The primary objective of this study will assess safety and treatment activity of datopotamab
deruxtecan (Dato-DXd) in combination with pembrolizumab with or without 4 cycles of platinum
chemotherapy in participants with advanced or metastatic NSCLC who have either been
previously treated or are treatment naïve in a metastatic setting.
Two dose levels of Dato-DXd (4.0 mg/kg and 6.0 mg/kg) will be studied in combination with 200
mg fixed-dose pembrolizumab in 6 study cohorts. This study will be conducted sequentially and
dose escalation will occur according to lower dose to higher dose in the same combination
regimen (4.0 mg/kg to 6.0 mg/kg) and from 2-drug combination (Dato-DXd and pembrolizumab) to
3-drug combination regimen (Dato-DXd, pembrolizumab, and carboplatin or cisplatin).
Inclusion Criteria:
- Advanced or metastatic NSCLC, histologically confirmed at diagnosis of NSCLC,
documented negative test results for EGFR and ALK genomic alterations, and no known
genomic alterations in ROS1, NTRK, BRAF, RET, MET, or other driver oncogenes with
approved therapies (actionable genomic alterations).
- Is not a candidate for surgical resection or chemoradiation with curative intent.
- Documentation of radiological disease progression while on or after receiving the most
recent treatment regimen, if any, for advanced or metastatic NSCLC.
- Must meet the following prior therapy requirements for advanced or metastatic NSCLC:
- Dose escalation (all cohorts): Has received ≤2 lines of prior anticancer therapy
for locally advanced or metastatic NSCLC.
- Dose expansion (cohorts with 4.0 mg/kg or 6.0 mg/kg Dato-DXd in combination with
200 mg fixed dose of pembrolizumab): Has not received PD-1/PD-L1, PD-L2, CTLA-4
directed immunotherapy and may or may not have been treated with systemic
chemotherapy for advanced or metastatic NSCLC.
- Dose expansion (cohorts with 4.0 mg/kg or 6.0 mg/kg Dato-DXd in combination with
200 mg fixed dose of pembrolizumab and 4 cycles of AUC 5 carboplatin or cisplatin
75 mg/m^2): Has not been treated with systemic anticancer therapy for advanced or
metastatic NSCLC.
- Willing and able to undergo a mandatory tumor biopsy.
- Archival tumor tissue from initial diagnosis, to the extent that archival tumor tissue
is available, for measurement of TROP2 expression levels or other biomarkers.
- Has adequate bone marrow reserve and organ function at baseline within 7 days prior to
Cycle 1 Day 1.
Exclusion Criteria:
- Experienced grade 3 or higher immune-related adverse events (AEs) with prior treatment
of anti-programmed cell death 1 (anti-PD-1), anti-programmed cell death ligand 1
(anti-PD-L1), or anti-PD-L2 agent or with an agent directed to another stimulatory or
co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
- Received a live vaccine within 30 days prior to the first dose of study treatment.
- Active, known, or suspected autoimmune disease.
- Concomitant use of chronic systemic (IV or oral) corticosteroids or other
immunosuppressive medications, except for managing AEs.
- Prior organ transplantation, including allogeneic tissue or solid organ
transplantation.
- Has 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.
- History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required
steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be
ruled out by imaging at screening.
- Clinically severe pulmonary compromise resulting from intercurrent pulmonary
illnesses.
- Has a history of malignancy, other than NSCLC, except (a) adequately resected
non-melanoma skin cancer, (b) curatively treated in situ disease, or (c) other solid
tumors curatively treated, with no evidence of disease for ≥3 years.