Abstract 1500TiP
Background
For patients (pts) with HER2-overexpressing metastatic gastric cancer, trastuzumab + chemotherapy is a standard first-line option but provides only a modest overall survival (OS) benefit vs chemotherapy. T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and a membrane-permeable topoisomerase I inhibitor payload. Results from a phase I trial showed promising antitumor activity (confirmed objective response rate [ORR], 43.2%) in pts with heavily pretreated HER2+ metastatic gastric cancer who received T-DXd (5.4 or 6.4 mg/kg; Shitara K, et al. Lancet Oncol. 2019;20:827-836). Here we describe the phase Ib/II DESTINY-Gastric03 trial (NCT04379596) evaluating T-DXd monotherapy and combinations in pts with HER2-overexpressing gastric cancer.
Trial design
This is an open-label, multicenter, 2-part, phase Ib/II study in pts with HER2-overexpressing (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization positive) locally advanced, unresectable or metastatic gastric or gastroesophageal junction cancer. In part 1 (dose escalation), pts who had received prior trastuzumab-containing therapy will be assigned to 1 of 5 arms: (1) T-DXd + 5-fluorouracil (5-FU); (2) T-DXd + capecitabine (C); (3) T-DXd + durvalumab; (4) T-DXd + 5-FU or C + oxaliplatin (Ox); or (5) T-DXd + 5-FU or C + durvalumab. In part 2 (dose expansion), pts with no prior treatment for metastatic disease will be randomized across 4 arms: (1) T-DXd; (2) trastuzumab + 5-FU or C + Ox or cisplatin; (3) T-DXd + 5-FU or C ± Ox; or (4) T-DXd + 5-FU or C + durvalumab. In part 2, pts will be stratified by HER2 status. Primary endpoints are safety, determination of recommended phase II doses (part 1), and investigator-assessed confirmed ORR per RECIST v1.1 (part 2). Secondary endpoints include confirmed ORR (part 1), disease control rate, duration of response, progression-free survival (all per investigator), OS, safety (part 2), pharmacokinetics, and immunogenicity.
Clinical trial identification
NCT04379596.
Editorial acknowledgement
Medical writing support/editorial support provided by bMichael Demars, PhD, of ArticulateScience LLC, Hamilton, NJ, USA, and funded by AstraZeneca Pharmaceuticals LP, Gaithersburg, MD, USA, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).
Legal entity responsible for the study
AstraZeneca Pharmaceuticals LP.
Funding
AstraZeneca Pharmaceuticals LP.
Disclosure
Y.Y. Janjigian: Shareholder/Stockholder/Stock options: Rgenix; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Eli Lilly; Honoraria (self), Travel/Accommodation/Expenses: ASCO; Honoraria (self), Advisory/Consultancy: Michael J. Hennessy Associates; Honoraria (self): Paradigm Medical Communications LLC; Honoraria (self), Advisory/Consultancy: Zymeworks Inc.; Honoraria (self), Advisory/Consultancy: Jounce Therapeutics; Honoraria (self), Advisory/Consultancy: Seattle Genetics; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: ONO Pharma; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Merck & Co. Inc.; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Bristol-Myers Squibb; Research grant/Funding (self): Boehringer Ingelheim; Research grant/Funding (self): Bayer; Research grant/Funding (self): Genentech/Roche. N. Viglianti: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. F. Liu: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. A. Mendoza-Naranjo: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. S. Puvvada: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca.