U3-1402 for Non-Small Cell Lung Cancer

Recruiting at 30 trial locations

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

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Daiichi Sankyo

Must be taking: EGFR TKIs

Must not be taking: Anti-HER3, Topoisomerase I inhibitors

Disqualifiers: Small cell histology, ILD, others

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

Compensation: Varies

Number of Visits: 6

309 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called HER3-DXd (also known as U3-1402) to determine its safety and ability to shrink tumors in people with non-small cell lung cancer (NSCLC) that has spread or cannot be surgically removed. The trial has two main parts: one for those whose cancer has a mutation and has progressed despite previous treatments, and another for those with a specific mutation called KRAS-G12C after trying other treatments. Suitable candidates include those with advanced NSCLC, for whom surgery isn't an option, and who have experienced disease progression despite prior therapy. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

If you are currently taking erlotinib, gefitinib, afatinib, or osimertinib, you will need to stop these medications to participate in the trial. The protocol does not specify about other medications, so it's best to discuss with the study team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that HER3-DXd, also known as U3-1402, has been tested for safety in treating non-small cell lung cancer (NSCLC). In one study, 47 patients received HER3-DXd at a dose of 5.6 mg/kg every three weeks. The results suggested that most participants tolerated the treatment well.

While some side effects occurred, they were mostly manageable. Common issues included tiredness, nausea, and low blood cell counts, while serious side effects were less common. This indicates that, even in early studies, the treatment appears safe for people with advanced NSCLC.

Overall, HER3-DXd remains under investigation, but early data suggests it could be a promising option for further research in clinical trials. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for non-small cell lung cancer?

Researchers are excited about U3-1402 for non-small cell lung cancer (NSCLC) because it targets a specific protein called HER3, which is overexpressed in many cancers and not directly addressed by current treatments. Unlike standard treatments that target EGFR or KRAS mutations directly, U3-1402 uses an antibody-drug conjugate to deliver chemotherapy precisely to cancer cells, potentially reducing side effects and enhancing effectiveness. This targeted approach could lead to improved outcomes for patients with advanced or resistant forms of NSCLC, offering hope where traditional therapies may fall short.

What evidence suggests that this trial's treatment could be effective for non-small cell lung cancer?

Research shows that HER3-DXd, also known as U3-1402, may help treat non-small cell lung cancer (NSCLC) with certain genetic changes. In this trial, participants with NSCLC and EGFR mutations will receive HER3-DXd in various dose expansion cohorts. Previous studies have shown that in patients with NSCLC who have EGFR mutations and have already tried other treatments, HER3-DXd significantly increased the time they lived without their cancer worsening. Another study found that HER3-DXd helped patients live longer overall. These studies suggest that HER3-DXd could be an effective treatment option for NSCLC, especially for those with specific genetic changes in their cancer. ^{2 6 7 8 9}

Who Is on the Research Team?

Global Clinical Lead

Principal Investigator

Daiichi Sankyo

Are You a Good Fit for This Trial?

This trial is for adults with advanced or inoperable non-small cell lung cancer (NSCLC) who have previously been treated with EGFR tyrosine kinase inhibitors. Participants must have at least one measurable lesion, be in good physical condition (ECOG status of 0 or 1), and not have other active cancers or serious heart conditions.

Inclusion Criteria

My cancer has a specific EGFR mutation.

You have at least one specific area of your body that can be measured to see if the treatment is working.

I am currently taking a specific cancer medication but can stop if needed.

Exclusion Criteria

You have any important irregularities in your resting electrocardiogram (ECG).

My cancer biopsy shows small cell or mixed small cell and non-small cell features.

I cannot or will not stop taking medications that may affect my heart's rhythm.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

HER3-DXd is evaluated in participants with metastatic or unresectable NSCLC with EGFR activating mutation after disease progression during/after EGFR TKI therapy to assess safety and tolerability and determine the recommended dose for expansion

Approximately 36 months

Every 3 weeks

Dose Expansion

HER3-DXd is evaluated in participants with metastatic or unresectable NSCLC with EGFR activating mutation or squamous or non-squamous NSCLC with disease progression during/after systemic treatment for locally advanced or metastatic disease to investigate antitumor activity

Approximately 36 months

Every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Approximately 24 months

What Are the Treatments Tested in This Trial?

Interventions

• U3-1402

Trial Overview The study tests U3-1402, a new drug for NSCLC. It has two parts: Dose Escalation to find the safe dosage for those with an EGFR mutation after TKI therapy failure, and Dose Expansion to assess effectiveness in broader NSCLC cases post systemic treatment failure.

How Is the Trial Designed?

Group I: Dose Expansion: Cohort 5, KRAS-G12C mutant NSCLC Experimental Treatment 1 Intervention

Participants with locally advanced or metastatic NSCLC whose tumors harbor a KRAS-G12C mutation and that have progressed on the most recent line of therapy will receive HER3-DXd IV at 5.6 mg/kg every 3 weeks.

