Pemigatinib + Pembrolizumab vs Pemigatinib Alone vs Standard of Care for Urothelial Carcinoma (FIGHT-205)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of pemigatinib plus pembrolizumab or pemigatinib alone versus the standard of care for participants with metastatic or unresectable urothelial carcinoma who are not eligible to receive cisplatin, are harboring FGFR3 mutation or rearrangement, and who have not received prior treatment.

Official Title
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A Phase 2, Open-Label, Randomized, Multicenter Study to Evaluate the Efficacy and Safety of Pemigatinib Plus Pembrolizumab Versus Pemigatinib Alone Versus Standard of Care as First-Line Treatment for Metastatic or Unresectable Urothelial Carcinoma in Cisplatin-Ineligible Participants Whose Tumors Express FGFR3 Mutation or Rearrangement (FIGHT-205)

Conditions
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Metastatic Urothelial Carcinoma, Unresectable Urothelial Carcinoma

Intervention / Treatment
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* Drug: Pemigatinib
* Drug: Pembrolizumab
* Drug: Gemcitabine
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically documented metastatic or unresectable urothelial carcinoma. Both transitional cell and mixed transitional cell histologies are allowed, provided urothelial component is ≥ 50%. At least 1 measurable target lesion per RECIST v1.1. Must be ineligible to receive cisplatin. Patients ineligible for any platinum-based chemotherapy are allowed. Known FGFR3 mutation or rearrangement confirmed by the central laboratory prior to randomization. Central laboratory test result of PD-L1 status is mandatory at screening. Have received no prior systemic chemotherapy for metastatic or unresectable urothelial carcinoma (except adjuvant platinum-based chemotherapy following radical cystectomy, with recurrence > 12 months from completion of therapy, or neo-adjuvant platinum-based chemotherapy, with recurrence > 12 months since completion of therapy). Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. Willingness to avoid pregnancy or fathering children. Exclusion Criteria: Prior receipt of a selective FGFR inhibitor for any indication or reason. Prior receipt of an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or with an agent directed to another co-inhibitory T-cell receptor. Receipt of anticancer medications or investigational drugs for unresectable and/or metastatic disease. Concurrent anticancer therapy, except for treatment allowed per protocol. Has disease that is suitable for local therapy administered with curative intent. Has tumor with any neuroendocrine or small cell component. Current evidence of clinically significant corneal or retinal disorder as confirmed by ophthalmologic examination. Has received prior radiotherapy to a metastatic site without the use of chemotherapy radiosensitization within 3 weeks of the first dose of study treatment, with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks before the start of study treatment. Has central nervous system metastases, unless the participant has completed local therapy (eg, whole brain radiation therapy, surgery, radiosurgery) and has discontinued use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Known additional malignancy that is progressing or required active treatment within the past 3 years Laboratory values outside the protocol-defined range at screening. Clinically significant or uncontrolled cardiac disease. History of autoimmune disease that has required systemic treatment in past 2 years.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pemigatinib + Pembrolizumab<br>Combination of pemigatinib (13.5 milligrams [mg] once a day orally) plus pembrolizumab (200 mg every 3 weeks [Q3W] intravenously [IV]) | Drug: Pemigatinib<br>* 13.5 mg once a day orally<br>* Other names: INCB054828;Drug: Pembrolizumab<br>* 200 mg Q3W intravenously<br>* Other names: Keytruda®;|
| Experimental: Pemigatinib<br>Pemigatinib (13.5 mg once a day orally) alone | Drug: Pemigatinib<br>* 13.5 mg once a day orally<br>* Other names: INCB054828;|
