UC (Urothelial Cancer)
Conditions
Keywords
Urothelial carcinoma, fibroblast growth factor (FGF), fibroblast growth factor receptor (FGFR), FGF/FGFR alterations
Brief summary
The purpose of this study is to evaluate the overall response rate (ORR) of pemigatinib as a monotherapy in the treatment of metastatic or surgically unresectable urothelial carcinoma harboring FGF/FGFR alterations.
Interventions
DRUGpemigatinib
Pemigatinib once a day by mouth for 2 consecutive weeks and 1 week off therapy.
Sponsors
Incyte Corporation
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
* 20 years and older in Japan * Histologically documented metastatic or surgically unresectable urothelial carcinoma; may include primary site from urethra, ureters, upper tract, renal pelvis, and bladder. * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. * Life expectancy ≥ 12 weeks. * Radiographically measurable per RECIST v1.1. * Documented FGF/FGFR alteration and have either 1a) failed at least 1 previous treatment for their metastatic or surgically unresectable urothelial carcinoma (ie, chemotherapy, immunotherapy) or 1b) have not received chemotherapy due to poor ECOG status or 2) have insufficient renal function.
Exclusion criteria
* Prior receipt of a selective FGFR inhibitor. * Use of any potent CYP3A4 inhibitors or inducers within 14 days or 5 half-lives (whichever is shorter) before the first dose of study drug. * Inability or unwillingness to swallow pemigatinib or significant gastrointestinal disorder(s) that could interfere with the absorption, metabolism, or excretion of pemigatinib.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) in Participants With FGFR3 Mutations or Fusions on a CD Regimen | up to 1138 days | ORR was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) at any post-Baseline visit prior to first progressive disease (PD), per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1). CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 millimeters (mm). PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. Response was based on review of scans by an independent centralized radiological review committee. Response was confirmed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ORR in Participants With All Other FGF/FGFR Alterations | up to 1198 days | ORR was defined as the percentage of participants with a best overall response of CR or PR at any post-Baseline visit prior to first PD, per RECIST v1.1. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 millimeters (mm). PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. Response was based on review of scans by an independent centralized radiological review committee. Response was confirmed. |
| ORR in All Participants on an ID or CD Regimen in Combined Cohorts | up to 1198 days | ORR was defined as the percentage of participants with a best overall response of CR or PR at any post-Baseline visit prior to first PD, per RECIST v1.1. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 millimeters (mm). PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. Response was based on review of scans by an independent centralized radiological review committee. Response was confirmed. |
| Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | up to approximately 25 weeks | An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results occurring after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or required changes in the study drug(s). A TEAE was any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug and within 30 days of the last dose of study drug. |
| ORR in Participants With FGFR3 Mutations or Fusions on an ID Regimen | up to 817 days | ORR was defined as the percentage of participants with a best overall response of CR or PR at any post-Baseline visit prior to first PD, per RECIST v1.1. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 millimeters (mm). PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. Response was based on review of scans by an independent centralized radiological review committee. Response was confirmed. |
| Duration of Response (DOR) | up to 1075 days | DOR was defined as the time from the first overall response contributing to an objective response (CR or PR) to the earlier of death or first overall response of PD occurring after the first overall response contributing to the objective response. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 millimeters (mm). PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. Response was based on review of scans by an independent centralized radiological review committee. Response was confirmed |
| Overall Survival | up to 1610 days | Overall survival was defined as the length of time from the start of the study drug (Day 1) until the date of death due to any cause. |
| Progression-free Survival (PFS) | up to 1138 days | PFS was defined as the length of time from the start of the study drug (Day 1) to the earlier of death or disease progression by RECIST v1.1, as assessed by the independent centralized radiological review committee. |
Countries
Belgium, Denmark, France, Germany, Israel, Italy, Japan, Netherlands, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
The study was conducted at a total of 73 study centers in 11 countries (United States, France, Italy, Spain, Israel, Belgium, United Kingdom, Germany, Japan, Denmark, and the Netherlands).
