HER2-mutant Non-Small Cell Lung Cancer
Conditions
Keywords
DL05, T-DXd, HER2-mutant Non-Small Cell Lung Cancer, NSCLC, Trastuzumab deruxtecan, ERBB2
Brief summary
The purpose of this study is to evaluate the efficacy and safety of T-DXd in participants with HER2 mutant metastatic non-squamous NSCLC.
Interventions
DRUGTrastuzumab deruxtecan
administered as an IV infusion
Sponsors
AstraZeneca
Daiichi Sankyo
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pathologically documented metastatic non-squamous NSCLC. * Has relapsed from or is refractory to at least one-line of anticancer treatment. * Documented HER2 exon 19 or 20 mutation from central FFPE tumour tissue testing. * WHO or ECOG performance status of 0 or 1. * Presence of at least one measurable lesion assessed by the investigator based on RECIST 1.1. * LVEF ≥ 50% within 28 days before enrolment.
Exclusion criteria
* Mixed small cell lung cancer, squamous histology NSCLC, and sarcomatoid histology variant NSCLC. * Corrected QT interval (QTcF) prolongation to \> 470 ms (females) or \> 450 ms (males), based on average of the screening triplicate 12-lead ECG. * History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. * Has unresolved toxicities from previous anticancer therapy, defined as toxicities (excluding alopecia) not yet resolved to Grade ≤1 or baseline. Participants with clinically stable chronic Grade 2 toxicity not reasonably expected to be exacerbated by study intervention may be included only after consultation with the AstraZeneca study physician or designee. * Has been previously treated with HER2-targeted therapies, except for pan-HER class TKIs or has received prior treatment with an ADC which consists of an exatecan derivative that is a topoisomerase I inhibitor.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ICR-assessed ORR (Objective Response Rate) | Tumour assessments (per RECIST 1.1) every 6 weeks for the first 48 weeks relative to the date of enrolment and then every 9 weeks thereafter. Assessed up to 28 months. (from date of enrolment to final analysis data cut-off) | Confirmed ORR, defined as the percentage of participants with confirmed complete response or partial response, as assessed by independent central review(ICR) based on RECIST 1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-assessed ORR (Objective Response Rate) | Tumour assessments (per RECIST 1.1) every 6 weeks for the first 48 weeks relative to the date of enrolment and then every 9 weeks thereafter. Assessed up to 28 months. (from date of enrolment to final analysis data cut-off) | Confirmed ORR is defined as the percentage of participants who have a confirmed CR or confirmed PR, as determined by the investigator at local site per RECIST 1.1 |
| ICR-assessed DoR (Duration of Response) | Tumour assessments (per RECIST 1.1) every 6 weeks for the first 48 weeks relative to the date of enrolment and then every 9 weeks thereafter. Assessed up to 28 months. | DoR is time from the initial confirmed response (CR or PR) until documented tumour progression or death from any cause. |
| Investigator-assessed DoR (Duration of Response) | Tumour assessments (per RECIST 1.1) every 6 weeks for the first 48 weeks relative to the date of enrolment and then every 9 weeks thereafter. Assessed up to 28 months. | DoR is time from the initial confirmed response (CR or PR) until documented tumour progression or death from any cause. |
| ICR-assessed and Investigator-assessed DCR (Disease Control Rate) | Tumour assessments (per RECIST 1.1) every 6 weeks for the first 48 weeks relative to the date of enrolment and then every 9 weeks thereafter. Assessed up to 28 months. | DCR is the percentage of participants who achieved confirmed CR, PR, or SD during study intervention. |
| ICR-assessed and Investigator-assessed PFS (Progression-free Survival) | Tumour assessments every 6 weeks after enrolment for the first 48 weeks and then every 9 weeks thereafter until date of RECIST 1.1 defined radiological progressive disease or death. Assessed up to 28 months. | PFS is the time from date of enrolment until first objective radiographic tumour progression or death from any cause. |
| OS (Overall Survival) | From date of enrolment until death due to any cause. Assessed up to 28 months. | OS is the time from date of enrolment until death from any cause. |
| ICR-assessed CNS-PFS (Central Nervous System Progression-free Survival) | Tumour assessments every 6 weeks after enrolment for the first 48 weeks and then every 9 weeks thereafter until date of RECIST 1.1 defined CNS tumour progressive disease or death in the absence of CNS progression. Assessed up to 28 months. | CNS-PFS is the time from date of enrolment until CNS tumour progression per RECIST 1.1 as assessed by ICR or death due to any cause in the absence of CNS progression. |
| Serum Concentrations of T-DXd | 24 weeks from day 1 of cycle 1 to cycle 8 | Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for T-DXd. |
| Serum Concentrations of Total Anti-HER2 Antibody | 24 weeks from day 1 of cycle 1 to cycle 8 | Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for total anti-HER2 antibody. |
| Serum Concentrations of DXd | 24 weeks from day 1 of cycle 1 to cycle 8 | Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for DXd. |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| T-DXd Arm Participants will receive T-DXd as an IV infusion Q3W, on Day 1 of each 3-week cycle. | 72 |
| Total | 72 |
Baseline characteristics
| Characteristic | T-DXd Arm |
|---|---|
| Age, Continuous | 57.0 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 72 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 72 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 41 Participants |
| Sex: Female, Male Male | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 41 / 72 |
| other Total, other adverse events | 72 / 72 |
| serious Total, serious adverse events | 41 / 72 |
Outcome results
Primary
ICR-assessed ORR (Objective Response Rate)
Confirmed ORR, defined as the percentage of participants with confirmed complete response or partial response, as assessed by independent central review(ICR) based on RECIST 1.1.
