A trial to learn how safe Dato-DXd is and how well it works in people with NSCLC that has advanced after receiving osimertinib

Phase 3

Recruiting

• Conditions: Non squamous non-small cell lung cancer (NSCLC)

• Registration Number: 2024-511362-37-00
• Lead Sponsor: AstraZeneca AB

Brief Summary

To demonstrate the superiority of Dato-DXd monotherapy compared to chemotherapy in terms of PFS.

To demonstrate the superiority of Dato DXd combined with osimertinib compared to chemotherapy in terms of PFS.

Detailed Description

This is a Phase III, open-label, 3-arm, multicenter study assessing the effects of Dato-DXd in combination with osimertinib or Dato-DXd monotherapy versus platinum-based doublet chemotherapy in participants with epidermal growth factor receptor gene mutation (EGFRm) locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on prior osimertinib treatment.

Participants will be randomized in a 1:1:1 ratio to one of the following intervention groups:

1. Dato-DXd + osimertinib combination therapy

2. Dato-DXd monotherapy

3. Platinum-based doublet chemotherapy

Participants will receive study intervention until Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) -defined radiological progression by the investigator, unacceptable toxicity, or other discontinuation criterion is met.

After study intervention discontinuation, all participants will undergo an end of treatment (EoT) visit within 35 days of discontinuation and will be followed up for safety assessments 28 (+ 7) days after their last dose of study intervention.

Study Timeline

• Study First Submitted: 2024-05-13
• Study First Submitted QC: 2024-05-13
• Study First Posted: 2024-05-16
• Study Start: 2024-10-04
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-15
• Last Update Posted: 2025-07-16
• Primary Completion: 2026-06-11
• Study Completion: 2028-05-29

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Not specified
• Target Recruitment: 157

Inclusion Criteria

Histologically or cytologically confirmed non-squamous NSCLC.

Must have evidence of documented pre-existing EGFRm information (EGFRm known to be associated with (epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor [TKis] sensitivity [Ex19del, L858R, G719X, S768I, or L861Q], either alone or in combination with other EGFR mutations, which may include T790M).

Documented extra-cranial radiologic progression on prior osimertinib monotherapy (as most recent line of treatment) in the adjuvant, locally advanced, or metastatic setting.

Less than or equal to (<=2) prior lines of EGFR TKIs (osimertinib is the only permitted prior third generation EGFR TKI).

At least one lesion, not previously irradiated, that qualifies as a RECIST v1.1 TL at baseline and can be accurately measured at baseline.

World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Adequate bone marrow reserve and organ function within 7 days before randomization.

Exclusion Criteria

Use of chemotherapy, vascular endothelial growth factor inhibitor, immunotherapy or any anti-cancer therapy in the palliative setting. Platinum-based chemotherapy in curative setting within 12 months prior to randomization.

Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals, suspected infections or inability to rule out infections.

Has known human immunodeficiency virus (HIV) infection that is not well controlled.

History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 2 years before the first dose of study intervention.

Any evidence of severe or uncontrolled systemic diseases, including, but not limited to active bleeding diseases, active infection, active ILD/pneumonitis, cardiac disease.

Has significant third-space fluid retention (example [eg.], ascites or pleural effusion) as judged by the investigator and is not amenable for required repeated drainage.

History of ILD/pneumonitis including radiation pneumonitis that required steroids or drug-induced ILD, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.

Has severe pulmonary function compromise resulting from intercurrent pulmonary illnesses.

Unstable spinal cord compression and/or unstable brain metastases.

Participants with symptomatic brain metastases (including leptomeningeal involvement).

