A Study of Valemetostat Tosylate in Combination With DXd ADCs in Subjects With Solid Tumors

Inclusion Criteria

• Key Inclusion Criteria All participants must meet all of the following criteria, as well as all criteria from the relevant sub-protocol to be eligible for enrollment: - At least 18 years or the minimum legal adult age (whichever is greater) at the time the informed consent form (ICF) is signed. - Has at least 1 measurable lesion based on investigator imaging assessment (computed tomography or magnetic resonance imaging) using RECIST v 1.1 at Screening. - Is willing to provide an adequate tumor sample. - Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at Screening. Additional Key Inclusion for Sub-Protocol A: - Diagnosed with pathologically documented breast cancer that: 1. Is unresectable or metastatic. 2. Has progressed on and would no longer benefit from endocrine therapy in hormone receptor-positive subjects in the opinion of the investigator. 3. Has been treated with at least 1 and at most 2 prior lines of chemotherapy in the recurrent or metastatic setting. 4. Has a history of low HER2 expression, defined as immunohistochemistry (IHC) 2+ /in situ hybridization (ISH)-negative or IHC 1+ (ISH-negative or untested), as classified by the American Society of Clinical Oncology/College of American Pathologists 2023 HER2 testing guidelines. 5. Was never previously HER2-positive (IHC 3+ or IHC 2+/ISH+) on prior pathology testing (per American Society of Clinical Oncology/College of American Pathologists guidelines Additional Key Inclusion for Sub-Protocol B: • Gastric or gastro-esophageal junction (GEJ) adenocarcinoma that is (a) unresectable or metastatic (b) has progressed on HER2-directed monoclonal antibody (mAb) containing therapy, such as trastuzumab or approved trastuzumab biosimilar-containing regimen. Additional Key Inclusion for Sub-Protocol C: - Pathologically documented Stage IIIB, IIIC, or IV non-squamous NSCLC with or without actionable genomic alterations (AGA) at the time of enrollment. - Must meet prior therapy requirements: - Participants without AGA: (a) received platinum-based chemotherapy in combination with α-PD-1/α -PD-L1 mAb as the only prior line of therapy or (b) received platinum-based chemotherapy and α -PD-1/ α -PD-L1 mAb (in either order) sequentially as the only 2 prior lines of therapy. - Participants with AGA: (a) has been treated with 1 or 2 prior lines of applicable targeted therapy that is locally approved for participant's genomic alteration at the time of Screening, (b) participants who have received platinum-based chemotherapy as the only prior line of cytotoxic therapy, (c) may have received α -PD-1/α -PD-L1 mAb alone or in combination with a cytotoxic agent Key Exclusion Criteria - Has previously been treated with any enhancer of zeste homolog inhibitors. - Uncontrolled or significant cardiovascular disease. - Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. - Has leptomeningeal carcinomatosis or metastasis. - Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses. - Current use of moderate or strong cytochrome P450 (CYP)3A inducers. - Systemic treatment with corticosteroids (>10 mg daily prednisone equivalents). - History of severe hypersensitivity reactions to other monoclonal antibodies (mAbs). - Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection requiring treatment with intravenous (IV) antibiotics, antivirals, or antifungals. - Female who is pregnant or breastfeeding or intends to become pregnant during the study. - Psychological, social, familial, or geographical factors that would prevent regular follow-up. Additional Key Exclusion for Sub-Protocol A: - Has previously received any anti-HER2 therapy in the metastatic setting. - Has received prior treatment with an antibody-drug conjugate that consists of an exatecan derivative that is a topoisomerase I inhibitor, including either as part of prior treatment history or within prior participation in a clinical study. Additional Key Exclusion for Sub-Protocol B: * Participants who have received an antibody-drug conjugate consisting of an exatecan derivative that is a topoisomerase I inhibitor. Additional Key Exclusion for Sub-Protocol C: * Has received any agent, including an ADC, containing a chemotherapeutic agent targeting topoisomerase I or TROP2-targeted therapy including Dato-DXD