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

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 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:
• Is unresectable or metastatic.
• Has progressed on and would no longer benefit from endocrine therapy in hormone receptor-positive subjects in the opinion of the investigator.
• Has been treated with at least 1 and at most 2 prior lines of chemotherapy in the recurrent or metastatic setting.
• Has a history of low HER2 expression, defined as IHC 2+ /ISH-negative or IHC 1+ (ISH-negative or untested). ), as classified by the American Society of Clinical Oncology/College of American Pathologists 2018 HER2 testing guidelines.
• 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 GEJ adenocarcinoma that is (a) unresectable or metastatic or (b) has progressed on 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 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 a prior line of therapy or (b) received platinum-based chemotherapy and α -PD-1/ α -PD-L1 mAb (in either order) sequentially as 2 prior lines of therapy.
• Participants with AGA: (a) has been treated with at least 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 a 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