Study of Rogaratinib (BAY1163877) vs Chemotherapy in Patients With FGFR (Fibroblast Growth Factor Receptor)-Positive Locally Advanced or Metastatic Urothelial Carcinoma

• Rogaratinib (BAY1163877) (Drug): Rogaratinib administered as oral (p.o.) tablets twice daily (b.i.d.) continuously
• Chemotherapy (Drug): Chemotherapy as taxane (docetaxel or paclitaxel) or vinflunine administered through intravenous (i.v.) infusion every 3 weeks (on day 1 of a 21-day cycle) The choice of the chemotherapy is at the discretion of the investigator, taking into consideration the status of the authorization or treatment guidelines in the given country.

Primary outcomes

• Objective Response Rate (ORR) - Central Assessment [From start of treatment up to end of active follow-up, approximately 29 months]: ORR is defined as the percentage of participants with complete response (CR) or partial response (PR). participants for whom overall best response is not CR or PR, as well as participants without any post-baseline tumor assessment will be considered non-responders.

Secondary outcomes

• Disease-control Rate (DCR) - Central Assessment [From start of treatment till end of active follow-up, approximately 29 months]: DCR was defined as the percentage of participants whose overall best response was not a progressive disease (i.e., CR, PR, stable disease \[SD\] or Non CR/Non PD).
• Progression-free Survival (PFS) - Central Assessment [From start of treatment till end of active follow-up, approximately 29 months]: Progression free survival (PFS) was defined as the time (days) from randomization to date of first observed disease progression (radiological or clinical assessment or both) or death due to any cause (if death occurred before progression was documented).
• Duration of Response (DOR) - Central Assessment [From start of treatment till end of active follow-up, approximately 29 months]: DOR (for patients with PR and CR only) was defined as the time from the first documented objective response of PR or CR, whichever was noted earlier, to disease progression (including symptomatic deterioration) or death, whichever was earlier
• Number of Participants With Treatment Emergent Adverse Events [From start of treatment up to 30 days after the last administration of study treatment, approximately 29 months]: A treatment-emergent event was defined as any event arising or worsening after the start of study drug administration until 30 days after the last administration of study treatment

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Existence of archival or fresh biopsy for FGFR testing. Mandatory FGFR testing of patients will be performed prior to start of screening. The timing of the FGFR test is at the discretion of the investigator. Investigators should ensure all patients will be eligible in terms of disease status and lines of treatment.
* Documented urothelial carcinoma (transitional cell carcinoma) including urinary bladder, renal pelvis, ureters, urethra meeting all of the following criteria

  * Histologically confirmed (Patients with mixed histologies are required to have a dominant transitional cell pattern.)
  * Locally advanced (T4, any N; or any T, N 2-3) or metastatic disease (any T, any N and M1). Locally advanced bladder cancer must be unresectable i.e. invading the pelvic or abdominal wall (stage T4b) or presenting with bulky nodal disease (N2-3).
* ECOG (Eastern Cooperative Oncology Group) Performance Status of 0 or 1
* Disease progression during or following treatment with at least one platinum-containing regimen (patients should have been treated for at least 2 cycles). In patients who received prior adjuvant/ neoadjuvant platinum-containing chemotherapy, progression had to occur within 12 months of treatment.
* High FGFR1 or 3 mRNA expression levels in archival or fresh tumor biopsy specimen quantified as outlined in the lab manual
* At least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST v.1.1) in contrast enhanced (unless contraindicated) CT or MRI

Exclusion Criteria:

* Previous or concurrent cancer except

  * cervical carcinoma in situ
  * treated basal-cell or squamous cell skin carcinoma
  * any cancer curatively treated > 3 years before randomization
  * curatively treated incidental prostate cancer (T1/T2a)
* Ongoing or previous treatment with anti-FGFR directed therapies (e.g. receptor tyrosine kinase inhibitors including rogaratinib or FGFR-specific antibodies) or with taxanes or vinflunine
* More than two prior lines of systemic anti-cancer therapy for urothelial carcinoma given for advanced unresectable/ metastatic disease
* Ongoing or previous anti-cancer treatment within 4 weeks before randomization.
* Unresolved toxicity higher than National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.03 (CTCAE v.4.03) Grade 1 attributed to any prior therapy/ procedure excluding alopecia, anemia and/ or hypothyroidism
* History or current condition of an uncontrolled cardiovascular disease including any of the following conditions:

  * Congestive heart failure (CHF) NYHA (New York Heart Association) > Class 2
  * Unstable angina (symptoms of angina at rest) or new-onset angina (within last 3 months before randomization)
  * Myocardial infarction (MI) within past 6 months before randomization
  * Unstable cardiac arrhythmias requiring anti-arrhythmic therapy. Patients with arrhythmia under control with anti-arrhythmic therapy such as beta-blockers or digoxin are eligible.
* Arterial or venous thrombotic events or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before randomization
* Current evidence of endocrine alteration of calcium phosphate homeostasis (e.g. parathyroid disorder, history of parathyroidectomy, tumor lysis, tumoral calcinosis, paraneoplastic hypercalcemia)
* Current diagnosis of any retinal detachment, retinal pigment epithelial detachment (RPED), serous retinopathy or retinal vein occlusion
* Any hemorrhage / bleeding event ≥ CTCAE v.4.03 Grade 3 within 4 weeks before randomization

Participant flow

Outcome results

• Objective Response Rate (ORR) - Central Assessment (Primary), Number, percentage of participants: Rogaratinib (BAY1163877)_Overall Population 19.5 (11.8 to 29.4); Chemotherapy_Overall Population 21.6 (13.5 to 31.6); Rogaratinib_WT Population 19.4 (10.4 to 31.4); Chemotherapy_WT Population 23.8 (14.0 to 36.2) (p =0.6991)
• Disease-control Rate (DCR) - Central Assessment (Secondary), Number, percentage of participants: Rogaratinib (BAY1163877)_Overall Population 50.6 (39.6 to 61.5); Chemotherapy_Overall Population 55.7 (44.7 to 66.3); Rogaratinib_WT Population 53.2 (40.1 to 66.0); Chemotherapy_WT Population 63.5 (50.4 to 75.3) (p =0.7962)
• Progression-free Survival (PFS) - Central Assessment (Secondary), Median, months: Rogaratinib (BAY1163877)_Overall Population 2.7 (1.6 to 4.6); Chemotherapy_Overall Population 3.2 (2.7 to 4.4); Rogaratinib_WT Population 2.8 (2.6 to 5.1); Chemotherapy_WT Population 4.0 (2.8 to 6.1) (p = 0.8672)
• Duration of Response (DOR) - Central Assessment (Secondary), Median, months: Rogaratinib (BAY1163877)_Overall Population 4.9 (2.2 to 7.0); Chemotherapy_Overall Population 5.8 (3.5 to 7.7); Rogaratinib_WT Population 5.1 (1.5 to 9.2); Chemotherapy_WT Population 7.0 (2.7 to 8.4)
• Number of Participants With Treatment Emergent Adverse Events (Secondary), Count of participants, Participants: Rogaratinib (BAY1163877) 86; Chemotherapy 82

Adverse events

Time frame: Approximately 29 months

Serious adverse events by term

19 more terms not shown.

Other adverse events by term

61 more sites not listed.

• Results publication: Sternberg CN, Petrylak DP, Bellmunt J, Nishiyama H, Necchi A, Gurney H, Lee JL, van der Heijden MS, Rosenbaum E, Penel N, Pang ST, Li JR, Garcia Del Muro X, Joly F, Papai Z, Bao W, Ellinghaus P, Lu C, Sierecki M, Coppieters S, Nakajima K, Ishida TC, Quinn DI. FORT-1: Phase II/III Study of Rogaratinib Versus Chemotherapy in Patients With Locally Advanced or Metastatic Urothelial Carcinoma Selected Based on FGFR1/3 mRNA Expression. J Clin Oncol. 2023 Jan 20;41(3):629-639. doi: 10.1200/JCO.21.02303. Epub 2022 Oct 14. PMID 36240478
• Results publication: Grunewald S, Politz O, Bender S, Heroult M, Lustig K, Thuss U, Kneip C, Kopitz C, Zopf D, Collin MP, Boemer U, Ince S, Ellinghaus P, Mumberg D, Hess-Stumpp H, Ziegelbauer K. Rogaratinib: A potent and selective pan-FGFR inhibitor with broad antitumor activity in FGFR-overexpressing preclinical cancer models. Int J Cancer. 2019 Sep 1;145(5):1346-1357. doi: 10.1002/ijc.32224. Epub 2019 Mar 13. PMID 30807645

• Study Protocol (PDF, 2019-11-19)
• Statistical Analysis Plan (PDF, 2020-08-19)

• Bayer Study Director, Study director, Bayer

NIH grants: 2016