Abstract 501TiP
Background
Valemetostat tosylate (valemetostat), a novel and selective dual inhibitor of enhancer of zeste homolog-2 (EZH2) and EZH1, has demonstrated clinical efficacy and tolerability in multiple hematologic cancers (200 mg PO QD). EZH2 inhibition by valemetostat is expected to upregulate DNA/RNA helicase Schlafen 11 expression and sensitize tumor cells to DNA damaging agents such as topoisomerase I inhibitor antibody–drug conjugates (ADCs). Topoisomerase inhibitors cause DNA strand breaks, which may synergize with valemetostat. HER2 gene amplification or protein expression has been associated with gastric cancer (GC) and GEJ adenocarcinoma. Patients with HER2+ locally advanced or metastatic gastric adenocarcinoma who progress after 1L treatment have poor prognosis and limited therapeutic options. T-DXd is approved globally for HER2+ locally advanced or metastatic GC previously treated with a trastuzumab-based regimen. This study evaluates the clinical activity and safety of valemetostat in combination with T-DXd in patients with GC or GEJ adenocarcinoma, as part of a Master Protocol trial evaluating valemetostat in combination with ADCs in solid tumors.
Trial design
This global, phase 1b, multicenter, open-label Master Protocol study (NCT06244485) will enroll ∼ 70 patients per sub-protocol in multiple regions, including the US and Japan. The gastric cohort enrolls patients with previously treated advanced or metastatic HER2+ GC or GEJ adenocarcinoma. The dose-escalation (Part 1) will determine the recommended dose for expansion (RDE), combining valemetostat 50–200 mg PO QD with T-DXd 5.4 or 6.4 mg/kg IV Q3W. The dose-expansion (Part 2) will assess the efficacy of valemetostat + T-DXd at the RDE. Primary endpoints include safety and tolerability in Part 1 and the objective response rate in Part 2. Secondary endpoints include response duration, progression-free and overall survival, pharmacokinetics, and HER2 expression by IHC and ISH with clinical response. An interim futility analysis will be performed when 20 patients are enrolled with ≥ 6 months of follow-up.
Clinical trial identification
NCT06244485.
Editorial acknowledgement
Naomi Blommaert of Excerpta Medica BV.
Legal entity responsible for the study
Daiichi Sankyo.
Funding
Daiichi Sankyo.
Disclosure
K. Shitara: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, Takeda, Ono Pharmaceutical, MSD, Novartis, Daiichi Sankyo, Amgen, Astellas Pharma, Guardant Health, Bayer, Zymeworks, AstraZeneca, ALX Oncology; Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb, Janssen, AstraZeneca, Lilly, Ono Pharmaceutical, Astellas Pharma; Financial Interests, Institutional, Funding: MSD, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharma, Ono Pharmaceutical, Astellas Pharma, Eisai, Amgen, PRA Health Sciences. P.C. Enzinger: Financial Interests, Personal, Advisory Role: Merck, Astellas Pharma, Taiho Pharmaceutical, Ioxo, Celgene, Daiichi Sankyo, AstraZeneca, Takeda, Arcus biosciences, Blueprint Medicines, Bristol-Myers-Squibb/Celgene, Coheres Biosciences, Ideaya Biosciences, Legend Biotech, Lilly, Novartis, Ono Pharmaceuticals, Servier, Turning Point Therapeutics, Xencor, ALX Oncology, Chimeric Therapeutics, Boehringer Ingelheim, Legend Biotech, Loxo, Zymeworks, Eisai, Oncolys BioPharma, Regeneron. A.S. Mohapatra: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. Y.Y. Janjigian: Financial Interests, Personal, Advisory Role: Pfizer, Merck, Bristol Myers Squibb, Daiichi Sankyo, Bayer, Imugene, AstraZeneca, Lilly, Zymeworks, Basilea Pharmaceutical, Michael J. Hennessy Associates, Paradigm, Seagen, AmerisourceBergen, Arcus Biosciences, Geneos, GSK, Imedex, LynxHealth, Silverback Therapeutics, Mersana, Research to Practice, AskGene Pharma, AbbVie, Astellas Pharma, Guardant Health, Jazz Pharmaceuticals, Clinical Care Options, HMP Education, Inspirna, Peerview, Eisai, Genzyme, Ed Med Resource (OncLive), H.C. Wainwright & Co., Physicians' Education Resource, LLC; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Bristol Myers Squibb, Merck; Financial Interests, Personal, Other: Clinical Care Options, Axis Medical Education, Research to Practice; Financial Interests, Personal, Stocks/Shares: Inspirna; Financial Interests, Personal, Other, Honoraria: Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Master Clinician Alliance, Michael J. Hennessy Associates, Merck, Research to Practice, Peerview, AbbVie, AmerisourceBergen, AskGene Pharma, Arcus Biosciences, Basilea Pharmaceuticals, Bayer, Clinical Care Options, Lilly, Geneos, GSK, Guardant Health, HMP Education, Imedex, Imugene, Inspirna, Lynx Health, Merck Serono, Mersana, Paradigm, Pfizer, Seagen, Silverback Therapeutics, Zymeworks, Eisai, Genzyme, Ed Med Resources (OncInfo), H.C. Wainwright & Co., Physicians' Education Resources, LLC; Financial Interests, Institutional, Funding: Bayer, Bristol Myers Squibb, Merck, Lilly, NCI, Department of Defense, Cycle for Survival, Fred's Team, Genentech/Roche, AstraZeneca, Arcus Biosciences, Transcenta, Inspirna, Stand up to Cancer.