Background: Valemetostat tosylate (valemetostat) is a novel, potent, and selective dual inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1. Valemetostat 200 mg PO QD has demonstrated clinical efficacy and favorable tolerability in multiple hematologic malignancies. EZH2 controls gene expression, including the expression of genes involved in DNA damage response, like DNA/RNA helicase Schlafen 11 (SLFN11). In response to DNA damage, SLFN11 binds to chromatin, causing a replication block and inducing apoptosis. Expression levels of SLFN11 indicate sensitivity to DNA-damaging agents (DDAs) in various solid tumors and are downregulated in chemotherapy-resistant tumor cells due to trimethylation of H3K27 at the SLFN11 gene locus. EZH2 inhibition by valemetostat is expected to upregulate SLFN11 and sensitize tumor cells to DDAs. Topoisomerase inhibition causes DNA strand breaks, which may synergize with valemetostat. This study will combine valemetostat with topoisomerase-I inhibitor ADCs, T-DXd or Dato-DXd, for the first time in patients (pts) with HER2-positive (HER2+) gastric cancer (GC) and non-squamous non-small-cell lung cancer (NSCLC), respectively. T-DXd is globally approved for the treatment of pts with locally advanced or metastatic HER2+ GC and other cancers, having received prior anti-HER2–based treatment. In the phase 3 TROPION-Lung01 trial, Dato-DXd significantly improved progression-free survival (PFS) vs standard chemotherapy in previously treated, locally advanced or metastatic NSCLC. Methods: This global, phase 1b, multicenter, two-part, open-label study is structured as a Master Protocol with independent sub-protocols defined by disease and treatment combination, including valemetostat + T-DXd in pts with 2L+ advanced or metastatic HER2+ GC or gastro-esophageal junction adenocarcinoma, and valemetostat + Dato-DXd in pts with 2L+ locally advanced, unresectable, or metastatic non-squamous NSCLC. Target enrollment is 70 pts per sub-protocol across 35 sites in US and Japan. Part 1 will determine the valemetostat recommended dose for expansion (RDE), combining escalating doses of valemetostat 50–200 mg PO QD with T-DXd at 5.4 mg/kg or 6.4 mg/kg (dose after first escalation) IV Q3W (GC protocol), or with fixed dose Dato-DXd 6.0 mg/kg IV Q3W (NSCLC protocol). Part 2 will evaluate the efficacy of valemetostat QD + Dato-DXd or T-DXd at the RDE. The main eligibility criteria for both protocols include at least 1 measurable lesion (per RECIST v1.1), an ECOG PS score of 0–1, and adequate organ function. Primary endpoints of this study are safety and tolerability of valemetostat in Part 1 and objective response rate in Part 2. Secondary endpoints include duration of response, PFS, overall survival and pharmacokinetics. Clinical trial information: NCT06244485.