HERTHENA-Lung01: Patritumab Deruxtecan in Subjects With Metastatic or Locally Advanced EGFR-mutated Non-Small Cell Lung Cancer

• ClinicalTrials.gov Identifier: NCT04619004
• Recruitment Status: Active, not recruiting
• First Posted: November 6, 2020
• Results First Posted: April 2, 2024
• Last Update Posted: April 2, 2024
• Sponsor: Daiichi Sankyo
• Collaborator: Daiichi Sankyo Co., Ltd.
• Information provided by (Responsible Party): Daiichi Sankyo

Tracking Information

• First Submitted Date: October 29, 2020
• First Posted Date: November 6, 2020
• Results First Submitted Date: March 4, 2024
• Results First Posted Date: April 2, 2024
• Last Update Posted Date: April 2, 2024
• Actual Study Start Date: February 2, 2021
• Actual Primary Completion Date: November 21, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 4, 2024)

Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR) [ Time Frame: Data collected from screening until time of disease progression by BICR, death, lost to follow up, study discontinuation, whichever occurs first, assessed up to approximately 21 months ]

ORR is defined as the proportion of participants with a best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) as assessed by BICR per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions based on RECIST v1.1.

Original Primary Outcome Measures (submitted: November 5, 2020)

Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR) [ Time Frame: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months ]

ORR is defined as the proportion of participants with a best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) as assessed by BICR per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

Current Secondary Outcome Measures (submitted: March 4, 2024)

• Duration of Response (DoR) [ Time Frame: Data collected from screening until time of disease progression by BICR, death, lost to follow up, study discontinuation, whichever occurs first, assessed up to approximately 21 months ]
  DoR is defined as the time from the first documented confirmed response (CR or PR) to the date of progression or death due to any cause as assessed by BICR and Investigator per RECIST v1.1, respectively. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions.
• Progression-free Survival (PFS) [ Time Frame: Data collected from screening until time of disease progression by BICR, death, lost to follow up, study discontinuation, whichever occurs first, assessed up to approximately 21 months ]
  PFS is defined as the time from the start of study treatment to the first documentation of objective progressive disease (PD) per RECIST v1.1 or death due to any cause. PFS will be determined by BICR and by Investigator, respectively.
• Objective Response Rate (ORR) as Assessed by the Investigator [ Time Frame: Data collected from screening until time of disease progression, death, lost to follow up, study discontinuation, whichever occurs first, assessed up to approximately 21 months ]
  ORR is defined as the proportion of participants with a BOR of confirmed CR or confirmed PR as assessed by the Investigator per RECIST v1.1. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions.
• Disease Control Rate (DCR) [ Time Frame: Data collected from screening until time of disease progression by BICR, death, lost to follow up, study discontinuation, whichever occurs first, assessed up to approximately 21 months ]
  DCR is defined as the proportion of participants who achieved a BOR of confirmed CR, confirmed PR, or stable disease (SD) as assessed by BICR and by the Investigator per RECIST v1.1, respectively. CR was defined as a disappearance of all target lesions, PR was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions.
• Time to Tumor Response (TTR) [ Time Frame: Data collected from screening until time of disease progression by BICR, death, lost to follow up, study discontinuation, whichever occurs first, assessed up to approximately 21 months ]
  TTR is defined as the time from the start of study treatment to the date of the first documentation of confirmed response (CR or PR) as assessed by BICR and Investigator per RECIST v1.1, respectively. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions.
• Best Percentage Change in the Sum of Diameters (SoD) of Measurable Tumors [ Time Frame: Data collected from screening until time of disease progression by BICR, death, lost to follow up, study discontinuation, whichever occurs first, assessed up to approximately 21 months ]
  The best percentage change in the SoD of measurable tumors is defined as the percentage change in the smallest SoD from all post-baseline tumor assessments, taking as reference the baseline SoD.
• Overall Survival (OS) [ Time Frame: Death date is collected until the participant discontinues the study or up to approximately 45 months ]
  OS defined as the time from the start of study treatment to the date of death due to any cause.
• Incidence of Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events of Special Interest (AESIs) [ Time Frame: From baseline up to Day 47 post last dose ]
  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. Adverse events will be coded using MedDRA and will be graded using NCI-CTCAE v5.0.

