LBPO.CL01 · 临床研究 · Late-Breaking

一线（1L）曲妥珠单抗德鲁替康（T-DXd）方案用于晚期HER2阳性（HER2+）胃癌（GC）、胃食管交界处腺癌（GEJA）或食管腺癌（EA）：DESTINY-Gastric03（DG-03）第2部分中基线HER2相关生物标志物的探索性分析

First-line (1L) trastuzumab deruxtecan (T-DXd) regimens in advanced HER2-positive (HER2+) gastric cancer (GC), gastroesophageal junction adenocarcinoma (GEJA), or esophageal adenocarcinoma (EA): Exploratory analysis of baseline HER2-related biomarkers in DESTINY-Gastric03 (DG-03) Part 2

编号 LB010 展板 10 时间 4/19 02:00–05:00 区域 Section 50 主讲 Yelena Janjigian, MD

分会场 Late-Breaking Research: Clinical Research 1

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作者与单位 Authors & Affiliations

Yelena Y. Janjigian¹, Hanneke van Laarhoven², Sun Young Rha³, Vadim Kozlov⁴, Keun-Wook Lee⁵, Do-Youn Oh⁶, Adriano Gravina⁷, Min-Hee Ryu⁸, Liane Rapatoni⁹, Luís Antunes¹⁰, Filippo Pietrantonio¹¹, Hirokazu Shoji¹², Ralf-Dieter Hofheinz¹³, Maxime Chénard-Poirier¹⁴, Li-Tzong Chen¹⁵, Aleksandr Vasiliev¹⁶, Svetlana Kutukova¹⁷, Arthur W. Lambert¹⁸, Kun Yu¹⁹, Megan Scott²⁰, Roy Rabbie²¹, Jeeyun Lee²²

¹Gastrointestinal Oncology, Memorial Sloan Kettering Cancer Center, New York, NY,²Department of Medical Oncology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands,³Department of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea, Republic of,⁴State Budgetary Health Care Institution, Novosibirsk Regional Clinical Oncology Dispensary, Novosibirsk, Russian Federation,⁵Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea, Republic of,⁶Department of Internal Medicine, Seoul National University Hospital Cancer, Research Institute, Seoul, Korea, Republic of,⁷SC Sperimentazioni Cliniche, Istituto Nazionale Tumori, IRCCS, Fondazione Pascale, Naples, Italy,⁸Department of Oncology, Asan Medical Center, Seoul, Korea, Republic of,⁹Division of Clinical Oncology, Department of Medical Imaging, Haematology and Clinical Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil,¹⁰University Hospital of Santa Maria, Federal University of Santa Maria, and Viver Research Center, Santa Maria, Brazil,¹¹Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy,¹²Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan,¹³Mannheim Cancer Center, University of Heidelberg, Heidelberg, Germany,¹⁴Hematology and Medical Oncology Department, CHU de Québec, Québec, QC, Canada,¹⁵Kaohsiung Medical University Hospital, and Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan,¹⁶Clinical Research Department, RZD Medicine Clinical Hospital of Saint Petersburg, Saint Petersburg, Russian Federation,¹⁷Municipal Clinical Oncology Dispensary, Pavlov University, Saint Petersburg, Russian Federation,¹⁸Translational Medicine, Oncology R&D, AstraZeneca, Waltham, MA,¹⁹Oncology Data Science & AI, Oncology R&D, AstraZeneca, Waltham, MA,²⁰Oncology Biometrics, Oncology R&D, AstraZeneca, Cambridge, United Kingdom,²¹Global Medicines Development, Late Development Oncology, Oncology R&D, AstraZeneca, Cambridge, United Kingdom,²²Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic of

