Abstract 1401O
Background
T-DXd is a HER2-directed antibody-drug conjugate; T-DXd 6.4 mg/kg is approved for pts with metastatic HER2+ gastric/GEJA who have received a prior trastuzumab-based regimen. Dual PD-1 and HER2 blockade together with fluoropyrimidine (FP; 5-fluorouracil or capecitabine)/platinum has improved outcomes vs chemotherapy/trastuzumab in the first-line (1L) setting. We explored T-DXd in combination with FP and an anti-PD-1 in 1L esophageal/gastric/GEJA.
Methods
DG-03 Part 2 (dose expansion; NCT04379596) enrolled pts with 1L HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization-positive by local testing) esophageal/gastric/GEJA globally, irrespective of PD-L1 status. Pts were randomized (except to arm F), as feasible, to standard of care (SOC), T-DXd monotherapy or T-DXd-based combinations, and stratified by HER2 status (Table). Primary endpoint was investigator-assessed (INV) confirmed objective response rate (ORR) per RECIST 1.1. Safety and tolerability were assessed.
Results
At data cutoff (Jan 31, 2024), 307 pts were enrolled; 229 pts received treatment. Baseline/disease characteristics were not balanced across arms. Combining T-DXd with FP/pembrolizumab (pembro) 200 mg showed durable clinical benefit in pts with HER2+ central PD-L1 CPS ≥1 esophageal/gastric/GEJA. Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis occurred in 21 (11%) T-DXd-treated pts (arm B [6.4 mg/kg], n=4; arm C [6.4 mg/kg + FP], n=4; arm D [6.4 mg/kg + FP + pembro], n=8; arm E [6.4 mg/kg + pembro], n=5), with 3 deaths (arm D, n=2; arm E, n=1). Summary efficacy and safety are in the table. Table: 1401O
| A Trastuzumab + platinum + FP (SOC; n=29) | B T-DXd 6.4 mg/kg (n=43)* | C T-DXd 6.4 mg/kg + FP (n=41) | D T-DXd 6.4 mg/kg + FP + pembro (n=43) | E T-DXd 6.4 mg/kg + pembro (n=41) | F T-DXd 5.4 mg/kg + FP + pembro (n=32) | |
| Median follow up, months | 18.4 | 16.7 | 22.0 | 16.2 | 14.6 | 1.5 |
| Confirmed ORR, n (%) | 22 (76) | 21 (49) | 32 (78) | 25 (58) | 26 (63) | 4 (13) |
| PD-L1 CPS ≥1, n/N (%) | 17/20 (85) | 12/21 (57) | 17/22 (77) | 14/20 (70) | 14/18 (78) | NA |
PD-L1 CPS ConclusionsCombination of T-DXd + FP + pembro showed promising antitumor activity warranting further study in esophageal/gastric/GEJA. Tolerability was lower with T-DXd 6.4 mg/kg + FP + pembro; however, the overall safety profile was manageable. Clinical trial identificationNCT04379596. Editorial acknowledgementUnder guidance of the authors, medical writing support was provided by Carmen Grimaldos, PhD, of Helios Medical Communications, part of Helios Global Group. Legal entity responsible for the studyAstraZeneca, Daiichi Sankyo. FundingAstraZeneca. In March 2019, AstraZeneca entered into a global development and commercialization collaboration agreement with Daiichi Sankyo for trastuzumab deruxtecan (T-DXd; DS-8201). DisclosureY.Y. Janjigian: Financial Interests, Personal, Stocks or ownership: Inspirna; Financial Interests, Personal, Other, Honoraria: AbbVie, Amerisource Bergen, Ask-Gene Pharma, Inc., Arcus Biosciences, Astellas, AstraZeneca, Basilea Pharmaceutica, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Ed Med Resources (Onc Info), Eisai, Eli Lilly, Geneos Therapeutics, GSK, Guardant Health, Inc., H.C. Wainwright & Co., HMP Education, Imedex, Imugene, Inspirna, Lynx Health, Merck, Merck Serono, Mersana Therapeutics, Paradigm Medical Communications, Pfizer, Physician’s Education Resource, LLC, Research to Practice, Sanofi Genzyme, Seagen, Silverback Therapeutics, TotalCME, Zymeworks Inc.; Financial Interests, Personal, Advisory Role: AbbVie, Amerisource Bergen, Ask-Gene Pharma, Inc., Arcus Biosciences, Astellas, AstraZeneca, Basilea Pharmaceutica, Bayer, Bristol Myers Squibb, Clinical Care Options, Daiichi Sankyo, Ed Med Resources (Onc Info), Eisai, Eli Lilly, Geneos Therapeutics, GSK, Guardant Health, Inc., H.C. Wainwright & Co., HMP Education, Imedex, Imugene, Inspirna, Lynx Health, Merck, Merck Serono, Mersana Therapeutics, Michael J. Hennessy Associates, Paradigm Medical Communications, PeerView Institute, Pfizer, Physician’s Education Resource, LLC, Research to Practice, Sanofi Genzyme, Seagen, Silverback Therapeutics, Total CME, Zymeworks Inc. Financial Interests, Personal, Research Funding: Astellas, AstraZeneca, Arcus Biosciences, Bayer, Bristol