Inclusion Criteria:
General Inclusion Criteria
- Measurable disease according to RECIST v1.1
- Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
Dose Escalation and Optimization Phase Inclusion Criteria
- Histologically or cytologically confirmed diagnosis of gastric or gastroesophageal junction adenocarcinoma or breast carcinoma
- Locally-advanced, unresectable, or metastatic stage
- 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 intolerance to endocrine therapy or 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.
- Participants with HR negative, HER2-low and PD-L1-positive (CPS 10 or greater) tumors must have received pembrolizumab (or other PD-(L)1 inhibitor) with chemotherapy if available as local standard of care therapy and not medically contraindicated.
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 for advanced disease.
- 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
Cohort D (HER2+ LA/mGC/GEJC) Inclusion Criteria
- Histologically or cytologically confirmed diagnosis of gastric or gastroesophageal junction adenocarcinoma
- 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 plus fluoropyrimidine and platinum containing chemotherapy if no contraindication.
- Prior T-DXd treatment is allowed
- Prior PD1 inhibitor therapy is allowed
- No more than 2 prior systemic cytotoxic chemotherapy regimens (including ADCs) for LA/mGC/GEJC
Exclusion Criteria:
- 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
