Summary

This is a Phase I/II, multi-site, open-label, two-part study designed to evaluate the
efficacy, safety, optimized dose and contribution of components of BNT323 (also known as
trastuzumab pamirtecan and DB-1303) in combination with BNT327 (also known as pumitamig
and PM8002) in participants with hormone receptor-positive (HR+) or hormone
receptor-negative (HR-), Human epidermal growth factor receptor (HER)2-positive, HER2-low
(immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization -), HER2-ultralow (IHC 0,
with membrane staining) or HER2-null breast cancer (BC), or triple-negative breast cancer
(TNBC).

Objectives

The study consists of two parts:

- Part 1 - Dose escalation: In this part of the study, participants with
histologically confirmed, chemotherapy-pretreated advanced HR+, HER2-low or
HER2-ultralow BC will receive BNT323 in combination with BNT327 (BNT323 + BNT327) in
a dose escalation design. This will define the recommended Phase 2 dose (RP2D) for
the BNT323 + BNT327 combination therapy.

- Part 2 - Dose optimization and exploratory cohorts: This part of the study will be
an expansion phase, aiming to evaluate the efficacy and safety of the optimal dose
combination and providing a more robust comparison against the other treatments. It
will start once the enrollment in Part 1 is completed and the sponsor in conjunction
with the Safety Review Committee has assessed available Part 1 efficacy and safety
data. Part 2 of the study will have four cohorts, i.e., Cohorts 1 (dose optimization
cohort), and Cohorts 2, 3, and 4 (exploratory cohorts). Recruitment to Cohorts 2, 3,
and 4 will begin with RP2D from Part 1 and in parallel to randomization in Cohort 1.

Randomization is planned for Cohort 1 in Part 2, i.e., participants will be randomized in
2:2:1:1 ratio into one of the four arms (Arms 1-4). No randomization is planned for any
other cohort in Part 2.

Eligibility

1. Key Inclusion Criteria (applicable to all participants and all parts unless otherwise specified): - Have pathologically documented BC that: - Is locally advanced, unresectable or metastatic. - Has a confirmed HER2 status as determined by the local laboratory as standard of care testing prior to study screening (Part 1, Part 2 Cohorts 2 and 4) or the central laboratory (Part 2, Cohorts 1 and 3) from the most recently collected pre-randomization tumor sample. - Has a documented history of HER2 expression consistent with the subgroup definitions (i.e., HER2-low, HER2-ultralow, HER2-null, HER2-positive, or TNBC) as per current American Society of Clinical Oncology/College of American Pathologists guidelines. - Have measurable disease defined by RECIST v1.1. - Has left ventricular ejection fraction =55% by either echocardiography or multi-gated acquisition (scanning) within 28 days before randomization/enrollment. Key Exclusion Criteria: - Have history of small bowel obstruction requiring hospitalization within the past 3 months prior to the first dose of IMP. - Have an uncontrolled intercurrent illness that would limit compliance with study requirement or substantially increase risk of incurring adverse events. - Have clinically uncontrolled pleural effusion, ascites or pericardial effusion requiring drainage, peritoneal shunt, or cell-free concentrated ascites reinfusion therapy within 2 weeks prior to randomization/enrollment. - Have a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, have current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. - Had prior treatment with topoisomerase I inhibitors, including antibody-drug conjugates with topoisomerase I inhibitor payloads such as trastuzumab deruxtecan. - Have received any of the following therapies or drugs prior to the initiation of the study: - Participants who have received prior treatment with BNT323. - Participants who received prior treatment with a programmed death-ligand 1 (PD-L1) / vascular endothelial growth factor (VEGF) bispecific antibody. Note: Prior treatment with programmed death 1 (PD-1)/VEGF bispecific antibodies, PD-1/PD-L1 inhibitors or anti-VEGF therapies are permitted. - Have received other systemic immunostimulatory agents or immunosuppressive therapies (such as interferon-a, interleukin-2, or methotrexate) within 4 weeks prior to the initiation of study treatment or are within five half-lives of the treatment drug (whichever is longer). Exception: excluding local, intranasal, intraocular, intra-articular or inhaled corticosteroids, short term use (=7 days) of corticosteroids for prophylaxis (e.g., prevention of contrast agent allergy) or treatment of non-autoimmune conditions (e.g., delayed hypersensitivity reactions caused by exposure to allergens). - Have received systemic corticosteroids (at a dosage greater than 10 mg/day of prednisone or an equivalent dose of other corticosteroids) within 3 weeks prior to the initiation of study treatment. NOTE: Other protocol defined Inclusion/Exclusion criteria apply.