Time frame: At an average of approximately 14 months
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| T-DXd Arm | ICR-assessed ORR (Objective Response Rate) | 58.3 Percentage of participants |
Secondary
ICR-assessed and Investigator-assessed DCR (Disease Control Rate)
DCR is the percentage of participants who achieved confirmed CR, PR, or SD during study intervention.
Time frame: Approximately 6 weeks
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| T-DXd Arm | ICR-assessed and Investigator-assessed DCR (Disease Control Rate) | ICR-assessed | 91.7 Percentage of participants |
| T-DXd Arm | ICR-assessed and Investigator-assessed DCR (Disease Control Rate) | Investigator-assessed | 93.1 Percentage of participants |
Secondary
ICR-assessed and Investigator-assessed DoR (Duration of Response)
DoR is time from the initial confirmed response (CR or PR) until documented tumour progression or death from any cause.
Time frame: At an average of approximately 14 months
Population: Full analysis set (patients with confirmed objective response included in the analysis)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| T-DXd Arm | ICR-assessed and Investigator-assessed DoR (Duration of Response) | ICR-assessed | NA Months |
| T-DXd Arm | ICR-assessed and Investigator-assessed DoR (Duration of Response) | Investigator-assessed | 9.0 Months |
Secondary
ICR-assessed and Investigator-assessed PFS (Progression-free Survival)
PFS is the time from date of enrolment until first objective radiographic tumour progression or death from any cause.
Time frame: An average of approximately 14 months
Population: Full analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| T-DXd Arm | ICR-assessed and Investigator-assessed PFS (Progression-free Survival) | ICR-assessed | NA Months |
| T-DXd Arm | ICR-assessed and Investigator-assessed PFS (Progression-free Survival) | Investigator-assessed | 10.8 Months |
Secondary
ICR-assessed CNS-PFS (Central Nervous System Progression-free Survival)
CNS-PFS is the time from date of enrolment until CNS tumour progression per RECIST 1.1 as assessed by ICR due to any cause in the absence of CNS progression.
Time frame: An average of approximately 14 months
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| T-DXd Arm | ICR-assessed CNS-PFS (Central Nervous System Progression-free Survival) | NA Months |
Secondary
Investigator-assessed ORR (Objective Response Rate)
Confirmed ORR is defined as the percentage of participants who have a confirmed CR or confirmed PR, as determined by the investigator at local site per RECIST 1.1
Time frame: An average of approximately 14 months
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| T-DXd Arm | Investigator-assessed ORR (Objective Response Rate) | 58.3 Percentage of participants |
Secondary
OS (Overall Survival)
OS is the time from date of enrolment until death from any cause.
Time frame: An average of approximately 22 months
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| T-DXd Arm | OS (Overall Survival) | NA Months |
Secondary
Serum Concentrations of DXd
Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for DXd.
Time frame: An average of approximately 14 months
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| T-DXd Arm | Serum Concentrations of DXd | Cycle 4 Pre-dose | 0.3226 ng/mL | Geometric Coefficient of Variation 53.71 |
| T-DXd Arm | Serum Concentrations of DXd | Cycle 4 End of infusion | 2.139 ng/mL | Geometric Coefficient of Variation 51.35 |
| T-DXd Arm | Serum Concentrations of DXd | Cycle 6 Pre-dose | 0.3295 ng/mL | Geometric Coefficient of Variation 58.92 |
| T-DXd Arm | Serum Concentrations of DXd | Cycle 1 Pre-dose | NA ng/mL | — |
| T-DXd Arm | Serum Concentrations of DXd | Cycle 1 End of infusion | 5.384 ng/mL | Geometric Coefficient of Variation 47.55 |
| T-DXd Arm | Serum Concentrations of DXd | Cycle 1 5 hour post-dose | 12.90 ng/mL | Geometric Coefficient of Variation 69.38 |
| T-DXd Arm | Serum Concentrations of DXd | Cycle 2 Pre-dose | 0.1751 ng/mL | Geometric Coefficient of Variation 119.4 |
| T-DXd Arm | Serum Concentrations of DXd | Cycle 2 End of infusion | 2.657 ng/mL | Geometric Coefficient of Variation 70.96 |
| T-DXd Arm | Serum Concentrations of DXd | Cycle 3 Pre-dose | 0.2423 ng/mL | Geometric Coefficient of Variation 110.6 |
| T-DXd Arm | Serum Concentrations of DXd | Cycle 3 End of infusion | 2.310 ng/mL | Geometric Coefficient of Variation 50.12 |
| T-DXd Arm | Serum Concentrations of DXd | Cycle 8 Pre-dose | 0.3714 ng/mL | Geometric Coefficient of Variation 57.45 |
Secondary
Serum Concentrations of T-DXd
Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for T-DXd.
