HER3-DXd (Patritumab Deruxtecan; U3-1402) in Combination With Osimertinib in Subjects With Locally Advanced or Metastatic EGFR-mutated Non-Small Cell Lung Cancer

NCT04676477 | Active Not Recruiting Phase 1 FDA Drug

• 2 other identifiers: U31402-A-U1032020-003064-87
• Study Type: interventional
• Target: 246
• Locations: 4 countries
• Sites: 31

Brief Summary

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.

Conditions

Non-Small Cell Lung Cancer (NSCLC)

Keywords

Advanced Non-small Cell Lung Cancer; Inoperable Non-small Cell Lung Cancer; HER3-DXd (Patritumab Deruxtecan; U3-1402); Unresectable; Epidermal growth factor receptor; Metastatic; EGFR; Osimertinib; HER3

Outcome Measures

Primary Outcomes (2)

• Dose Escalation: Incidence of Dose-limiting Toxicities (DLT), Treatment-emergent Adverse Events (TEAE), Serious Adverse Events (SAE), Adverse Events of Special Interest (AESI)

  A DLT is defined as any TEAE not attributable to disease or disease-related processes that occurs during the DLT evaluation period and is ≥Grade 3, as defined in the protocol. A TEAE is defined as an adverse event (AE) with a start or worsening date during the on-treatment period. A serious AE is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is an important medical event, or may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes noted. AESIs will also be assessed. AEs will be coded using MedDRA and graded using NCI-CTCAE v5.0.

  From signing of informed consent form up to 40 days (+7 days) after the last dose of study drugs, up to approximately 9 months

• Second-line Dose Expansion and First-line Dose Expansion: Objective Response Rate (ORR)

  ORR is defined as the proportion of participants who achieved a best overall response of confirmed complete response (CR) or confirmed partial response (PR) as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors version (RECIST) v1.1.

  From start of study treatment until date of documented disease progression or other protocol-defined reason for discontinuation from the study (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 18 months

Secondary Outcomes (13)

• Dose Escalation: Objective Response Rate (ORR)

  From start of treatment until date of disease progression or other reason for discontinuation (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 9 months (Dose Escalation) and 18 months (Dose Expansion)

• Second-line Dose Expansion and First-line Dose Expansion: Objective Response Rate (ORR)

  From start of study treatment until the date of documented disease progression or other protocol-defined reason for discontinuation from the study (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 18 months

• Dose Escalation, Second-line Dose Expansion, and First-Line Dose Expansion: Duration of Response (DoR)

  From start of treatment until date of disease progression or other reason for discontinuation (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 9 months (Dose Escalation) and 18 months (Dose Expansion)

• Second-line Dose Expansion: Clinical Benefit Rate (CBR)

  From start of treatment until date of disease progression or other reason for discontinuation (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 9 months (Dose Escalation) and 18 months (Dose Expansion)

• Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Disease Control Rate (DCR)

  From start of treatment until date of disease progression or other reason for discontinuation (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 9 months (Dose Escalation) and 18 months (Dose Expansion)

Study Arms (6)

Dose Escalation: HER3-DXd + osimertinib

EXPERIMENTAL

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.

Drug: HER3-DXd; Drug: Osimertinib

Second-line Dose Expansion: HER3-DXd + osimertinib (RCD)

EXPERIMENTAL

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

Drug: HER3-DXd; Drug: Osimertinib

Second-line Dose Expansion: HER3-DXd

EXPERIMENTAL

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

Drug: HER3-DXd

First-line Dose Expansion: HER3-DXd + osimertinib (Cohort 3; RCD)

EXPERIMENTAL

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

Drug: HER3-DXd; Drug: Osimertinib

First-line Dose Expansion: HER3-DXd + osimertinib (Cohort 4a)

EXPERIMENTAL

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.

Drug: HER3-DXd; Drug: Osimertinib

First-line Dose Expansion: HER3-DXd + osimertinib (Cohort 4b)

EXPERIMENTAL

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.

Drug: HER3-DXd; Drug: Osimertinib

Interventions

HER3-DXd DRUG

Intravenous infusion at a starting dose of 3.2 mg/kg Q3W

Also known as: U3-1402, Patritumab deruxtecan

Dose Escalation: HER3-DXd + osimertinib

Osimertinib DRUG

Oral administration at 40 mg or 80 mg once daily

Dose Escalation: HER3-DXd + osimertinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Documentation of EGFR exon 19 deletion or L858R mutation detected from tumor tissue
• Must have received osimertinib for locally advanced or metastatic disease at a dose of 80 mg once daily (QD) for at least 6 weeks and must not miss more than two doses during the 2 weeks prior to the first day of study treatment (Cycle 1, Day 1)
• Must not have received any other prior systemic cancer therapies in the locally advanced/metastatic setting
• Has documentation of radiological disease progression following first-line treatment with osimertinib in the locally advanced or metastatic setting
• The tumor tissue harbors one of the 2 common EGFR mutations occurring in NSCLC known to be associated with EGFR-TKI sensitivity (exon 19 deletion or L858R) as assessed by Clinical Laboratory Improvement Amendments (CLIA)-certified (United States \[US\] sites), accredited (outside of the US), local laboratory or central laboratory. Only tissue-based testing will be accepted.
• Participants must have previously untreated locally advanced or metastatic NSCLC and must be eligible to receive first-line treatment with osimertinib, according to the judgment of the investigator. Prior adjuvant or neo-adjuvant therapy (chemotherapy, radiotherapy, investigational agents; except with osimertinib) is permitted.
• All Participants:
• Histologically or cytologically documented locally advanced or metastatic NSCLC not amenable to curative surgery or radiation.
• At least 1 measurable lesion as assessed by Investigator as per Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
• Tissue requirements
• For Dose Escalation (all cohorts): provide an optional pre-treatment tumor tissue of sufficient quantity, as defined in the laboratory manual. The optional pre-treatment tumor tissue can be provided as either:
• Pre-treatment tumor biopsy from at least 1 lesion not previously irradiated and amenable to core biopsy OR
• Archival tissue collected from a biopsy performed prior to signing of the tissue consent, and since progression while on treatment with the most recent cancer therapy
• For First-line Dose Expansion (Cohorts 3, 4a, and 4b): provide an optional pre-treatment and optional on-treatment tumor tissues of sufficient quantity, as defined in the laboratory manual. The optional pre-treatment tumor tissue can be provided as either:
• Pre-treatment tumor biopsy from at least 1 lesion not previously irradiated and amenable to core biopsy OR

