A Study of Disitamab Vedotin With Other Anticancer Drugs in Solid Tumors

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 gastroesophagealjunction adenocarcinoma or breast carcinoma

• Locally-advanced, unresectable, or metastatic stage

• Must have experienced disease progression on or after standard of care therapies orbe 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 whereavailable 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 ofcare therapy

• Participants with HR+ tumors must have intolerance to endocrine therapy orendocrine therapy refractory disease:

• Progressed on ≥2 lines of endocrine therapy for LA/mBC AND had received aCDK4/6 inhibitor in the adjuvant or metastatic setting OR

• Progressed on 1 line of endocrine therapy for LA/mBC AND had a relapsewhile on adjuvant endocrine therapy after definitive surgery for primarytumor AND had received a CDK4/6 inhibitor in the adjuvant or advancedsetting

• Participants with HR negative, HER2-low and PD-L1-positive (CPS 10 or greater)tumors must have received pembrolizumab with chemotherapy if available as localstandard 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) withchemotherapy if available as local standard of care therapy and not medicallycontraindicated.

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 localstandard of care therapy for advanced disease.

• Have progression on or after, or intolerant to, T-DXd or other topoisomerase Iinhibitor 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 gastroesophagealjunction adenocarcinoma

• Locally-advanced, unresectable, or metastatic stage

• HER2-low expression defined as IHC 1+ or IHC 2+/ISH-negative determined by mostrecent local assessment

• Willing and able to provide archival or newly obtained formalin-fixedparaffin-embedded (FFPE) tumor tissue blocks

• Participants must have received:

• Prior systemic therapy with platinum, fluorouracil, or taxane for locallyadvanced unresectable or metastatic disease

• Progression within 6 months of last dose of (neo)adjuvant cytotoxicchemotherapy 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 gastroesophagealjunction 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 containingchemotherapy 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 ofdisitamab 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 includinginvestigational agents within 4 weeks prior to first dose of study treatment

• History of other invasive malignancy within 3 years before the first dose of studyintervention, or any evidence of residual disease from a previously diagnosedmalignancy.

• Unable to swallow oral tablets or capsules or any significant GI disease which wouldpreclude the adequate oral absorption of medications