Brief Summary
Disease progression is typical for patients with epidermal growth factor receptor mutated (EGFRm) non-small cell lung cancer (NSCLC). Standard platinum-based chemotherapy offers limited efficacy and an unfavorable safety profile.There is an urgent need for more effective and tolerable therapies for patients with EGFRm NSCLC who have exhausted available targeted therapies. Clinical evidence suggest that patritumab deruxtecan constitutes a promising investigational therapy for patients with EGFRm NSCLC.
Brief Title
HERTHENA-Lung02: A Study of Patritumab Deruxtecan Versus Platinum-based Chemotherapy in Metastatic or Locally Advanced EGFRm NSCLC After Failure of EGFR TKI Therapy
Detailed Description
Patritumab deruxtecan (HER3-DXd, U3-1402) is an antibody-drug conjugate (ADC) comprising an anti-HER3 mAb linked to a topoisomerase I inhibitor that is in clinical development for patients with NSCLC, metastatic breast cancer, and colorectal cancer.
The primary objective of the current study is to compare the efficacy of patritumab deruxtecan versus platinum-based chemotherapy, as measured by progression-free survival (PFS) and the key secondary endpoint of overall survival (OS), in participants with metastatic or locally advanced NSCLC with an EGFR-activating mutation (exon 19 deletion or L858R) after failure of third-generation (eg, osimertinib, lazertinib, aumolertinib, alflutinib) EGFR TKI therapy.
The primary objective of the current study is to compare the efficacy of patritumab deruxtecan versus platinum-based chemotherapy, as measured by progression-free survival (PFS) and the key secondary endpoint of overall survival (OS), in participants with metastatic or locally advanced NSCLC with an EGFR-activating mutation (exon 19 deletion or L858R) after failure of third-generation (eg, osimertinib, lazertinib, aumolertinib, alflutinib) EGFR TKI therapy.
Categories
Completion Date
Completion Date Type
Estimated
Conditions
Nonsquamous Non-small Cell Lung Cancer
EGFR L858R
EGFR Exon 19 Deletion
Eligibility Criteria
Inclusion Criteria:
1. Is a male or female subject aged ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is \>18 years old).
2. Has histologically or cytologically documented metastatic or locally advanced non-squamous NSCLC not amenable to curative surgery or radiation.
3. Has documentation of an EGFR-activating mutation detected from tumor tissue or blood sample: exon 19 deletion or L858R at diagnosis or thereafter.
4. Received 1 or 2 prior line(s) of an approved EGFR TKI treatment in the metastatic or locally advanced setting, which must include a third -generation EGFR TKI
5. May have received either neoadjuvant and/or adjuvant treatment if progression to metastatic or locally advanced disease occurred at least 12 months after the last dose of such therapy and subsequently experienced disease progression on or after third-generation EGFR TKI treatment administered in the metastatic or locally advanced setting.
6. Has not received any other prior systemic therapies in the metastatic or locally advanced setting (including chemotherapy, immunotherapy etc) (even if administered in combination with EGFR TKI).
7. Has documentation of radiographic disease progression while receiving or after receiving a third generation EGFR TKI for metastatic or locally advanced disease.
8. Has at least 1 measurable lesion as per RECIST v1.1 by Investigator assessment.
9. Is willing to have a tumor biopsy or provide recently obtained tumor tissue.
10. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at Screening.
