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:

1. Histologically documented unresectable locally advanced/metastatic non-squamous NSCLC
2. Part 1: Progression after 1 or 2 lines of systemic therapy for recurrent or metastatic setting.
3. Part 3: Treatment-naïve for non curative treatment for locally advanced or metastatic NSCLC.
4. Part 3: Patients must have tumors without known genomic alterations or actionable driver kinases, as determined by existing local test results, for which approved therapies are available are allowed. Patients who received prior adjuvant, neoadjuvant chemotherapy, or definitive chemoradiation for advanced disease are eligible, provided that progression has occurred > 6 months from end of last therapy
5. HER2overexpression status as determined by central review of tumor tissue
6. WHO / ECOG performance status of 0 or 1
7. Measurable target disease assessed by the investigator using RECIST 1.1
8. Has protocol defined adequate organ and bone marrow function
9. Part 3: Minimum body weight of 35 kg.

Exclusion criteria:

1. HER2 mutation if previously known
2. Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
3. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder and prior pneumonectomy
4. Active primary immunodeficiency known HIV infection, or active hepatitis B (positive hepatitis B virus surface antigen or hepatitis B virus core antibody) or hepatitis C infection
5. Active infection including tuberculosis and uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
6. 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
7. Medical history of myocardial infarction within 6 months before treatment assignment, symptomatic CHF (New York Heart Association Class II to IV), clinically important cardiac arrhythmias, or a recent (< 6 months) cardiovascular event including stroke
8. Cardiomyopathy of any etiology, symptomatic CHF (as defined by New York Heart Association Class > II), unstable angina pectoris, history of MI within the past 12 months, or cardiac arrhythmia (Part 3).
9. A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or CART (Concentrated Ascites Reinfusion Therapy)
10. Unresolved toxicities not yet resolved to Grade ≤ 1 or baseline from previous anticancer therapy OR prior discontinuation of any planned study therapy due to toxicity.
11. must not have any medical contraindication to platinum-based chemotherapy.
12. Part 3 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 any setting.