Metastatic Breast Cancer
Conditions
Brief summary
The purpose of this study is to demonstrate that SYD985 \[(vic-)trastuzumab duocarmazine\] is superior to physician's choice in prolonging progression free survival.
Detailed description
This study is designed as a randomized, active-controlled, superiority study in patients with unresectable locally advanced or metastatic HER2-positive breast cancer. The patients should have had either progression during or after at least two HER2-targeting treatment regimens for locally advanced or metastatic disease or progression during or after (ado-)trastuzumab emtansine treatment. Eligible patients will be randomly assigned (2:1) to receive SYD985 or physician's choice treatment until disease progression, unacceptable toxicity or study termination by the Sponsor. During treatment, patients will have to visit the clinical site to assess efficacy, quality of life (QoL), and safety using standardized criteria.
Interventions
DRUG(vic-)trastuzumab duocarmazine
Intravenous SYD985, Q3W
See drug label
Sponsors
Byondis B.V.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Main Inclusion Criteria: * Female patients with histologically-confirmed, unresectable locally advanced or metastatic breast cancer; * Patients should have had either progression during or after at least two HER2-targeting treatment regimens for locally advanced or metastatic disease or progression during or after (ado-)trastuzumab emtansine treatment for locally advanced or metastatic disease; * HER2-positive tumor status; * Patients must have measurable or non-measurable disease that is evaluable per RECIST 1.1; * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; * Estimated life expectancy \> 12 weeks at randomization; * Adequate organ function and blood cell counts. Main
Exclusion criteria
* Current or previous use of a prohibited medication as listed in the protocol; * History of infusion-related reactions and/or hypersensitivity to trastuzumab, (ado-)trastuzumab emtansine; * History of keratitis; * Severe, uncontrolled systemic disease at screening; * Left Ventricular Ejection Fraction (LVEF) \< 50%, or a history of clinically significant decrease in LVEF during previous treatment with trastuzumab or (ado-)trastuzumab emtansine; * Cardiac troponin value above the Upper Limit of Normal (ULN); * History of clinically significant cardiovascular disease; * Untreated brain metastases, symptomatic brain metastases, brain metastases requiring steroids to manage symptoms, or treatment for brain metastases within 8 weeks prior to randomization; * History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | baseline until primary analysis data cut-off date of 31March2021 | Progression-free survival is defined as the time from the date of randomization to the date of first documented disease progression by central assessment according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 or death due to any cause, whichever occurred earlier. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | baseline until final Overall Survival analysis data cut-off date of 30June2022 | Overall survival is defined as the time from date of randomization to death due to any cause. |
| Objective Response Rate | baseline until primary analysis data cut-off date of 31March2021 | Objective Response Rate is defined as the proportion of patients with a centrally assessed best overall response of complete response or partial response according to RECIST v1.1. |
| Investigator Assessed Progression Free Survival | baseline until primary analysis data cut-off date of 31March2021 | Progression-free survival is defined as the time from the date of randomization to the date of first documented disease progression by investigator assessment according to RECIST v1.1 or death due to any cause, whichever occurred earlier. |
| Patient Reported Outcomes for Health Related Quality of Life | baseline until primary analysis data cut-off date of 31March2021 | Change in the global health status/Quality of Life (QoL) scale score of the European Organization for Research and Treatment for Cancer (EORTC) Quality of Life Questionnaire C30 from baseline (cycle 1). The raw score (1 to 7) has been transformed to a score ranging from 0 to 100. A higher score means a better outcome: hence a positive change from baseline means an improvement in global health status/Quality of Life and a negative change from baseline means a worsening of global health status/Quality of Life. |
Countries
Belgium, Canada, Denmark, France, Italy, Netherlands, Singapore, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
A total of 751 participants were screened, out of which, 437 participants were randomized into the study.