Participants by arm
| Arm | Count |
|---|---|
| Cohort A-ID: FGFR3 Mutations or Fusions Participants with fibroblast growth factor (FGF) receptor 3 (FGFR3) mutations or fusions self-administered oral pemigatinib at a starting dose of 13.5 milligrams (mg) once daily (QD) on an intermittent dose (ID) (2-weeks-on/1-week-off therapy) schedule in 21-day cycles. Participants who did not reach the target serum phosphate level of \> 5.5 mg/deciliter (dL) could have increased the daily dose to 18 mg, provided they had no ongoing Grade 2 or higher treatment-related treatment-emergent adverse events (TEAEs), and they had been compliant with taking the study drug. | 103 |
| Cohort B-ID: All Other FGF/FGFR Alterations Participants with all other FGF/FGFR alterations self-administered oral pemigatinib at a starting dose of 13.5 mg QD on an ID (2-weeks-on/1-week-off therapy) schedule in 21-day cycles. Participants who did not reach the target serum phosphate level of \> 5.5 mg/dL could have increased the daily dose to 18 mg, provided they had no ongoing Grade 2 or higher treatment-related TEAEs, and they had been compliant with taking the study drug. | 44 |
| Other-ID Participants with no FGF/FGFR alterations or with an undetermined FGF/FGFR status self-administered oral pemigatinib at a starting dose of 13.5 mg QD on an ID (2-weeks-on/1-week-off therapy) schedule in 21-day cycles. Participants who did not reach the target serum phosphate level of \> 5.5 mg/dL could have increased the daily dose to 18 mg, provided they had no ongoing Grade 2 or higher treatment-related TEAEs, and they had been compliant with taking the study drug. | 9 |
| Cohort A-CD: FGFR3 Mutations or Fusions Participants with FGFR3 mutations or fusions self-administered oral pemigatinib at a starting dose of 13.5 mg QD on a continuous dose (CD) (no planned dose hold) schedule in 21-day cycles. Participants who did not reach the target serum phosphate level of \> 5.5 mg/dL could have increased the daily dose to 18 mg, provided they had no ongoing Grade 2 or higher treatment-related TEAEs, and they had been compliant with taking the study drug. | 101 |
| Other-CD Participants with no FGF/FGFR alterations or with an undetermined FGF/FGFR status self-administered oral pemigatinib at a starting dose of 13.5 mg QD on a continuous dose (CD) (no planned dose hold) schedule in 21-day cycles. Participants who did not reach the target serum phosphate level of \> 5.5 mg/dL could have increased the daily dose to 18 mg, provided they had no ongoing Grade 2 or higher treatment-related TEAEs, and they had been compliant with taking the study drug. | 3 |
| Total | 260 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Captured as Other | 2 | 0 | 0 | 1 | 0 |
| Overall Study | Death | 87 | 36 | 8 | 81 | 2 |
| Overall Study | Lost to Follow-up | 2 | 1 | 0 | 3 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Progressive Disease | 1 | 2 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 3 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Total | Cohort A-ID: FGFR3 Mutations or Fusions | Cohort B-ID: All Other FGF/FGFR Alterations | Other-ID | Cohort A-CD: FGFR3 Mutations or Fusions | Other-CD |
|---|---|---|---|---|---|---|
| Age, Continuous | 67.5 years STANDARD_DEVIATION 9.53 | 67.6 years STANDARD_DEVIATION 9.09 | 65.1 years STANDARD_DEVIATION 10.83 | 69.3 years STANDARD_DEVIATION 7.98 | 68.5 years STANDARD_DEVIATION 9.39 | 60.3 years STANDARD_DEVIATION 9.02 |
| Race/Ethnicity, Customized Asian | 17 Participants | 2 Participants | 2 Participants | 0 Participants | 12 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African-American | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Captured as Other | 11 Participants | 5 Participants | 0 Participants | 0 Participants | 6 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Missing | 10 Participants | 5 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 171 Participants | 64 Participants | 32 Participants | 7 Participants | 66 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Reported | 59 Participants | 23 Participants | 11 Participants | 2 Participants | 22 Participants | 1 Participants |
| Race/Ethnicity, Customized Persian | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Turkish | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 9 Participants | 5 Participants | 1 Participants | 0 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 66 Participants | 30 Participants | 13 Participants | 1 Participants | 22 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 164 Participants | 64 Participants | 29 Participants | 6 Participants | 63 Participants | 2 Participants |
| Sex: Female, Male Female | 68 Participants | 29 Participants | 14 Participants | 1 Participants | 23 Participants | 1 Participants |
| Sex: Female, Male Male | 192 Participants | 74 Participants | 30 Participants | 8 Participants | 78 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 88 / 103 | 39 / 44 | 8 / 9 | 83 / 101 | 2 / 3 |
| other Total, other adverse events | 101 / 103 | 43 / 44 | 9 / 9 | 99 / 101 | 3 / 3 |
| serious Total, serious adverse events | 45 / 103 | 26 / 44 | 3 / 9 | 48 / 101 | 1 / 3 |
Outcome results
Primary
Objective Response Rate (ORR) in Participants With FGFR3 Mutations or Fusions on a CD Regimen
ORR was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) at any post-Baseline visit prior to first progressive disease (PD), per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1). CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 millimeters (mm). PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. Response was based on review of scans by an independent centralized radiological review committee. Response was confirmed.