Time frame: An average of approximately 14 months
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| T-DXd Arm | Serum Concentrations of T-DXd | Cycle 1 Pre-dose | NA μg/mL | — |
| T-DXd Arm | Serum Concentrations of T-DXd | Cycle 1 End of infusion | 120.5 μg/mL | Geometric Coefficient of Variation 18.33 |
| T-DXd Arm | Serum Concentrations of T-DXd | Cycle 1 5 hour post-dose | 106.1 μg/mL | Geometric Coefficient of Variation 77.96 |
| T-DXd Arm | Serum Concentrations of T-DXd | Cycle 2 Pre-dose | 3.072 μg/mL | Geometric Coefficient of Variation 121.6 |
| T-DXd Arm | Serum Concentrations of T-DXd | Cycle 2 End of infusion | 117.4 μg/mL | Geometric Coefficient of Variation 18.79 |
| T-DXd Arm | Serum Concentrations of T-DXd | Cycle 3 Pre-dose | 5.262 μg/mL | Geometric Coefficient of Variation 111.2 |
| T-DXd Arm | Serum Concentrations of T-DXd | Cycle 3 End of infusion | 120.9 μg/mL | Geometric Coefficient of Variation 17.04 |
| T-DXd Arm | Serum Concentrations of T-DXd | Cycle 4 Pre-dose | 8.014 μg/mL | Geometric Coefficient of Variation 60.69 |
| T-DXd Arm | Serum Concentrations of T-DXd | Cycle 4 End of infusion | 118.4 μg/mL | Geometric Coefficient of Variation 18.44 |
| T-DXd Arm | Serum Concentrations of T-DXd | Cycle 6 Pre-dose | 9.046 μg/mL | Geometric Coefficient of Variation 67.91 |
| T-DXd Arm | Serum Concentrations of T-DXd | Cycle 8 Pre-dose | 10.05 μg/mL | Geometric Coefficient of Variation 68.29 |
Secondary
Serum Concentrations of Total Anti-HER2 Antibody
Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for total anti-HER2 antibody.
Time frame: An average of approximately 14 months
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| T-DXd Arm | Serum Concentrations of Total Anti-HER2 Antibody | Cycle 1 End of infusion | 127.5 ug/mL | Geometric Coefficient of Variation 21.93 |
| T-DXd Arm | Serum Concentrations of Total Anti-HER2 Antibody | Cycle 1 5 hour post-dose | 118.0 ug/mL | Geometric Coefficient of Variation 18.85 |
| T-DXd Arm | Serum Concentrations of Total Anti-HER2 Antibody | Cycle 2 Pre-dose | 2.866 ug/mL | Geometric Coefficient of Variation 148.7 |
| T-DXd Arm | Serum Concentrations of Total Anti-HER2 Antibody | Cycle 2 End of infusion | 120.1 ug/mL | Geometric Coefficient of Variation 39.66 |
| T-DXd Arm | Serum Concentrations of Total Anti-HER2 Antibody | Cycle 3 Pre-dose | 4.582 ug/mL | Geometric Coefficient of Variation 126.4 |
| T-DXd Arm | Serum Concentrations of Total Anti-HER2 Antibody | Cycle 3 End of infusion | 125.9 ug/mL | Geometric Coefficient of Variation 16.87 |
| T-DXd Arm | Serum Concentrations of Total Anti-HER2 Antibody | Cycle 1 Pre-dose | NA ug/mL | — |
| T-DXd Arm | Serum Concentrations of Total Anti-HER2 Antibody | Cycle 4 Pre-dose | 6.974 ug/mL | Geometric Coefficient of Variation 84.38 |
| T-DXd Arm | Serum Concentrations of Total Anti-HER2 Antibody | Cycle 4 End of infusion | 121.3 ug/mL | Geometric Coefficient of Variation 16.8 |
| T-DXd Arm | Serum Concentrations of Total Anti-HER2 Antibody | Cycle 6 Pre-dose | 8.083 ug/mL | Geometric Coefficient of Variation 95.47 |
| T-DXd Arm | Serum Concentrations of Total Anti-HER2 Antibody | Cycle 8 Pre-dose | 9.193 ug/mL | Geometric Coefficient of Variation 87.45 |