Bladder Cancer, Ureteral Cancer, Urothelial Cancer
Conditions
Keywords
antibody drug conjugate, enfortumab vedotin (EV), ASG-22ME, ASG-22CE, urothelial cancer
Brief summary
The purpose of this study was to compare the overall survival (OS) of participants with locally advanced or metastatic urothelial cancer treated with enfortumab vedotin (EV) to the OS of participants treated with chemotherapy. This study compared progression-free survival on study therapy (PFS1); the overall response rate (ORR) and the disease control rate (DCR) per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 of participants treated with EV to participants treated with chemotherapy. In addition, this study evaluated the duration of response (DOR) per RECIST V1.1 of EV and chemotherapy and assessed the safety and tolerability of EV, as well as, the quality of life (QOL) and Patient Reported Outcomes (PRO) parameters.
Detailed description
Japan PMDA has approved enfortumab vedotin (Padcev) for the treatment of advanced urothelial cancer. The study will continue as a post marketing study in Japan. Participants considered an adult according to local regulation at the time of obtaining informed consent participated in the study.
Interventions
DRUGEnfortumab Vedotin
Intravenous infusion
DRUGDocetaxel
Intravenous infusion
DRUGVinflunine
Intravenous infusion
DRUGPaclitaxel
Intravenous infusion
Sponsors
Seagen Inc.
Astellas Pharma Global Development, Inc.
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
* Subject is legally an adult according to local regulation at the time of signing informed consent. * Subject has histologically or cytologically confirmed urothelial carcinoma (i.e., cancer of the bladder, renal pelvis, ureter, or urethra). Subjects with urothelial carcinoma (transitional cell) with squamous differentiation or mixed cell types are eligible. * Subject must have experienced radiographic progression or relapse during or after a checkpoint inhibitor (CPI) (anti-programmed cell death protein 1 (PD1) or anti-programmed death-ligand 1 (PD-L1)) for locally advanced or metastatic disease. Subjects who discontinued CPI treatment due to toxicity are eligible provided that the subjects have evidence of disease progression following discontinuation. The CPI need not be the most recent therapy. Subjects for whom the most recent therapy has been a non-CPI based regimen are eligible if the subjects have progressed/relapsed during or after the subjects most recent therapy. Locally advanced disease must not be amenable to resection with curative intent per the treating physician. * Subject must have received a platinum containing regimen (cisplatin or carboplatin) in the metastatic/locally advanced, neoadjuvant or adjuvant setting. If platinum was administered in the adjuvant/neoadjuvant setting subject must have progressed within 12 months of completion. * Subject has radiologically documented metastatic or locally advanced disease at baseline. * An archival tumor tissue sample should be available for submission to central laboratory prior to study treatment. If an archival tumor tissue sample is not available, a fresh tissue sample should be provided. If a fresh tissue sample cannot be provided due to safety concerns, enrollment into the study must be discussed with the medical monitor. * Subject has ECOG PS of 0 or 1 * The subject has the following baseline laboratory data: * absolute neutrophil count (ANC) ≥ 1500/mm3 * platelet count ≥ 100 × 10\^9/L * hemoglobin ≥ 9 g/dL * serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for subjects with Gilbert's disease * creatinine clearance (CrCl) ≥ 30 mL/min as estimated per institutional standards or as measured by 24 hour urine collection (glomerular filtration rate \[GFR\] can also be used instead of CrCl) * alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 3 x ULN for subjects with liver metastases * Female subject must either: * Be of nonchildbearing potential: Postmenopausal (defined as at least 1 year without any menses for which there is no other obvious pathological or physiological cause) prior to screening, or documented surgically sterile (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy). * Or, if of childbearing potential: Agree not to try to become pregnant during the study and for at least 6 months after the final study drug administration, and have a negative urine or serum pregnancy test within 7 days prior to Day 1 (Females with false positive results and documented verification of negative pregnancy status are eligible for participation), and if heterosexually active, agree to consistently use a condom plus 1 form of highly effective birth control per locally accepted standards starting at screening and throughout the study period and for at least 6 months after the final study drug administration. * Female subject must agree not to breastfeed or donate ova starting at screening and throughout the study period, and for at least 6 months after the final study drug administration. * A sexually active male subject with female partner(s) who is of childbearing potential is eligible if: * Agrees to use a male condom starting at screening and continue throughout the study treatment and for at least 6 months after final study drug administration. If the male subject has not had a vasectomy or is not sterile as defined below the subjects female partner(s) is utilizing 1 form of highly effective birth control per locally accepted standards starting at screening and continue throughout study treatment and for at least 6 months after the male subject receives final study drug administration. * Male subject must not donate sperm starting at screening and throughout the study period, and for at least 6 months after the final study drug administration. * Male subject with a pregnant or breastfeeding partner(s) must agree to abstinence or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for at least 6 months after the final study drug administration. * Subject agrees not to participate in another interventional study while on treatment in present study. Inclusion Criteria for COE: * Subject is eligible for the COE if they continue to meet all inclusion criteria from the main protocol in addition to the following when the patient is evaluated for eligibility to participate in the COE portion of the study: * Institutional review board (IRB)/ independent ethics committee (IEC) approved written COE informed consent and privacy language as per national regulations (e.g., health insurance portability and accountability act \[HIPAA\] Authorization for US sites) must be obtained from the subject prior to any study-related procedures (including withdrawal of prohibited medication, if applicable). * Subject was randomized to Arm B and is either currently on study treatment or has discontinued study treatment due to intolerance, AE or progression of disease and has not started a new systemic anticancer treatment.
