HER3-DXd + Osimertinib for Non-Small Cell Lung Cancer

Recruiting at 32 trial locations

Overseen By (Japan sites) Daiichi Sankyo Contact for Clinical Trial Information

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Daiichi Sankyo

Must be taking: Osimertinib

Must not be taking: Corticosteroids, Anticonvulsants, Chloroquine, others

Disqualifiers: Small cell disease, ILD, CNS metastases, others

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

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

Compensation: Varies

Number of Visits: 42

280 Participants Needed

Trial Summary

What is the purpose of this trial?

This study includes a Dose Escalation Part to identify the recommended combination dose (RCD) and a Dose Expansion Part to further evaluate efficacy and safety. The primary objectives: Dose Escalation: To assess the safety and tolerability of HER3-DXd (patritumab deruxtecan; U3-1402) and osimertinib in subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with an EGFR exon 19 deletion or L858R mutation with tumor progression after treatment with osimertinib, and to determine the recommended combination dose (RCD). Second-Line Dose Expansion Arm 1 and Arm 1b: To assess the preliminary antitumor activity of HER3-DXd and osimertinib in subjects with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation with tumor progression after treatment with osimertinib. Note: One or both of the study arms may open with one or two distinct dosing schedules. Second-Line Dose Expansion Arm 2: To assess the preliminary antitumor activity of HER3-DXd monotherapy in subjects with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation with tumor progression after treatment with osimertinib. First-Line Dose Expansion Cohorts 3, 4a, and 4b: To assess the preliminary antitumor activity of HER3-DXd and osimertinib in subjects with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation without prior systemic treatment for locally advanced or metastatic disease.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention a washout period for certain treatments. It's best to discuss your specific medications with the trial team to understand any potential requirements.

What data supports the effectiveness of the drug Osimertinib for treating non-small cell lung cancer?

Osimertinib has been shown to be effective in treating non-small cell lung cancer with specific genetic mutations, leading to 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 HER3-DXd and Osimertinib safe for humans?

Osimertinib has been generally well tolerated in clinical trials for non-small cell lung cancer, with common side effects including diarrhea, rash, dry skin, and nail issues. Serious side effects occurred in some patients, leading to treatment discontinuation in a small percentage. No new safety concerns were identified in recent studies. ^{2 3 5 6 7}

What makes the drug combination of HER3-DXd and Osimertinib unique for treating non-small cell lung cancer?

The combination of HER3-DXd and Osimertinib is unique because it targets specific genetic mutations in non-small cell lung cancer (NSCLC), with Osimertinib focusing on the EGFR T790M mutation, a common resistance mechanism, and HER3-DXd potentially enhancing the treatment's effectiveness by targeting the HER3 receptor, which is involved in cancer cell growth. ^{1 2 3 4 5}

Research Team

Global Clinical Leader

Principal Investigator

Daiichi Sankyo

Eligibility Criteria

This trial is for adults with advanced or metastatic non-small cell lung cancer (NSCLC) that has specific mutations (EGFR exon 19 deletion or L858R). Participants must have progressed after osimertinib treatment, not received other systemic cancer therapies in the advanced setting, and have adequate organ function. Those with significant cardiovascular disease, uncontrolled diseases, certain lung conditions, active brain metastases requiring steroids or anticonvulsants, a history of interstitial lung disease, or on high-dose corticosteroids are excluded.

Inclusion Criteria

I have advanced lung cancer and haven't been treated with osimertinib yet.

Participants must meet all criteria to be eligible for inclusion in this study

My lung cancer cannot be cured with surgery or radiation.

Exclusion Criteria

My side effects from previous cancer treatments are mostly gone or mild.

I am on long-term steroids or immunosuppressants, but I can use inhaled or topical steroids.

I do not have active brain metastases requiring steroids or seizure medications.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive HER3-DXd and osimertinib to assess safety, tolerability, and determine the recommended combination dose (RCD)

9 months

Every 21 days

Dose Expansion

Participants receive HER3-DXd and osimertinib to evaluate efficacy and safety in both first-line and second-line settings

18 months

Every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Osimertinib
• Patritumab Deruxtecan

Trial Overview The study tests HER3-DXd combined with osimertinib to find the safest dose and assess its effectiveness against NSCLC. It includes initial dose escalation to determine the recommended combination dose followed by expansion phases to evaluate efficacy in different patient groups based on prior treatments.

Participant Groups

Group I: Second-line Dose Expansion: HER3-DXd + osimertinib (RCD) Experimental Treatment 2 Interventions

Participants in the Second-line Dose Expansion phase will be randomized to receive HER3-DXd + osimertinib at the RCD

Group II: Second-line Dose Expansion: HER3-DXd Experimental Treatment 1 Intervention

Participants in the Second-line Dose Expansion phase will be randomized to receive HER3-DXd 5.6 mg/kg IV Q3W

Group III: First-line Dose Expansion: HER3-DXd + osimertinib (Cohort 4b) Experimental Treatment 2 Interventions

Participants in the First-line Dose Expansion phase will be randomized to receive HER3-DXd 4.8 mg/kg IV Q3W and osimertinib dose of 80 mg PO once daily.

Group IV: First-line Dose Expansion: HER3-DXd + osimertinib (Cohort 4a) Experimental Treatment 2 Interventions

Participants in the First-line Dose Expansion phase will be randomized to receive HER3-DXd 5.6 mg/kg IV Q3W and osimertinib dose of 80 mg PO once daily.

Group V: First-line Dose Expansion: HER3-DXd + osimertinib (Cohort 3; RCD) Experimental Treatment 2 Interventions

If the RCD includes an osimertinib dose of 80 mg PO once daily, then participants will receive treatment with HER3-DXd and osimertinib at the RCD

Group VI: Dose Escalation: HER3-DXd + osimertinib Experimental Treatment 2 Interventions

Participants in the Dose Escalation phase will receive HER3-DXd IV Q3W + osimertinib PO once daily. The dose of HER3-DXd in the first cohort will be 3.2 mg/kg Q3W. The dose of osimertinib in the first cohort will be 80 mg PO once daily.

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?

Daiichi Sankyo

Lead 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

Daiichi Sankyo, Inc.

Lead Sponsor

Trials

390

Recruited

442,000+

Yuki Abe

Daiichi Sankyo, Inc.

Chief Medical Officer since 2022

MD

Hiroyuki Okuzawa

Daiichi Sankyo, Inc.

Chief Executive Officer

Degree in Social Sciences from Hitotsubashi University

AstraZeneca

Industry 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

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

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 (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 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 (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 significantly improves progression-free survival (PFS) in patients with metastatic non-small cell lung cancer (NSCLC) with the EGFR T790M mutation, showing a median PFS of 10.1 months compared to 4.4 months with chemotherapy in a trial of 419 patients.

The safety profile of osimertinib is favorable compared to other EGFR tyrosine kinase inhibitors and chemotherapy, with common side effects including diarrhea and rash, making it a viable treatment option for patients who have progressed on previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Benefit-Risk Assessment of Osimertinib for the Treatment of Metastatic Non-Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor T790M Mutation. Odogwu, L., Mathieu, L., Goldberg, KB., 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]

References

1. 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]

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

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

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

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

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

Osimertinib: First Global Approval. [2022]

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

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

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

FDA Benefit-Risk Assessment of Osimertinib for the Treatment of Metastatic Non-Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor T790M Mutation. [2022]

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

New Adjuvant Drug for Lung Cancer. [2023]