Inclusion Criteria:
Participants eligible for inclusion in the study must meet all inclusion criteria within 28 days of randomization into the study.
* Sign and date the inform consent form (ICF) prior to the start of any study specific qualification procedures.
* Adults ≥18 years (if the legal age of consent is \>18 years old, then follow local regulatory requirements)
* Life expectancy ≥3 months
* Has pathologically documented Stage IIIB, IIIC, or stage IV NSCLC disease with or without actionable genomic alterations (AGA) at the time of randomization (based on the American Joint Committee on Cancer, Eighth Edition) and meets following criteria for NSCLC:
* Participants without AGA:
1. Must have documented negative test results for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK).
2. Must have no known genomic alterations in ROS proto-oncogene 1 (ROS1), neurotrophic tyrosine receptor kinase (NTRK), proto oncogene B-raf (BRAF), mesenchymal-epithelial transition (MET) exon 14 skipping, or rearranged during transfection (RET).
* Participants with AGA must have one or more documented actionable genomic alteration(s): EGFR, ALK, ROS1, NTRK, BRAF, MET exon 14 skipping, or RET.
* Has documentation of radiographic disease progression while on or after receiving the most recent treatment regimen for advanced or metastatic NSCLC.
* Participant without AGA must meet 1 of the following prior therapy requirements for advanced or metastatic NSCLC:
1. Received platinum-based chemotherapy in combination with α-PD-1/α-PD-L1 monoclonal antibody as the only prior line of therapy.
* Includes participants who received prior platinum-based/chemotherapy with or without radiotherapy with maintenance α-PD-1/α-PD-L1 monoclonal antibody for Stage III disease and relapsed/progressed within 6 months from the last dose of platinum-based chemotherapy.
* Includes participants who received prior platinum-based/chemotherapy with or without radiotherapy (with or without maintenance α-PD-1/α-PD-L1 monoclonal antibody) for Stage III disease and subsequently received α-PD-1/α-PD-L1 monoclonal antibody therapy (with or without platinum-based chemotherapy) for recurrent disease.
2. Received platinum-based chemotherapy and α-PD-1/α-PD-L1 monoclonal antibody (in either order) sequentially as the only 2 prior lines of therapy.
* Participants with AGA must meet the following for advanced or metastatic NSCLC:
1. Participants who have been treated with 1 or 2 prior lines of applicable targeted therapy that is locally approved for the participant's genomic alteration at the time of screening;
* Participants who have tumors with EGFR L858R or exon 19 deletion mutations must have received prior Osimertinib.
* Those who received a targeted agent as adjuvant therapy for early-stage disease must have relapsed or progressed while on the treatment or within 6 months of the last dose OR received at least one additional course of targeted therapy for the same genomic alteration (which may or may not be same agent used in the adjuvant setting) for relapsed/progressive disease.
* Participants who have been treated with a prior tyrosine kinase inhibitor (TKI ) must receive additional approved targeted therapy, if locally available and clinically appropriate, for the applicable genomic alteration, or the participant will not be allowed in the study.
2. Participants who have received platinum-based chemotherapy as the only prior line of cytotoxic therapy:
* One platinum-containing regimen for advanced disease
* Those who received a platinum-containing regimen as adjuvant therapy for early-stage disease must have relapsed or progressed while on the treatment or within 6 months of the last dose OR received at least one additional course of platinum-containing therapy (which may or may not be same as in the adjuvant setting) for relapsed/progressive disease.
