≥ 18 years old
Has pathologically documented Stage IIIB, IIIC, or Stage IV non-squamous NSCLC without AGA at the time of randomization (based on the American Joint Committee on Cancer, 9th Edition) and meets the following criteria for NSCLC:
Participants must have documented negative test results for EGFR (eg, exon 19 deletion or exon 21 L858R, exon 21 L861Q, exon 18 G719X, or exon 20 S768I mutation), ALK, and ROS1 genomic alterations.
Has no known tumor genomic alterations in NTRK, BRAF, RET, MET exon 14 skipping, KRAS G12C, HER2 or any other actionable driver oncogenes for which there are locally approved and available targeted first-line therapies.
Prospectively assessed TROP2 QCS-NMR positive based on results from an appropriately validated investigational TROP2 RxDx device in a Sponsor designated, regulatory compliant central laboratory.
Participants must have documentation of radiographic disease progression while on or after receiving the most recent treatment regimen for advanced or metastatic NSCLC.
Participants must have received PBC in combination with anti-PD-1/anti-PD-L1 mAb as the only prior line of therapy or received PBC and anti-PD-1/anti-PD-L1 monoclonal antibody (in either order) sequentially as the only 2 prior lines of therapy. This will include participants initially diagnosed with:
Metastatic NSCLC who have received:
PBC in combination with anti-PD-1/anti-PD-L1 mAb as the only prior line of systemic therapy. OR
Received PBC and anti-PD-1/anti-PD-L1 mAbs sequentially (in either order) as the only 2 prior lines of therapy.
Locally advanced disease who received PBC with or without radiotherapy, followed by maintenance anti-PD-1/anti-PD-L1 mAbs and progressed within 12 months after completion of PBC or who has subsequently received anti-PD-1/anti-PD-L1 mAb therapy (with or without platinum) for recurrent disease.
Participants initially presenting with resectable disease who received neoadjuvant and/or adjuvant PBC and anti-PD-1/anti-PD-L1 mAbs concurrently and progressed within 12 months after completion PBC or who has subsequently received anti-PD-1/anti-PD-L1 mAb therapy (with or without platinum) for recurrent disease.
Must provide an acceptable FFPE tumor sample for assessment of TROP2. The sample must be newly acquired tumor biopsy from the current disease setting (preferred) or an archival tumor sample taken less than 24 months prior to signing the ICF. If the archival tumor sample is more than 24 months old and a new tumor biopsy cannot be obtained, the use of such a sample must be discussed with the Study Clinical Lead on a case-by-case basis.
The FFPE sample must meet the requirements specified in the Laboratory Manual or Pathology Manual
At least one lesion not previously irradiated that qualifies as a RECIST 1.1 TL at baseline and can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with CT or MRI and is suitable for accurate repeated measurements. If only one measurable lesion exists, it is acceptable to be used (as a TL) as long as it has not been previously irradiated. Lesions biopsied during the screening period are only accepted as measurable lesions if they are the only lesion available and in that case the baseline scan must be performed at least 2 weeks after the biopsy.
ECOG PS of 0 or 1, with no deterioration over the previous 2 weeks prior to screening.
Has life expectancy ≥ 3 months based on Investigator’s opinion.
Adequate bone marrow reserve and organ function within 7 days before randomization defined as:
Haemoglobin ≥ 9.0 g/dL (red blood cell/plasma transfusion is not allowed within 1 week prior to screening assessment).
Absolute neutrophil count ≥ 1.5 × 109 /L (granulocyte colony stimulating factor administration is not allowed within 1 week prior to screening assessment).
Platelet count ≥ 100 × 109 /L (platelet transfusion is not allowed within 1 week prior to screening assessment).
TBL ≤ 1.5 × ULN or ≤ 3 × ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinaemia).
Except in the setting of HBV, ALT and AST ≤ 2.5 × ULN; for participants with hepatic metastases, ALT and AST ≤ 5 × ULN. See Exclusion Criterion 10 for requirements in the setting of HBV.
Calculated CrCL eg, ≥ 30 mL/min as determined by Cockcroft Gault
Has LVEF ≥ 50% by either ECHO or MUGA scan within 28 days before randomization.
Has adequate blood clotting function defined as INR/prothrombin time and either partial thromboplastin or aPTT ≤ 1.5 × ULN.
Contraceptive use by males and females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Capable of giving signed informed consent , which includes compliance with the requirements and restrictions listed in the ICF and in this CSP.
All races, gender and ethnic groups are eligible for this study.
Squamous, mixed NSCLC, or SCLC histology.
NSCLC disease that is eligible for definitive local therapy alone.
As judged by the Investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including active bleeding diseases and significant cardiac or psychological conditions), history of allogenic organ transplant, and/or substance abuse which, in the Investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol.
History of another primary malignancy other than NSCLC, except for malignancy treated with curative intent with no known active disease within 3 years before randomization and of low potential risk for recurrence. Exceptions include adequately resected non-melanoma skin cancer (basal cell carcinoma of the skin or squamous cell carcinoma of the skin) and curatively treated in situ disease.