You may not qualify if:

• Any previously documented histologic or cytologic evidence of small cell OR combined small cell/non-small cell disease
• Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required corticosteroid therapy, has current ILD, or is suspected to have such disease by imaging during screening.
• Clinically severe pulmonary compromise (based on Investigator's assessment) resulting from intercurrent pulmonary illnesses including, but not limited to:
• Any underlying pulmonary disorder (eg, pulmonary emboli within three months of the study enrollment or randomization, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion);
• Any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis); OR prior complete pneumonectomy.
• Is receiving chronic systemic corticosteroids dosed at \>10 mg prednisone or equivalent anti-inflammatory activity or any form of immunosuppressive therapy prior to Cycle 1, Day 1. Participants who require use of bronchodilators, inhaled or topical steroids, or local steroid injections may be included in the study.
• Evidence of any leptomeningeal disease.
• Has spinal cord compression or clinically active central nervous system metastases, defined as symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Participants with clinically inactive brain metastases may be included in the study. Participants with treated brain metastases who are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study, but must have a stable neurologic status for at least 4 weeks prior to Cycle 1, Day 1. Participants with asymptomatic brain metastases and treated with anticonvulsants as prophylaxis are able to enroll following a 14-day washout period. Note: A CT or MRI scan of the brain at baseline is required for all participants.
• Inadequate washout period prior to Cycle 1, Day 1 defined as:
• Whole brain radiation therapy \<28 days or stereotactic brain radiation therapy \<7 days;
• Any systemic anticancer therapy (excluding osimertinib in all Dose Escalation Cohorts and in Second-line Dose Expansion \[Arm 1, Arm 2, and Arm 1b\]), including investigational agents, \<14 days or 5 half-lives, whichever is longer
• Immune checkpoint inhibitor therapy ≤21 days
• Major surgery (excluding placement of vascular access) \<4 weeks
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation \< 28 days or palliative radiation therapy \<7 days
• Chloroquine or hydroxychloroquine ≤14 days

Sponsors & Collaborators

• Daiichi Sankyo: lead
• AstraZeneca: collaborator
• Merck Sharp & Dohme LLC: collaborator

Study Sites (31)

UCLA

Santa Monica, California, 90404, United States

Location

Yale University School of Medicine - Yale-New Haven Hospital

New Haven, Connecticut, 06510, United States

Location

Georgetown University Medical Center

Washington D.C., District of Columbia, 20057, United States

Location

Northwestern University Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Henry Ford Cancer Institute

Detroit, Michigan, 48202, United States

Location

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, 03756, United States

Location

Columbia University Irving Medical Center

New York, New York, 10032, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Sarah Cannon and HCA Research Institute

Nashville, Tennessee, 37203, United States

Location

Virginia Cancer Specialists, PC

Fairfax, Virginia, 22031, United States

Location

National Hospital Organization Shikoku Cancer Center

Matsuyama, Ehime, 791-0280, Japan

Location

National Hospital Organization Kyushu Cancer Center

Fukuoka, Fukuoka, 811-1395, Japan

Location

National Hospital Organization Hokkaido Cancer Center

Sapporo, Hokkaido, 003-0804, Japan

Location

Kanagawa Cancer Center

Yokohama, Kanagawa, 241-8515, Japan

Location

Okayama University Hospital

Okayama, Okayama-ken, 700-8558, Japan

Location

National Cancer Center Hospital

Chuo Ku, Tokyo, 104-0045, Japan

Location

National Hospital Organization Iwakuni Clinical Center

Iwakuni-shi, Yamaguchi, 740-8510, Japan

Location

Kindai University Hospital

Ōsaka-sayama, 589-8511, Japan

Location

Shizuoka Cancer Center

Shizuoka, 411-8777, Japan

Location

The Cancer Institute Hospital of JFCR

Tokyo, 135-8550, Japan

Location

Seoul National University Hospital

Seoul, 03080, South Korea

Location

Yonsei University Health System - Severance Hospital

Seoul, 03722, South Korea

Location

Asan Medical Center

Seoul, 05505, South Korea

Location

Samsung Medical Center

Seoul, 06351, South Korea

Location

Chung Shan Medical University Hospital

Taichung, 40201, Taiwan

Location

National Taiwan University Hospital

Taipei, 100, Taiwan

Location

Taipei Medical University Hospital

Taipei, 110301, Taiwan

Location

Taipei Veterans General Hospital

Taipei, 11217, Taiwan

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Neoplasm Metastasis

Interventions

patritumab deruxtecan; osimertinib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Global Clinical Leader

  Daiichi Sankyo

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 15, 2020
• First Posted: December 21, 2020
• Study Start: June 11, 2021
• Primary Completion: January 31, 2025
• Study Completion (Estimated): April 30, 2027
• Last Updated: June 22, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Completed studies that has reached a global end or completion with all data set collected and analyzed, and for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents on completed clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.

Locations

US (13); TW (4); KR (4); JP (10)