11. Has adequate bone marrow reserve and organ function based on local laboratory evaluation within 14 days prior to randomization:
* Platelet count: ≥100,000/mm\^3 or ≥100 × 10\^9/L within 14 days prior to the assessment of platelet count during the Screening Period
* Absolute neutrophil count: ≥1500/mm\^3 or ≥1.5 × 10\^9/L within 14 days prior to the assessment of absolute neutrophil count during the Screening Period
* Hemoglobin (Hgb): ≥9.0 g/dL within 14 days prior to the assessment of hemoglobin during the Screening Period
* Creatine clearance (CrCl): CrCl ≥45 mL/min calculated by using the Cockcroft-Gault equation or measured CrCl
* Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT): AST/ALT ≤3× Upper limit of normal (ULN)
* Total bilirubin (TBL): TBL ≤1.5 × ULN
* Serum albumin: ≥2.5 g/dL
* Prothrombin time (PT) or Prothrombin time-International normalized ratio (PT-INR) and activated partial thromboplastin time (aPTT)/partial thromboplastin time (PTT): ≤1.5 × ULN, except for participants receiving coumarin-derivative anticoagulants or other similar anticoagulant therapy who must have PT-INR within therapeutic range as deemed appropriate by the Investigator
Exclusion Criteria:
1. Has 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, or squamous NSCLC histology
2. Has any history of interstitial lung disease (ILD) (including pulmonary fibrosis or radiation pneumonitis), has current ILD, or is suspected to have such disease by imaging during Screening
3. Has clinically severe respiratory compromise (based on the Investigator's assessment) resulting from intercurrent pulmonary illnesses including, but not limited to the following:
* Any underlying pulmonary disorder, restrictive lung disease, or pleural effusion
* Any autoimmune, connective tissue, or inflammatory disorders where there is documented, or a suspicion of pulmonary involvement at the time of Screening
* OR prior complete pneumonectomy
4. Is receiving chronic systemic corticosteroids dosed at \>10 mg prednisone or equivalent anti-inflammatory activity or any form of immunosuppressive therapy prior to randomization
5. Has any history of or evidence of current leptomeningeal disease
6. Has evidence of clinically active spinal cord compression or brain metastases, defined as being symptomatic and untreated, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
7. Any prior treatment with any agent including an antibody drug conjugate (ADC) containing a chemotherapeutic agent targeting topoisomerase I, human epidermal growth factor receptor 3 (HER3) antibody, and any systemic therapies (other than EGFR TKIs) in the metastatic/locally advanced setting, including chemotherapy or any other systemic therapy in combination with an EGFR TKI
8. Has history of other active malignancy within 3 years prior to randomization, except for adequately resected nonmelanoma skin cancer, adequately treated intraepithelial carcinoma of the cervix, and any other curatively treated in situ disease
9. Has uncontrolled or significant cardiovascular disease prior to randomization
10. Has active hepatitis B and/or hepatitis C infection, such as those with serologic evidence of active viral infection within 28 days of randomization
11. Has a known human immunodeficiency virus (HIV) infection that is not well controlled
12. Has clinically significant corneal disease
1. Is a male or female subject aged ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is \>18 years old).
2. Has histologically or cytologically documented metastatic or locally advanced non-squamous NSCLC not amenable to curative surgery or radiation.
3. Has documentation of an EGFR-activating mutation detected from tumor tissue or blood sample: exon 19 deletion or L858R at diagnosis or thereafter.
4. Received 1 or 2 prior line(s) of an approved EGFR TKI treatment in the metastatic or locally advanced setting, which must include a third -generation EGFR TKI
5. May have received either neoadjuvant and/or adjuvant treatment if progression to metastatic or locally advanced disease occurred at least 12 months after the last dose of such therapy and subsequently experienced disease progression on or after third-generation EGFR TKI treatment administered in the metastatic or locally advanced setting.
6. Has not received any other prior systemic therapies in the metastatic or locally advanced setting (including chemotherapy, immunotherapy etc) (even if administered in combination with EGFR TKI).
7. Has documentation of radiographic disease progression while receiving or after receiving a third generation EGFR TKI for metastatic or locally advanced disease.
8. Has at least 1 measurable lesion as per RECIST v1.1 by Investigator assessment.
9. Is willing to have a tumor biopsy or provide recently obtained tumor tissue.
10. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at Screening.