Original Secondary Outcome Measures (submitted: November 5, 2020)

• Duration of Response (DoR) [ Time Frame: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months ]
  DoR is defined as the time from the first documented confirmed response (CR or PR) to the date of progression or death due to any cause as assessed by BICR and Investigator per RECIST v1.1, respectively.
• Progression-free Survival (PFS) [ Time Frame: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months ]
  PFS is defined as the time from the start of study treatment to the earlier of the dates of the first documentation of objective progressive disease (PD) per RECIST v1.1 or death due to any cause. PFS will be determined by BICR and by Investigator, respectively.
• Objective Response Rate (ORR) as Assessed by the Investigator [ Time Frame: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months ]
  ORR is defined as the proportion of participants with a BOR of confirmed CR or confirmed PR as assessed by the Investigator per RECIST v1.1.
• Disease Control Rate (DCR) [ Time Frame: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months ]
  DCR is defined as the proportion of participants who achieved a BOR of confirmed CR, confirmed PR, or stable disease (SD) as assessed by BICR and by the Investigator per RECIST v1.1, respectively.
• Time to Tumor Response (TTR) [ Time Frame: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months ]
  TTR is defined as the time from the start of study treatment to the date of the first documentation of confirmed response (CR or PR) as assessed by BICR and Investigator per RECIST v1.1, respectively.
• Best percentage change in the sum of diameters (SoD) of measurable tumors [ Time Frame: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months ]
  The best percentage change in the SoD of measurable tumors is defined as the percentage change in the smallest SoD from all post-baseline tumor assessments, taking as reference the baseline SoD.
• Overall Survival (OS) [ Time Frame: Death date is collected until the participant discontinues the study or up to approximately 26 months ]
  OS defined as the time from the start of study treatment to the date of death due to any cause.
• Incidence of treatment emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) [ Time Frame: From baseline up to Day 47 post last dose ]
  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. Adverse events will be coded using MedDRA and will be graded using NCI-CTCAE v5.0.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: HERTHENA-Lung01: Patritumab Deruxtecan in Subjects With Metastatic or Locally Advanced EGFR-mutated Non-Small Cell Lung Cancer
• Official Title: HERTHENA-Lung01: A Phase 2 Randomized Open-Label Study of Patritumab Deruxtecan (U3-1402) in Subjects With Previously Treated Metastatic or Locally Advanced EGFR-mutated Non-Small Cell Lung Cancer (NSCLC)
• Brief Summary: This study is designed to evaluate the antitumor activity of patritumab deruxtecan in participants with metastatic or locally advanced NSCLC with an activating EGFR mutation (exon 19 deletion or L858R) who have received and progressed on or after at least 1 EGFR TKI and 1 platinum-based chemotherapy-containing regimen.
• Detailed Description: This study will initially randomize participants to one of 2 arms in a 1:1 ratio to receive either a 5.6 mg/kg fixed dose regimen or an up-titration dose regimen of patritumab deruxtecan (HER3-DXd, U3-1402).
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Non-Small Cell Lung Cancer Metastatic
• Non-Small Cell Lung Cancer With Mutation in Epidermal Growth Factor Receptor

Intervention

• Drug: Patritumab Deruxtecan (Fixed dose)
  Patritumab deruxtecan will be dosed at 5.6 mg/kg as an intravenous (IV) infusion administered on Day 1 of each 21-day cycle.
  Other Names:

  • U3-1402
  • HER3-DXd
• Drug: Patritumab Deruxtecan (Up-Titration)
  Patritumab deruxtecan will be dosed as an intravenous (IV) infusion administered at Cycle 1, 3.2 mg/kg; Cycle 2, 4.8 mg/kg; Cycle 3 and subsequent cycles, 6.4 mg/kg administered on Day 1 of each 21-day cycle.
  Other Names:

