## Protocol Section
### Identification Module
**NCT ID:** NCT06417814

**Acronym:** TROPION-Lung15

**Brief Title:** A Study to Investigate the Efficacy and Safety of Dato-DXd With or Without Osimertinib Compared With Platinum Based Doublet Chemotherapy in Participants With EGFR-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer

**Official Title:** 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)

#### Organization Study ID Info
**ID:** D516KC00001
#### Organization
**Class:** INDUSTRY
**Full Name:** AstraZeneca
### Status Module
#### Completion Date
**Date:** 2028-02-08

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-16

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-13

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2026-09-08

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-08-12

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-16
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-13
**Study First Submit QC Date:** 2024-05-13
### Sponsor Collaborators Module

#### Collaborators

**Class:** INDUSTRY

**Name:** Daiichi Sankyo

#### Lead Sponsor

**Class:** INDUSTRY

**Name:** AstraZeneca

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** True

**Oversight Has DMC:** True

### Description Module

**Brief 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).

**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.

### Conditions Module

**Conditions:**

- Metastatic Non-small Cell Lung Cancer

**Keywords:**

- Epidermal growth factor receptor gene mutation

- Standard of Care

- Locally, advanced carcinoma

- Metastatic carcinoma

- Non-small cell lung cancer

- Dato-dxd

- Datopotamab deruxtecan

- Osimertinib

- Tagrisso

- Pemetrexed

- Carboplatin

- Cisplatin

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 630

**Type:** ESTIMATED

**Phases:**

- PHASE3

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Participants will receive Dato-DXd 6 mg/kg as IV infusion 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.

**Intervention Names:**

- Drug: Dato-DXd

- Drug: Osimertinib

**Label:** Group 1: Dato-DXd + Osimertinib Combination Therapy

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** 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, until RECIST v1.1-defined radiological progression by investigator, unacceptable toxicity, or other discontinuation criterion is met.

**Intervention Names:**

- Drug: Dato-DXd

**Label:** Group 2: Dato-DXd Monotherapy

**Type:** EXPERIMENTAL

#### Arm Group 3

**Description:** 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.

**Intervention Names:**

- Drug: Pemetrexed

- Drug: Carboplatin

- Drug: Cisplatin

**Label:** Group 3: Platinum-based Doublet Chemotherapy

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Group 1: Dato-DXd + Osimertinib Combination Therapy

- Group 2: Dato-DXd Monotherapy

**Description:** Dato-DXd will be administered as IV infusion.

**Name:** Dato-DXd

**Other Names:**

- DS-1062a

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Group 1: Dato-DXd + Osimertinib Combination Therapy

**Description:** Osimertinib will be administered orally.

**Name:** Osimertinib

**Other Names:**

- Tagrisso

- AZD9291

**Type:** DRUG

#### Intervention 3

**Arm Group Labels:**

- Group 3: Platinum-based Doublet Chemotherapy

**Description:** Pemetrexed will be administered as IV infusion.

**Name:** Pemetrexed

**Type:** DRUG

#### Intervention 4

**Arm Group Labels:**

- Group 3: Platinum-based Doublet Chemotherapy

**Description:** Carboplatin will be administered as IV infusion.

**Name:** Carboplatin

**Type:** DRUG

#### Intervention 5

**Arm Group Labels:**

- Group 3: Platinum-based Doublet Chemotherapy

**Description:** Cisplatin will be administered as IV infusion.

**Name:** Cisplatin

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** PFS is defined as the time from randomization to Blinded Independent Central Review (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.

**Measure:** Progression free Survival (PFS)

**Time Frame:** Up to 2.5 years

#### Secondary Outcomes

**Description:** OS is defined as time from randomization until the date of death due to any cause.

**Measure:** Overall Survival (OS)

**Time Frame:** Up to 3.5 years

**Description:** 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.

**Measure:** Central Nervous System Progression-free Survival (CNS PFS)

**Time Frame:** Up to 2.5 years

**Description:** ORR is defined as the percentage of participants who have a confirmed complete response (CR) or confirmed partial response (PR), as determined by BICR per RECIST v1.1.

**Measure:** Objective Response Rate (ORR)

**Time Frame:** Up to 2.5 years

**Description:** 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.

**Measure:** Duration of Response (DoR)

**Time Frame:** Up to 2.5 years

**Description:** PFS2 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.

**Measure:** Progression-free Survival-2 (PFS-2)

**Time Frame:** Up to 3.5 years

**Description:** ORR is defined as the percentage of participants who have a confirmed CR or confirmed PR, using CNS modified RECIST v1.1.