Participants by arm
| Arm | Count |
|---|---|
| (Vic-)Trastuzumab Duocarmazine SYD985, every 3 weeks (Q3W)
(vic-)trastuzumab duocarmazine: Intravenous SYD985, Q3W | 291 |
| Physician's Choice 1. Lap/Cap
2. T/Cap
3. T/Vino
4. T/Eri
Physician's choice: See drug label | 146 |
| Total | 437 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 181 | 94 |
| Overall Study | End Of Follow Up By Sponsor | 90 | 41 |
| Overall Study | Lost to Follow-up | 9 | 4 |
| Overall Study | Other reason | 5 | 0 |
| Overall Study | Withdrawal by Subject | 6 | 7 |
Baseline characteristics
| Characteristic | Total | (Vic-)Trastuzumab Duocarmazine | Physician's Choice |
|---|---|---|---|
| Age, Continuous | 56.4 years STANDARD_DEVIATION 11.13 | 55.9 years STANDARD_DEVIATION 11.2 | 57.3 years STANDARD_DEVIATION 10.97 |
| BMI | 25.28 kg/m2 STANDARD_DEVIATION 5.4 | 25.14 kg/m2 STANDARD_DEVIATION 5 | 25.54 kg/m2 STANDARD_DEVIATION 6.1 |
| Childbearing potential No - postmenopausal | 309 Participants | 204 Participants | 105 Participants |
| Childbearing potential No - surgically sterilized | 32 Participants | 23 Participants | 9 Participants |
| Childbearing potential Yes | 96 Participants | 64 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 19 Participants | 11 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 328 Participants | 225 Participants | 103 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 90 Participants | 55 Participants | 35 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 46 Participants | 29 Participants | 17 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 87 Participants | 55 Participants | 32 Participants |
| Race (NIH/OMB) White | 297 Participants | 202 Participants | 95 Participants |
| Region of Enrollment Belgium | 40 participants | 25 participants | 15 participants |
| Region of Enrollment Canada | 24 participants | 15 participants | 9 participants |
| Region of Enrollment Denmark | 10 participants | 7 participants | 3 participants |
| Region of Enrollment France | 68 participants | 46 participants | 22 participants |
| Region of Enrollment Italy | 70 participants | 50 participants | 20 participants |
| Region of Enrollment Netherlands | 3 participants | 3 participants | 0 participants |
| Region of Enrollment Singapore | 35 participants | 20 participants | 15 participants |
| Region of Enrollment Spain | 67 participants | 44 participants | 23 participants |
| Region of Enrollment Sweden | 8 participants | 4 participants | 4 participants |
| Region of Enrollment United Kingdom | 59 participants | 43 participants | 16 participants |
| Region of Enrollment United States | 53 participants | 34 participants | 19 participants |
| Sex: Female, Male Female | 437 Participants | 291 Participants | 146 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 181 / 288 | 94 / 137 |
| other Total, other adverse events | 278 / 288 | 132 / 137 |
| serious Total, serious adverse events | 53 / 288 | 12 / 137 |
Outcome results
Primary
Progression Free Survival
Progression-free survival is defined as the time from the date of randomization to the date of first documented disease progression by central assessment according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 or death due to any cause, whichever occurred earlier.
Time frame: baseline until primary analysis data cut-off date of 31March2021
Population: Full-analysis set (FAS) was used for this primary endpoint analysis. FAS comprises all randomized patients, which were analyzed according to the treatment group and strata they have been assigned to during the randomization procedure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| (Vic-)Trastuzumab Duocarmazine | Progression Free Survival | 7.0 months |
| Physician's Choice | Progression Free Survival | 4.9 months |
Comparison: A stratified Cox regression analysis was used to estimate the hazard ratio of PFS, along with 95% CIs. Stratification factors assigned at randomization were world region (Europe, Singapore, and North America), number of prior treatment lines for locally advanced or metastatic breast cancer (excluding hormone therapy) (1 to 2, \>2), and prior treatment with pertuzumab (yes, no).p-value: =0.00295% CI: [0.4885, 0.8389]Log Rank
Secondary
Investigator Assessed Progression Free Survival
Progression-free survival is defined as the time from the date of randomization to the date of first documented disease progression by investigator assessment according to RECIST v1.1 or death due to any cause, whichever occurred earlier.
