Phase III Study of Datopotamab Deruxtecan Versus Docetaxel in Patients With Previously Treated TROP2-Positive Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer

Trial ID: 2024-520101-39-00
Protocol: D763QC00001
Sponsor: AstraZeneca AB

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Diseases & Conditions

Non-small cell lung cancer

Objectives

The primary objective of this study is to evaluate the superiority of datopotamab deruxtecan compared to docetaxel in patients with non-squamous non-small cell lung cancer expressing TROP2. Clinical efficacy is determined through the assessment of progression-free survival via blinded independent central review and overall survival. Secondary objectives include the evaluation of the objective response rate, duration of response, and time to second progression or death. Additional assessments focus on the exposure-response relationship, immunogenicity, and the performance of TROP2 diagnostic tests in relation to other tumor-derived biomarkers. The study also evaluates safety, tolerability, and patient-reported outcomes, including lung cancer symptoms, physical functioning, and quality of life.

Participants

This study involves 297 participants diagnosed with non-squamous non-small cell lung cancer. The study population includes both male and female individuals. The participants are identified within specific age ranges. Eligibility requires a pathologically documented Stage IIIB, Stage IIIC, or Stage IV disease status. A key requirement is a TROP2 NMR-positive status determined by a validated investigational device. Subjects must lack actionable genomic alterations, specifically negative test results for EGFR, ALK, ROS1, NTRK, BRAF, RET, MET exon 14 skipping, KRAS G12C, or HER2. Clinical inclusion necessitates documented radiographic disease progression following prior treatment with platinum-based chemotherapy in combination with anti-PD-1/anti-PD-L1 monoclonal antibodies. Participants must demonstrate an ECOG performance status of 0 or 1 and possess adequate bone marrow reserve and organ function. Furthermore, the presence of at least one measurable lesion according to RECIST 1.1 criteria is required.

Plans and Procedures

This Phase III, randomised, open-label, multicentre study is designed to evaluate the efficacy and safety of datopotamab deruxtecan compared to docetaxel in patients with non-squamous non-small cell lung cancer. The primary objective is to assess progression-free survival and overall survival. The methodology involves the comparison of the investigational product against a comparator in individuals with TROP2-positive advanced or metastatic disease lacking actionable genomic alterations. The study includes a screening period to confirm eligibility based on TROP2 status, radiographic disease progression, and previous exposure to platinum-based chemotherapy and anti-PD-1/anti-PD-L1 therapies. Following randomisation, participants receive treatment via intravenous use. The trial involves periodic assessments to monitor objective response rate, duration of response, and safety profiles. The duration of participant involvement is not explicitly stated, though the overall study is estimated to conclude in early 2029. Early termination of participation may occur based on clinical criteria or disease progression.

Treatment

The investigational medicinal product is datopotamab deruxtecan, which is administered as a solution for infusion via intravenous use. The dosage for this substance is specified as 00 mg/kg.

The comparator treatment consists of docetaxel, administered through intravenous use at a dosage of 00 mg/ml.

Efficacy

The efficacy of datopotamab deruxtecan will be evaluated in comparison to docetaxel for the treatment of non-squamous non-small cell lung cancer. The primary endpoints include progression-free survival (PFS) and overall survival (OS). Progression-free survival will be assessed by Blinded Independent Central Review (BICR) in accordance with RECIST v1.1.

Secondary efficacy parameters consist of the following:

Objective response rate (ORR)
Duration of response (DoR)
Time to second progression or death (PFS2)
Time to deterioration (TTD) in pulmonary symptoms, physical functioning, and quality of life (QoL)

The study will also involve the characterization of population pharmacokinetics (PK) and its relationship with efficacy and safety endpoints, the evaluation of antidrug antibodies (ADAs), and the assessment of TROP2 diagnostic test performance in relation to other tumor-derived biomarkers.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Pathologically documented Stage IIIB, IIIC, or Stage IV non-squamous NSCLC without AGA at the time of randomisation and meets the criteria for NSCLC: * Participants must have documented negative test results for EGFR, ALK, and ROS1 genomic alterations. * Has no known tumour 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.
Documentation of radiographic disease progression while on or after receiving the most recent treatment regimen for advanced or metastatic NSCLC.
Participants must have received platinum-based chemotherapy (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.
Provision of acceptable FFPE tumour sample for assessment of TROP2.
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 ≥ 15mm) with CT or MRI and is suitable for accurate repeated measurements.
ECOG PS of 0 or 1.
Adequate bone marrow reserve and organ function within 7 days before randomisation.

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Exclusion Criteria

Squamous, mixed NSCLC, or SCLC histology.
NSCLC disease that is eligible for definitive local therapy alone.
History of another primary malignancy other than NSCLC, except for malignancy treated with curative intent with no known active disease within 3 years before randomisation and of low potential risk for recurrence.
Spinal cord compression or brain metastases, unless asymptomatic, stable, and not requiring treatment with corticosteroids or anticonvulsants for at least 7 days prior to randomisation.
Clinically significant corneal disease.
Has active or uncontrolled hepatitis B or C virus infection.
Known HIV infection that is not well controlled.
Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
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.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Recruiting	31 Oct 2025	11
Belgium	Recruiting	31 Oct 2025	10
France	Recruiting	31 Oct 2025	12
Germany	Recruiting	31 Oct 2025	22
Hungary	Recruiting	31 Oct 2025	13
Italy	Not Yet Recruiting	31 Oct 2025	12
Poland	Recruiting	31 Oct 2025	10
Spain	Recruiting	31 Oct 2025	13