**Measure:** Objective Response Rate (ORR) Using CNS Modified RECIST v1.1

**Time Frame:** Up to 2.5 years

**Description:** 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.

**Measure:** Duration of Response (DoR) Using CNS Modified RECIST v1.1

**Time Frame:** Up to 2.5 years

**Description:** 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.

**Measure:** Time to Deterioration in Pulmonary Symptoms

**Time Frame:** Up to 3.5 years

**Description:** 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.

**Measure:** Time to Deterioration in Physical Functioning

**Time Frame:** Up to 3.5 years

**Description:** 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.

**Measure:** Time to Deterioration in Global Health Status (GHS)/Quality of Life (QoL)

**Time Frame:** Up to 3.5 years

**Description:** Concentration of Dato-DXd, total anti-TROP2 antibody and DXd in plasma.

**Measure:** Pharmacokinetics (PK) of Dato-DXd

**Time Frame:** Up to 3.5 years

**Description:** Presence of antidrug antibody (ADAs) for Dato-DXd (confirmatory results: positive or negative, titers).

**Measure:** Immunogenicity of Dato-DXd

**Time Frame:** Up to 3.5 years

### Eligibility Module

**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 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.

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** information.center@astrazeneca.com

**Name:** AstraZeneca Clinical Study Information Center

**Phone:** 1-877-240-9479

**Role:** CONTACT

### IPD Sharing Statement Module

**Access Criteria:** When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment Vivli.org. A Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

**Description:** Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

"Yes", indicates that AZ are accepting requests for IPD, but this does not mean all requests will be approved.

**Info Types:**

- STUDY_PROTOCOL

- SAP

**IPD Sharing:** YES

**Time Frame:** AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles.

For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

**URL:** https://astrazenecagroup-dt.pharmacm.com/DT/Home

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000012142

- Term: Respiratory Tract Neoplasms

- ID: D000013899

- Term: Thoracic Neoplasms

- ID: D000009371

- Term: Neoplasms by Site

- ID: D000009369

- Term: Neoplasms

- ID: D000008171

- Term: Lung Diseases

- ID: D000012140

- Term: Respiratory Tract Diseases

- ID: D000002283

- Term: Carcinoma, Bronchogenic

- ID: D000001984

- Term: Bronchial Neoplasms

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: BC08

- Name: Respiratory Tract (Lung and Bronchial) Diseases

- Abbrev: All

- Name: All Conditions

### Condition Browse Module - Browse Leaves

- ID: M5546

- Name: Carcinoma, Non-Small-Cell Lung

- Relevance: HIGH

- As Found: Non-Small Cell Lung Cancer

- ID: M5534

- Name: Carcinoma

- Relevance: LOW

- As Found: Unknown

- ID: M11172

- Name: Lung Neoplasms

- Relevance: HIGH

- As Found: Lung Cancer

- ID: M14979

- Name: Respiratory Tract Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M16658

- Name: Thoracic Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M11168

- Name: Lung Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M14977

- Name: Respiratory Tract Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M5540

- Name: Carcinoma, Bronchogenic

- Relevance: LOW

- As Found: Unknown

- ID: M5260

- Name: Bronchial Neoplasms

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000008175

- Term: Lung Neoplasms

- ID: D000002289

- Term: Carcinoma, Non-Small-Cell Lung

### Intervention Browse Module - Ancestors

- ID: D000000970

- Term: Antineoplastic Agents

- ID: D000004791

- Term: Enzyme Inhibitors

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

- ID: D000005493

- Term: Folic Acid Antagonists

- ID: D000019384

- Term: Nucleic Acid Synthesis Inhibitors

- ID: D000092004

- Term: Tyrosine Kinase Inhibitors

- ID: D000047428

- Term: Protein Kinase Inhibitors

### Intervention Browse Module - Browse Branches

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: Micro

- Name: Micronutrients

- Abbrev: Hemat

- Name: Hematinics

- Abbrev: Vi

- Name: Vitamins

- Abbrev: AA

- Name: Amino Acids

### Intervention Browse Module - Browse Leaves

- ID: M18650

- Name: Carboplatin

- Relevance: HIGH

- As Found: System

- ID: M145673

- Name: Osimertinib

- Relevance: HIGH

- As Found: Angioplasty

- ID: M264

- Name: Pemetrexed

- Relevance: HIGH

- As Found: Strategies

- ID: M6182

- Name: Cisplatin

- Relevance: LOW

- As Found: Unknown

- ID: M11900

- Name: Mitogens

- Relevance: LOW

- As Found: Unknown

- ID: M7951

- Name: Enzyme Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M8618

- Name: Folic Acid

- Relevance: LOW

- As Found: Unknown

- ID: M17546

- Name: Vitamin B Complex

- Relevance: LOW

- As Found: Unknown

- ID: M8619

- Name: Folic Acid Antagonists

- Relevance: LOW

- As Found: Unknown

- ID: M2889

- Name: Tyrosine Kinase Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M25820

- Name: Protein Kinase Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: T447

- Name: Folinic Acid

- Relevance: LOW

- As Found: Unknown

- ID: T446

- Name: Folic Acid

- Relevance: LOW

- As Found: Unknown

- ID: T448

- Name: Folate

- Relevance: LOW

- As Found: Unknown

- ID: T475

- Name: Vitamin B9

- Relevance: LOW

- As Found: Unknown

- ID: T22

- Name: Tyrosine

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000016190

- Term: Carboplatin

- ID: D000068437

- Term: Pemetrexed

- ID: C000596361

- Term: Osimertinib

### Misc Info Module

- Version Holder: 2024-05-31