11. Has adequate bone marrow reserve and organ function based on local laboratory evaluation within 14 days prior to randomization:
* Platelet count: ≥100,000/mm\^3 or ≥100 × 10\^9/L within 14 days prior to the assessment of platelet count during the Screening Period
* Absolute neutrophil count: ≥1500/mm\^3 or ≥1.5 × 10\^9/L within 14 days prior to the assessment of absolute neutrophil count during the Screening Period
* Hemoglobin (Hgb): ≥9.0 g/dL within 14 days prior to the assessment of hemoglobin during the Screening Period
* Creatine clearance (CrCl): CrCl ≥45 mL/min calculated by using the Cockcroft-Gault equation or measured CrCl
* Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT): AST/ALT ≤3× Upper limit of normal (ULN)
* Total bilirubin (TBL): TBL ≤1.5 × ULN
* Serum albumin: ≥2.5 g/dL
* Prothrombin time (PT) or Prothrombin time-International normalized ratio (PT-INR) and activated partial thromboplastin time (aPTT)/partial thromboplastin time (PTT): ≤1.5 × ULN, except for participants receiving coumarin-derivative anticoagulants or other similar anticoagulant therapy who must have PT-INR within therapeutic range as deemed appropriate by the Investigator
Exclusion Criteria:
1. Has 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, or squamous NSCLC histology
2. Has any history of interstitial lung disease (ILD) (including pulmonary fibrosis or radiation pneumonitis), has current ILD, or is suspected to have such disease by imaging during Screening
3. Has clinically severe respiratory compromise (based on the Investigator's assessment) resulting from intercurrent pulmonary illnesses including, but not limited to the following:
* Any underlying pulmonary disorder, restrictive lung disease, or pleural effusion
* Any autoimmune, connective tissue, or inflammatory disorders where there is documented, or a suspicion of pulmonary involvement at the time of Screening
* OR prior complete pneumonectomy
4. Is receiving chronic systemic corticosteroids dosed at \>10 mg prednisone or equivalent anti-inflammatory activity or any form of immunosuppressive therapy prior to randomization
5. Has any history of or evidence of current leptomeningeal disease
6. Has evidence of clinically active spinal cord compression or brain metastases, defined as being symptomatic and untreated, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
7. Any prior treatment with any agent including an antibody drug conjugate (ADC) containing a chemotherapeutic agent targeting topoisomerase I, human epidermal growth factor receptor 3 (HER3) antibody, and any systemic therapies (other than EGFR TKIs) in the metastatic/locally advanced setting, including chemotherapy or any other systemic therapy in combination with an EGFR TKI
8. Has history of other active malignancy within 3 years prior to randomization, except for adequately resected nonmelanoma skin cancer, adequately treated intraepithelial carcinoma of the cervix, and any other curatively treated in situ disease
9. Has uncontrolled or significant cardiovascular disease prior to randomization
10. Has active hepatitis B and/or hepatitis C infection, such as those with serologic evidence of active viral infection within 28 days of randomization
11. Has a known human immunodeficiency virus (HIV) infection that is not well controlled
12. Has clinically significant corneal disease
Inclusion Criteria
Inclusion Criteria:
1. Is a male or female subject aged ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is \>18 years old).
2. Has histologically or cytologically documented metastatic or locally advanced non-squamous NSCLC not amenable to curative surgery or radiation.
3. Has documentation of an EGFR-activating mutation detected from tumor tissue or blood sample: exon 19 deletion or L858R at diagnosis or thereafter.
4. Received 1 or 2 prior line(s) of an approved EGFR TKI treatment in the metastatic or locally advanced setting, which must include a third -generation EGFR TKI
5. May have received either neoadjuvant and/or adjuvant treatment if progression to metastatic or locally advanced disease occurred at least 12 months after the last dose of such therapy and subsequently experienced disease progression on or after third-generation EGFR TKI treatment administered in the metastatic or locally advanced setting.
6. Has not received any other prior systemic therapies in the metastatic or locally advanced setting (including chemotherapy, immunotherapy etc) (even if administered in combination with EGFR TKI).
7. Has documentation of radiographic disease progression while receiving or after receiving a third generation EGFR TKI for metastatic or locally advanced disease.
8. Has at least 1 measurable lesion as per RECIST v1.1 by Investigator assessment.
9. Is willing to have a tumor biopsy or provide recently obtained tumor tissue.
10. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at Screening.
11. Has adequate bone marrow reserve and organ function based on local laboratory evaluation within 14 days prior to randomization:
* Platelet count: ≥100,000/mm\^3 or ≥100 × 10\^9/L within 14 days prior to the assessment of platelet count during the Screening Period
* Absolute neutrophil count: ≥1500/mm\^3 or ≥1.5 × 10\^9/L within 14 days prior to the assessment of absolute neutrophil count during the Screening Period
* Hemoglobin (Hgb): ≥9.0 g/dL within 14 days prior to the assessment of hemoglobin during the Screening Period
* Creatine clearance (CrCl): CrCl ≥45 mL/min calculated by using the Cockcroft-Gault equation or measured CrCl
* Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT): AST/ALT ≤3× Upper limit of normal (ULN)
* Total bilirubin (TBL): TBL ≤1.5 × ULN
* Serum albumin: ≥2.5 g/dL
* Prothrombin time (PT) or Prothrombin time-International normalized ratio (PT-INR) and activated partial thromboplastin time (aPTT)/partial thromboplastin time (PTT): ≤1.5 × ULN, except for participants receiving coumarin-derivative anticoagulants or other similar anticoagulant therapy who must have PT-INR within therapeutic range as deemed appropriate by the Investigator
1. Is a male or female subject aged ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is \>18 years old).
2. Has histologically or cytologically documented metastatic or locally advanced non-squamous NSCLC not amenable to curative surgery or radiation.