摘要 Abstract

中文摘要

背景： DG-03第2部分显示，1L T-DXd方案在晚期HER2+ GC中具有令人鼓舞的抗肿瘤活性。我们报告了DG-03第2部分中当地与中心HER2 IHC结果之间的一致率，以及根据基线HER2相关生物标志物的客观缓解率（ORR）。方法： DG-03（NCT04379596）是一项1b/2期、开放标签、多部分试验。在第2部分中，既往未经治疗的晚期HER2+（IHC 3+或IHC 2+/ISH+；当地检测）GC/GEJA/EA患者（pts）被纳入六个组，并接受以下治疗之一：曲妥珠单抗+化疗（CT；氟嘧啶[FP；5-氟尿嘧啶或卡培他滨]+顺铂/奥沙利铂）、T-DXd 6.4 mg/kg、T-DXd 6.4 mg/kg + FP、T-DXd 6.4 mg/kg + FP + 帕博利珠单抗（pembro）、T-DXd 6.4 mg/kg + pembro，或T-DXd 5.4 mg/kg + FP + pembro。按当地和中心HER2 IHC/ISH状态（中心IHC采用HercepTest）以及按血浆（GuardantOMNI）和肿瘤（FoundationOne CDx）HER2（ERBB2）扩增（amp）报告了经确认的研究者评估ORR。结果：截至2025年2月28日，共纳入230例患者；229例接受了治疗。总体而言（n/N），经当地检测为HER2+（IHC 3+或IHC 2+/ISH+）的GC中，80%（160/199）经中心评分为HER2+；经当地检测为IHC 3+和IHC 2+/ISH+的GC中，分别有86%（143/166）和52%（17/33）经中心评分为HER2+（当地IHC有n=2、当地ISH有n=1、中心ISH有n=3、中心IHC有n=24例结果数据缺失/未知）。基线HER2相关生物标志物分析见表。结论：一致性结果与既往GC研究大体一致。与HER2表达较低和/或无HER2扩增者相比，基线HER2 IHC表达升高和HER2扩增通常与接受1L T-DXd方案治疗的HER2+ GC患者更高的ORR相关。数据进一步证明了1L T-DXd联合方案在HER2+ GC中的抗肿瘤活性。 ORR %；95% CI n/N 曲妥珠单抗 + CT；T-DXd；T-DXd + FP；T-DXd 6.4 mg/kg + FP + pembro；T-DXd + pembro；T-DXd 5.4 mg/kg + FP + pembro n 29 43 41 43 41 32 当地* IHC 3+ 77；56, 91 20/26 57；40, 73 21/37 80；63, 92 28/35 60；42, 76 21/35 63；44, 79 20/32 73；52, 88 19/26 IHC 2+/ISH+ 67；9, 99 2/3 0；0, 52 0/5 60；15, 95 3/5 57；18, 90 4/7 67；30, 93 6/9 83；36, 100 5/6 中心* IHC 3+ / IHC 2+/ISH+ 79；54, 94 15/19 58；39, 76 18/31 81；64, 93 26/32 65；47, 80 22/34 65；44, 83 17/26 70；46, 88 14/20 IHC 2+/ISH− / IHC 1+/0 100；40, 100 4/4 14；0, 58 1/7 40；5, 85 2/5 20；1, 72 1/5 50；21, 79 6/12 71；29, 96 5/7 肿瘤† 扩增 90；56, 100 9/10 63；38, 84 12/19 76；53, 92 16/21 63；38, 84 12/19 71；42, 92 10/14 - 无扩增 100；29, 100 3/3 20；1, 72 1/5 67；9, 99 2/3 20；1, 72 1/5 56；21, 86 5/9 血浆† 扩增 73；45, 92 11/15 68；43, 87 13/19 87；66, 97 20/23 68；45, 86 15/22 94；70, 100 15/16 82；60, 95 18/22 无扩增 75；19, 99 3/4 23；5, 54 3/13 60；32, 84 9/15 23；5, 54 3/13 35；14, 62 6/17 60；26, 88 6/10 未知结果已排除 *HER2 IHC/ISH；† HER2扩增

