Non-Small Cell Lung Cancer
Conditions
Keywords
HER2 over-expression, HER2 mutation, Unresectable or metastatic, Non-squamous, NSCLC
Brief summary
The primary objective of this trial is to evaluate the efficacy of trastuzumab deruxtecan in HER2-overexpressing and/or HER2-mutated advanced NSCLC participants.
Interventions
DRUGTrastuzumab deruxtecan
Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion.
Sponsors
Daiichi Sankyo Co., Ltd.
AstraZeneca
Daiichi Sankyo
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥20 years old in Japan, ≥18 years old in other countries * Pathologically documented unresectable and/or metastatic non-squamous NSCLC * Has relapsed from or is refractory to standard treatment or for which no standard treatment is available * For Cohort 1 and Cohort 1a: HER2-overexpression (IHC 2+ or 3+) status must be assessed and confirmed by Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory or equivalent, from an archival tumor tissue sample * For Cohort 2 only: Participant has any known documented activating HER2 mutation from an archival tumor tissue sample analyzed by CLIA laboratory or equivalent. Note: HER2 mutation documented only from a liquid biopsy sample cannot be used for enrollment. * Presence of at least 1 measurable lesion assessed by the investigator and based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 * Is willing and able to provide an adequate archival tumor tissue sample * Is willing to undergo a tissue biopsy, after the completion of the most recent treatment regimen * Has Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1
Exclusion criteria
* Had been previously treated with HER2-targeted therapies, except for pan-HER class tyrosine kinase inhibitors * For Cohort 1 and Cohort 1a: Has known HER2 mutation * Has a medical history of myocardial infarction, symptomatic congestive heart failure (CHF) (NYHA classes II-IV), unstable angina or serious cardiac arrhythmia * Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, or current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out due to imaging at screening * Has a QT interval corrected by Fridericia's formula (QTcF) prolongation to \> 450 millisecond (ms) in males and \> 470 ms in females * Has a medical history of clinically significant lung disease * Is suspected to have certain other protocol-defined diseases based on imaging at screening period * Has history of any disease, metastatic condition, drug/medication use or other condition that might, per protocol or in the opinion of the investigator, compromise: 1. safety or well-being of the participant or offspring 2. safety of study staff 3. analysis of results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Objective Response Rate (ORR) Based on Independent Central Review Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | From screening, up to 36 months (data cut-off) | The Objective Response Rate (ORR) was the defined as the percentage of participants who achieved a best overall response of confirmed Complete Response (CR) or Partial Response (PR), assessed by independent central review (ICR) committee based on RECIST version 1.1. 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. Confirmed ORR based on ICR is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Objective Response Rate (ORR) Based on Investigator Assessment Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | From screening, up to 36 months (data cut-off) | The Objective Response Rate (ORR) was defined as the percentage of participants who achieved a best overall response of confirmed Complete Response (CR) or Partial Response (PR), assessed by investigator assessment based on RECIST version 1.1. 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. Confirmed ORR based on investigator assessment is reported. |
| Duration of Response (DoR) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | From screening to documented tumor progression or death from any cause, up to 36 months (data cut-off) | Duration of Response (DoR) was defined as the time from the date of the first documentation of objective response (complete response \[CR\] or partial response \[PR\]) to the date of the first objective documentation of progressive disease (PD) or death due to any cause. DoR in participants with confirmed CR/PR based on independent central review and investigator assessment is reported. |
| Progression-Free Survival (PFS) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | From date of enrollment to first objective radiographic tumor progression or death from any cause,, up to 36 months (data cut-off) | Progression-free survival (PFS) was defined as the time from the date of enrollment to the earlier of the dates of the first objective documentation of disease progression (as per RECIST v1.1) or death due to any cause. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. PFS based on independent central review and investigator assessment is reported. |
| Overall Survival (OS) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | From date of enrollment to death from any cause, up to 36 months (data cut-off) | Overall survival (OS) was defined as the time from the date of first dose of study drug to the date of death due to any cause. |
| Percentage of Participants With Disease Control Rate (DCR) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | From first dose, up to 36 months (data cut-off) | Disease Control Rate (DCR) was defined as the percentage of participants who achieved a best overall response of CR, PR, or stable disease (SD) during study treatment. Confirmation of CR/PR was required. DCR based on independent central review and investigator assessment is reported. |
Countries
France, Japan, Netherlands, Spain, United States
Participant flow
Recruitment details
A total of 181 participants were enrolled and treated at clinic centers in Japan, United States, France, Netherlands, and Spain.
Pre-assignment details
Duration of follow-up (months) was defined as ((last visit date - enrollment date + 1)/365.25) × 12. Last visit date was the date of last clinical visit for ongoing participants, date of death for participants who died, or the last known contact date in survival follow-up for other participants who discontinued study drug.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: HER2 Overexpressing Participants with HER2-overexpressing(immunohistochemistry \[IHC\] 3+ or IHC 2+), unresectable and/or metastatic NSCLC adenocarcinoma who received 6.4 mg/kg trastuzumab deruxtecan (DS-8201a).