Persistent toxicities caused by previous anti-cancer therapy, excluding alopecia, not yet improved to Grade ≤ 1 or baseline. Note: participants may be enrolled with some chronic, stable Grade 2 toxicities (defined as no worsening to > Grade 2 for at least 3 months prior to randomization and managed with SoC treatment) which the Investigator deems related to previous anti-cancer therapy, including (but not limited to):
Chemotherapy-induced neuropathy.
Fatigue.
Residual toxicities from prior immunotherapy treatment: Grade 1 or Grade 2 endocrinopathies, which may include but are not limited to hypothyroidism/hyperthyroidism, Type I diabetes, hyperglycaemia, adrenal insufficiency, or adrenalitis; and skin hypopigmentation (vitiligo).
Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the Investigator may be included (eg, hearing loss).
Spinal cord compression or brain metastases, unless asymptomatic, stable, and not requiring treatment with corticosteroids or anticonvulsants for at least 7 days prior to randomization. Participants with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants must have recovered from the acute toxic effect of radiotherapy (eg, dizziness and signs of increased intracranial pressure). A minimum of 2 weeks must have elapsed between the end of brain radiotherapy and randomization.
Leptomeningeal carcinomatosis or metastasis.
Has significant third-space fluid retention (for example ascites or pleural effusion) and is not amenable for required repeated drainage.
Clinically significant corneal disease.
Has active or uncontrolled hepatitis B or C virus infection. Participants are eligible if they:
Have been curatively treated for HCV infection as demonstrated clinically and by viral serologies.
Have received HBV vaccination with only anti-HBs positivity and no clinical signs of hepatitis
Are HBsAg- and anti-HBc+
Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) and meet conditions i-iii below:
HBV DNA viral load < 2000 IU/mL.
Have normal transaminase values, or, if liver metastases are present, abnormal transaminases, with a result of AST/ALT < 3 × ULN, which are not attributable to HBV infection.
Start or maintain antiviral treatment if clinically indicated as per the Investigator.
Known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA, CD4+ count ≥ 350, no history of AIDS defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV medications (meaning there are no expected further changes in that time to the number or type of antiretroviral drugs in the regimen). If an HIV infection meets the above criteria, monitoring of viral RNA load and CD4+ count is recommended. Participants must be tested for HIV during the screening period if acceptable by local regulations or an IRB/IEC.
Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals; suspected infections (eg, prodromal symptoms); or inability to rule out infections (participants with localized fungal infections of skin or nails are eligible).
Known to have active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).
Resting ECG with clinically abnormal findings per Investigator discretion.
Uncontrolled or significant cardiac disease including:
Myocardial infarction or uncontrolled/unstable angina within 6 months before randomization.
Congestive heart failure (New York Heart Association Class II to IV).
Uncontrolled hypertension (resting systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg).
Cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted based on the Investigator judgement with cardiologist consultation recommended.
History of non-infectious ILD/pneumonitis including radiation pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
Has severe pulmonary function compromise per Investigator discretion.
Prior treatment with:
Any agent, including an ADC, containing a chemotherapeutic agent targeting topoisomerase TROP2-targeted therapy
Docetaxel
Chloroquine/hydroxychloroquine without an adequate treatment washout period of > 14 days before randomization
Received prior radiotherapy to the brain within 2 weeks of start of study intervention or received radiotherapy to the chest within 4 weeks of start of study intervention or has ongoing radiation-related toxicities requiring corticosteroids.
Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, targeted therapy, biologic therapy, tumor embolization, or mAbs) without adequate washout prior to randomization. If sufficient washout time has not occurred due to the schedule or PK properties of an agent, a washout period will be required, as agreed by the Sponsor and the Investigator or 5 half-lives of the respective agent. Herbal or natural products intended as treatment or prophylaxis for any type of cancer that may interfere with the activity of the study intervention are excluded. Concurrent use of hormonal therapy for noncancer-related conditions (eg, HRT) is allowed. An appropriate treatment wash-out period before randomization for anti-cancer treatment is listed below:
≥ 2 weeks or 5 times the terminal elimination t1/2 of the chemotherapeutic agent, whichever is longer
Antibody-based anti-cancer therapy: ≥ 4 weeks
Receipt of live, attenuated vaccine within 30 days prior to the first dose of docetaxel.
Palliative radiotherapy with a limited field of radiation within ≤ 2 weeks, or with wide field of radiation to chest or to more than 30% of the bone marrow within ≤ 4 weeks, prior to randomization.
Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within ≤ 3 weeks of randomization or an anticipated need for major surgery during the study.
Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks (unless the safety profile is known prior to randomization), randomization into an investigational arm containing Dato-DXd in a prior clinical study, or concurrent enrolment in another clinical study (unless the study is observational [non-interventional], or the participant is in the washout period (≤ 4 weeks) of an interventional study).
Participants with a known history of severe hypersensitivity reactions to either Dato-DXd/docetaxel or any excipients (including but not limited to polysorbate 80) of Dato-DXd/docetaxel.
Participants with a known history of severe hypersensitivity reactions to other mAbs
Involvement in the planning and/or conduct of the study (applies to both the Sponsor staff and/or staff at the study site).
Judgement by the Investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
Previous randomization in the present study.
For females only: is pregnant (confirmed with positive serum pregnancy test) or breastfeeding or planning to become pregnant.