Time frame: baseline until primary analysis data cut-off date of 31March2021
Population: Full-analysis set (FAS) was used for this primary endpoint analysis. FAS comprises all randomized patients, which were analyzed according to the treatment group and strata they have been assigned to during the randomization procedure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| (Vic-)Trastuzumab Duocarmazine | Investigator Assessed Progression Free Survival | 6.9 months |
| Physician's Choice | Investigator Assessed Progression Free Survival | 4.6 months |
Comparison: A stratified Cox regression analysis was used to estimate the HR of PFS, along with the 95% CI. The treatment groups were compared using the 2-sided stratified log-rank test.p-value: <0.00195% CI: [0.4666, 0.7703]Log Rank
Secondary
Objective Response Rate
Objective Response Rate is defined as the proportion of patients with a centrally assessed best overall response of complete response or partial response according to RECIST v1.1.
Time frame: baseline until primary analysis data cut-off date of 31March2021
Population: Full-analysis set (FAS) was used for this primary endpoint analysis. FAS comprises all randomized patients, which were analyzed according to the treatment group and strata they have been assigned to during the randomization procedure. Only patients with measurable disease at baseline were included in the analysis of ORR.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| (Vic-)Trastuzumab Duocarmazine | Objective Response Rate | 27.8 percentage of patients |
| Physician's Choice | Objective Response Rate | 29.5 percentage of patients |
Comparison: The Cochran-Mantel-Haenszel test (strata based on the baseline stratification factors) was used to compare the two treatment groups with respect to the ORR at two-sided 5% level of significance.p-value: =0.732Cochran-Mantel-Haenszel
Secondary
Overall Survival
Overall survival is defined as the time from date of randomization to death due to any cause.
Time frame: baseline until final Overall Survival analysis data cut-off date of 30June2022
Population: Full-analysis set (FAS) was used for the overall survival analysis. FAS comprises all randomized patients, which were analyzed according to the treatment group and strata they have been assigned to during the randomization procedure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| (Vic-)Trastuzumab Duocarmazine | Overall Survival | 21.0 months |
| Physician's Choice | Overall Survival | 19.5 months |
Comparison: A stratified Cox regression analysis was used to estimate the hazard ratio of OS, along with 95% CIs. Stratification factors assigned at randomization were world region (Europe, Singapore, and North America), number of prior treatment lines for locally advanced or metastatic breast cancer (excluding hormone therapy) (1 to 2, \>2), and prior treatment with pertuzumab (yes, no).p-value: =0.23695% CI: [0.676, 1.1145]Log Rank
Secondary
Patient Reported Outcomes for Health Related Quality of Life
Change in the global health status/Quality of Life (QoL) scale score of the European Organization for Research and Treatment for Cancer (EORTC) Quality of Life Questionnaire C30 from baseline (cycle 1). The raw score (1 to 7) has been transformed to a score ranging from 0 to 100. A higher score means a better outcome: hence a positive change from baseline means an improvement in global health status/Quality of Life and a negative change from baseline means a worsening of global health status/Quality of Life.
Time frame: baseline until primary analysis data cut-off date of 31March2021
Population: Full-analysis set (FAS) was used for the overall survival analysis. FAS comprises all randomized patients, which were analyzed according to the treatment group and strata they have been assigned to during the randomization procedure. Here, 'Number analyzed' = participants with available QoL for each specified cycle.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| (Vic-)Trastuzumab Duocarmazine | Patient Reported Outcomes for Health Related Quality of Life | Cycle 5 | -2.51 scores on a scale |
| (Vic-)Trastuzumab Duocarmazine | Patient Reported Outcomes for Health Related Quality of Life | Cycle 15 | -11.90 scores on a scale |