Trastuzumab deruxtecan: Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion. | 49 |
| Cohort 1a: HER2 Overexpressing Participants with HER2-overexpressing (immunohistochemistry \[IHC\] 3+ or IHC 2+), unresectable and/or metastatic NSCLC adenocarcinoma who received 5.4 mg/kg trastuzumab deruxtecan (DS-8201a).
Trastuzumab deruxtecan: Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion. | 41 |
| Cohort 2: HER2 Mutated Participants with HER2-mutated, unresectable and/or metastatic NSCLC to who received 6.4 mg/kg trastuzumab deruxtecan (DS-8201a).
Trastuzumab deruxtecan: Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion. | 91 |
| Total | 181 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 12 | 6 | 28 |
| Overall Study | Clinical Progression | 6 | 8 | 3 |
| Overall Study | Death | 4 | 5 | 6 |
| Overall Study | Other Reasons | 1 | 1 | 1 |
| Overall Study | Physician Decision | 1 | 1 | 2 |
| Overall Study | Progressive Disease | 24 | 17 | 43 |
| Overall Study | Study Terminated by Sponsor | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 3 | 7 |
Baseline characteristics
| Characteristic | Cohort 1: HER2 Overexpressing | Cohort 1a: HER2 Overexpressing | Cohort 2: HER2 Mutated | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 22 Participants | 14 Participants | 36 Participants | 72 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants | 27 Participants | 55 Participants | 109 Participants |
| Age, Continuous | 62.2 Years STANDARD_DEVIATION 9.58 | 60.3 Years STANDARD_DEVIATION 10.22 | 60.3 Years STANDARD_DEVIATION 11.94 | 60.8 Years STANDARD_DEVIATION 10.94 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 13 Participants | 4 Participants | 31 Participants | 48 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 1 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 19 Participants | 23 Participants |
| Race (NIH/OMB) White | 31 Participants | 31 Participants | 40 Participants | 102 Participants |
| Region of Enrollment France | 0 participants | 3 participants | 15 participants | 18 participants |
| Region of Enrollment Japan | 12 participants | 3 participants | 23 participants | 38 participants |
| Region of Enrollment Netherlands | 10 participants | 8 participants | 13 participants | 31 participants |
| Region of Enrollment Spain | 8 participants | 14 participants | 5 participants | 27 participants |
| Region of Enrollment United States | 19 participants | 13 participants | 35 participants | 67 participants |
| Sex: Female, Male Female | 19 Participants | 19 Participants | 60 Participants | 98 Participants |
| Sex: Female, Male Male | 30 Participants | 22 Participants | 31 Participants | 83 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 42 / 49 | 32 / 41 | 72 / 91 |
| other Total, other adverse events | 46 / 49 | 41 / 41 | 91 / 91 |
| serious Total, serious adverse events | 28 / 49 | 18 / 41 | 40 / 91 |
Outcome results
Primary
Percentage of Participants With Objective Response Rate (ORR) Based on Independent Central Review Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC)
The Objective Response Rate (ORR) was the defined as the percentage of participants who achieved a best overall response of confirmed Complete Response (CR) or Partial Response (PR), assessed by independent central review (ICR) committee based on RECIST version 1.1. 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. Confirmed ORR based on ICR is reported.
Time frame: From screening, up to 36 months (data cut-off)
Population: Objective response rate was assessed in the Full Analysis Set at data cut-off date of 03 December 2021.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: HER2 Overexpressing | Percentage of Participants With Objective Response Rate (ORR) Based on Independent Central Review Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | 26.5 Percentage of Participants |
| Cohort 1a: HER2 Overexpressing | Percentage of Participants With Objective Response Rate (ORR) Based on Independent Central Review Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | 34.1 Percentage of Participants |
| Cohort 2: HER2 Mutated | Percentage of Participants With Objective Response Rate (ORR) Based on Independent Central Review Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | 54.9 Percentage of Participants |
Secondary
Duration of Response (DoR) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC)
Duration of Response (DoR) was defined as the time from the date of the first documentation of objective response (complete response \[CR\] or partial response \[PR\]) to the date of the first objective documentation of progressive disease (PD) or death due to any cause. DoR in participants with confirmed CR/PR based on independent central review and investigator assessment is reported.
