Adults ≥ 18 years of age in the United States or ≥ 20 years old in Japan on the day of signing the informed consent form (ICF). (Follow local regulatory requirements if the legal age of consent for study participation is > 18 years old.)
Histologically confirmed diagnosis of NSCLC that:
Is advanced or metastatic;
Has documented negative test results for EGFR and ALK genomic alterations. If documented negative test results for EGFR and ALK are not available, subjects are required to have testing performed locally for these genomic alterations;
Has no known genomic alterations in ROS1, NTRK, BRAF, or other driver oncogenes with approved therapies (actionable genomic alterations).
Has documentation of radiological disease progression while on or after receiving the most recent treatment regimen for advanced or metastatic NSCLC.
Must meet the following prior therapy requirements for advanced or metastatic NSCLC:
Has received at least 1 regimen of platinum-based chemotherapy; and
Has at least 1 regimen of PD-1/PD-L1 directed immunotherapy, either in combination or sequentially. Subjects with a documented PD-L1 TPS of < 1% must have been previously treated with at least 1 regimen of platinum-based chemotherapy with or without prior PD-1/PD-L1 immunotherapy. Subjects who meet these prior therapy requirements and who may have received additional lines of therapy are also eligible.
Willing and able to undergo a mandatory tumor biopsy for the measurement of trophoblast cell surface protein 2 (TROP2) expression levels by immunohistochemistry and for assessment of other biomarkers. Biopsies may not be collected from a lesion that has been irradiated. If available, a tumor biopsy that was recently collected (within 3 months before screening) after the most recent anticancer treatment regimen and that has a minimum of 10 × 4 micron sections or a tissue block equivalent of 10 × 4 micron sections may be substituted for the biopsy collected during screening. Results from the TROP2 testing of the pre-treatment tumor biopsy will not be used to determine eligibility for the study. There is no PD-L1 level required for inclusion. The screening biopsy should only be collected after all other eligibility criteria are met.
Archival tumor tissue from initial diagnosis, to the extent that archival tumor tissue is available, for measurement of TROP2 expression levels or other biomarkers.
Measurable disease based on local reading using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST V1.1). Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to Cycle 1 Day 1.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at screening.
Within 28 days before Cycle 1 Day 1, have left ventricular ejection fraction (LVEF) ≥ 50% by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan.
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-programmed cell death ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) and experienced a Grade 3 or higher immune-related adverse event (irAE).
Has received a live vaccine within 30 days prior to the first dose of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
Currently participating in or has participated in a study of an investigational agent or has used. an investigational device within 4 weeks or 5 times the half-life of the prior investigational product, whichever is longer, prior to Cycle 1 Day 1.
Note: Subjects who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks or 5 times the half-life of the prior investigational product, whichever is longer, after the last dose of the previous investigational agent.
History of severe hypersensitivity reactions (≥ Grade 3) to either the drug substances or inactive ingredients (including but not limited to polysorbate 80).
Active, known, or suspected autoimmune disease (has an active autoimmune disease that has required systemic treatment in the past 2 years [i.e., with use of systemic disease-modifying agents, corticosteroids or immunosuppressive drugs]). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of Cycle 1 Day 1. Inhaled intranasal, intraocular, intra-articular, or topical steroids and adrenal replacement steroids are permitted in the absence of active autoimmune disease.
History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
Known psychiatric or substance abuse disorder that would increase the safety risk to the subject or interfere with participation of the subject or the evaluation of the clinical study in the opinion of the investigator.
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. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases who are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment.
Has leptomeningeal carcinomatosis.
Uncontrolled or significant cardiac disease including:
Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) prolongation to > 470 ms (females) or > 450 ms (males) based on the average of the screening triplicate 12-lead electrocardiograms (ECGs);
History of myocardial infarction or unstable angina within 6 months before Cycle 1 Day 1;
History of symptomatic congestive heart failure (New York Heart Association classes II–IV) or a serious cardiac arrhythmia requiring treatment;
Uncontrolled hypertension (resting systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg.
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 including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within 3 months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, etc), or any autoimmune, connective tissue, or inflammatory disorders with pulmonary involvement (i.e., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.), or prior pneumonectomy.
Clinically significant corneal disease Has other primary malignancies, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other solid tumors curatively treated, with no evidence of disease for ≥ 3 years.