Osimertinib + Datopotamab Deruxtecan for Lung Cancer

(TROPION-Lung14 Trial)

Recruiting at 129 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must not be taking: Antibiotics, Antivirals, Antifungals

Disqualifiers: Uncontrolled infection, Cardiac disease, ILD, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: Event-driven, up to 9 years

582 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate efficacy and safety of osimertinib (tablet) in combination with Datopotamab Deruxtecan (i.v. infusion) compared with osimertinib (tablet) monotherapy as a first-line therapy in participants with locally advanced or metastatic EGFRm (Ex19del and/or L858R) NSCLC. Study details include: 1. The study duration will be event-driven, with an estimated duration of approximately 9 years. 2. Participants may receive study treatment until disease progression, unacceptable toxicity, or other specific discontinuation criteria are met. 3. The visit frequency will be every 3 weeks during the treatment period. Note: Participants on osimertinib treatment (osimertinib only arm or who have discontinued Datopotamab Deruxtecan while are still receiving osimertinib) are required to attend visits to perform assessments every 6 weeks from Cycle 7 until Cycle 17 and then visits every 12 weeks until disease progression, IP discontinuation or primary PFS DCO. Participants who are receiving osimertinib + Datopotamab Deruxtecan are still required to attend visit to perform assessment every 3 weeks (q3w) per SoA.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, it does mention that participants should not have received prior EGFR TKIs or other systemic therapy for their lung cancer.

What data supports the effectiveness of the drug Osimertinib + Datopotamab Deruxtecan for lung cancer?

Osimertinib has shown effectiveness in treating non-small cell lung cancer (NSCLC) with specific genetic mutations, achieving significant tumor response rates in clinical trials. It is particularly effective for patients with the EGFR T790M mutation, which is a common resistance mechanism to earlier treatments. ^{1 2 3 4 5}

Is the combination of Osimertinib and Datopotamab Deruxtecan safe for humans?

Osimertinib has been used in various studies for lung cancer and is generally well tolerated, with common side effects including diarrhea, rash, dry skin, and nail issues. Serious side effects occurred in 28% of patients, and 5.6% stopped treatment due to these effects. No specific safety data for Datopotamab Deruxtecan in combination with Osimertinib is provided in the available research. ^{1 4 6 7 8}

What makes the drug combination of Osimertinib and Datopotamab Deruxtecan unique for lung cancer?

This drug combination is unique because Osimertinib is a third-generation drug that specifically targets a mutation in lung cancer cells, while Datopotamab Deruxtecan is an antibody-drug conjugate that delivers chemotherapy directly to cancer cells, potentially enhancing effectiveness and reducing side effects. ^{3 5 9 10 11}

Eligibility Criteria

This trial is for adults with advanced or metastatic non-squamous Non-Small Cell Lung Cancer (NSCLC) that has specific EGFR mutations. Participants must not have had prior treatments for this stage of cancer and should be in good physical condition (WHO performance status of 0 or 1). A tissue sample confirming the mutation is required.

Inclusion Criteria

I am at least 18 years old.

I am at least 18 years old, or 20 if I am from Japan.

My condition matches the specific disease this trial is studying.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive osimertinib with or without Datopotamab Deruxtecan until disease progression or unacceptable toxicity

Event-driven, up to 9 years

Every 3 weeks for osimertinib + Datopotamab Deruxtecan; every 6 weeks from Cycle 7 to Cycle 17, then every 12 weeks for osimertinib monotherapy

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 3-7 years

Open-label extension (optional)

Participants may opt into continuation of treatment long-term

Long-term

Treatment Details

Interventions

• Datopotamab Deruxtecan
• Osimertinib

Trial Overview The study compares the effectiveness and safety of osimertinib alone versus combined with Datopotamab Deruxtecan as a first-line treatment. Patients will receive these treatments over an estimated period of nine years until disease progression, unacceptable side effects, or other criteria lead to discontinuation.

Participant Groups

Group I: Arm 1: Osimertinib in combination with Datopotamab Deruxtecan Experimental Treatment 2 Interventions

Participants in this group will receive osimertinib 80 mg QD as oral tablet with Datopotamab Deruxtecan 6mg/kg as i.v. infusion q3w of Day 1 of every 21-day cycle.