3. Has documentation of an EGFR-activating mutation detected from tumor tissue or blood sample: exon 19 deletion or L858R at diagnosis or thereafter.
4. Received 1 or 2 prior line(s) of an approved EGFR TKI treatment in the metastatic or locally advanced setting, which must include a third -generation EGFR TKI
5. May have received either neoadjuvant and/or adjuvant treatment if progression to metastatic or locally advanced disease occurred at least 12 months after the last dose of such therapy and subsequently experienced disease progression on or after third-generation EGFR TKI treatment administered in the metastatic or locally advanced setting.
6. Has not received any other prior systemic therapies in the metastatic or locally advanced setting (including chemotherapy, immunotherapy etc) (even if administered in combination with EGFR TKI).
7. Has documentation of radiographic disease progression while receiving or after receiving a third generation EGFR TKI for metastatic or locally advanced disease.
8. Has at least 1 measurable lesion as per RECIST v1.1 by Investigator assessment.
9. Is willing to have a tumor biopsy or provide recently obtained tumor tissue.
10. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at Screening.
11. Has adequate bone marrow reserve and organ function based on local laboratory evaluation within 14 days prior to randomization:
* Platelet count: ≥100,000/mm\^3 or ≥100 × 10\^9/L within 14 days prior to the assessment of platelet count during the Screening Period
* Absolute neutrophil count: ≥1500/mm\^3 or ≥1.5 × 10\^9/L within 14 days prior to the assessment of absolute neutrophil count during the Screening Period
* Hemoglobin (Hgb): ≥9.0 g/dL within 14 days prior to the assessment of hemoglobin during the Screening Period
* Creatine clearance (CrCl): CrCl ≥45 mL/min calculated by using the Cockcroft-Gault equation or measured CrCl
* Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT): AST/ALT ≤3× Upper limit of normal (ULN)
* Total bilirubin (TBL): TBL ≤1.5 × ULN
* Serum albumin: ≥2.5 g/dL
* Prothrombin time (PT) or Prothrombin time-International normalized ratio (PT-INR) and activated partial thromboplastin time (aPTT)/partial thromboplastin time (PTT): ≤1.5 × ULN, except for participants receiving coumarin-derivative anticoagulants or other similar anticoagulant therapy who must have PT-INR within therapeutic range as deemed appropriate by the Investigator
Gender
All
Gender Based
false
Keywords
Nonsquamous Non-small Cell Lung Cancer
EGFR L858R
EGFR exon 19 deletion
Patritumab deruxtecan
HER3-DXd
U3-1402
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT05338970
Org Class
Industry
Org Full Name
Daiichi Sankyo
Org Study Id
U31402-A-U301
Overall Status
Active, not recruiting
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Phase 3, Randomized, Open-label Study of Patritumab Deruxtecan Versus Platinum-based Chemotherapy in Metastatic or Locally Advanced Epidermal Growth Factor Receptor-mutated (EGFRm) Non-small Cell Lung Cancer (NSCLC) After Failure of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) Therapy (HERTHENA-Lung02)
Primary Outcomes
Outcome Description
Progression-free survival (PFS) is defined as the time from the date of randomization to the earlier of the dates of the first documentation of objective progression of disease or death due to any cause.
Outcome Measure
Progression-free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) Based on RECIST v1.1
Outcome Time Frame
Baseline up to approximately 49 months
Secondary Ids
Secondary Id
2021-005879-40
Secondary Id
jRCT 2021220002
Secondary Outcomes
Outcome Description
Overall survival (OS) is defined as the time from the date of randomization to the date of death due to any cause.
Outcome Time Frame
Baseline up to approximately 49 months
Outcome Measure
Overall Survival (OS)
Outcome Description
Progression-free survival (PFS) is defined as the time from the date of randomization to the earlier of the dates of the first documentation of objective progression of disease or death due to any cause.
Outcome Time Frame
Baseline up to approximately 49 months
Outcome Measure
Progression-free Survival (PFS) as Assessed by Investigator Review Based on RECIST v1.1
Outcome Description
Progression-free survival (PFS) by local standard clinical practice is defined as the time from date of randomization to the documented progression on the first new anticancer therapy (if administered) or death due to any cause, whichever occurred first.
Outcome Time Frame
Baseline up to approximately 49 months
Outcome Measure
Progression-free Survival (PFS) as Assessed by Local Standard Clinical Practice
Outcome Description
Objective response rate (ORR) is defined as the proportion of participants who have a confirmed best overall response (BOR) of complete response (CR) or partial response (PR).
