Erdafitinib Monotherapy or in Combination With Cetrelimab in Muscle-invasive Bladder Cancer Patients With Fibroblast Growth Factor Receptor (FGFR ) Gene Alterations

The aim of the study is to assess the antitumor activity measured as ypT0 rate, defined as no evidence of residual disease based on pathological review of the surgical specimen (pCR) and tumour downstaging (<ypT2). Patients must have a MIBC (cT2-T4a N0/N1 M0) who harbour selected FGFR alterations stated in the protocol and are either ineligible for or refuse cisplatin-based neoadjuvant chemotherapy, as defined by consensus criteria (see 6.1 Inclusion criteria).

Once it is confirmed that the subjects fulfil the eligibility criteria and have signed the informed consent form, they will receive erdafitinib alone (cohort 1) or erdafitinib in combination with cetrelimab (cohort 2).

Patients will receive neoadjuvant treatment with erdafitinib alone (cohort 1) or erdafitinib plus cetrelimab (cohort 2) before proceeding to Radical Cystectomy (RC) (to be performed within 2 - 6 weeks after the last study drug treatment)

Cohort 1: patients will receive erdafitinib Cohort 2: patients will receive erdafitinib in combination with cetrelimab intravenously (IV)

Radiological assessment: A Computed Tomography /Magnetic Resonance Imaging and/or Positron Emission Tomography (per standard local imaging practices) will be scheduled as follow:

• Basal assessment: during screening period (no more than 28 days before Cycle1, Day 1(C1D1)
• Response assessment: At the end of treatment period allowing time for imaging review in advance of Radical cystectomy (RC).
• Follow-up assessment: an image evaluation must be done at first follow-up visit and thereafter, it will be schedule according to local standards and as clinically indicated.

A local pathological assessment will be done on specimens obtained during RC (for co-primary endpoints). Thereafter, during the follow-up period, pathological assessments will be scheduled according to local standards and as clinically indicated.

Patients with disease progression during the treatment phase will be discontinued from the study and will receive their treatment according to the investigator's judgment and monitored to evaluate Overal Survival .

Inclusion criteria

• Written informed consent stating that he or she understands the purpose of the study and the procedures involved and agrees to participate in the study.
• Histologically confirmed diagnosis of MIBC (Stage T2-4a N0/N1 M0) obtained via a diagnostic or maximal Transurethral Resection of Bladder Tumor (TURBT) performed no later than 3 months prior to start the screening visit.
• Pure or predominant (≥50%) urotelial Cancer (UC) histology as determined at the local site.
• Age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Decline or ineligible ("unfit") for cisplatin-based chemotherapy
• Presence of a selected FGFR alteration on analysis of tumour biopsy
• Adequate organ function
• No other malignancy
• Willingness to avoid pregnancy or fathering children

Exclusion criteria

• Clinical evidence of N2-N3 tumours or metastatic bladder cancer.
• Has tumour with any neuroendocrine or small cell component.
• Patients who are not considered fit for cystectomy or reject cystectomy.
• Prior FGFR-targeted or an immune checkpoint inhibitor (antiPD1/PDL1 )systemic therapy.
• Prior systemic therapy, radiation therapy, or surgery for bladder cancer