Clinically significant corneal disease.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
PFS is defined as the time from randomization to BICR assessed progression using RECIST v1.1 or death due to any cause, regardless of whether the participant withdraws from study therapy, receives other anti cancer therapy, or clinical progression.		PFS is defined as the time from randomization to BICR assessed progression using RECIST v1.1 or death due to any cause, regardless of whether the participant withdraws from study therapy, receives other anti cancer therapy, or clinical progression.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS) is defined as time from randomization until the date of death due to any cause. The comparison will include all randomized participants, as randomized, regardless of whether the participant withdraws from therapy or receives another anti-cancer therapy.		Overall Survival (OS) is defined as time from randomization until the date of death due to any cause. The comparison will include all randomized participants, as randomized, regardless of whether the participant withdraws from therapy or receives another anti-cancer therapy.
Central Nervous System Progression-free Survival (CNS PFS) is defined as the time from randomization to BICR confirmed progression in the CNS or death due to any cause, regardless of whether the participant withdraws from study therapy, receives other anti-cancer therapy, or clinically progresses prior to BICR-confirmed CNS modified RECIST v1.1 progression.		Central Nervous System Progression-free Survival (CNS PFS) is defined as the time from randomization to BICR confirmed progression in the CNS or death due to any cause, regardless of whether the participant withdraws from study therapy, receives other anti-cancer therapy, or clinically progresses prior to BICR-confirmed CNS modified RECIST v1.1 progression.
Objective Response Rate (ORR) is defined as the proportion of participants who have a confirmed complete response (CR) or confirmed partial response (PR), as determined by BICR per RECIST v1.1.		Objective Response Rate (ORR) is defined as the proportion of participants who have a confirmed complete response (CR) or confirmed partial response (PR), as determined by BICR per RECIST v1.1.
Duration of Response (DoR) is defined as the time from the date of first documented response until date of documented progression per RECIST v1.1, as assessed by BICR or death due to any cause.		Duration of Response (DoR) is defined as the time from the date of first documented response until date of documented progression per RECIST v1.1, as assessed by BICR or death due to any cause.
Progression-free Survival-2 (PFS-2) is defined as the time from randomization to the earliest of the progression event (following the initial investigator assessed progression), after first subsequent therapy, or death.		Progression-free Survival-2 (PFS-2) is defined as the time from randomization to the earliest of the progression event (following the initial investigator assessed progression), after first subsequent therapy, or death.
ORR is defined as the proportion of participants who have a confirmed CR or confirmed PR, using CNS modified RECIST v1.1.		ORR is defined as the proportion of participants who have a confirmed CR or confirmed PR, using CNS modified RECIST v1.1.
DoR is defined as the time from the date of first documented response until date of documented progression or death due to any cause using CNS modified RECIST v1.1.		DoR is defined as the time from the date of first documented response until date of documented progression or death due to any cause using CNS modified RECIST v1.1.
Time to deterioration (in pulmonary symptoms [dyspnea, cough, and chest pain]) is defined as the time from randomization until the date of deterioration. Deterioration is defined as change from baseline that reaches a meaningful change threshold.		Time to deterioration (in pulmonary symptoms [dyspnea, cough, and chest pain]) is defined as the time from randomization until the date of deterioration. Deterioration is defined as change from baseline that reaches a meaningful change threshold.
Time to deterioration in physical functioning as measured by Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function short form 8c will be evaluated. Time to deterioration (in physical functionating) is defined as the time from randomization until the date of deterioration. Deterioration is defined as change from baseline that reaches a meaningful change threshold.		Time to deterioration in physical functioning as measured by Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function short form 8c will be evaluated. Time to deterioration (in physical functionating) is defined as the time from randomization until the date of deterioration. Deterioration is defined as change from baseline that reaches a meaningful change threshold.
Time to deterioration in GHS/QoL as measured by the GHS/QoL scale from EORTC IL172 will be reported. Time to deterioration (in GHS/QoL) is defined as the time from randomization until the date of deterioration. Deterioration is defined as change from baseline that reaches a meaningful change threshold.		Time to deterioration in GHS/QoL as measured by the GHS/QoL scale from EORTC IL172 will be reported. Time to deterioration (in GHS/QoL) is defined as the time from randomization until the date of deterioration. Deterioration is defined as change from baseline that reaches a meaningful change threshold.
Concentration of Dato-DXd, total anti-TROP2 antibody and DXd in plasma.		Concentration of Dato-DXd, total anti-TROP2 antibody and DXd in plasma.
Presence of antidrug antibody (ADAs) for Dato-DXd (confirmatory results: positive or negative, titers).		Presence of antidrug antibody (ADAs) for Dato-DXd (confirmatory results: positive or negative, titers).

Trial Locations

Locations (80)

Pratia Hematologia Sp. z o.o.; 🇵🇱 Katowice, Poland

Instytut Msf Sp. z o.o.; 🇵🇱 Lodz, Poland

Pratia S.A.; 🇵🇱 Cracow, Poland

Wielkopolskie Centrum Pulmonologii I Torakochirurgii Im. Eugenii I Janusza Zeylandow; 🇵🇱 Poznan, Poland

Warminsko-Mazurskie Centrum Chorob Pluc W Olsztynie; 🇵🇱 Olsztyn, Poland

Hospital Del Mar; 🇪🇸 Barcelona, Spain

Hospital De La Santa Creu I Sant Pau; 🇪🇸 Barcelona, Spain

Hospital Quironsalud Malaga; 🇪🇸 Malaga, Spain

Clinica Universidad De Navarra; 🇪🇸 Madrid, Spain

Hospital Universitario De Cruces; 🇪🇸 Barakaldo, Spain

Scroll for more (70 remaining)

Pratia Hematologia Sp. z o.o.

🇵🇱Katowice, Poland

Agata Kachel - Flis

Site contact

+48508956071

agata.kachel-flis@pratia.com