Exclusion criteria
* Subject has preexisting sensory or motor neuropathy Grade ≥ 2. * Subject has active central nervous system (CNS) metastases. Subjects with treated CNS metastases are permitted on study if all the following are true: * CNS metastases have been clinically stable for at least 6 weeks prior to screening * If requiring steroid treatment for CNS metastases, the subject is on a stable dose ≤ 20 mg/day of prednisone or equivalent for at least 2 weeks * Baseline scans show no evidence of new or enlarged brain metastasis * Subject does not have leptomeningeal disease * Subject has ongoing clinically significant toxicity (Grade 2 or higher with the exception of alopecia) associated with prior treatment (including systemic therapy, radiotherapy or surgery). Subject with ≤ Grade 2 immunotherapy-related hypothyroidism or panhypopituitarism may be enrolled when well-maintained/controlled on a stable dose of hormone replacement therapy (if indicated). Subjects with ongoing ≥ Grade 3 immunotherapy-related hypothyroidism or panhypopituitarism are excluded. Subjects with ongoing immunotherapy related colitis, uveitis, or pneumonitis or subjects with other immunotherapy related AEs requiring high doses of steroids (\> 20 mg/day of prednisone or equivalent) are excluded. * Subject has prior treatment with EV or other monomethyl auristatin E (MMAE)-based Antibody drug conjugates (ADCs). * Subject has received prior chemotherapy for urothelial cancer with all available study therapies in the control arm (i.e., both prior paclitaxel and docetaxel in regions where vinflunine is not an approved therapy, or prior paclitaxel, docetaxel and vinflunine in regions where vinflunine is an approved therapy). * Subject has received more than 1 prior chemotherapy regimen for locally advanced or metastatic urothelial cancer, including chemotherapy for adjuvant or neo-adjuvant disease if recurrence occurred within 12 months of completing therapy. The substitution of carboplatin for cisplatin does not constitute a new regimen provided no new chemotherapeutic agents were added to the regimen. * Subject has history of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Subjects with nonmelanoma skin cancer, localized prostate cancer treated with curative intent with no evidence of progression, low-risk or very low-risk (per standard guidelines) localized prostate cancer under active surveillance/watchful waiting without intent to treat, or carcinoma in situ of any type (if complete resection was performed) are allowed. * Subject is currently receiving systemic antimicrobial treatment for viral, bacterial, or fungal infection at the time of first dose of EV. Routine antimicrobial prophylaxis is permitted. * Subject has known active Hepatitis B (e.g., hepatitis B surface antigen (HBsAg) reactive) or active hepatitis C (e.g., hepatitis C virus (HCV) Ribonucleic Acid (RNA) \[qualitative\] is detected). * Subject has known history of human immunodeficiency virus (HIV) infection (HIV 1 or 2). * Subject has documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms (including congestive heart failure) consistent with New York Heart Association Class III-IV within 6 months prior to the first dose of study drug. * Subject has radiotherapy or major surgery within 4 weeks prior to first dose of study drug. * Subject has had chemotherapy, biologics, investigational agents, and/or antitumor treatment with immunotherapy that is not completed 2 weeks prior to first dose of study drug. * Subject has known hypersensitivity to EV or to any excipient contained in the drug formulation of EV; OR subject has known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary (CHO) cells. * Subject has known hypersensitivity to the following: docetaxel or to any of the other excipients listed in product label, including polysorbate 80, paclitaxel or to any of the other excipients listed in product label, such as macrogolglycerol ricinoleate 35 (Ph.Eur.); and vinflunine or to any of the other excipients listed in product label such as other vinca alkaloids (vinblastine,vincristine, vindesine, vinorelbine). * Subject has known active keratitis or corneal ulcerations. * Subject has other underlying medical condition that would impair the ability of the subject to receive or tolerate the planned treatment and follow-up. * History of uncontrolled diabetes mellitus within 3 months of the first dose of study drug. Uncontrolled diabetes is defined as hemoglobin A1C (HbA1c) ≥ 8% or HbA1c between 7 and \< 8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months) | OS was defined as the time from the date of randomization until the documented date of death from any cause. OS was analyzed using Kaplan-Meier estimates. Participants who were still alive at the time of data cutoff date were to be censored at the last known alive date or at the data cutoff date, whichever was earlier. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) as Per RECIST V1.1 | From randomization until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months) | ORR was defined as the percentage of participants with complete response (CR) or partial response (PR) based on the RECIST v1.1. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. ORR was analysed using exact method based on binomial distribution (Clopper-Pearson). Median time of follow up for ORR was based on data cut-off and is same as median follow-up time for OS. |
