Non-Small Cell Lung Cancer Metastatic, Non-Small Cell Lung Cancer With Mutation in Epidermal Growth Factor Receptor
Conditions
Keywords
Non-Small Cell Lung Cancer Metastatic, Non-Small Cell Lung Cancer with Mutation in Epidermal Growth Factor Receptor, Epidermal growth factor receptor, HER3-DXd, Patritumab Deruxtecan, U3-1402
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).
Interventions
DRUGPatritumab 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.
DRUGPatritumab 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.
Sponsors
Daiichi Sankyo
Daiichi Sankyo Co., Ltd.
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DoR) | 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) | 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 | 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) | 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) | 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 | 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) | 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) | 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. |
Countries
Australia, Austria, Belgium, Bulgaria, China, France, Germany, Italy, Japan, Netherlands, Singapore, South Korea, Spain, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Daiichi Sankyo
Participant flow
Recruitment details
A total of 277 participants were enrolled and randomized to treatment at clinical sites in the United States, Japan, Republic of Korea, Singapore, Taiwan, Austria, Belgium, Bulgaria, France, Germany, Italy, Netherlands, Spain, United Kingdom, and Australia. Two participants did not receive any treatment. (1 person in each treatment arm).
Participants by arm
| Arm | Count |
|---|---|
| Patritumab Deruxtecan 5.6 mg/kg Participants with metastatic or locally advanced NSCLC with an EGFR-activating mutation and who received patritumab deruxtecan 5.6 mg/kg IV every 3 weeks (Q3W) | 226 |
| Patritumab Deruxtecan Up-Titration Participants with metastatic or locally advanced NSCLC with an EGFR-activating mutation and received a patritumab deruxtecan up-titration regimen | 51 |
| Total | 277 |
Baseline characteristics
| Characteristic | Patritumab Deruxtecan 5.6 mg/kg | Patritumab Deruxtecan Up-Titration | Total |
|---|---|---|---|
| Age, Continuous | 62.7 years STANDARD_DEVIATION 9.86 | 59.8 years STANDARD_DEVIATION 10.07 | 62.2 years STANDARD_DEVIATION 9.95 |
| Age, Customized <65 years | 122 Participants | 36 Participants | 158 Participants |
| Age, Customized ≥65 years | 104 Participants | 15 Participants | 119 Participants |
| Age, Customized <75 years | 201 Participants | 49 Participants | 250 Participants |
| Age, Customized ≥75 years | 25 Participants | 2 Participants | 27 Participants |
| Race/Ethnicity, Customized Asian | 106 Participants | 32 Participants | 138 Participants |
| Race/Ethnicity, Customized Black or African-American | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 24 Participants | 3 Participants | 27 Participants |
| Race/Ethnicity, Customized White | 92 Participants | 15 Participants | 107 Participants |
| Sex: Female, Male Female | 133 Participants | 29 Participants | 162 Participants |
| Sex: Female, Male Male | 93 Participants | 22 Participants | 115 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 114 / 225 | 28 / 50 |
| other Total, other adverse events | 223 / 225 | 49 / 50 |
| serious Total, serious adverse events | 90 / 225 | 16 / 50 |
Outcome results
Primary
Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR)
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.
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
Population: Objective response rate was assessed in the Efficacy Analysis Set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Patritumab Deruxtecan 5.6 mg/kg | Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR) | 64 Participants |
| Patritumab Deruxtecan Up-Titration | Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR) | 8 Participants |
Secondary
Best Percentage Change in the Sum of Diameters (SoD) of Measurable Tumors
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.
