Study of Patritumab Deruxtecan With Other Anticancer Agents in Participants With HER2 Positive Breast Cancer That Has Spread and Cannot Be Surgically Removed (MK-1022-009)

The following countries will be participating in the trial: Canada, United Kingdom, Israel, Japan, South Korea, and USA.

• Patritumab deruxtecan (Biological), also known as MK-1022, HER3-DXd, U3-1402: Patritumab deruxtecan administered via IV infusion
• Trastuzumab (Biological), also known as Herceptin®: Trastuzumab administered via IV infusion
• Trastuzumab Biosimilar (Biological), also known as Trazimera®, Ogivri®, Herzuma®, Ontruzant®, Kanjinti®, Hercessi®: Trastuzumab biosimilar administered via IV infusion
• Pertuzumab (Biological): Pertuzumab administered via IV infusion
• Tucatinib (Biological): Tucatinib administered as oral tablets

Primary outcomes

• Part 1: Number of Participants Experiencing Dose-Limiting Toxicity (DLT) [Up to 21 days]: DLT will be defined as any drug-related AE observed during the DLT evaluation period that results in a change to a given dose or a delay in initiating the next cycle. The number of participants who experience a DLT will be presented.
• Part 1: Number of Participants with One or More Adverse Events (AEs) [Up to approximately 36 months]: An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. The number of participants who experience an AE will be presented.
• Part 1: Number of Participants who Discontinue Study Intervention Due to an AE [Up to approximately 12 months]: An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. The number of participants who discontinue study treatment due to an AE will be presented.
• Part 2: Objective Response Rate (ORR) [Up to approximately 36 months]: ORR is defined as the percentage of participants with Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The percentage of participants who experience CR or PR as assessed by Blinded Independent Central Review (BICR)will be presented.

Secondary outcomes

• Part 1: Maximum Plasma Concentration (Cmax) of Patritumab Deruxtecan Antibody-Drug Conjugate (ADC) [At designated time points (up to ~13 months)]: Blood samples collected at designated time points will be used to determine the Cmax of patritumab deruxtecan ADC.
• Part 1: Trough Concentration (Ctrough) of Patritumab Deruxtecan ADC [At designated time points (up to ~13 months)]: Blood samples collected at designated time points will be used to determine the Ctrough of patritumab deruxtecan ADC.
• Part 1: Area Under the Plasma Concentration-Time Curve (AUC) of Patritumab Deruxtecan ADC [At designated time points (up to ~13 months)]: Blood samples collected at designated time points will be used to determine the AUC of patritumab deruxtecan ADC.
• Part 1: Maximum Plasma Concentration (Cmax) of Total Patritumab Deruxtecan Antidrug Antibody (ADA) [At designated time points (up to ~13 months)]: Blood samples collected at designated time points will be used to determine the Cmax of total patritumab deruxtecan ADA.
• Part 1: Trough Concentration (Ctrough) of Total Patritumab Deruxtecan ADA [At designated time points (up to ~13 months)]: Blood samples collected at designated time points will be used to determine the Ctrough of total patritumab deruxtecan ADA.
• Part 1: Area Under the Plasma Concentration-Time Curve (AUC) of Total Patritumab Deruxtecan ADA [At designated time points (up to ~13 months)]: Blood samples collected at designated time points will be used to determine the AUC of total patritumab deruxtecan ADA.
• Part 1: Maximum Plasma Concentration (Cmax) of Patritumab Deruxtecan Free Payload [At designated time points (up to ~13 months)]: Blood samples collected at designated time points will be used to determine the Cmax of patritumab deruxtecan free payload.
• Part 1: Trough Concentration (Ctrough) of Patritumab Deruxtecan Free Payload [At designated time points (up to ~13 months)]: Blood samples collected at designated time points will be used to determine the Ctrough of patritumab deruxtecan free payload.
• Part 1: Area Under the Plasma Concentration-Time Curve (AUC) of Patritumab Deruxtecan Free Payload [At designated time points (up to ~13 months)]: Blood samples collected at designated time points will be used to determine the AUC of patritumab deruxtecan free payload.
• Part 2: Duration of Response (DOR) [Up to approximately 36 months]: For participants who demonstrate a confirmed Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD is defined as at least a20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is alsoc onsidered PD. DOR as assessed by BICR will be presented.
• Part 2: Progression Free Survival (PFS) [Up to approximately 36 months]: PFS is defined as the time from first day of study intervention to the first documented progressive disease (PD)or death due to any cause, whichever occurs first as assessed by BICR. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. The appearance of one or more new lesions is also considered PD. PFS as assessed by BICR will be presented.
• Part 2: Number of Participants with One or More AEs [Up to approximately 36 months]: An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. The number of participants who experience an AE will be presented.
• Part 2: Number of Participants who Discontinue Study Intervention Due to an AE [Up to approximately 12 months]: An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. The number of participants who experience an AE will be presented.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

The main inclusion criteria include but are not limited to the following:

* Has histologically confirmed HER2+ locally advanced unresectable breast cancer or metastatic breast cancer
* Human immunodeficiency virus (HIV)-infected participants must have well-controlled HIV on antiretroviral therapy (ART)
* Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received HBV antiviral therapy for at least 4 weeks, and have undetectable hepatitis B virus (HBV) viral load before allocation
* Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable
* Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 within 7 days before start of study intervention

Part 1 Arm 1:

* Has received at least a minimum of 2 and a maximum of 5 prior lines of anti-HER2 therapy in the locally advanced or metastatic setting
* Had disease progression on or after any previous trastuzumab deruxtecan (T-DXd) treatment

Part 1 Arm 2:

-Has received no more than 5 prior lines of anti-HER2 therapy in the locally advanced or metastatic setting

Part 1 Arm 3:

-Has received and had disease progression from T-DXd treatment in any setting and a maximum of 3 prior lines of anti-HER2 therapy in the locally advanced or metastatic setting. T-DXd must be the most recent therapy received before enrollment.

Part 2 : Has not received prior systemic therapy (including T-DXd) for recurrent locally advanced or metastatic breast cancer (mBC).

Exclusion Criteria:

The main exclusion criteria include but are not limited to the following:

* Uncontrolled or significant cardiovascular disease
* Has any history of (noninfectious) interstitial lung disease (ILD)/ pneumonitis irrespective of steroid use or has current ILD or suspected ILD
* Has clinically severe respiratory compromise
* Has any history of or evidence of any current leptomeningeal disease
* Has clinically significant corneal disease
* Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection
* HIV infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
* Known additional malignancy that is progressing or has required active treatment within the past 3 years
* Part 1: Evidence of spinal cord compression or brain metastases
* Part 2: Evidence of spinal cord compression or brain/CNS metastases.
* Has an active infection requiring systemic therapy
* Concurrent active HBV and HCV infection
* Has had major surgical procedure (excluding placement of vascular access) less than 28 days

Part1: Arm 3 ONLY

\- Has received prior treatment with tucatinib, lapatinib, or neratinib, or any investigational HER2-targeted tyrosine kinase inhibitors in the locally advanced or metastatic setting

• Medical Director, Study director, Merck Sharp & Dohme LLC