Osimertinib + Datopotamab Deruxtecan for Lung Cancer

(TROPION-Lung14 Trial)

Recruiting at 166 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments to determine if it outperforms the current standard for certain types of advanced lung cancer. It compares the effectiveness and safety of taking the drug osimertinib alone versus in combination with Datopotamab Deruxtecan, a TROP2-directed antibody-drug conjugate. Individuals with advanced non-small cell lung cancer (NSCLC) who have specific mutations in the EGFR gene and have not received certain prior treatments may qualify. Participants will undergo treatments and assessments over several years, with visits every three weeks initially. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to potentially groundbreaking treatment advancements.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that using osimertinib with datopotamab deruxtecan (Dato-DXd) is generally safe. In earlier studies, patients who took this combination experienced expected side effects that were not too severe. Importantly, no new safety issues emerged when these drugs were used together.

Osimertinib is already approved for treating some lung cancers, indicating its safety is well understood. Dato-DXd has also been tested in other studies and demonstrated good safety results. Overall, evidence suggests that most patients tolerate this treatment well. However, as with any treatment, individual reactions can vary, so monitoring for any side effects is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Osimertinib and Datopotamab Deruxtecan for lung cancer because it represents a novel approach to treatment. While standard therapies often include targeted drugs like Osimertinib alone, this combination introduces Datopotamab Deruxtecan, an antibody-drug conjugate that delivers chemotherapy directly to cancer cells, potentially enhancing effectiveness. This dual mechanism aims to not only inhibit cancer cell growth but also precisely target and kill cancer cells, offering a promising avenue for improved outcomes in patients.

What evidence suggests that this trial's treatments could be effective for lung cancer?

This trial will compare two treatment approaches for advanced non-small cell lung cancer (NSCLC) with specific genetic changes called EGFR mutations. Participants in one arm will receive a combination of osimertinib and datopotamab deruxtecan. Research has shown that this combination may be effective, as studies have found positive results in patients whose cancer continued to grow after previous treatments. This combination appears to slow the cancer's progression more effectively than osimertinib alone. Participants in the other arm will receive osimertinib monotherapy. Early results from other trials suggest that adding datopotamab deruxtecan can help delay cancer worsening, indicating a potential benefit for people with certain lung cancer mutations. ^{1 2 3 4 6}

Are You a Good Fit for This Trial?

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, or 20 if I am from Japan.

My condition matches the specific disease this trial is studying.

My lung cancer is non-squamous based on tissue analysis.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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 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]

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 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]

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]

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 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]

Citations

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Osimertinib Plus Dato-DXd Shows Efficacy in Post- ... “Encouraging outcomes were observed with osimertinib plus Dato-DXd in patients with EGFR-mutated advanced NSCLC whose cancer had progressed on ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS8647

TROPION-Lung14: A phase 3 study of osimertinib ± ... TROPION-Lung14 is evaluating the efficacy and safety of osimertinib ± Dato-DXd as 1L therapy in patients with EGFR-mutated LA/M NSCLC.

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NCT06350097 | Phase III, Open-label Study of First-line ... The purpose of this study is to evaluate efficacy and safety of osimertinib (tablet) in combination with Dato-DXd (i.v. infusion) compared with osimertinib ...

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1O: Osimertinib (osi) + datopotamab deruxtecan (Dato-DXd ... Osi + Dato-DXd showed promising efficacy and manageable safety in pts with EGFRm aNSCLC who progressed on 1L osi. There were no new safety signals. Considering ...

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Adding Dato-DXd After Progression on Osimertinib ... Early efficacy data from the phase 2 ORCHARD platform trial suggest that adding datopotamab deruxtecan to osimertinib may stave off disease progression longer ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S1556086425007610

A Pooled Analysis of Datopotamab Deruxtecan in Patients ... Cecere, et al. First-line osimertinib in patients with EGFR-mutant advanced non-small cell lung cancer: outcome and safety in the real world: ...