Group II: Dose Expansion: Cohort 4, EGFR mutant Experimental Treatment 1 Intervention

Participants with NSCLC (including any histology other than small-cell or combined small-cell and non-small cell) with an EGFR-activating mutation will receive HER3-DXd IV at 5.6 mg/kg every 3 weeks.

Group III: Dose Expansion: Cohort 3b, EGFR mutant Experimental Treatment 1 Intervention

Randomized participants with NSCLC and EGFR mutations in the Dose Expansion Cohort 3b will receive HER3-DXd IV once every three weeks following an up-titration regimen (Cycle 1, Day 1: 57% of RDE or aRDE; Cycle 2, Day 1: 86% of RDE or, if applicable aRDE; Cycle 3 and subsequent cycles, Day 1: 114% of RDE or aRDE).

Group IV: Dose Expansion: Cohort 3a, EGFR mutant Experimental Treatment 1 Intervention

Randomized participants with NSCLC and EGFR mutations in the Dose Expansion Cohort 3a will receive HER3-DXd IV once every three weeks at the established recommended dose for expansion (RDE) or, if applicable, adjusted RDE (aRDE).

Group V: Dose Expansion: Cohort 2, EGFR wild-type Experimental Treatment 1 Intervention

Participants with squamous or non-squamous NSCLC without EGFR-activating mutations in the Dose Expansion Cohort 2 will receive HER3-DXd IV once every three weeks at the established recommended dose for expansion (RDE).

Group VI: Dose Expansion: Cohort 1, EGFR mutant Experimental Treatment 1 Intervention

Participants with adenocarcinoma NSCLC with EGFR mutations in the Dose Expansion Cohort 1 will receive HER3-DXd IV once every three weeks at the established recommended dose for expansion (RDE).

Group VII: Dose Escalation: Cohort 4, 6.4 mg/kg Experimental Treatment 1 Intervention

Participants in Dose Escalation Cohort 3 will receive HER3-DXd intravenously (IV) once every three weeks at 6.4 mg/kg.

Group VIII: Dose Escalation: Cohort 3, 5.6 mg/kg Experimental Treatment 1 Intervention

Participants in Dose Escalation Cohort 3 will receive HER3-DXd intravenously (IV) once every three weeks at 5.6 mg/kg.

Group IX: Dose Escalation: Cohort 2, 4.8 mg/kg Experimental Treatment 1 Intervention

Participants in Dose Escalation Cohort 2 will receive HER3-DXd intravenously (IV) once every three weeks at 4.8 mg/kg.

Group X: Dose Escalation: Cohort 1, 3.2 mg/kg Experimental Treatment 1 Intervention

Participants in the Dose Escalation Cohort 1 will receive HER3-DXd intravenously (IV) once every three weeks at 3.2 mg/kg.

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

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

Published Research Related to This Trial

Patritumab deruxtecan, an antibody-drug conjugate targeting HER3, was analyzed using pharmacokinetics data from 425 patients with solid tumors, showing a well-defined clearance and distribution profile that supports its use in clinical settings.

The study found that factors like weight, albumin levels, sex, and tumor type had mild effects on drug exposure, indicating that no significant dose adjustments are needed for different patient subpopulations in future treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Patritumab Deruxtecan in Patients With Solid Tumors. Lu, Y., Shimizu, S., Sawamura, R., et al.[2023]

The study is investigating the HER3-directed antibody drug conjugate patritumab deruxtecan (HER3-DXd) in patients with HR-positive/HER2-negative early breast cancer, focusing on its biological effects after a single dose.

The primary endpoint is to assess the CelTIL score, which will help evaluate the drug's impact on the tumor microenvironment and resistance mechanisms, providing valuable insights into its efficacy and potential as a treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SOLTI-1805 TOT-HER3 Study Concept: A Window-of-Opportunity Trial of Patritumab Deruxtecan, a HER3 Directed Antibody Drug Conjugate, in Patients With Early Breast Cancer. Pascual, T., Oliveira, M., Ciruelos, E., et al.[2021]

In a phase II study involving 225 patients with advanced EGFR-mutated non-small-cell lung cancer, HER3-DXd demonstrated a confirmed objective response rate of 29.8%, indicating meaningful efficacy after prior treatments with EGFR tyrosine kinase inhibitors and platinum-based chemotherapy.

The safety profile of HER3-DXd was manageable and tolerable, with median overall survival of 11.9 months and notable efficacy in patients with nonirradiated brain metastases, showing a CNS objective response rate of 33.3%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy. Yu, HA., Goto, Y., Hayashi, H., et al.[2023]

Patritumab deruxtecan (HER3-DXd) showed promising efficacy in treating advanced breast cancer, with objective response rates of 30.1% in hormone receptor-positive/HER2-negative patients and 42.9% in HER2-positive patients, indicating its potential as a treatment option for various breast cancer subtypes.