Group II: Arm 2: Osimertinib monotherapy Active Control 1 Intervention

Participants in this group will receive osimertinib 80 mg QD as oral tablet.

Osimertinib is already approved in United States, European Union for the following indications:

Approved in United States as Tagrisso for:

• Locally advanced or metastatic non-small-cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R mutations
• Metastatic EGFR T790M mutation-positive NSCLC

Approved in European Union as Tagrisso for:

• Locally advanced or metastatic non-small-cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R mutations
• Metastatic EGFR T790M mutation-positive NSCLC

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Daiichi Sankyo

Industry Sponsor

Trials

443

Recruited

493,000+

Hiroyuki Okuzawa

Daiichi Sankyo

Chief Executive Officer

Degree in Social Sciences from Hitotsubashi University

Yuki Abe

Daiichi Sankyo

Chief Medical Officer since 2023

MD

Findings from Research

Osimertinib (Tagrisso) is a targeted therapy approved by the FDA for patients with metastatic non-small cell lung cancer (NSCLC) who have the EGFR T790M mutation and have progressed after previous treatments.

The drug received special designations from the FDA, including breakthrough therapy and priority review, highlighting its significance in treating resistant forms of NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the Gatekeeper: Osimertinib in EGFR T790M Mutation-Positive Non-Small Cell Lung Cancer. Skoulidis, F., Papadimitrakopoulou, VA.[2022]

In a study of 240 advanced non-small-cell lung cancer (NSCLC) patients with acquired resistance to EGFR TKIs, 52.9% had the T790M mutation after rebiopsy, highlighting the mutation's prevalence in treatment resistance.

Patients with the T790M mutation who had previously used osimertinib experienced significantly longer post-progression survival (42.6 months) compared to those without osimertinib (18.0 months) or without the mutation (18.8 months), suggesting osimertinib's effectiveness as a standard treatment for T790M-positive NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-Progression Survival in Secondary EGFR T790M-Mutated Non-Small-Cell Lung Cancer Patients With and Without Osimertinib After Failure of a Previous EGFR TKI. Chiang, CL., Huang, HC., Shen, CI., et al.[2022]

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, effectively inhibited the growth of a brain metastasis in a patient with lung adenocarcinoma that was resistant to both radiotherapy and surgery.

The case highlights the importance of re-biopsy in patients with EGFR-mutated non-small cell lung cancer who develop resistance to TKI treatments, as it can provide critical information for effective treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid Intracranial Response to Osimertinib in a Patient with Epidermal Growth Factor Receptor T790M-Positive Adenocarcinoma of the Lung. Reichegger, H., Jochum, W., Förbs, D., et al.[2022]

Osimertinib (TAGRISSO) received accelerated FDA approval for treating metastatic non-small cell lung cancer with the EGFR T790M mutation, showing significant tumor response rates of 57% and 61% in two major trials involving 411 patients.

While osimertinib demonstrated promising efficacy, common side effects included diarrhea (42%) and rash (41%), with 28% of patients experiencing severe adverse events, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib for the Treatment of Metastatic EGFR T790M Mutation-Positive Non-Small Cell Lung Cancer. Khozin, S., Weinstock, C., Blumenthal, GM., et al.[2022]

In a retrospective analysis of 32 patients with EGFR T790M-mutant non-small-cell lung cancer, osimertinib showed a 50% objective response rate and a median progression-free survival of 11.3 months, indicating its efficacy in clinical practice.

The median overall survival was 18.3 months, with better outcomes observed in patients without cerebral metastases and those with better performance status, highlighting the importance of these factors in treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of osimertinib in patients with lung adenocarcinoma in clinical practice - the Expanded Drug Access Program in Poland. Knetki-Wróblewska, M., Kowalski, DM., Czyżewicz, G., et al.[2022]

Osimertinib, a treatment for metastatic EGFRm T790M non-small-cell lung cancer, has been analyzed using newly developed and validated LC-MC/MS methods across various biological matrices, including plasma, urine, and cerebrospinal fluid.

