Mass General - Division of Clinical Research

General Inclusion Criteria - Measurable disease according to RECIST v1.1 - Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 Dose Escalation Phase Inclusion Criteria - Histologically or cytologically confirmed diagnosis of gastric or gastroesophageal junction adenocarcinoma or breast carcinoma - Locally-advanced, unresectable, or metastatic stage - HER2 status IHC 1+ or higher by most recent local assessment. - Must have experienced disease progression on or after standard of care therapies or be intolerant of standard of care therapies. Cohort A (HER2-Low Breast Cancer) Inclusion Criteria - Histologically or cytologically confirmed diagnosis of breast carcinoma - Locally-advanced, unresectable, or metastatic stage - HER2-low status determined by most recent local assessment (IHC 1+ or IHC 2+/ISH-negative) - Prior therapies requirements - No more than 3 prior systemic cytotoxic chemotherapy regimens (including ADCs) for LA/mBC. - Participants with known BRCA mutation must have received a PARP-inhibitor where available and not medically contraindicated - Have progression on or after, or intolerant to, T-DXd, sacituzumab govitecan, or other topoisomerase I inhibitor therapies, if available as local standard of care therapy - Participants with HR+ tumors must have endocrine therapy refractory disease: - Progressed on ≥2 lines of endocrine therapy for LA/mBC AND had received a CDK4/6 inhibitor in the adjuvant or metastatic setting OR - Progressed on 1 line of endocrine therapy for LA/mBC AND had a relapse while on adjuvant endocrine therapy after definitive surgery for primary tumor AND had received a CDK4/6 inhibitor in the adjuvant or advanced setting - Participants with HR negative, HER2-low and PD-L1-positive (CPS 10 or greater) tumors must have received pembrolizumab with chemotherapy if available as local standard of care therapy. Cohort B (HER2+ Breast Cancer) Inclusion Criteria - Histologically or cytologically confirmed diagnosis breast carcinoma - Locally-advanced, unresectable, or metastatic stage - HER2+ status determined by most recent local assessment (IHC 3+ or IHC 2+/ISH+) - Participants must have: - Received prior trastuzumab, pertuzumab and a taxane if available as local standard of care therapy. - Have progression on or after, or intolerant to, T-DXd or other topoisomerase I inhibitor therapies - No more than 3 prior systemic cytotoxic chemotherapy regimens (including ADCs) for LA/mBC Cohort C (HER2-Low Gastric or Gastroesophageal Junction Adenocarcinoma) Inclusion Criteria - Histologically or cytologically confirmed diagnosis of gastric or gastroesophageal junction adenocarcinoma - Locally-advanced, unresectable, or metastatic stage - HER2-low expression defined as IHC 1+ or IHC 2+/ISH-negative determined by most recent local assessment - Willing and able to provide archival or newly obtained formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks - Participants must have received: - Prior systemic therapy with platinum, fluorouracil, or taxane for locally advanced unresectable or metastatic disease - Progression within 6 months of last dose of (neo)adjuvant cytotoxic chemotherapy is considered as 1 line of systemic therapy for LA/mGC/GEJC - Prior anti-PD-(L)1 therapy is allowed - No more than 2 prior systemic cytotoxic chemotherapy regimens (including ADC) for LA/mGC/GEJC - Must not have received prior treatment with HER2 directed therapy

• Known hypersensitivity to any excipient contained in the drug formulation of disitamab vedotin or tucatinib - Prior therapy with ADCs with MMAE payload - Prior therapy with tucatinib - Active CNS and/or leptomeningeal metastasis. - Participants who have received prior systemic anticancer treatment including investigational agents within 4 weeks prior to first dose of study treatment - History of other invasive malignancy within 3 years before the first dose of study intervention, or any evidence of residual disease from a previously diagnosed malignancy. - Unable to swallow oral tablets or capsules or any significant GI disease which would preclude the adequate oral absorption of medications