A Study of Disitamab Vedotin in Adults With HER2 Expressing Advanced Breast Cancer

A PHASE 1b/2, OPEN-LABEL, MULTICOHORT STUDY OF DISITAMAB VEDOTIN IN ADULTS WITH HER2 EXPRESSING ADVANCED BREAST CANCER

The purpose of this clinical study is to learn about the safety and effects of the study medicine (called disitamab vedotin) for the possible treatment of people with breast cancer that is hard to treat and has spread in the body (advanced cancer).

This study is seeking participants who:

• have breast cancer that is hard to treat and has spread in the body (advanced cancer)
• have tumors that have HER2 on them
• have received previous treatment for their advanced breast cancer

All participants in this study will receive disitamab vedotin at the study clinic once every 2 weeks as an intravenous (IV) infusion (given directly into a vein).

Participants will take the study medicine until they or their doctor decides to stop. This might be because their cancer is getting worse, the study medicine is no longer helping, they have bad side effects, or they wish to stop taking the study medicine. During this time, the participants will have study visits every 2 weeks. After the participants have stopped taking the study medicine, they will have follow-up visits about every 6 weeks unless their cancer gets worse. After that, they will have follow-up phone calls about every 12 weeks.

The study team will look at the experiences of people receiving the study medicine. This will help the study team decide if the study medicine is safe and effective.

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of locally-advanced, unresectable, or metastatic breast carcinoma.
• Human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR) status appropriate for enrollment in cohort.
• HER2 status determined by most recent local assessment based on American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) guidelines for assessment of HER2 in BC for interpretation of HER2 expression and amplification
• HER2+: immunohistochemistry (IHC) 3+ or IHC 2+/in situ hybridization (ISH)+
• HER2-low: IHC 1+/ISH-negative or untested or IHC 2+/ISH-negative
• HER2-ultralow: IHC 0 with membrane staining (any staining of the membrane in >0 and ≤10% of cancer cells) o HR+ disease is determined as either estrogen receptor (ER) and/or progesterone receptor (PgR) positive [ER or PgR ≥1%]) and HR negative disease is determined as both ER and PR negative [ER and PgR <1%]) per ASCO/CAP guidelines in the advanced disease setting. If a patient has had multiple ER/PgR results for advanced disease, the most recent test result will be used to confirm eligibility.

Prior therapy requirements for Cohort 1 (HER2+, HR+ or HR- participants):

• Received prior trastuzumab, pertuzumab and a taxane if available as local first line standard of care therapy for advanced disease.
• Prior tucatinib based therapy is allowed.
• Must have progression on or after, or be intolerant to, T-DXd in any line advanced disease setting.
• No more than 3 prior systemic cytotoxic therapy regimens (including antibody drug conjugates [ADCs]) for Locally Advanced (LA)/metastatic breast cancer (mBC). Participants previously treated with (neo)adjuvant cytotoxic therapy and have disease relapsed within 6 months of cytotoxic treatment is considered to have received 1 line of cytotoxic therapy for LA/mBC.

Prior therapy requirements for Cohort 2 (HR+/HER2-low participants):

• No more than 3 prior systemic cytotoxic therapy regimens (including ADCs) for LA/mBC. Participants previously treated with (neo)adjuvant cytotoxic therapy and have disease relapsed within 6 months of cytotoxic treatment is considered to have received 1 line of cytotoxic therapy for LA/mBC.
• Participants with known germline breast cancer gene (BRCA) mutation must have received a poly-ADP ribose polymerase (PARP) inhibitor, where available and not medically contraindicated.
• Must have progression on or after, or be intolerant to, trastuzumab deruxtecan (T-DXd) in any line advanced disease setting.
• Must have intolerance to endocrine therapy (ET) or ET refractory disease:
• Progressed on ≥2 lines of ET for LA/mBC AND had received a cyclin-dependent kinase (CDK)4/6 inhibitor in the adjuvant or metastatic setting if available as local standard of care and not contraindicated.

OR

• Progressed on 1 line of ET for LA/mBC AND had a relapse while on adjuvant ET after definitive surgery for primary tumor AND had received a cyclin-dependent kinase (CDK) 4/6 inhibitor in the adjuvant or advanced setting if available as local standard of care and not contraindicated.

Prior therapy requirements for Cohort 3 (HR+/HER2-ultralow or HR-/HER2-low [HER2 low TNBC] participants):

• No more than 4 prior systemic cytotoxic chemotherapy regimens (including ADCs) for advanced or mBC. Participants previously treated with (neo)adjuvant cytotoxic therapy and have disease relapsed within 6 months of cytotoxic treatment is considered to have received 1 line of cytotoxic therapy for LA/mBC.
• Known germline BRCA mutation must have received a PARP-inhibitor if available as local standard of care therapy and not medically contraindicated.
• Prior sacituzumab govitecan is allowed.
• Prior T-DXd is allowed.
• Participants with HR negative (TNBC), HER2-low and programmed cell death receptor ligand 1 (PD-L1)-positive (combined positive score [CPS] ≥10) tumors must have received pembrolizumab (or other PD-L1 inhibitor) with chemotherapy if available as local standard of care therapy and not medically contraindicated.
• Participants with HR+/HER2-ultra low tumors must have received at least 1 antihormonal therapy in any setting or be ineligible for ET.
• Participants with HR+/HER2-ultra low tumors must have had prior therapy with a CDK4/6 inhibitor in the adjuvant or advanced setting.

Exclusion Criteria:

• Known hypersensitivity to any excipient contained in the drug formulation of disitamab vedotin.

• Active central nervous system (CNS) and/or leptomeningeal metastasis.

• Participants with a history of other invasive malignancy within 3 years before the Cycle 1 Day 1 (C1D1) of study intervention, or any evidence of residual disease from a previously diagnosed malignancy.

• Prior therapy with ADCs with MMAE payload.

• Participants who have received prior systemic anticancer treatment or radiotherapy within 2 weeks, or 5 half-lives, whichever is shorter, prior to C1D1 of study intervention. Note: If the last immediate anticancer treatment contained an antibody-based agent(s), then an interval of 28 days or 5 half-lives (whichever is shorter) of the agent(s) prior to receiving the study intervention treatment is required.

  • Participants must have recovered from all adverse events due to previous therapies.