The assays demonstrated high selectivity, accuracy, and robustness, successfully analyzing over 20,000 clinical samples, which supports the effective clinical development of osimertinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of osimertinib in human plasma, urine and cerebrospinal fluid. Mitchell, R., Bailey, C., Ewles, M., et al.[2022]

Osimertinib (Tagrisso) is an approved adjuvant treatment for non-small cell lung cancer patients with specific tumor mutations, highlighting its targeted therapeutic approach.

Common side effects of osimertinib include blood-related issues like leukopenia and thrombocytopenia, as well as gastrointestinal and skin reactions, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Adjuvant Drug for Lung Cancer. Aschenbrenner, DS.[2023]

Osimertinib significantly improves disease-free survival (DFS) in adults with completely resected, early-stage EGFR mutation-positive non-small cell lung cancer (NSCLC), as shown in the pivotal ADAURA trial, regardless of prior adjuvant chemotherapy.

The treatment is well tolerated with a manageable safety profile, and it does not negatively impact health-related quality of life, making it a suitable option for adjuvant therapy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib: A Review in Completely Resected, Early-Stage, EGFR Mutation-Positive NSCLC. Frampton, JE.[2022]

Osimertinib is an oral medication specifically designed to target the EGFR T790M mutation in advanced non-small cell lung cancer (NSCLC), which helps overcome resistance to previous EGFR TKI therapies.

It received accelerated approval in the USA in November 2015 for patients with metastatic EGFR T790M mutation-positive NSCLC who have progressed after EGFR TKI treatment, and is currently undergoing further development for broader treatment applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib: First Global Approval. Greig, SL.[2022]

Osimertinib, an irreversible tyrosine kinase inhibitor, showed excellent activity in treating a 69-year-old man with metastatic EGFR-mutated non-small cell lung cancer, leading to a rapid treatment response despite initial severe pancytopenia.

After experiencing pancytopenia, the patient's dose of osimertinib was reduced from 80 mg to 40 mg daily, which allowed for continued effective treatment without further adverse events, demonstrating the potential for safe dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancytopenia During Osimertinib Treatment in a Patient with EGFR-Mutated Non-Small Cell Lung Cancer. Di Marino, P., Chiapperino, C., Primavera, FC., et al.[2022]

Osimertinib is effective as a first-line treatment for advanced EGFR-mutated non-small cell lung cancer (NSCLC), showing a 76% objective response rate and a median progression-free survival of 12.6 months in a study of 104 patients.

At the time of disease progression, common resistance mechanisms identified included MET amplification in 15% of patients and the EGFR C797S mutation in 11%, highlighting the need for further treatment strategies beyond osimertinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Histomolecular Resistance Mechanisms to First-Line Osimertinib in EGFR-Mutated Advanced Non-Small Cell Lung Cancer: A Multicentric Retrospective French Study. Akli, A., Girard, N., Fallet, V., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Targeting the Gatekeeper: Osimertinib in EGFR T790M Mutation-Positive Non-Small Cell Lung Cancer. [2022]

2. France pubmed.ncbi.nlm.nih.gov

Post-Progression Survival in Secondary EGFR T790M-Mutated Non-Small-Cell Lung Cancer Patients With and Without Osimertinib After Failure of a Previous EGFR TKI. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Rapid Intracranial Response to Osimertinib in a Patient with Epidermal Growth Factor Receptor T790M-Positive Adenocarcinoma of the Lung. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Osimertinib for the Treatment of Metastatic EGFR T790M Mutation-Positive Non-Small Cell Lung Cancer. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Effectiveness of osimertinib in patients with lung adenocarcinoma in clinical practice - the Expanded Drug Access Program in Poland. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Determination of osimertinib in human plasma, urine and cerebrospinal fluid. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

New Adjuvant Drug for Lung Cancer. [2023]

8. France pubmed.ncbi.nlm.nih.gov

Osimertinib: A Review in Completely Resected, Early-Stage, EGFR Mutation-Positive NSCLC. [2022]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Osimertinib: First Global Approval. [2022]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Pancytopenia During Osimertinib Treatment in a Patient with EGFR-Mutated Non-Small Cell Lung Cancer. [2022]

11. France pubmed.ncbi.nlm.nih.gov

Histomolecular Resistance Mechanisms to First-Line Osimertinib in EGFR-Mutated Advanced Non-Small Cell Lung Cancer: A Multicentric Retrospective French Study. [2022]