查看英文原文 English abstract

Background: DG-03 Part 2 showed promising antitumor activity for 1L T-DXd regimens in advanced HER2+ GCs. We report concordance rates between local and central HER2 IHC results, and ORRs according to baseline HER2-related biomarkers, in DG-03 Part 2. Methods: DG-03 (NCT04379596) is a Phase 1b/2, open-label, multipart trial. In Part 2, patients (pts) with previously untreated advanced HER2+ (IHC 3+ or IHC 2+/ISH+; local test) GC/GEJA/EA were enrolled across six arms and received either trastuzumab + chemotherapy (CT; fluoropyrimidine [FP; 5-fluorouracil or capecitabine] + cisplatin/oxaliplatin), T-DXd 6.4 mg/kg, T-DXd 6.4 mg/kg + FP, T-DXd 6.4 mg/kg + FP + pembrolizumab (pembro), T-DXd 6.4 mg/kg + pembro, or T-DXd 5.4 mg/kg + FP + pembro. Confirmed investigator-assessed ORRs were reported by local and central HER2 IHC/ISH status (HercepTest for central IHC) and by plasma (GuardantOMNI) and tumoral (FoundationOne CDx) HER2 (ERBB2) amplification (amp). Results: As of Feb 28, 2025, 230 pts were enrolled; 229 received treatment. Overall (n/N), 80% (160/199) of HER2+ (IHC 3+ or IHC 2+/ISH+) GCs by local test were centrally scored as HER2+; 86% (143/166) and 52% (17/33) of IHC 3+ and IHC 2+/ISH+ GCs by local test were centrally scored as HER2+, respectively (missing/unknown data for n=2 local IHC, n=1 local ISH, n=3 central ISH, and n=24 central IHC results). Baseline HER2-related biomarker analyses are in the Table. Conclusions: Concordance results were broadly consistent with prior studies in GC. Elevated baseline HER2 IHC expression and HER2 amp were generally associated with higher ORRs for pts with HER2+ GCs treated with 1L T-DXd regimens, versus those with lower HER2 expression and/or without amplified HER2 . Data provide further evidence of antitumor activity for 1L T-DXd combinations in HER2+ GCs. ORR %; 95% CI n/N Trastuzumab + CT T-DXd T-DXd + FP T-DXd 6.4 mg/kg + FP + pembro T-DXd + pembro T-DXd 5.4 mg/kg + FP + pembro n 29 43 41 43 41 32 Local* IHC 3+ 77 ; 56, 91 20/26 57 ; 40, 73 21/37 80 ; 63, 92 28/35 60 ; 42, 76 21/35 63 ; 44, 79 20/32 73 ; 52, 88 19/26 IHC 2+/ISH+ 67 ; 9, 99 2/3 0 ; 0, 52 0/5 60 ; 15, 95 3/5 57 ; 18, 90 4/7 67 ; 30, 93 6/9 83 ; 36, 100 5/6 Central* IHC 3+ / IHC 2+/ISH+ 79 ; 54, 94 15/19 58 ; 39, 76 18/31 81 ; 64, 93 26/32 65 ; 47, 80 22/34 65 ; 44, 83 17/26 70 ; 46, 88 14/20 IHC 2+/ISH− / IHC 1+/0 100 ; 40, 100 4/4 14 ; 0, 58 1/7 40 ; 5, 85 2/5 20 ; 1, 72 1/5 50 ; 21, 79 6/12 71 ; 29, 96 5/7 Tumor † Amp 90 ; 56, 100 9/10 63 ; 38, 84 12/19 76 ; 53, 92 16/21 63 ; 38, 84 12/19 71 ; 42, 92 10/14 - No amp 100 ; 29, 100 3/3 20 ; 1, 72 1/5 67 ; 9, 99 2/3 20 ; 1, 72 1/5 56 ; 21, 86 5/9 Plasma † Amp 73 ; 45, 92 11/15 68 ; 43, 87 13/19 87 ; 66, 97 20/23 68 ; 45, 86 15/22 94 ; 70, 100 15/16 82 ; 60, 95 18/22 No amp 75 ; 19, 99 3/4 23 ; 5, 54 3/13 60 ; 32, 84 9/15 23 ; 5, 54 3/13 35 ; 14, 62 6/17 60 ; 26, 88 6/10 Unknown results excluded *HER2 IHC/ISH; † HER2 amp