Outcome Time Frame
Baseline up to approximately 49 months
Outcome Measure
Objective Response Rate (ORR) as Assessed by BICR and Investigator Review Based on RECIST v1.1
Outcome Description
Duration of response (DoR) is defined as the time from the first documentation of objective response (CR or PR) to the earlier of the dates of the first documentation of objective progression of disease or death due to any cause.
Outcome Time Frame
Baseline up to approximately 49 months
Outcome Measure
Duration of Response (DoR) as Assessed by BICR and Investigator Review Based on RECIST v1.1
Outcome Description
Clinical benefit rate (CBR) will be assessed by BICR and Investigator based on RECIST v1.1. CBR is defined as the proportion of participants who have a confirmed BOR of CR, PR, or stable disease (SD) that lasts for at least 180 days.
Outcome Time Frame
Baseline up to approximately 49 months
Outcome Measure
Clinical Benefit Rate (CBR) as Assessed by BICR and Investigator Review Based on RECIST v1.1
Outcome Description
Disease control rate (DCR) is defined as the proportion of participants who have a confirmed BOR of CR, PR, or SD.
Outcome Time Frame
Baseline up to approximately 49 months
Outcome Measure
Disease Control Rate (DCR) as Assessed by BICR and Investigator Review Based on RECIST v1.1
Outcome Description
Time to response (TTR) is defined as the time from the date of randomization to the date of the first documentation of response (CR or PR) that is subsequently confirmed.
Outcome Time Frame
Baseline up to approximately 49 months
Outcome Measure
Time to Response (TTR) as Assessed by BICR and Investigator Review Based on RECIST v1.1
Outcome Description
Intracranial PFS is defined as the time from the date of randomization to the earlier of the dates of the first documented radiographic intracranial disease progression or death, whichever comes first, as assessed by BICR per CNS-RECIST, in participants with CNS lesion(s) at baseline by BICR per CNS-RECIST.
Outcome Time Frame
Baseline up to approximately 49 months
Outcome Measure
Intracranial PFS as Assessed by BICR
Outcome Description
The NSCLC-SAQ will assess disease-related symptom change in patients with NSCLC.
Outcome Time Frame
Baseline up to approximately 49 months
Outcome Measure
Mean Change from Baseline in Non-small Cell Lung Cancer - Symptom Assessment Questionnaire
Outcome Description
The PGI-C is a 7-point scale depicting a participant's rating of overall improvement.
Outcome Time Frame
Baseline up to approximately 49 months
Outcome Measure
Mean Change from Baseline in Patient's Global Impression of Change
Outcome Description
The PGI-S is a one-item questionnaire that contains six response options.
Outcome Time Frame
Baseline up to approximately 49 months
Outcome Measure
Mean Change from Baseline in Patient's Global Impression of Severity
Outcome Description
The PGI-TT will capture the patient's overall impression of treatment tolerability.
Outcome Time Frame
Baseline up to approximately 49 months
Outcome Measure
Mean Change from Baseline in Patient's Global Impression of Treatment Tolerability
Outcome Description
The EORTC-QLQ-C30 will assess the patient's overall quality of life (QoL).
Outcome Time Frame
Baseline up to approximately 49 months
Outcome Measure
Mean Change from Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)
Outcome Description
The EQ-5D-5L is a standardized instrument that will be used for measuring generic health status required for health technology assessments.
Outcome Time Frame
Baseline up to approximately 49 months
Outcome Measure
Mean Change from Baseline in EuroQol Questionnaire-5 dimensions-5 levels (EQ-5D-5L)
Outcome Description
TEAEs will be graded by using National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0.
Outcome Time Frame
Baseline up to approximately 49 months
Outcome Measure
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Outcome Description
The immunogenicity of patritumab deruxtecan will be confirmed by assessing the anti-drug antibodies.
Outcome Time Frame
Baseline up to approximately 49 months
Outcome Measure
Percentage of Participants Who Are Anti-Drug Antibody (ADA)-Positive (Baseline and Post-Baseline)
Outcome Description
The immunogenicity of patritumab deruxtecan will be confirmed by assessing the anti-drug antibodies.
Outcome Time Frame
Baseline up to approximately 49 months
Outcome Measure
Percentage of Participants Who Have Treatment-emergent ADA
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Balazs Halmos
Investigator Email
bahalmos@montefiore.org