Myers Squibb, Cycle for Survival, Department of Defense, Eli Lilly, Fred’s Team, Genentech/Roche, Inspirna, Merck, NCI, Stand Up 2 Cancer, Transcenta ; Financial Interests, Personal, Other, Travel/Accommodations/Expenses: Bristol Myers Squibb Japan, Merck; Financial Interests, Personal, Other: Clinical Care Options, Axis Medical Education, Research to Practice. H.W.M. van Laarhoven: Financial Interests, Institutional, Invited Speaker: Astellas, BeiGene, Benecke, BMS, Daiichi Sankyo, JAAP, Medtlaks, Novartis, Springer, Travel Congress Management BV; Financial Interests, Institutional, Advisory Board: Amphera, Anocca, Astellas, AstraZeneca, BeiGene, Boehringer Ingelheim, Daiichi Sankyo, Dragonfly, MSD, Servier; Financial Interests, Institutional, Other, Advices on protocol development: Myeloid; Financial Interests, Institutional, Other, Selection of articles for Framingham: Framingham; Financial Interests, Institutional, Research Grant, LyRICX study: Servier; Financial Interests, Institutional, Research Grant, TAPESTRY study: Merck; Financial Interests, Institutional, Research Grant, AUSPICIOUS study: Incyte; Financial Interests, Institutional, Research Grant, LOAD study: ORCA; Financial Interests, Institutional, Coordinating PI: Auristone; Financial Interests, Institutional, Local PI, DESTINY-GASTRIC03: AstraZeneca; Non-Financial Interests, Leadership Role, Chair upper GI Faculty: ESMO; Non-Financial Interests, Institutional, Product Samples, For all clinical study mentioned, study medication is provided: See 'research funding'. S.Y. Rha: Financial Interests, Institutional, Research Grant: AstraZeneca, Ono Pharmaceutical, Eisai, Ipsen, Merck Sharp & Dohme, Merck KGaA, Pfizer, BeiGene, Astellas Pharma, Amgen, ALX Oncology, Zymeworks, Macrogenics, Seagen, Bold Therapeutics, MedPacto, ABLBIO, Daiichi Sankyo, Taiho Pharmaceutical, Leap Therapeutics, Arcus Biosciences; Financial Interests, Personal, Speaker, Consultant, Advisor: LG Biochem, Indivumed; Financial Interests, Personal, Other, Honoraria: MSD, Lilly, Daiichi Sankyo, Eisai; Financial Interests, Personal, Advisory Board: Amgen. V. Kozlov: Non-Financial Interests, Personal, Principal Investigator: LLC MSCH "Klinitsist-Klinika Pretor". D. Oh: Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok; Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, Aslan, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD. A. Gravina: Financial Interests, Institutional, Local PI, Grants for Clinical Trials: Pfizer, Janssen, Roche, Daiichi-Sankyo, Exelixis, Incyte, MSD, Bayer, Merck; Financial Interests, Institutional, Coordinating PI, Grants for Clinical Trials: AstraZeneca; Financial Interests, Institutional, Local PI, Grants for Clinical Trial: GSK-Tesaro, Sutro, Boehringer Ingelheim, HiFiBiO Inc.; Non-Financial Interests, Member: AIOM, ESMO. L. Rapatoni: Financial Interests, Personal, Invited Speaker: Ipsen, Novartis; Financial Interests, Personal and Institutional, Local PI: AstraZeneca, Daiichi Sankyo, MSD. H. Shoji: Financial Interests, Personal, Advisory Board: Ono Pharmaceutical Co., Ltd., Zymeworks inc., Astellas; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Institutional, Local PI: Ono Pharmaceutical Co., Ltd., MSD, Astellas, Amgen, Daiichi Sankyo, AbbVie, AstraZeneca, Taiho Pharmaceutical, Elevation Oncology; Financial Interests, Institutional, Funding: Ono Pharmaceutical Co., Ltd., Takeda Pharmaceuticals. R.D. Hofheinz: Financial Interests, Personal, Advisory Board: Amgen, BMS, MSD, Sanofi, Roche, AstraZeneca, Lilly, Roche, Merck, Daiichi Sankyo, Nordic Pharma, AbbVie, BeiGene. H.E.R. Ford: Non-Financial Interests, Personal and Institutional, Principal Investigator: AstraZeneca, MSD, Daiichi Sankyo, Amgen. M. Chenard-Poirier: Financial Interests, Personal, Invited Speaker: Merck, Pfizer, Incyte; Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb; Financial Interests, Institutional, Local PI: Sanofi, Amgen, AstraZeneca, Merck. S. Raoufmoghaddam: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. C. Lloyd, C. Mateo: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. C. Zhang: Financial Interests, Personal, Full or part-time Employment, Study Statistician: AstraZeneca. All other authors have declared no conflicts of interest. 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