利益披露 Disclosure

Y. Y. Janjigian, Abbvie; AmerisourceBergen; Arcus Biosciences; AskGene Pharma; Astellas Pharma; AstraZeneca; Basilea Pharmaceutical; Bayer; Boehringer Ingelheim; Bristol-Myers Squibb; Clinical Care Options Other, Consulting or advisory role. Daiichi Sankyo; Debbies Dream Foundation; Eisai; Genzyme; Geneos; GlaxoSmithKline; Guardant Health; H.C. Wainwright & Co.; HMP Education; Imedex; Imugene; Inspirna; Jazz Pharmaceuticals Other, Consulting or advisory role. Lilly; Lynx Health; Merck; Merck Serono; Mersana; Michael J. Hennessy Associates; OncLive; OncoDaily; Paradigm; Peerview; Pfizer; Physicans' Education Resource; Research to Practice; Seagen Other, Consulting or advisory role. Signatera; Silverback Therapeutics; WebMD; Zymeworks Other, Consulting or advisory role. Bristol-Myers Squibb Japan; Merck Travel. Axis Medical Education; Clinical Care Options; Giants of Cancer Care; Research to Practice Other, Other relationships. Inspirna; OncoDaily; Veeda Oncology Stock, Stock Option. Abbvie; AmerisourceBergen; Arcus Biosciences; AskGene Pharma; Astellas Pharma; AstraZeneca; Basilea Pharmaceutical; Bayer; BeOne Medicines; Boehringer Ingelheim; Bristol-Myers Squibb Other, Honoraria. Clinical Care Options; Daiichi Sankyo; eChinaHealth; Eisai; Geneos; Genzyme; Gilead Sciences; GlaxoSmithKline; Guardant Health; H.C. Wainwright & Co.; HMP Education; IDEOlogy Health; Imedex; Imugene Other, Honoraria. i3 Health; Inspirna; Lilly; Lynx Health; Master Clinician Alliance; Merck; Merck Serono; Mersana; Michael J. Hennessy Associates; Oncology Information Group; Paradigm; Peerview; Pfizer Other, Honoraria. Physicans' Education Resource; Regeneron; Research to Practice; Seagen; Silverback Therapeutics; Suzhou Liangyihui Network Technology; Talem Health; TotalCME; WebMD; Zymeworks Other, Honoraria. Arcus Biosciences; Astellas Pharma; AstraZeneca; Bayer; Bristol-Myers Squibb; Cycle for Survival; Department of Defense; Fred's Team; Genentech/Roche; Inspirna; Lilly; Merck; NCI; Stand up to Cancer ). Transcenta ). H. van Laarhoven, Amgen; Amphera; Astellas Pharma; AstraZeneca; BeiGene; Boehringer Ingelheim; Bristol-Myers Squibb; Daiichi Sankyo; MSD Oncology; MyeoloidTx Other, Consulting or advisory role. AstraZeneca; Bristol-Myers Squibb; CongressCare; Daiichi Sankyo; MedTalks; Travel Congress Management; Uitgeverij Jaap Other, Speakers' Bureau. AstraZeneca Travel. Amgen; Auristone; Bristol-Myers Squibb; Incyte; Merck KGaA; ORCA Therapeutics; Servier ). S. Y. Rha, Amgen; Arcus Biosciences; Astellas Pharma; AstraZeneca; BeOne Medicines; Daiichi Sankyo; Eisai; indivumed; LG Chem; MSD Oncology; Ono Pharmaceutical; Toray Industries Other, Consulting or advisory role. Amgen; Astellas Pharma; AstraZeneca; Bristol-Myers Squibb/Ono Pharmaceutical; Daiichi Sankyo/UCB Japan; Eisai; MSD Oncology Other, Speakers' Bureau. V. Kozlov, None. K. Lee, Abbvie; Amgen; Astellas Pharma; BeiGene; Daiichi Sankyo; Metafines; MSD; Ono Pharmaceutical; PIN therapeutics; Takeda Other, Consulting or advisory role. Astellas Pharma; Bayer; Celltrion; Merck KGaA; MSD Oncology; Ono Pharmaceutical Other, Honoraria. ALX Oncology; Amgen; Arcus Biosciences; Astellas Pharma; AstraZeneca; Avelos Therapeutics; Bayer; BeiGene; Boehringer Ingelheim; Bolt Biotherapeutics; Daiichi Sankyo; Erasca, Inc; Exelixis ). Genome & Company; GlaxoSmithKline; Hanmi; IDRx; IgM Biosciences; Ildong Pharmaceutical; InventisBio; Jazz Pharmaceuticals; Jiangsu Hengrui Pharmaceuticals; Leap Therapeutics; MedPacto; Medicenna ). Metafines; MSD; Ono Pharmaceutical; Panolos Bioscience; Pfizer; Roche; Taiho Pharmaceutical; Torl Biotherapeutics; Trishula Therapeutics; Wellmarker Bio; Yuhan ). ALX Oncology Other, Uncompensated relationship. D. Oh, Abbvie; Alligator Bioscience AB; Arcus Biosciences; Astellas; ASLAN; AstraZeneca; Basilea; Bayer; BeiGene; BMS/Celgene; Eutilex; Genentech/Roche; Halozyme; Hana Pharm; Hanmi; Idience; IQVIA; J-Pharma Other, Advisory board. Mirati Therapeutics, Eutilex, Moderna, Idience, Alligator Bioscience AB, Hana Pharm, Revolution Medicine, Tallac Therapeutics, Hanmi Other, Advisory board. Array; AstraZeneca; BeiGene; Eli Lilly; Handok; Hanmi; MSD; Novartis; Servier ). A. Gravina, None. M. Ryu, Astellas Pharma; AstraZeneca; BMS; DAE HWA Pharmaceutical; Daiichi Sankyo; Lilly; MSD; Novartis; Ono Pharmaceuticals; Taiho Pharmaceutical Other, Advisory board. AstraZeneca, BMS, Ono Pharmaceutical ). L. Rapatoni, None.. L. Antunes, None. F. Pietrantonio, Agenus; Amgen; AstraZeneca; BMS; BeOne; GSK; Incyte; Johnson&Johnson; Lilly; Rottapharm; Tempus ). Amgen; Astellas; AstraZeneca; Bayer; BMS; BeOne; Daiichi Sankyo; Incyte; Ipsen; Johnson & Johnson; Merck-Serono; MSD; Pierre-Fabre; Seagen; Servier; Takeda Other, Invited speaker. Agenus; Amgen; Astellas Pharma; AstraZeneca; Bayer; BMS; BeOne; Daiichi Sankyo; Gilead; GSK; Incyte; Italfarmaco; Jazz Pharmaceuticals; Johnson & Johnson; Merck-Serono; MSD; Pfizer; Pierre-Fabre Other, Advisory/consultancy. Revolution Medicine; Rottapharm; Servier; Takeda Other, Advisory/consultancy. Amgen; Astellas Pharma; Incyte; Johnson & Johnson; Merck-Serono; Pierre-Fabre; Servier Travel. H. Shoji, Astellas Pharma Other, Consulting or advisory role. AbbVie; Amgen; Astellas Pharma; AstraZeneca; Daiichi Sankyo; Elevation Oncology; MSD; Ono Pharmaceutical; Takeda ). R. Hofheinz, Abbvie; Amgen; Astellas Pharma; AstraZeneca; BeOne; Boehringer; BMS; Daiichi Sankyo; Esteve; INCYTE; Leo Pharma; Lilly; Merck; MSD; Nordic; Pierre-Fabre; Roche; Sanofi; Servier; Takeda; WALA Other, Advisory board and/or speaker fees. M. Chénard-Poirier, AstraZeneca; BMS; Incyte; Merck; Pfizer Other, Honoraria for advisory board and speaker fees. L. Chen, AbbVie; AstraZeneca; MSD; Revolution Medicine Other, Advisory board. BMS; Ipsen; Novartis; ONO Pharmaceuticals; PharmaEngine (TW); TTY (TW) Other, Invited speaker. Onward; ScinoPharm Taiwan Other, Advisory board and scientific advisory committee. AstraZeneca; ONO Pharmaceuticals; Pfizer; TransThera Other, Steering committee. GSK; Taiho Pharmaceutical Other, Local PI. Ipsen Other, Co-ordinating PI including medication and budget support for investigator-initiated trial in NET. Pfizer ). Syncore BioPharma; TTY, Taiwan Other, Trial Chair. OBI (TW) Other, DSMC member for clinical trials . Taivex (TW) Other, Medical Monitoring for clinical trial. ScinoPharm Taiwan, Ltd. g., Board of Directors, non-salaried role). HuniLife Biotechnology, Inc. Other Intellectual Property, Licencing fees for alpha-enolase specific antibodies. A. Vasiliev, None.. S. Kutukova, None. A. W. Lambert, AstraZeneca Employment, Stock, Stock Option. K. Yu, AstraZeneca Employment, Stock, Stock Option. M. Scott, AstraZeneca Employment, Stock, Stock Option. R. Rabbie, AstraZeneca Employment, Stock, Stock Option. J. Lee, Amgen; AstraZeneca; Daiichi Sankyo; Guardant Health AMEA; Immunoncia; Mirati Therapeutics; Trutino Biosciences Other, Consulting or advisory role. AstraZeneca; Merck Sharp & Dohme; Samsung Bioepis ).

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