  • U3-1402
  • HER3-DXd

Study Arms

• Experimental: Study Group 1: Patritumab deruxtecan 5.6 mg/kg
  Study Group 1 will be participants with metastatic or locally advanced NSCLC with an EGFR-activating mutation randomized to receive patritumab deruxtecan 5.6 mg/kg IV every 3 weeks (Q3W)
  Intervention: Drug: Patritumab Deruxtecan (Fixed dose)
• Experimental: Study Group 2: Patritumab deruxtecan Up-Titration
  Study Group 2 will be participants with metastatic or locally advanced NSCLC with an EGFR-activating mutation randomized to receive patritumab deruxtecan up-titration IV every 3 weeks (Q3W)
  Intervention: Drug: Patritumab Deruxtecan (Up-Titration)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 4, 2024): 277
• Original Estimated Enrollment (submitted: November 5, 2020): 300
• Estimated Study Completion Date: November 1, 2024
• Actual Primary Completion Date: November 21, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Participants must meet all of the following criteria to be eligible for inclusion in this study.

• Sign and date the tissue informed consent form (ICF) and the main ICF, prior to the start of any study-specific qualification procedures.
• Male or female participants aged ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is >18 years old).
• Histologically or cytologically documented locally advanced or metastatic NSCLC not amenable to curative surgery or radiation.

• Documentation of radiological disease progression while on/after receiving most recent treatment regimen for locally advanced or metastatic disease. Participants must have received both of the following:

  • Prior treatment with osimertinib. Participants receiving an EGFR TKI at the time of signing informed consent should continue to take the EGFR TKI until 5 days prior to Cycle 1 Day 1. Participants in South Korea known to harbor a clinically actionable genomic alteration in addition to EGFR mutation (e.g., anaplastic lymphoma kinase [ALK] or ROS1 protocol oncogene 1 [ROS1] fusion) for which treatment is available must have also received prior treatment with at least 1 approved genotype-directed therapy, unless unable (i.e., if contraindicated). No new testing for these genomic alterations (e.g., ALK or ROS1 fusion) is required for Screening.
  • Systemic therapy with at least 1 platinum-based chemotherapy regimen.
• Documentation of an EGFR-activating mutation detected from tumor tissue or blood sample: exon 19 deletion or L858R.
• At least 1 measurable lesion confirmed by BICR as per RECIST v1.1

• Consented and willing to provide required tumor tissue of sufficient quantity and of adequate tumor tissue content. Required tumor tissue can be provided as either:

  • Pretreatment tumor biopsy from at least 1 lesion not previously irradiated and amenable to core biopsy OR
  • Archival tumor tissue collected from a biopsy performed within 3 months prior to signing of the tissue consent and since progression while on or after treatment with the most recent cancer therapy regimen.
• Eastern Cooperative Oncology Group Performance Standard of 0 or 1 at Screening.

• Has adequate bone marrow reserve and organ function based on local laboratory data within 14 days prior to Cycle 1 Day 1:

  • Platelet count : ≥100,000/mm^3 or ≥100 × 10^9/L (platelet transfusions are not allowed up to 14 days prior to Cycle 1 Day 1 to meet eligibility)
  • Hemoglobin: ≥9.0 g/dL (transfusion and/or growth factor support is allowed)
  • Absolute neutrophil count: ≥1500/mm^3 or ≥1.5 × 10^9/L
  • Serum creatinine (SCr) or creatinine clearance (CrCl): SCr ≤1.5 × upper limit of normal (ULN), OR CrCl ≥30 mL/min as calculated using the Cockcroft-Gault equation or measured CrCl
  • Aspartate aminotransferase/alanine aminotransferase: ≤3 × ULN (if liver metastases are present, ≤5 × ULN)
  • Total bilirubin: ≤1.5 × ULN if no liver metastases (<3 × ULN in the presence of documented Gilbert's syndrome [unconjugated hyperbilirubinemia] or liver metastases)
  • Serum albumin: ≥2.5 g/dL
  • Prothrombin time (PT) or PT-International normalized ratio (INR) and activated partial thromboplastin time (aPTT)/PTT: ≤1.5 × ULN, except for subjects on coumarin-derivative anticoagulants or other similar anticoagulant therapy, who must have PT-INR within therapeutic range as deemed appropriate by the Investigator

