Abstract 264TiP
Background
T-DXd is a human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugate. T-DXd 6.4 mg/kg is approved in the US, EU, Republic of Korea, and Singapore for patients (pts) with metastatic HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]–positive) gastric/GEJA who have received a prior trastuzumab-based regimen, and in Japan for metastatic HER2+ gastric cancer that has progressed after chemotherapy. Recent data have shown a benefit with the combination of trastuzumab, immunotherapy, and chemotherapy in HER2+ gastric cancer in the first-line (1L) setting. DESTINY-Gastric03 (DG-03) is evaluating T-DXd as a monotherapy and as part of combination regimens in pts with HER2-expressing (HER2+ and HER2-low) gastric/GEJA. The protocol was amended in Nov 2023 to add Part 4, which will investigate 1L T-DXd in combination with rilvegostomig, a PD-1/-TIGIT bispecific antibody, and a fluoropyrimidine (FP) in HER2+ or HER2-low gastric cancers.
Trial design
In DG-03 (NCT04379596) Part 4 (dose expansion), pts with esophageal/gastric/GEJA (treatment-naïve for metastatic disease) will be enrolled. HER2 and PD-L1 status for enrollment will be based on local tissue testing results. Initially, T-DXd 5.4 mg/kg intravenous (IV) infusion Q3W, rilvegostomig 750 mg IV Q3W, and an FP (5-fluorouracil or capecitabine) will be evaluated in a safety cohort of ≥6 pts with HER2+ (IHC 3+ or IHC 2+/ISH-positive) or HER2-low (IHC 2+/ISH-negative or IHC 1+) esophageal/gastric/GEJA. After safety review, a higher rilvegostomig dose may be evaluated; once tolerability is confirmed, a rilvegostomig dose recommendation will be made for the T-DXd + rilvegostomig + FP combination for arms 4A (HER2+) and 4B (HER2-low), with an additional 24–30 pts allocated per arm. Primary endpoint: investigator-assessed (INV) confirmed objective response rate per RECIST v1.1. Secondary endpoints include INV disease control rate, duration of response, progression-free survival, and overall survival. Safety and tolerability will be assessed. Enrollment is ongoing.
Clinical trial identification
NCT04379596.
Legal entity responsible for the study
AstraZeneca/Daiichi Sankyo.
Funding
This study is sponsored by AstraZeneca. In March 2019, AstraZeneca entered into a global development and commercialization collaboration agreement with Daiichi Sankyo for trastuzumab deruxtecan (T-DXd; DS-8201).
Disclosure
Y.Y. Janjigian: Financial Interests, Personal, Advisory Board: AbbVie, Arcus Biosciences, Ask- Gene Pharma, Inc., AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Inc., Eli Lilly, GSK, Guardant Health, Inc., Imugene, Lynx Health, Merck, Sanofi Genzyme, Seagen, Zymeworks Inc.; Financial Interests, Personal, Other, Consulting: Amerisource Bergen, Astellas, Basilea Pharmaceutica, Geneos Therapeutics, Imedex, Inspirna, Mersana Therapeutics, Paradigm Medical Communications, Pfizer, Silverback Therapeutics; Financial Interests, Personal, Other, Consulting and Invited Speaker: Arcus Biosciences, AstraZeneca, Clinical Care Options, HMP Education, Merck Serono, PeerView Institue, Research to Practice; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Ed MedResources (OncInfo), H.C. Wainwright & Co., LLC, Merck, TotalCME, Talem Health; Financial Interests, Personal, Other, Consulting, Invited Speaker and Chair of Giants of Cancer Care Steering Committee: Michael J. Hennessy Associates; Financial Interests, Personal, Other, Consulting and Moderator: Physicians' Education Resource, LLC; Financial Interests, Personal, Stocks/Shares, Stock option: Inspirna; Financial Interests, Personal and Institutional, Research Grant: NCI, Department of Defense, Cycle for Survival, Fred's Team, Inspirna, Bayer, Genetech/Roche, Bristol Myers Squibb, Eli Lilly, Merck, Transcenta, Stand Up To Cancer, AstraZeneca, Arcus Biosciences, Astellas; Financial Interests, Personal, Steering Committee Member: AstraZeneca, Transcenta Holding Limited. C. Lloyd: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. V.G. de Giorgio-Miller: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. Y. Chang: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. All other authors have declared no conflicts of interest.