DESTINY-BTC01 / D781PC00001

1) Participants must be ≥ 18 years of age at the time of screening. Other age restrictions may apply as per local regulations;

2) Male and female;

3) Unresectable, previously untreated, locally advanced or metastatic BTC. Prior treatment in the perioperative and/or adjuvant setting is permissible provided there is > 6 months (180 days) between the end of adjuvant treatment and the diagnosis of locally advanced or metastatic disease.

4) Histologically confirmed HER2-expressing (IHC 3+ or IHC 2+) BTC;

5) Provision of FFPE tumor sample that is no older than 3 years;

6) At least one target lesion assessed by the Investigator based on RECIST v1.1 (randomized portion only);

7) WHO/ECOG performance status of 0 or 1;

8) Adequate organ and bone marrow function within 14 days before randomization;

9) Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential;

1) Prior exposure to other HER2 targeting therapies, ADCs, immune checkpoint inhibitors and therapeutic anticancer vaccines;

2) Histologically confirmed ampullary carcinoma;

3) History of substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions;

4) Spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms;

5) Medical history of myocardial infarction within 6 months before randomization/enrollment, symptomatic congestive heart failure (New York Heart Association Class II to IV), unstable angina pectoris, clinically important cardiac arrhythmias, or a recent (< 6 months) cardiovascular event including stroke;

6) Serious chronic gastrointestinal conditions associated with diarrhea (e.g., active inflammatory bowel disease); active non-infectious skin disease (including any grade rash, urticaria, dermatitis, ulceration, or psoriasis) requiring systemic treatment;

7) Active autoimmune, connective tissue or inflammatory disorders that has required systemic treatment in the past 2 years, or where there is documented, or a suspicion of pulmonary involvement at the time of screening;

8) Corrected QT interval (QTcF) prolongation to > 470 msec (females) or > 450 msec (males) based on average of the screening triplicate 12-lead ECG;

9) History of (non-infectious) ILD/pneumonitis, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening;

10) Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder;

11) Prior pneumonectomy (complete);

12) Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals;

13) Active primary immunodeficiency, known uncontrolled active HIV infection or HCV;

14) Pregnant or breastfeeding female patients, or patients who are planning to become pregnant;

15) Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 6 months prior to randomization, or concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study (only randomized portion).

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