3. May have received up to one α-PD-1/α-PD-L1 monoclonal antibody alone or in combination with a cytotoxic agent.
* Must undergo a pre-treatment tumor biopsy procedure or if available, tumor tissue previously retrieved from a biopsy procedure performed within 2 years prior to the participant signing informed consent 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 pre-treatment biopsy procedure during Screening. If a documented law or regulation prohibits (or does not approve) sample collection, then such samples will not be collected/submitted
* Measurable disease based on local imaging assessment using RECIST v1.1
* Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at Screening
* Within 7 days before randomization, has adequate bone marrow, hepatic, and renal function
* Left ventricular ejection fraction (LVEF) ≥50% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before randomization
* Adequate blood clotting function defined as international normalized ratio/prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤1.5 × upper limit of normal (ULN)
* Adequate treatment washout period before randomization
* Females of childbearing potential must have a negative serum pregnancy test at screening and must be willing to use highly effective birth control from the time of enrollment up to 7 months after the last dose of DS-1062a or for at least 6 months after the last dose of docetaxel
* Males must be surgically sterile or must use a condom in addition to highly effective birth control if his partners are of reproductive potential from the time of enrollment and for at least 4 months after last dose of DS-1062a or for at least 6 months after the last dose of docetaxel
* Male participants must not freeze or donate sperm from the time of Screening and throughout the study period and for at least 4 months after the last dose of DS-1062a or for at least 6 months after the last dose of docetaxel
* Female participants must not donate, or retrieve for their own use, ova from the time of Screening and throughout the study period and for at least 7 months after the last dose of DS-1062a and for at least 6 months after the last dose of docetaxel
Exclusion Criteria:
* Mixed small-cell lung cancer (SCLC) and NSCLC histology
* 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. Participants with clinically inactive brain metastases may be included in the study. Participants 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.
* Has leptomeningeal carcinomatosis or metastasis
* Had prior treatment with:
* Any agent including antibody drug conjugate (ADC) containing a chemotherapeutic agent targeting topoisomerase I
* TROP2-targeted therapy
* Docetaxel
* Had prior treatment with platinum-based chemotherapy and prior immunotherapy for Stage II NSCLC disease (eg, in the neo-adjuvant or adjuvant setting) without subsequently meeting the prior therapy requirements for Stage III or metastatic NSCLC disease
* Has NSCLC disease that is eligible for definitive local therapy alone
* Has uncontrolled or significant cardiac disease, including:
* Mean QT interval corrected for heart rate using Fridericia's formula \>470 msec (based on the average of Screening triplicate 12-lead electrocardiogram \[ECG\] determinations).
* Myocardial infarction or uncontrolled/unstable angina within 6 months before randomization
* Congestive heart failure (CHF) (New York Heart Association Class II to IV) at Screening. Participants with a history of Class II to IV CHF prior to Screening, must have returned to Class I CHF and have LVEF ≥50% (by either an ECHO or MUGA scan within 28 days before randomization) in order to be eligible.
* Uncontrolled or significant cardiac arrhythmia
* LVEF \<50% by ECHO or MUGA scan within 28 days before randomization
* Uncontrolled hypertension (resting systolic blood pressure \>180 mmHg or diastolic blood pressure \>110 mmHg) within 28 days before randomization
* Has a 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 (ie, pulmonary emboli within 3 months before randomization, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc.), or any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (ie, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.), or prior pneumonectomy.
* Significant third-space fluid retention (for example ascites or pleural effusion) and is not amenable for required repeated drainage
* Clinically significant corneal disease
* Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals; suspected infections (eg, prodromal symptoms); or inability to rule out infections
* Has known human immunodeficiency virus (HIV) infection that is not well controlled
* Has an active or uncontrolled hepatitis B and/or hepatitis C infection, is positive for hepatitis B or C virus based on the evaluation of results of tests for hepatitis B (hepatitis B surface antigen \[HBsAg\], anti-hepatitis B surface antibody \[anti-HBs\], anti-hepatitis B core antibody \[anti-HBc\], or hepatitis B virus \[HBV\] DNA), and/or hepatitis C infection (as per hepatitis C virus \[HCV\] RNA) within 28 days of randomization.
* Has a history of malignancy, other than NSCLC, 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
* Toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet improved to NCI-CTCAE version 5.0 Grade ≤1 or baseline
* Has a history of severe hypersensitivity reactions to either the drug substances, inactive ingredients (including but not limited to polysorbate 80) of DS-1062a or docetaxel, or monoclonal antibodies
* Pregnant or breastfeeding
* Has substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions
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