A Study of DS-3939a in Participants With Solid Tumors

The study includes 2 independent substudies, which have been defined by treatment combination and participant population as follows:

• Substudy 1 will evaluate the safety and efficacy of DS-3939a in combination with immunotherapy with or without chemotherapy (carboplatin or pemetrexed) in participants with locally advanced unresectable or metastatic non-squamous (NSQ) NSCLC in the first-line setting.
• Substudy 2 will evaluate the safety and efficacy of DS-3939a in combination with DS-1103a or as a monotherapy in participants with locally advanced unresectable or metastatic NSQ NSCLC who are pretreated.

Each sub study will be conducted in 2 parts: Dose escalation (Part 1) and Dose expansion (Part 2). The allocation of participants in Part 1 will be non-randomized, and in Part 2, it will be randomized for both substudies.

Inclusion criteria

• Sign and date the Main Trial informed consent form (ICF), prior to the start of any trial-specific procedures.
• Adults greater than or equal to (≥)18 years of age at the time the Main Trial ICF is signed (follow local regulatory requirements if the legal age of consent for trial participation is >18 years old).
• Histologically documented Stage IIIB, IIIC disease who is not candidate for surgical resection or definitive chemoradiation, or Stage IV NSQ NSCLC.
• Has a left ventricular ejection fraction (LVEF) ≥50 percent (%) by either an echocardiogram (ECHO) or multigated acquisition scan (MUGA) within 28 days of the first trial intervention.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 assessed no more than 14 days prior to initiation of trial interventions.
• Has adequate organ function.
• Participants must have measurable disease by investigator assessment according to RECIST v1.1.

Additional Inclusion Criteria for Substudy 1:

• Participants must not have received prior systemic therapy for locally advanced unresectable or metastatic NSCLC.

Additional Inclusion Criteria for Substudy 2:

• Participants with AGA (excluding EGFR mutation): Participants have been previously treated with targeted therapy for the AGA and platinum-based chemotherapy for the advanced disease setting.
• Participants without AGA: Participants have been previously treated with platinum-based chemotherapy and anti-programmed death-1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) antibody
• Part 2 only: Participants must have received only 1 or 2 prior lines of anticancer therapy for the advanced disease setting.

Exclusion criteria

• Prior systemic anticancer therapy targeting MUC1 or TA-MUC1.
• Prior systemic anticancer therapy with topoisomerase 1 inhibitor or topoisomerase 1 inhibitor-based antibody-drug conjugate (ADCs) (e.g., datopotamab deruxtexan and Sacituzumab govitecan).
• Has spinal cord compression or clinically active central nervous system (CNS) metastases.
• Has multiple primary malignancies.
• Has any history of interstitial lung disease (ILD)/pneumonitis irrespective of steroid use, or current ILD, or suspected ILD, or ILD that cannot be ruled out by imaging at screening
• Has active or uncontrolled human immunodeficiency virus (HIV) infection.
• Has active or uncontrolled hepatitis B virus (HBV)/hepatitis C virus (HCV) infection.
• Any of the following within the past 6 months: cerebrovascular accident, transient ischemic attack, or other arterial thromboembolic event.
• Current participation in other therapeutic investigational procedures, except for participation in long term survival follow-up (LTSFU) without any investigational treatment.