| Disease Control Rate (DCR) as Per RECIST V1.1 | From randomization until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months) | DCR was defined as the percentage of participants with a CR, PR or a stable disease (SD) based on RECIST v1.1. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. SD was defined as neither sufficient decrease to qualify for PR nor sufficient increase to qualify for progressive disease taking as reference the smallest sum of diameters while on study drug. Progressive disease is defined in PFS1 endpoint. DCR was analysed using exact method based on binomial distribution (Clopper-Pearson). Median time of follow up for DCR was based on data cut-off and is same as median follow-up time for OS. |
| Duration of Response (DOR) as Per RECIST V1.1 | From date of first objective response until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months) | DOR: time from the date of the first CR/PR (whichever is first recorded) that was subsequently confirmed as assessed by investigator to the date of documented PD or death due to any cause whichever occurred first. If a participant has neither progressed nor died, the participant was censored at the date of last RA or at the date of first CR/PR if no subsequent post-baseline RA was available. Participants who received any further ACT for the disease before radiological progression were censored at the date of the last RA before the ACT started. In addition, participants who had PD/death after \>= 2 missed RAs were censored at the last RA prior to the 2 or more missed RAs. Kaplan-Meier estimates was used. Median time of follow up for DOR was based on data cut-off and is same as median follow-up time for OS. CR/PR and PD were defined in ORR and PFS1 endpoints, respectively. |
| Progression Free Survival on Study Therapy (PFS1) as Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | From randomization until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months) | PFS: time from date of randomization until date of documented radiological disease progression (PD) per investigator based on RECIST V1.1, or until death due to any cause, whichever occurred first. PD: \>= 20% increase in sum of diameters of target lesions taking as reference the smallest sum, and sum must also demonstrate an absolute increase of \>= 5 mm. Appearance of 1 or more new lesions is also considered progression. A participant who neither progressed nor died was censored at date of last radiological assessment (RA)/ date of randomization if no post-baseline RA was available. Participants who received any further anticancer therapy (ACT) for disease before radiological progression was censored at date of last RA before ACT started and participants who had PD/death after \>=2 missed RAs were censored at last RA prior to 2 or more missed RAs. Kaplan-Meier estimates was used. Median time of follow-up for PFS was based on data cut-off & is same as median follow-up time for OS. |
| Change From Baseline to Week 12 in EuroQOL 5-dimension 5-level Questionnaire [EQ-5D-5L] Visual Analog Scale (VAS) | Baseline and week 12 | EQ-5D-5L is a health status instrument for self-reported assessment of 5 domains of health: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each domain is rated by selecting 1 of 5 standardized categorizations ranging from no problem to extreme problem. The final question is a visual analogue scale (VAS) to rank health status from 0 (best health imaginable) to 100 (worst health imaginable). |
| Number of Participants With Treatment Emergent Adverse Events | From first dose up to 30 days after last dose (Median (range) time on study drug was 4.99 (0.5, 19.4) months in enfortumab vedotin and 3.45 (0.2, 15.0) months in chemotherapy group) | An AE is any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. A TEAE is defined as an AE observed or worsened after starting administration of the study drug. |
| Number of Participants With ECOG Performance Status | End of treatment (EOT) (Median (range) time on study drug was 4.99 (0.5, 19.4) months in enfortumab vedotin and 3.45 (0.2, 15.0) months in chemotherapy group) | ECOG performance status was measured on an 6 point scale. 0-Fully active, able to carry on all pre-disease performance without restriction. 1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2. Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. 3. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5. Dead. Number of participants with ECOG PS was reported. |
