Phase Ib Study of the Safety of T-DXd and Immunotherapy Agents With and Without Chemotherapy in Advanced or Metastatic HER2+, Non-squamous NSCLC

Inclusion criteria:

• Histologically documented unresectable locally advanced/metastatic non-squamousNSCLC

• Part 1: Progression after 1 or 2 lines of systemic therapy for recurrent ormetastatic setting.

• Part 3, Part 4 and Part 5: Patients must have tumors that do not harbor knowngenomic alterations or actionable driver kinases, for which approved therapies areavailable are allowed.

• Part 3, Part 4 and Part 5: Patient must be treatment-naïve for advanced ormetastatic NSCLC. Patients who have received prior adjuvant, or neoadjuvantchemotherapy, or definitive chemoradiation for advanced disease are eligible,provided that progression has occurred > 6 months from end of last therapy

• HER2overexpression status as determined by central review of tumor tissue

• WHO / ECOG performance status of 0 or 1

• Measurable target disease assessed by the investigator using RECIST 1.1

• Has protocol defined adequate organ and bone marrow function

• Part 3, Part 4 and Part 5: Minimum body weight of 35 kg.

Exclusion criteria:

• HER2 mutation if previously known

• Has a history of (non-infectious) ILD/pneumonitis that required steroids, hascurrent ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out byimaging at screening

• Lung-specific intercurrent clinically significant illnesses including, but notlimited to, any underlying pulmonary disorder and prior pneumonectomy

• Active primary immunodeficiency known HIV infection, or active chronic and resolvedhepatitis B (positive hepatitis B virus surface antigen [HBsAg+ve] or hepatitis Bvirus core antibody (anti-HBc +ve) regardless of HBV DNA level)) or hepatitis Cinfection. Patients positive for HCV antibody are eligible only if polymerase chainreaction is negative for HCV RNA. Patients should be tested for HIV prior totreatment assignment if required by local regulations or IRB/EC

• Active infection including tuberculosis and uncontrolled infection requiring IVantibiotics, antivirals, or antifungals

• 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 before treatmentassignment, symptomatic CHF (New York Heart Association Class II to IV), clinicallyimportant cardiac arrhythmias, or a recent (< 6 months) cardiovascular eventincluding stroke

• For Part 3, Part 4 and Part 5: Cardiomyopathy of any etiology, symptomatic CHF (asdefined by New York Heart Association Class > II), unstable angina pectoris, historyof MI within the past 12 months, or cardiac arrhythmia are to be excluded. Patientswith troponin levels above ULN at screening (as defined by the manufacturer), andwithout any myocardial related symptoms, should have a cardiologic consultationbefore treatment assignment to rule out acute cardiopulmonary events.

• Ascites or pericardial effusion that requires drainage, peritoneal shunt,Pleuroperitoneal shunt or CART (Concentrated Ascites Reinfusion Therapy)

• For Part 3, Part 4 and Part 5: Active non-infectious skin disease (including anygrade rash, urticarial, dermatitis, ulceration, or psoriasis) requiring systemictreatment, active or prior documented autoimmune or inflammatory disorders requiringchronic treatment with steroids or other immunosuppressive treatment.

• Unresolved toxicities not yet resolved to Grade ≤ 1 or baseline from previousanticancer therapy OR prior discontinuation of any planned study therapy due totoxicity.

• must not have any medical contraindication to platinum-based chemotherapy.

• Part 3, Part 4 and Part 5 patients must not have had prior exposure to anti-PD-1,anti-PD-L1, anti-CTLA-4, anti-TIGIT or any other experimental immunotherapy in anysetting.

• For Part 3, Part 4 and Part 5: History of substance abuse or any other medical orpsychological conditions that may, in the opinion of the Investigator, interferewith the subject's participation in the clinical study or evaluation of the clinicalstudy results

• For Part 3, Part 4 and Part 5: History of thromboembolic events within 3 monthsbefore the first dose of IP (limited to pulmonary embolism, deep vein thrombosis, orcerebral venous sinus thrombosis).