Time frame: up to 1138 days
Population: Efficacy Evaluable Population: all participants enrolled in the study who had a known FGF/FGFR alteration confirmed by the sponsor's central laboratory and who had received at least 1 dose of study drug. The confidence interval was calculated based on the exact method for binomial distribution.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A-CD: FGFR3 Mutations or Fusions | Objective Response Rate (ORR) in Participants With FGFR3 Mutations or Fusions on a CD Regimen | 17.8 percentage of participants |
Secondary
Duration of Response (DOR)
DOR was defined as the time from the first overall response contributing to an objective response (CR or PR) to the earlier of death or first overall response of PD occurring after the first overall response contributing to the objective response. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 millimeters (mm). PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. Response was based on review of scans by an independent centralized radiological review committee. Response was confirmed
Time frame: up to 1075 days
Population: Efficacy Evaluable Population. The Other-ID and Other-CD treatment groups were not included in the Efficacy Evaluable Population. Only participants with a CR or PR were analyzed. The 95% confidence interval was calculated using the Brookmeyer and Crowley's method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A-ID: FGFR3 Mutations or Fusions | Duration of Response (DOR) | 6.21 months |
| Cohort B-ID: All Other FGF/FGFR Alterations | Duration of Response (DOR) | 10.02 months |
| Cohort A-CD: FGFR3 Mutations or Fusions | Duration of Response (DOR) | 6.23 months |
Secondary
Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results occurring after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or required changes in the study drug(s). A TEAE was any AE either reported for the first time or the worsening of a pre-existing event after the first dose of study drug and within 30 days of the last dose of study drug.
Time frame: up to approximately 25 weeks
Population: Safety Population: all participants enrolled in the study who had received at least 1 dose of study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A-ID: FGFR3 Mutations or Fusions | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 103 Participants |
| Cohort B-ID: All Other FGF/FGFR Alterations | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 44 Participants |
| Other-ID | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 9 Participants |
| Cohort A-CD: FGFR3 Mutations or Fusions | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 100 Participants |
| Other-CD | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) | 3 Participants |
Secondary
ORR in All Participants on an ID or CD Regimen in Combined Cohorts
ORR was defined as the percentage of participants with a best overall response of CR or PR at any post-Baseline visit prior to first PD, per RECIST v1.1. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 millimeters (mm). PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. Response was based on review of scans by an independent centralized radiological review committee. Response was confirmed.
Time frame: up to 1198 days
Population: Efficacy Evaluable Population. The confidence interval was calculated based on the exact method for binomial distribution.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A-ID + Cohort B-ID | ORR in All Participants on an ID or CD Regimen in Combined Cohorts | 18.4 percentage of participants |
| Cohort A-ID + Cohort A-CD | ORR in All Participants on an ID or CD Regimen in Combined Cohorts | 20.6 percentage of participants |
| Cohort A-ID + Cohort B-ID + Cohort A-CD | ORR in All Participants on an ID or CD Regimen in Combined Cohorts | 18.1 percentage of participants |
Secondary
ORR in Participants With All Other FGF/FGFR Alterations
ORR was defined as the percentage of participants with a best overall response of CR or PR at any post-Baseline visit prior to first PD, per RECIST v1.1. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 millimeters (mm). PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. Response was based on review of scans by an independent centralized radiological review committee. Response was confirmed.
Time frame: up to 1198 days
Population: Efficacy Evaluable Population. The confidence interval was calculated based on the exact method for binomial distribution.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort B-ID: All Other FGF/FGFR Alterations | ORR in Participants With All Other FGF/FGFR Alterations | 6.8 percentage of participants |
Secondary
ORR in Participants With FGFR3 Mutations or Fusions on an ID Regimen
ORR was defined as the percentage of participants with a best overall response of CR or PR at any post-Baseline visit prior to first PD, per RECIST v1.1. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 millimeters (mm). PR: complete disappearance or at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. Response was based on review of scans by an independent centralized radiological review committee. Response was confirmed.
Time frame: up to 817 days
Population: Efficacy Evaluable Population. The confidence interval was calculated based on the exact method for binomial distribution.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A-ID: FGFR3 Mutations or Fusions | ORR in Participants With FGFR3 Mutations or Fusions on an ID Regimen | 23.3 percentage of participants |
Secondary
Overall Survival
Overall survival was defined as the length of time from the start of the study drug (Day 1) until the date of death due to any cause.
Time frame: up to 1610 days
Population: Efficacy Evaluable Population. The Other-ID and Other-CD treatment groups were not included in the Efficacy Evaluable Population. The 95% confidence interval was calculated using the Brookmeyer and Crowley's method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A-ID: FGFR3 Mutations or Fusions | Overall Survival | 8.90 months |
| Cohort B-ID: All Other FGF/FGFR Alterations | Overall Survival | 9.13 months |
| Cohort A-CD: FGFR3 Mutations or Fusions | Overall Survival | 6.80 months |
Secondary
Progression-free Survival (PFS)
PFS was defined as the length of time from the start of the study drug (Day 1) to the earlier of death or disease progression by RECIST v1.1, as assessed by the independent centralized radiological review committee.
Time frame: up to 1138 days
Population: Efficacy Evaluable Population. The Other-ID and Other-CD treatment groups were not included in the Efficacy Evaluable Population. The 95% confidence interval was calculated using the Brookmeyer and Crowley's method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A-ID: FGFR3 Mutations or Fusions | Progression-free Survival (PFS) | 4.27 months |
| Cohort B-ID: All Other FGF/FGFR Alterations | Progression-free Survival (PFS) | 2.04 months |
| Cohort A-CD: FGFR3 Mutations or Fusions | Progression-free Survival (PFS) | 4.04 months |