Hong Kong Cancer Therapy Society (HKCTS); Other, Personal, Non remunerated activity, (2007 – 2019): International Association for the Study of Lung Cancer (IASLC); Other, Personal, Non remunerated activity, (2017 – Present): St. Stephen’s College & Prep. School; Other, Personal, Non remunerated activity, (2022 – Present): Hong Kong Academy of Sciences (ASHK); Financial Interests, Institutional, Research Grant: AstraZeneca, BMS, G1 Therapeutics, MSD, Merck Serono, Novartis, Pfizer, Roche, SFJ, Takeda, XCovery; Financial Interests, Personal, Steering Committee Member: Amgen, Takeda, Pfizer, Novocure, BMS, BeiGene, Novartis; Financial Interests, Personal, Stocks/Shares: AstraZeneca, Aurora Tele-Oncology Ltd., Biolidics Ltd., HutchMed, Prenetics Global Limited, D3 Bio, Lunit Inc., Yinson Capital Pte. Ltd., Alentis Therapeutics AG. All other authors have declared no conflicts of interest.