Phase 3 Study of T-DXd and Rilvegostomig Versus SoC in Advanced HER2-expressing Biliary Tract Cancer

Key Inclusion Criteria:

• Male and female patients must be at least 18 years of age at the time of signing theinformed consent. Other age restrictions may apply as per local regulations.

• Unresectable, previously untreated, locally advanced or metastatic biliary tractadenocarcinoma. Prior treatment in the perioperative and/or adjuvant setting ispermissible provided there is > 3 months (90 days) between the end of adjuvanttreatment and the diagnosis of locally advanced or metastatic disease.

• Histologically confirmed HER2-expressing (IHC 3+ or IHC 2+) BTC.

• Patients must provide an FFPE tumor sample that is no older than 3 years fortissue-based IHC staining to centrally determine HER2 expression, PD-L1 status, andother correlatives.

• Has at least one target lesion assessed by the Investigator based on RECIST v1.1. (Randomized portion only)

• WHO/ECOG performance status of 0 or 1 with no deterioration over the previous 2weeks prior to baseline or day of first dosing.

• Adequate organ and bone marrow function within 14 days before randomization.

• Evidence of post-menopausal status or negative serum pregnancy test for females ofchildbearing potential.

• Minimum life expectancy of 12 weeks.

Key Exclusion Criteria:

• Prior exposure to other HER2 targeting therapies, ADCs, immune checkpoint inhibitorsand therapeutic anticancer vaccines.

• Histologically confirmed ampullary carcinoma.

• Any other medical conditions such as clinically significant cardiac or psychologicalconditions, that may, in the opinion of the Investigator, interfere with thepatient's participation in the clinical study or evaluation of the clinical studyresults.

• Spinal cord compression or clinically active central nervous system metastases,defined as untreated and symptomatic, or requiring therapy with corticosteroids oranticonvulsants to control associated symptoms.

• Medical history of myocardial infarction within 6 months beforerandomization/enrollment, symptomatic congestive heart failure (New York HeartAssociation Class II to IV), unstable angina pectoris, clinically important cardiacarrhythmias, or a recent (< 6 months) cardiovascular event including stroke.

• Serious chronic gastrointestinal conditions associated with diarrhea (eg, activeinflammatory bowel disease); active non-infectious skin disease (including any graderash, urticaria, dermatitis, ulceration, or psoriasis) requiring systemic treatment.

• Active autoimmune, connective tissue or inflammatory disorders that has requiredsystemic treatment in the past 2 years, or where there is documented, or a suspicionof pulmonary involvement at the time of screening.

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

• History of (non-infectious) ILD/pneumonitis, has current ILD/pneumonitis, or wheresuspected ILD/pneumonitis cannot be ruled out by imaging at screening.

• Lung-specific intercurrent clinically significant illnesses including, but notlimited to, any underlying pulmonary disorder (eg, pulmonary emboli within threemonths of the study enrollment, severe asthma, severe chronic obstructive pulmonarydisease, restrictive lung disease, pleural effusion etc).

• Prior pneumonectomy (complete).

• Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.Patients with prior cholangitis/biliary tract infections/biliary intervention (eg,stent, external drain) should have completed a full course of antibiotics prior torandomization.

• Active primary immunodeficiency, known uncontrolled active HIV infection or HCV.

• History of another primary malignancy except for malignancy treated with curativeintent with no known active disease within 3 years before the first dose of studyintervention and of low potential risk for recurrence. Exceptions include adequatelyresected nonmelanoma skin cancer and curatively treated in situ disease. For certainparticipant populations, exceptions could also include carcinomas in-situ or Tatumors treated with curative intent.

• Pleural effusion, ascites or pericardial effusion that requires drainage, peritonealshunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (Drainage and Cellfree and Concentrated Ascites Reinfusion Therapy are not allowed within 2 weeksprior to screening assessment).

• Any concurrent anticancer treatment without an adequate washout period prior torandomization. Concurrent use of hormonal therapy for non-cancer related conditions (eg, hormone replacement therapy) is allowed.

• History of organ transplants or allogenic stem cell transplant.