The safety profile of HER3-DXd was manageable, with common treatment-emergent adverse events including gastrointestinal and hematologic toxicities; however, 71.4% of patients experienced grade ≥3 adverse events, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patritumab Deruxtecan (HER3-DXd), a Human Epidermal Growth Factor Receptor 3-Directed Antibody-Drug Conjugate, in Patients With Previously Treated Human Epidermal Growth Factor Receptor 3-Expressing Metastatic Breast Cancer: A Multicenter, Phase I/II Trial. Krop, IE., Masuda, N., Mukohara, T., et al.[2023]

Patritumab deruxtecan (HER3-DXd) is a promising new treatment for EGFR-mutated non-small cell lung cancer (NSCLC) that has progressed after standard therapies, showing antitumor activity and a tolerable safety profile in an ongoing phase I study.

HER3-DXd targets the HER3 receptor, which is often overexpressed in EGFR-mutated NSCLC, and is currently being further evaluated in a global phase II trial (HERTHENA-Lung01) to confirm its efficacy in patients who have already received other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HERTHENA-Lung01: a phase II study of patritumab deruxtecan (HER3-DXd) in previously treated metastatic EGFR-mutated NSCLC. Yu, HA., Yang, JC., Hayashi, H., et al.[2023]

In a study of 77 patients with early breast cancer, a single dose of patritumab deruxtecan (HER3-DXd) significantly increased the CelTIL score, indicating enhanced immune infiltration and a shift towards a less proliferative tumor phenotype.

The treatment showed a clinical response rate of 45% among patients, with most experiencing manageable side effects, suggesting HER3-DXd has a tolerable safety profile and warrants further investigation in early breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patritumab deruxtecan in untreated hormone receptor-positive/HER2-negative early breast cancer: final results from part A of the window-of-opportunity SOLTI TOT-HER3 pre-operative study. Oliveira, M., Falato, C., Cejalvo, JM., et al.[2023]

HER3 is commonly found in EGFR-mutant non-small cell lung cancer (NSCLC), making it an important target for treatment, especially in cases resistant to EGFR tyrosine kinase inhibitors.

Early clinical data suggest that patritumab deruxtecan may be an effective treatment option for patients with previously treated EGFR-mutant NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patritumab Deruxtecan: Paving the Way for EGFR-TKI-Resistant NSCLC. Lim, SM., Kim, CG., Lee, JB., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38369013/

Translational insights and overall survival in the U31402-A- ... Conclusions: In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.8506

Patritumab deruxtecan (HER3-DXd) in resistant <i>EGFR</i> HER3-DXd demonstrated statistically significant improvement in PFS vs PBC in pts with EGFRm NSCLC post EGFR TKI therapy.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03260491

U3-1402 in Metastatic or Unresectable Non-Small Cell ... This study was designed to evaluate safety and antitumor activity of HER3-DXd in two parts: Dose Escalation and Dose Expansion.

4. annalsofoncology.org annalsofoncology.org/article/S0923-7534(24)00047-4/fulltext

Translational insights and overall survival in the U31402-A- ... Translational insights and overall survival in the U31402-A-U102 study of patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC

5. merck.com merck.com/news/patritumab-deruxtecan-demonstrated-statistically-significant-improvement-in-progression-free-survival-versus-doublet-chemotherapy-in-patients-with-locally-advanced-or-metastatic-egfr-mutated-non-small/

Patritumab Deruxtecan Demonstrated Statistically ... Daiichi Sankyo and Merck's patritumab deruxtecan demonstrates a statistically significant progression-free survival improvement in this EGFR-mutated non-small ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.9017

Efficacy and safety of patritumab deruxtecan (HER3-DXd) ... These data show promising clinical activity in pts with NSCLC without EGFRm, including pts with other identified driver genomic alterations.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9401524/

Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in ... This phase I, dose escalation/expansion study included patients with locally advanced or metastatic EGFR-mutated non–small cell lung cancer (NSCLC) with prior ...

8. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(25)00465-6/abstract

Patritumab deruxtecan (HER3-DXd) in patients with active ... Patritumab deruxtecan (HER3-DXd) in patients with active brain metastases of non-small-cell lung cancer (TUXEDO-3): a multicentre, single-arm, phase 2 trial.

9. jto.org jto.org/article/S1556-0864(22)01660-4/fulltext

PP01.48 Efficacy and Safety of Patritumab Deruxtecan ... At the 28 January 2022 data cutoff (DCO), 47 patients were treated with HER3-DXd 5.6 mg/kg IV Q3W; 21 patients had an identified driver genomic alteration (4 ...