| Change From Baseline to Week 12 in European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire Global Health Status (QL2 Score) | Baseline and week 12 | EORTC QLQ-C30 is a generic questionnaire consisting of 30 items. The instrument yields functional scales (physical, role, emotional, cognitive, social), symptom scales/items (fatigue, Nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea), global health status, and financial impact score. Most items are scored 1 (not at all) to 4 (very much) except for the items contributing to the global health status/QoL, which are scored 1 (very poor) to 7 (excellent). The recall period for each question is during the past week. All raw domain scores are linearly transformed to a 0-100 scale with higher scores on symptoms indicate a worse health state. Higher scores on the global health status and functioning scales indicate better health status/function. |
Countries
Argentina, Australia, Austria, Belgium, Canada, Denmark, France, Germany, Italy, Japan, Netherlands, Portugal, Russia, South Korea, Spain, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Adult participants with locally advanced or metastatic urothelial cancer (mUC) who had received a platinum-containing chemotherapy and had experienced disease progression or relapse during or following treatment with programmed cell death protein-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors.
Pre-assignment details
Participants were stratified by Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0 vs 1), regions of the world Western EU vs US vs Rest of World) and liver metastasis (Yes vs No).
Participants by arm
| Arm | Count |
|---|---|
| Enfortumab Vedotin 1.25 mg/kg Participants received 1.25 mg/kg of body weight enfortumab vedotin by IV infusion over approximately 30 minutes on days 1, 8 and 15 of every 28day cycle. Participants received study treatment until radiological disease progression as determined per investigator assessment or other discontinuation criteria were met or upon study termination, or study completion, whichever occurred first. | 301 |
| Chemotherapy Participants received either 75 mg/m\^2 docetaxel by IV infusion over approximately 1 hour or 320 mg/m\^2 vinflunine by IV infusion over approximately 20 minutes or 175 mg/m\^2 paclitaxel by IV infusion over approximately 3 hours on day 1 of every 21-day cycle. Participants received study treatment until radiological disease progression as determined per investigator assessment or other discontinuation criteria were met or upon study termination, or study completion, whichever occurred first. | 307 |
| Total | 608 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 42 | 46 |
| Overall Study | Death | 2 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Miscellaneous | 1 | 6 |
| Overall Study | Physician Decision | 7 | 22 |
| Overall Study | Progressive Disease | 177 | 180 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 15 | 27 |
Baseline characteristics
| Characteristic | Total | Enfortumab Vedotin 1.25 mg/kg | Chemotherapy |
|---|---|---|---|
| Age, Continuous | 66.67 Years STANDARD_DEVIATION 9.53 | 66.52 Years STANDARD_DEVIATION 9.11 | 66.81 Years STANDARD_DEVIATION 9.93 |
| ECOG PS ECOG PS=0 | 244 participants | 120 participants | 124 participants |
| ECOG PS ECOG PS=1 | 364 participants | 181 participants | 183 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 53 Participants | 29 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 468 Participants | 230 Participants | 238 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 87 Participants | 42 Participants | 45 Participants |
| Liver Metastasis Liver Metastasis=No | 420 participants | 208 participants | 212 participants |
| Liver Metastasis Liver Metastasis=Yes | 188 participants | 93 participants | 95 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 200 Participants | 97 Participants | 103 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 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 | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 89 Participants | 43 Participants | 46 Participants |
| Race (NIH/OMB) White | 314 Participants | 159 Participants | 155 Participants |
| Region Rest of the World | 266 participants | 132 participants | 134 participants |
| Region United States | 87 participants | 43 participants | 44 participants |
| Region Western Europe | 255 participants | 126 participants | 129 participants |
| Sex: Female, Male Female | 138 Participants | 63 Participants | 75 Participants |
| Sex: Female, Male Male | 470 Participants | 238 Participants | 232 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 130 / 296 | 161 / 291 |
| other Total, other adverse events | 284 / 296 | 266 / 291 |
| serious Total, serious adverse events | 138 / 296 | 128 / 291 |
Outcome results
Primary
Overall Survival (OS)
OS was defined as the time from the date of randomization until the documented date of death from any cause. OS was analyzed using Kaplan-Meier estimates. Participants who were still alive at the time of data cutoff date were to be censored at the last known alive date or at the data cutoff date, whichever was earlier.