Time frame: From screening to documented tumor progression or death from any cause, up to 36 months (data cut-off)
Population: Duration of Response (DoR) was assessed in the Full Analysis Set of participants with confirmed CR/PR at data cut-off date of 03 May 2021.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1: HER2 Overexpressing | Duration of Response (DoR) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | Independent Central Review | 5.8 months |
| Cohort 1: HER2 Overexpressing | Duration of Response (DoR) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | Investigator Assessment | 5.8 months |
| Cohort 1a: HER2 Overexpressing | Duration of Response (DoR) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | Independent Central Review | 4.7 months |
| Cohort 1a: HER2 Overexpressing | Duration of Response (DoR) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | Investigator Assessment | 7.0 months |
| Cohort 2: HER2 Mutated | Duration of Response (DoR) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | Independent Central Review | 9.3 months |
| Cohort 2: HER2 Mutated | Duration of Response (DoR) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | Investigator Assessment | 11.7 months |
Secondary
Overall Survival (OS) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC)
Overall survival (OS) was defined as the time from the date of first dose of study drug to the date of death due to any cause.
Time frame: From date of enrollment to death from any cause, up to 36 months (data cut-off)
Population: Overall survival (OS) was assessed in the Full Analysis Set at data cut-off date of 03 May 2021.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: HER2 Overexpressing | Overall Survival (OS) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | 12.4 months |
| Cohort 1a: HER2 Overexpressing | Overall Survival (OS) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | NA months |
| Cohort 2: HER2 Mutated | Overall Survival (OS) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | 17.8 months |
Secondary
Percentage of Participants With Disease Control Rate (DCR) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC)
Disease Control Rate (DCR) was defined as the percentage of participants who achieved a best overall response of CR, PR, or stable disease (SD) during study treatment. Confirmation of CR/PR was required. DCR based on independent central review and investigator assessment is reported.
Time frame: From first dose, up to 36 months (data cut-off)
Population: Disease control rate was assessed in the Full Analysis Set at data cut-off date of 03 May 2021.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: HER2 Overexpressing | Percentage of Participants With Disease Control Rate (DCR) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | Independent Central Review | 68.9 Percentage of Participants |
| Cohort 1: HER2 Overexpressing | Percentage of Participants With Disease Control Rate (DCR) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | Investigator Assessment | 75.5 Percentage of Participants |
| Cohort 1a: HER2 Overexpressing | Percentage of Participants With Disease Control Rate (DCR) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | Independent Central Review | 77.5 Percentage of Participants |
| Cohort 1a: HER2 Overexpressing | Percentage of Participants With Disease Control Rate (DCR) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | Investigator Assessment | 78.0 Percentage of Participants |
| Cohort 2: HER2 Mutated | Percentage of Participants With Disease Control Rate (DCR) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | Independent Central Review | 93.0 Percentage of Participants |
| Cohort 2: HER2 Mutated | Percentage of Participants With Disease Control Rate (DCR) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | Investigator Assessment | 94.5 Percentage of Participants |
Secondary
Percentage of Participants With Objective Response Rate (ORR) Based on Investigator Assessment Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC)
The Objective Response Rate (ORR) was defined as the percentage of participants who achieved a best overall response of confirmed Complete Response (CR) or Partial Response (PR), assessed by investigator assessment based on RECIST version 1.1. 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. Confirmed ORR based on investigator assessment is reported.
Time frame: From screening, up to 36 months (data cut-off)
Population: Objective response rate was assessed in the Full Analysis Set at data cut-off date of 03 May 2021.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: HER2 Overexpressing | Percentage of Participants With Objective Response Rate (ORR) Based on Investigator Assessment Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | 28.6 Percentage of Participants |
| Cohort 1a: HER2 Overexpressing | Percentage of Participants With Objective Response Rate (ORR) Based on Investigator Assessment Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | 31.7 Percentage of Participants |
| Cohort 2: HER2 Mutated | Percentage of Participants With Objective Response Rate (ORR) Based on Investigator Assessment Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | 61.5 Percentage of Participants |
Secondary
Progression-Free Survival (PFS) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC)
Progression-free survival (PFS) was defined as the time from the date of enrollment to the earlier of the dates of the first objective documentation of disease progression (as per RECIST v1.1) or death due to any cause. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. PFS based on independent central review and investigator assessment is reported.
Time frame: From date of enrollment to first objective radiographic tumor progression or death from any cause,, up to 36 months (data cut-off)
Population: Progression-free survival (PFS) was assessed in the Full Analysis Set at data cut-off date of 03 May 2021.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1: HER2 Overexpressing | Progression-Free Survival (PFS) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | Independent Central Review | 5.7 months |
| Cohort 1: HER2 Overexpressing | Progression-Free Survival (PFS) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | Investigator Assessment | 5.7 months |
| Cohort 1a: HER2 Overexpressing | Progression-Free Survival (PFS) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | Independent Central Review | 6.7 months |
| Cohort 1a: HER2 Overexpressing | Progression-Free Survival (PFS) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | Investigator Assessment | 7.2 months |
| Cohort 2: HER2 Mutated | Progression-Free Survival (PFS) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | Independent Central Review | 8.2 months |
| Cohort 2: HER2 Mutated | Progression-Free Survival (PFS) Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC) | Investigator Assessment | 9.3 months |