Exclusion Criteria:

Participants meeting any exclusion criteria for this study will be excluded from this study.

• Any previous histologic or cytologic evidence of small cell OR combined small cell/non-small cell disease in the archival tumor tissue or pretreatment tumor biopsy.
• Any history of interstitial lung disease (including pulmonary fibrosis or radiation pneumonitis), has current interstitial lung disease (ILD), or is suspected to have such disease by imaging during screening.

• Clinically severe respiratory compromise (based on Investigator's assessment) resulting from intercurrent pulmonary illnesses including, but not limited to:

  • Any underlying pulmonary disorder (eg, pulmonary emboli within 3 months prior to the study enrollment, severe asthma, severe chronic obstructive pulmonary disease [COPD]), 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 or any form of immunosuppressive therapy prior to enrollment. 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.
• Evidence of clinically active spinal cord compression or brain metastases.

• Inadequate washout period prior to Cycle 1 Day 1, defined as:

  • Whole brain radiation therapy <14 days or stereotactic brain radiation therapy <7 days;
  • Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s) from a previous cancer treatment regimen or clinical study (other than EGFR TKI), <14 days or 5 half-lives, whichever is longer;
  • Monoclonal antibodies, other than immune checkpoint inhibitors, such as bevacizumab (anti-VEGF) and cetuximab (anti-EGFR) <28 days;
  • Immune checkpoint inhibitor therapy <21 days;
  • Major surgery (excluding placement of vascular access) <28 days;
  • Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation <28 days or palliative radiation therapy <14 days; or
  • Chloroquine or hydroxychloroquine <14 days.
• Prior treatment with an anti-human epidermal growth factor receptor 3 (HER3) antibody or single-agent topoisomerase I inhibitor.
• Prior treatment with an antibody drug conjugate (ADC) that consists of any topoisomerase I inhibitor
• Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0, Grade ≤1 or baseline. Participants with chronic Grade 2 toxicities may be eligible at the discretion of the Investigator after consultation with the Sponsor Medical Monitor or designee.

• Has history of other active malignancy within 3 years prior to enrollment, except:

  • Adequately treated non-melanoma skin cancer;
  • Superficial bladder tumors (Ta, Tis, T1);
  • Adequately treated intraepithelial carcinoma of the cervix uteri;
  • Low risk non-metastatic prostate cancer (with Gleason score <7, and following local treatment or ongoing active surveillance);
  • Any other curatively treated in situ disease.
• Uncontrolled or significant cardiovascular disease prior to Cycle 1 Day 1
• Active hepatitis B and/or hepatitis C infection, such as those with serologic evidence of viral infection within 28 days of Cycle 1 Day 1.
• Participant with any human immunodeficiency virus (HIV) infection.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Bulgaria, China, France, Germany, Italy, Japan, Korea, Republic of, Netherlands, Singapore, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT04619004
• Other Study ID Numbers: U31402-A-U201; 2020-000730-17 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Studies 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 from 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.
• URL: https://vivli.org/ourmember/daiichi-sankyo/

• Current Responsible Party: Daiichi Sankyo
• Original Responsible Party: Same as current
• Current Study Sponsor: Daiichi Sankyo
• Original Study Sponsor: Same as current
• Collaborators: Daiichi Sankyo Co., Ltd.

Investigators

• Study Director: Medical Director; Daiichi Sankyo

• PRS Account: Daiichi Sankyo
• Verification Date: March 2024