Dato-DXd ± Osimertinib for Lung Cancer

(TROPION-Lung15 Trial)

Recruiting at 299 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must be taking: EGFR TKIs

Must not be taking: Chemotherapy, Immunotherapy

Disqualifiers: Active 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

Compensation: Varies

Number of Visits: 3

Duration: Variable, until progression or unacceptable toxicity

744 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatments for individuals with non-squamous non-small cell lung cancer (NSCLC) that has progressed despite previous treatment with osimertinib, a common cancer drug. Researchers are examining the effectiveness of Dato-DXd, a potential new drug, on its own or combined with osimertinib, compared to standard chemotherapy. Participants should have specific lung cancer types sensitive to EGFR inhibitors and have experienced cancer progression despite osimertinib treatment. The study aims to determine if these new combinations can slow cancer progression more effectively than standard chemotherapy. As a Phase 3 trial, it represents the final step before FDA approval, offering participants access to potentially groundbreaking treatments.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it excludes those who have used certain cancer therapies recently, so it's best to discuss your specific medications with the trial team.

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

Research has shown that Dato-DXd yields promising results in treating advanced non-small cell lung cancer. In one study, about 35% of patients experienced tumor shrinkage, meaning roughly one in three patients saw positive changes. However, some side effects, such as tiredness and low blood cell counts, were reported, which are common with many cancer treatments.

Osimertinib, already approved by the FDA for certain lung cancers, is generally well-tolerated. It has been widely used and helps many patients live longer. Researchers are still collecting safety information when combined with Dato-DXd, but both drugs have shown promise individually.

This study is in a later phase, indicating some confidence in the treatment's safety. However, side effects can still occur, and individual reactions may vary. Always consult your doctor before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for lung cancer because they offer a fresh approach compared to current options like standard chemotherapy. Dato-DXd is a novel antibody-drug conjugate that specifically targets cancer cells, delivering a potent chemotherapy agent directly to the tumor. This precision reduces harm to healthy cells and potentially limits side effects. When combined with Osimertinib, a targeted therapy that disrupts cancer cell signaling, the treatment could be even more effective. This combination aims to enhance the overall response rate and improve outcomes for patients who might not respond as well to traditional treatments.

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

Research shows that Dato-DXd, which participants in this trial may receive as monotherapy, has promising results for treating advanced non-small cell lung cancer. Studies found that patients lived a median of 14.6 months, and 35% experienced tumor shrinkage with Dato-DXd alone. In this trial, some participants will receive a combination of Dato-DXd with osimertinib (also known as Tagrisso), which has shown positive results in patients with EGFR-mutated lung cancer, particularly those whose cancer worsened after other treatments. Many studies have proven osimertinib effective in treating EGFR-mutated lung cancer. Overall, these treatments have shown potential to improve outcomes for lung cancer patients. ^{1 2 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with non-squamous Non-Small Cell Lung Cancer (NSCLC) who have specific EGFR mutations. They must have shown progression after osimertinib treatment, had ≤2 lines of EGFR TKIs, and be in good physical condition (WHO/ECOG status 0 or 1). Adequate organ function is required.

Inclusion Criteria

I have a measurable tumor that has not been treated with radiation.

My organs and bone marrow are working well.

My lung cancer is non-squamous based on lab tests.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Dato-DXd with or without osimertinib or platinum-based doublet chemotherapy until progression or unacceptable toxicity

Variable, until progression or unacceptable toxicity

Every 3 weeks

End of Treatment

End of treatment visit conducted within 35 days of discontinuation

5 weeks

Follow-up

Participants are monitored for safety assessments 28 (+ 7) days after their last dose of study intervention

5 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Dato-DXd
• Osimertinib

Trial Overview The study compares the effectiveness of Dato-DXd alone or combined with osimertinib against standard platinum-based chemotherapy. The main focus is on how long patients live without their cancer getting worse (progression-free survival).

How Is the Trial Designed?

Group I: Group 3: Platinum-based Doublet Chemotherapy Experimental Treatment 3 Interventions

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.

Group II: Group 2: Dato-DXd Monotherapy Experimental Treatment 1 Intervention

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 III: Group 1: Dato-DXd + Osimertinib Combination Therapy Experimental Treatment 2 Interventions

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.

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

In vitro studies identified the BRAF G469A mutation as a key mechanism of acquired resistance to osimertinib in non-small cell lung cancer cells, indicating that this mutation allows cancer cells to continue growing despite treatment.

Treatment with selumetinib and trametinib was effective in restoring sensitivity to osimertinib and increasing cell death in resistant clones, suggesting potential strategies to overcome resistance in patients with this mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acquired BRAF G469A Mutation as a Resistance Mechanism to First-Line Osimertinib Treatment in NSCLC Cell Lines Harboring an EGFR Exon 19 Deletion. La Monica, S., Minari, R., Cretella, D., et al.[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 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 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 study of 81 Japanese patients with non-small-cell lung cancer (NSCLC) who had the T790M mutation, osimertinib showed a high objective response rate of 63.6% and a median progression-free survival of 13.8 months, indicating its efficacy in this population.

The safety profile of osimertinib was manageable, with most adverse events being mild (grade 1-2), although 6.2% of patients experienced interstitial lung disease, leading to two deaths, highlighting the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib for Japanese patients with T790M-positive advanced non-small-cell lung cancer: A pooled subgroup analysis. Hirashima, T., Satouchi, M., Hida, T., 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 (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 (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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO-24-01349

Results From the Phase II TROPION-Lung05 Study Encouraging and durable antitumor activity was observed with Dato-DXd in this heavily pretreated advanced/metastatic NSCLC population with actionable genomic ...

2. onclive.com onclive.com/view/osimertinib-plus-dato-dxd-shows-efficacy-in-post-osimertinib-egfr-mutated-advanced-nsclc

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 ...

3. astrazeneca.com astrazeneca.com/content/astraz/media-centre/press-releases/2025/new-study-results-reinforce-tagrisso-as-the-backbone-therapy-for-egfr-mutated-lung-cancer-across-stages-and-settings.html

New study results reinforce Tagrisso as the backbone ... In LAURA Phase III trial, Tagrisso continues to demonstrate improved overall survival trend in unresectable, Stage III setting

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06350097

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 ...

5. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2025/New-study-results-reinforce-TAGRISSO-osimertinib-as-the-backbone-therapy-for-EGFR-mutated-lung-cancer-across-stages-and-settings.html

New study results reinforce TAGRISSO® (osimertinib) as ... In LAURA Phase III trial, TAGRISSO continues to demonstrate improved overall survival trend in unresectable, Stage III setting.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06350097

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 ...

7. astrazeneca.com astrazeneca.com/content/astraz/media-centre/press-releases/2025/datopotamab-deruxtecan-granted-priority-review-in-the-us-for-patients-with-previously-treated-advanced-egfr-mutated-non-small-cell-lung-cancer.html

Datopotamab deruxtecan granted Priority Review in the US ... Datopotamab deruxtecan (Dato-DXd) has been accepted and granted Priority Review in the US for the treatment of adult patients with locally advanced or ...

8. 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.