| Active Comparator: Standard of Care<br>Either gemcitabine plus carboplatin or pembrolizumab as standard of care. Gemcitabine 1000 mg/meters squared (m^2) IV over 30 minutes on Days 1 and 8, followed by carboplatin (dosed to target area under the concentration-time curve [AUC] of 5 mg/milliliters [mL]/minute [min] or 4.5 mg/mL/min if required per local guidelines) on Day 1 or 2 of each 3-week cycle. Pembrolizumab 200 mg IV on Day 1 of each 21-day treatment cycle for up to 35 cycles or disease progression. | Drug: Gemcitabine<br>* 1000 mg/m^2 IV over 30 minutes on Days 1 and 8 of each 3-week cycle<br>Drug: Carboplatin<br>* Dosed to target AUC of 5 mg/mL/min or 4.5 mg/mL/min if required per local guidelines on Day 1 or 2 of each 3-week cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS was defined as the time from the randomization date until the date of disease progression (as measured by a blinded independent central review [BICR] per Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST v1.1]) or death due to any cause, whichever occurred first. | up to 130 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time from the date of randomization until death due to any cause. | up to 225 days | 
| Objective Response Rate (ORR) | ORR was defined as the proportion of participants with a best overall response of complete response (CR) or partial response (PR) per RECIST v1.1 (as measured by BICR). | up to 148 days | 
| Duration of Response (DOR) | DOR was defined as the time from the date of the first assessment of CR or PR until the date of the first disease progression (per RECIST v1.1) or death, whichever occurred first (as measured by BICR). | up to 148 days | 
| Number of Participants With Treatment-emergent Adverse Events | A treatment-emergent adverse event was defined as an adverse event that was either reported for the first time or the worsening of a pre-existing event after the first dose of study drug until 30 days after the last dose of study drug. | up to 178 days | 
| EORTC QLQ-C30 Score | The European Organization for the Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) contains 30 items and measures 5 functional dimensions (i.e., physical, role, emotional, cognitive, and social), 3 symptom items (i.e., fatigue, nausea/vomiting, and pain), 6 single items (i.e., dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global health and quality of life scale. For each scale and single item, a linear transformation was applied to standardize the scores between 0 (worst) and 100 (best) as described in the EORTC QLQ-C30 Scoring Manual. | up to 160 days | 
| Change From Baseline in the EORTC QLQ-C30 Score | The European Organization for the Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) contains 30 items and measures 5 functional dimensions (i.e., physical, role, emotional, cognitive, and social), 3 symptom items (i.e., fatigue, nausea/vomiting, and pain), 6 single items (i.e., dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global health and quality of life scale. For each scale and single item, a linear transformation was applied to standardize the scores between 0 (worst) and 100 (best) as described in the EORTC QLQ-C30 Scoring Manual. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; up to 160 days | 
| Number of Participants With the Indicated EQ-5D-5L Dimension Scores | The EQ-5D-5L is a standardized instrument for use as a measure of health outcome. The EQ-5D-5L descriptive system is composed of 5 dimensions (mobility, self-case, usual activities, pain/discomfort, and anxiety/depression). Each dimension has 5 response levels, which are coded by single-digit numbers: 1 = no problems, 2 = slight problems, 3 = moderate problems, 4 = severe problems, 5 = unable to/extreme problems. The EQ-5D-5L also includes a graded (0 [worst overall health] to 100 [best overall health]) vertical visual analog scale that provides a quantitative measure of the participant's perception of their overall health. | up to 160 days | 
| Change From Baseline in the EQ-5D-5L EQ Visual Analog Scale Score | The EQ-5D-5L is a standardized instrument for use as a measure of health outcome. The EQ-5D-5L descriptive system is composed of 5 dimensions (mobility, self-case, usual activities, pain/discomfort, and anxiety/depression). Each dimension has 5 response levels, which are coded by single-digit numbers: 1 = no problems, 2 = slight problems, 3 = moderate problems, 4 = severe problems, 5 = unable to/extreme problems. The EQ-5D-5L also includes a graded (0 [worst overall health] to 100 [best overall health]) vertical visual analog scale that provides a quantitative measure of the participant's perception of their overall health. | Baseline; up to 160 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Urothelial carcinoma, fibroblast growth factor receptor (FGFR) inhibitor, FGFR3 mutation, FGFR3 rearrangement, metastatic, unresectable, cisplatin-ineligible