Dato-DXd ± Osimertinib for Lung Cancer

(TROPION-Lung15 Trial)

Recruiting at 240 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

630 Participants Needed

Trial Summary

What is the purpose of this trial?

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).

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.

What safety information is available for the treatment Dato-DXd ± Osimertinib for lung cancer?

Osimertinib, used in treating certain types of lung cancer, has been generally well tolerated in studies, with common side effects including diarrhea, rash, dry skin, and nail issues. Serious side effects occurred in some patients, such as interstitial lung disease, which can be severe. Overall, it has a manageable safety profile with no new safety concerns identified in recent studies. ^{1 2 3 4 5}

What makes the drug Dato-DXd ± Osimertinib unique for lung cancer treatment?

Dato-DXd combined with Osimertinib is unique because it targets specific mutations in lung cancer cells, with Osimertinib being a third-generation drug that focuses on the EGFR T790M mutation, which is often resistant to other treatments. This combination aims to improve effectiveness by addressing resistance mechanisms in non-small cell lung cancer. ^{1 6 7 8 9}

Eligibility Criteria

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

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

Treatment Details

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).

Participant Groups

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 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.

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

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.

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) 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 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]

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 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]

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]

References

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

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

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

New Adjuvant Drug for Lung Cancer. [2023]

3. France pubmed.ncbi.nlm.nih.gov

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

4. England pubmed.ncbi.nlm.nih.gov

Osimertinib for Japanese patients with T790M-positive advanced non-small-cell lung cancer: A pooled subgroup analysis. [2022]

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

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

6. 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]

7. France 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. [2022]

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

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

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

Osimertinib: First Global Approval. [2022]