| (Vic-)Trastuzumab Duocarmazine | Patient Reported Outcomes for Health Related Quality of Life | Cycle 3 | -1.88 scores on a scale |
| (Vic-)Trastuzumab Duocarmazine | Patient Reported Outcomes for Health Related Quality of Life | Cycle 17 | -4.31 scores on a scale |
| (Vic-)Trastuzumab Duocarmazine | Patient Reported Outcomes for Health Related Quality of Life | Cycle 7 | -5.65 scores on a scale |
| (Vic-)Trastuzumab Duocarmazine | Patient Reported Outcomes for Health Related Quality of Life | Cycle 2 | 0.17 scores on a scale |
| (Vic-)Trastuzumab Duocarmazine | Patient Reported Outcomes for Health Related Quality of Life | Cycle 21 | 11.68 scores on a scale |
| (Vic-)Trastuzumab Duocarmazine | Patient Reported Outcomes for Health Related Quality of Life | Cycle 19 | -5.45 scores on a scale |
| (Vic-)Trastuzumab Duocarmazine | Patient Reported Outcomes for Health Related Quality of Life | Cycle 25 | 18.76 scores on a scale |
| (Vic-)Trastuzumab Duocarmazine | Patient Reported Outcomes for Health Related Quality of Life | Cycle 9 | -8.14 scores on a scale |
| (Vic-)Trastuzumab Duocarmazine | Patient Reported Outcomes for Health Related Quality of Life | Cycle 27 | 0.49 scores on a scale |
| (Vic-)Trastuzumab Duocarmazine | Patient Reported Outcomes for Health Related Quality of Life | Cycle 4 | -2.48 scores on a scale |
| (Vic-)Trastuzumab Duocarmazine | Patient Reported Outcomes for Health Related Quality of Life | Cycle 11 | -10.70 scores on a scale |
| (Vic-)Trastuzumab Duocarmazine | Patient Reported Outcomes for Health Related Quality of Life | Cycle 23 | 5.30 scores on a scale |
| (Vic-)Trastuzumab Duocarmazine | Patient Reported Outcomes for Health Related Quality of Life | Cycle 13 | -13.40 scores on a scale |
| Physician's Choice | Patient Reported Outcomes for Health Related Quality of Life | Cycle 29 | -6.54 scores on a scale |
| Physician's Choice | Patient Reported Outcomes for Health Related Quality of Life | Cycle 33 | -7.11 scores on a scale |
| Physician's Choice | Patient Reported Outcomes for Health Related Quality of Life | Cycle 21 | -11.23 scores on a scale |
| Physician's Choice | Patient Reported Outcomes for Health Related Quality of Life | Cycle 35 | -15.73 scores on a scale |
| Physician's Choice | Patient Reported Outcomes for Health Related Quality of Life | Cycle 2 | -3.88 scores on a scale |
| Physician's Choice | Patient Reported Outcomes for Health Related Quality of Life | Cycle 3 | -2.99 scores on a scale |
| Physician's Choice | Patient Reported Outcomes for Health Related Quality of Life | Cycle 4 | -9.01 scores on a scale |
| Physician's Choice | Patient Reported Outcomes for Health Related Quality of Life | Cycle 5 | -5.77 scores on a scale |
| Physician's Choice | Patient Reported Outcomes for Health Related Quality of Life | Cycle 7 | -6.75 scores on a scale |
| Physician's Choice | Patient Reported Outcomes for Health Related Quality of Life | Cycle 9 | -11.25 scores on a scale |
| Physician's Choice | Patient Reported Outcomes for Health Related Quality of Life | Cycle 11 | -10.38 scores on a scale |
| Physician's Choice | Patient Reported Outcomes for Health Related Quality of Life | Cycle 13 | -12.89 scores on a scale |
| Physician's Choice | Patient Reported Outcomes for Health Related Quality of Life | Cycle 15 | -14.12 scores on a scale |
| Physician's Choice | Patient Reported Outcomes for Health Related Quality of Life | Cycle 17 | -0.71 scores on a scale |
| Physician's Choice | Patient Reported Outcomes for Health Related Quality of Life | Cycle 19 | 1.66 scores on a scale |
| Physician's Choice | Patient Reported Outcomes for Health Related Quality of Life | Cycle 23 | -7.00 scores on a scale |
| Physician's Choice | Patient Reported Outcomes for Health Related Quality of Life | Cycle 25 | -11.48 scores on a scale |
| Physician's Choice | Patient Reported Outcomes for Health Related Quality of Life | Cycle 27 | -5.41 scores on a scale |
Comparison: The change from baseline in the global health status/QoL scale transformed score was analyzed using a mixed model repeated measurement (MMRM) approach.p-value: 0.473MMRM