A Phase III, Open-label, Sponsor-blind, Randomized Study of Dato-DXd With or Without Osimertinib Versus Platinum-based Doublet Chemotherapy for Participants With EGFR-mutated Locally Advanced or Metastatic Non-small Cell Lung Cancer Whose Disease Has Progressed on Prior Osimertinib Treatment (TROPION-Lung15)

Official Summary

This study will assess the effect of Dato-DXd in combination with osimertinib or Dato-DXd monotherapy versus platinum-based doublet chemotherapy in terms of progression-free survival (PFS).

Eligibility Requirements

• Minimum Age: 18 Years
• Maximum Age: 130 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 744 participants

Study Arms

• Group 1: Dato-DXd + Osimertinib Combination Therapy (EXPERIMENTAL)
  Participants will receive Dato-DXd 6 milligrams per kilogram (mg/kg) as intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of every 21-day cycle, and osimertinib 80 milligrams (mg) once daily (QD) orally, until RECIST v1.1-defined radiological progression by investigator, unacceptable toxicity, or other discontinuation criterion is met.
• Group 2: Dato-DXd Monotherapy (EXPERIMENTAL)
  Participants will receive Dato-DXd 6 mg/kg as IV infusion Q3W on Day 1 of every 21-day cycle, until RECIST v1.1-defined radiological progression by investigator, unacceptable toxicity, or other discontinuation criterion is met.
• Group 3: Platinum-based Doublet Chemotherapy (EXPERIMENTAL)
  Participants will receive pemetrexed 500 milligrams per meter square (mg/m2) in combination with carboplatin (AUC5) or cisplatin 75 mg/m2 as IV infusion Q3W for 4 cycles followed by pemetrexed maintenance 500 mg/m2 as IV infusion Q3W, until RECIST v1.1-defined radiological progression by investigator, unacceptable toxicity, or another discontinuation criterion is met.

Interventions

• DRUG: Dato-DXd — Dato-DXd will be administered as IV infusion.
• DRUG: Osimertinib — Osimertinib will be administered orally.
• DRUG: Pemetrexed — Pemetrexed will be administered as IV infusion.
• DRUG: Carboplatin — Carboplatin will be administered as IV infusion.
• DRUG: Cisplatin — Cisplatin will be administered as IV infusion.

Primary Outcomes

• Progression free Survival (PFS) (Up to 2.5 years)

Secondary Outcomes

• Overall Survival (OS) (Up to 3.5 years)
• Central Nervous System Progression-free Survival (CNS PFS) (Up to 2.5 years)
• Objective Response Rate (ORR) (Up to 2.5 years)
• Duration of Response (DoR) (Up to 2.5 years)
• Progression-free Survival-2 (PFS-2) (Up to 3.5 years)

Eligibility Criteria

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 metastatic setting. Platinum-based chemotherapy in non-metastatic setting within 12 months prior to randomization.
* 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 non-infectious 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.
* Uncontrolled infection requiring systemic antibiotics, antivirals, or antifungals, suspected infections or inability to rule out infections. Use of systemic antibiotics within 14 days of randomization.
* Has known human immunodeficiency virus (HIV) infection that is not well controlled.

Trial Locations

• Research Site, Fayetteville, Arkansas, United States
• Research Site, Duarte, California, United States
• Research Site, Fountain Valley, California, United States
• Research Site, La Jolla, California, United States
• Research Site, Los Angeles, California, United States
• Research Site, San Diego, California, United States
• Research Site, Colorado Springs, Colorado, United States
• Research Site, Fort Collins, Colorado, United States
• Research Site, Washington D.C., District of Columbia, United States
• Research Site, Gainesville, Florida, United States
• ...and 10 more locations

Contact Information

• AstraZeneca Clinical Study Information Center — CONTACT
  Phone: 1-877-240-9479
  Email: information.center@astrazeneca.com

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