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
Population: Percentage change in the sum of diameters was assessed in participants with available data in the Efficacy Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Patritumab Deruxtecan 5.6 mg/kg | Best Percentage Change in the Sum of Diameters (SoD) of Measurable Tumors | Sum of diameters (BICR) | -25.66 percentage change from baseline | Standard Deviation 30.39 |
| Patritumab Deruxtecan 5.6 mg/kg | Best Percentage Change in the Sum of Diameters (SoD) of Measurable Tumors | Sum of diameters (Investigator) | -20.84 percentage change from baseline | Standard Deviation 27.01 |
| Patritumab Deruxtecan Up-Titration | Best Percentage Change in the Sum of Diameters (SoD) of Measurable Tumors | Sum of diameters (BICR) | -17.48 percentage change from baseline | Standard Deviation 29.54 |
| Patritumab Deruxtecan Up-Titration | Best Percentage Change in the Sum of Diameters (SoD) of Measurable Tumors | Sum of diameters (Investigator) | -11.46 percentage change from baseline | Standard Deviation 29.25 |
Secondary
Disease Control Rate (DCR)
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 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
Population: Disease control rate was assessed in the Efficacy Analysis Set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Patritumab Deruxtecan 5.6 mg/kg | Disease Control Rate (DCR) | Disease control rate (BICR) | 166 Participants |
| Patritumab Deruxtecan 5.6 mg/kg | Disease Control Rate (DCR) | Disease control rate (Investigator) | 169 Participants |
| Patritumab Deruxtecan Up-Titration | Disease Control Rate (DCR) | Disease control rate (BICR) | 38 Participants |
| Patritumab Deruxtecan Up-Titration | Disease Control Rate (DCR) | Disease control rate (Investigator) | 37 Participants |
Secondary
Duration of Response (DoR)
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.
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
Population: Duration of response rate was assessed in participants with confirmed CR or PR in the Efficacy Analysis Set.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Patritumab Deruxtecan 5.6 mg/kg | Duration of Response (DoR) | Duration of response (BICR) | 6.0 months |
| Patritumab Deruxtecan 5.6 mg/kg | Duration of Response (DoR) | Duration of response (Investigator) | 6.9 months |
| Patritumab Deruxtecan Up-Titration | Duration of Response (DoR) | Duration of response (BICR) | 7.1 months |
| Patritumab Deruxtecan Up-Titration | Duration of Response (DoR) | Duration of response (Investigator) | 5.1 months |
Secondary
Incidence of Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events of Special Interest (AESIs)
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.
Time frame: From baseline up to Day 47 post last dose
Secondary
Objective Response Rate (ORR) as Assessed by the Investigator
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.
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
Population: Objective response rate was assessed in the Efficacy Analysis Set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Patritumab Deruxtecan 5.6 mg/kg | Objective Response Rate (ORR) as Assessed by the Investigator | 56 Participants |
| Patritumab Deruxtecan Up-Titration | Objective Response Rate (ORR) as Assessed by the Investigator | 8 Participants |
Secondary
Overall Survival (OS)
OS defined as the time from the start of study treatment to the date of death due to any cause.
Time frame: Death date is collected until the participant discontinues the study or up to approximately 45 months
Secondary
Progression-free Survival (PFS)
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.
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
Population: Progression-free survival was assessed in the Efficacy Analysis Set.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Patritumab Deruxtecan 5.6 mg/kg | Progression-free Survival (PFS) | Progression-free survival (BICR) | 5.5 months |
| Patritumab Deruxtecan 5.6 mg/kg | Progression-free Survival (PFS) | Progression-free survival (Investigator) | 5.5 months |
| Patritumab Deruxtecan Up-Titration | Progression-free Survival (PFS) | Progression-free survival (BICR) | 6.7 months |
| Patritumab Deruxtecan Up-Titration | Progression-free Survival (PFS) | Progression-free survival (Investigator) | 5.3 months |
Secondary
Time to Tumor Response (TTR)
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.
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
Population: Time to response rate was assessed in participants with confirmed CR or PR in the Efficacy Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Patritumab Deruxtecan 5.6 mg/kg | Time to Tumor Response (TTR) | Time to response (BICR) | 2.2 months | Standard Deviation 1.31 |
| Patritumab Deruxtecan 5.6 mg/kg | Time to Tumor Response (TTR) | Time to response (Investigator) | 2.5 months | Standard Deviation 1.78 |
| Patritumab Deruxtecan Up-Titration | Time to Tumor Response (TTR) | Time to response (BICR) | 1.7 months | Standard Deviation 0.61 |
| Patritumab Deruxtecan Up-Titration | Time to Tumor Response (TTR) | Time to response (Investigator) | 2.1 months | Standard Deviation 1.09 |