Time frame: From randomization until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months)
Population: FAS Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enfortumab Vedotin 1.25 mg/kg | Overall Survival (OS) | 12.88 months |
| Chemotherapy | Overall Survival (OS) | 8.97 months |
p-value: 0.0014295% CI: [0.556, 0.886]Stratified Log rank
Secondary
Change From Baseline to Week 12 in European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire Global Health Status (QL2 Score)
EORTC QLQ-C30 is a generic questionnaire consisting of 30 items. The instrument yields functional scales (physical, role, emotional, cognitive, social), symptom scales/items (fatigue, Nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea), global health status, and financial impact score. Most items are scored 1 (not at all) to 4 (very much) except for the items contributing to the global health status/QoL, which are scored 1 (very poor) to 7 (excellent). The recall period for each question is during the past week. All raw domain scores are linearly transformed to a 0-100 scale with higher scores on symptoms indicate a worse health state. Higher scores on the global health status and functioning scales indicate better health status/function.
Time frame: Baseline and week 12
Population: FAS population with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enfortumab Vedotin 1.25 mg/kg | Change From Baseline to Week 12 in European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire Global Health Status (QL2 Score) | -2.30 score on a scale | Standard Deviation 18.02 |
| Chemotherapy | Change From Baseline to Week 12 in European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire Global Health Status (QL2 Score) | -5.72 score on a scale | Standard Deviation 16.04 |
Secondary
Change From Baseline to Week 12 in EuroQOL 5-dimension 5-level Questionnaire [EQ-5D-5L] Visual Analog Scale (VAS)
EQ-5D-5L is a health status instrument for self-reported assessment of 5 domains of health: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each domain is rated by selecting 1 of 5 standardized categorizations ranging from no problem to extreme problem. The final question is a visual analogue scale (VAS) to rank health status from 0 (best health imaginable) to 100 (worst health imaginable).
Time frame: Baseline and week 12
Population: FAS population with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Enfortumab Vedotin 1.25 mg/kg | Change From Baseline to Week 12 in EuroQOL 5-dimension 5-level Questionnaire [EQ-5D-5L] Visual Analog Scale (VAS) | -1.8 score on a scale | Standard Deviation 16.6 |
| Chemotherapy | Change From Baseline to Week 12 in EuroQOL 5-dimension 5-level Questionnaire [EQ-5D-5L] Visual Analog Scale (VAS) | -5.3 score on a scale | Standard Deviation 14.5 |
Secondary
Disease Control Rate (DCR) as Per RECIST V1.1
DCR was defined as the percentage of participants with a CR, PR or a stable disease (SD) based on RECIST v1.1. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. SD was defined as neither sufficient decrease to qualify for PR nor sufficient increase to qualify for progressive disease taking as reference the smallest sum of diameters while on study drug. Progressive disease is defined in PFS1 endpoint. DCR was analysed using exact method based on binomial distribution (Clopper-Pearson). Median time of follow up for DCR was based on data cut-off and is same as median follow-up time for OS.
Time frame: From randomization until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months)
Population: RES Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Enfortumab Vedotin 1.25 mg/kg | Disease Control Rate (DCR) as Per RECIST V1.1 | 71.9 percentage of participants |
| Chemotherapy | Disease Control Rate (DCR) as Per RECIST V1.1 | 53.4 percentage of participants |
p-value: <0.001Stratified Cochran-Mantel-Haenszel
Secondary
Duration of Response (DOR) as Per RECIST V1.1
DOR: time from the date of the first CR/PR (whichever is first recorded) that was subsequently confirmed as assessed by investigator to the date of documented PD or death due to any cause whichever occurred first. If a participant has neither progressed nor died, the participant was censored at the date of last RA or at the date of first CR/PR if no subsequent post-baseline RA was available. Participants who received any further ACT for the disease before radiological progression were censored at the date of the last RA before the ACT started. In addition, participants who had PD/death after \>= 2 missed RAs were censored at the last RA prior to the 2 or more missed RAs. Kaplan-Meier estimates was used. Median time of follow up for DOR was based on data cut-off and is same as median follow-up time for OS. CR/PR and PD were defined in ORR and PFS1 endpoints, respectively.
