Phase 1b Study of Dato-DXd in Combination With Immunotherapy With or Without Carboplatin in Advanced or Metastatic Non-Small Cell Lung Cancer

Inclusion Criteria:

• Participant ≥18 years old on the day of signing the ICF (local regulatoryrequirement to consent should be followed).

• Histologically or cytologically confirmed diagnosis of advanced or metastatic NSCLC,without EGFR or ALK genomic alterations (testing not required for participants withdocumented squamous histology) and no known genomic alterations in other actionabledriver kinases with approved therapies. Participants whose tumors harbor KRASmutations are eligible for this study.

• For Cohorts 1 to 4, participants must be treatment-naïve or have received andradiologically progressed after only 1 prior line of systemic chemotherapy, withoutconcomitant immune checkpoint inhibitors for advanced or metastatic NSCLC. ForCohorts 4a, 5 to 11, and 14, participants must be treatment-naïve for advanced ormetastatic NSCLC. For Cohorts 12 to 13, participants must be CPI acquired resistantafter 1 or 2 prior lines of systemic therapy for advanced or metastatic NSCLC, ofwhich 1 should have contained an approved anti-PD-1/PD L1. Cohort 4a will enrollparticipants whose tumors have squamous histology only; Cohorts 5 Part 2A and Part 2B as well as Cohorts 12 and 13 will enroll participants whose tumors havenon-squamous histology only.

• Willing and able to undergo a mandatory tumor biopsy. A tumor biopsy that wasrecently collected (within 3 months of screening) after completion of the mostrecent anticancer treatment regimen may be substituted for the biopsy collectedduring screening. For Cohorts 12 and 13, a tumor sample taken ≤24 months prior toscreening is acceptable.

• Has measurable disease per RECIST1.1 within 28 days prior to Cycle 1 Day 1

• Eastern Co-operative Oncology Group (ECOG) performance status of 0 or 1 at screening

• Has adequate bone marrow reserve and organ function at baseline within 7 days priorto Cycle 1 day 1

• For Cohorts 5 to 14 only: Documented IHC PD-L1 expression per analytically validatedVentana PD-L1 (SP263) IHC assay, 22C3 PharmDx assay, or 28-8 PharmDx assay

Exclusion Criteria:

• Active or prior documented autoimmune or inflammatory disorders

• Uncontrolled or significant cardiac disease

• History of another primary malignancy with exceptions

• active or uncontrolled hepatitis B or C virus or uncontrolled HIV infection

• spinal cord compression or clinically active CNS metastases

• History of (non-infectious) ILD/pneumonitis that required steroids

• Clinically severe pulmonary compromise resulting from intercurrent pulmonary illness

• Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals

• Clinically significant corneal disease