Time frame: From date of first objective response until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months)
Population: RES population with available data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enfortumab Vedotin 1.25 mg/kg | Duration of Response (DOR) as Per RECIST V1.1 | 7.39 months |
| Chemotherapy | Duration of Response (DOR) as Per RECIST V1.1 | 8.11 months |
Secondary
Number of Participants With ECOG Performance Status
ECOG performance status was measured on an 6 point scale. 0-Fully active, able to carry on all pre-disease performance without restriction. 1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2. Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. 3. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5. Dead. Number of participants with ECOG PS was reported.
Time frame: End of treatment (EOT) (Median (range) time on study drug was 4.99 (0.5, 19.4) months in enfortumab vedotin and 3.45 (0.2, 15.0) months in chemotherapy group)
Population: Safety population with available data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Enfortumab Vedotin 1.25 mg/kg | Number of Participants With ECOG Performance Status | ECOG PS = 0 | 34 participants |
| Enfortumab Vedotin 1.25 mg/kg | Number of Participants With ECOG Performance Status | ECOG PS = 1 | 110 participants |
| Enfortumab Vedotin 1.25 mg/kg | Number of Participants With ECOG Performance Status | ECOG PS >1 | 40 participants |
| Chemotherapy | Number of Participants With ECOG Performance Status | ECOG PS = 0 | 57 participants |
| Chemotherapy | Number of Participants With ECOG Performance Status | ECOG PS >1 | 44 participants |
| Chemotherapy | Number of Participants With ECOG Performance Status | ECOG PS = 1 | 118 participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events
An AE is any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. A TEAE is defined as an AE observed or worsened after starting administration of the study drug.
Time frame: From first dose up to 30 days after last dose (Median (range) time on study drug was 4.99 (0.5, 19.4) months in enfortumab vedotin and 3.45 (0.2, 15.0) months in chemotherapy group)
Population: The safety analysis set (SAF) consisted of all participants who received any amount of study drug, and was used for safety analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Enfortumab Vedotin 1.25 mg/kg | Number of Participants With Treatment Emergent Adverse Events | 290 participants |
| Chemotherapy | Number of Participants With Treatment Emergent Adverse Events | 288 participants |
Secondary
Overall Response Rate (ORR) as Per RECIST V1.1
ORR was defined as the percentage of participants with complete response (CR) or partial response (PR) based on the RECIST v1.1. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \< 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. ORR was analysed using exact method based on binomial distribution (Clopper-Pearson). Median time of follow up for ORR was based on data cut-off and is same as median follow-up time for OS.
Time frame: From randomization until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months)
Population: Response Evaluable Set (RES): The RES was defined as all participants in the FAS who had measurable disease (per RECIST v1.1) per investigator at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Enfortumab Vedotin 1.25 mg/kg | Overall Response Rate (ORR) as Per RECIST V1.1 | 40.6 percentage of participants |
| Chemotherapy | Overall Response Rate (ORR) as Per RECIST V1.1 | 17.9 percentage of participants |
p-value: <0.001Stratified Cochran-Mantel-Haenszel
Secondary
Progression Free Survival on Study Therapy (PFS1) as Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
PFS: time from date of randomization until date of documented radiological disease progression (PD) per investigator based on RECIST V1.1, or until death due to any cause, whichever occurred first. PD: \>= 20% increase in sum of diameters of target lesions taking as reference the smallest sum, and sum must also demonstrate an absolute increase of \>= 5 mm. Appearance of 1 or more new lesions is also considered progression. A participant who neither progressed nor died was censored at date of last radiological assessment (RA)/ date of randomization if no post-baseline RA was available. Participants who received any further anticancer therapy (ACT) for disease before radiological progression was censored at date of last RA before ACT started and participants who had PD/death after \>=2 missed RAs were censored at last RA prior to 2 or more missed RAs. Kaplan-Meier estimates was used. Median time of follow-up for PFS was based on data cut-off & is same as median follow-up time for OS.
Time frame: From randomization until the analysis cut-off date of 15-Jul-2020 (median OS follow-up was 11.10 months)
Population: FAS Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Enfortumab Vedotin 1.25 mg/kg | Progression Free Survival on Study Therapy (PFS1) as Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 5.55 months |
| Chemotherapy | Progression Free Survival on Study Therapy (PFS1) as Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | 3.71 months |
p-value: <0.0000195% CI: [0.505, 0.748]Stratified Log Rank