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Targeted Therapies for Bladder Cancer and Beyond: Overview and Current Status of FGFR Inhibitors

Ignacio Duran, MD, PhD
Released: June 14, 2021

Targeting FGFR – Current Overview, Treatment, and FGFR Inhibitors Beyond Bladder Cancer

Targeting FGFR: Introduction

FGFR signaling is associated with several cancers, including UC. Preclinical studies with FGFR inhibitors have shown significant antitumor activity, which has led to clinical evaluation of multiple FGFR inhibitors. Recently, erdafitinib was approved by the FDA for advanced UC with FGFR genetic alterations. This review will start with the physiologic role of the FGF-FGFR pathway and the role of FGF and FGFR in carcinogenesis, the basic biology of FGFR and its ligand FGF. To follow, I discuss how FGFR can be an appropriate anticancer target, looking at the current scenario of therapeutics in metastatic UC. Different approaches to target this pathway will be considered giving special attention to erdafitinib. Finally, future avenues in this treatment setting will be discussed.

Overview of Systemic Treatment Options for Patients With Bladder Cancer

Here is an overview of our current clinical practice in metastatic bladder cancer, showing 3 possible scenarios. First, non-muscle–invasive bladder cancer is seen in approximately 70% of patients newly diagnosed with bladder cancer. Those patients are normally treated with intravesical treatment (eg, Bacillus Calmette-Guérin [BCG], mitomycin, or others), whereas a specific group of these patients may be candidates to receive pembrolizumab. Approximately 10% to 15% of these patients will progress to the more advanced muscle-invasive form of bladder cancer. However, this second scenario also includes approximately 20% of newly diagnosed patients.[1]

Patients with muscle-invasive bladder cancer are normally treated with perioperative chemotherapy followed by a local consolidation with cystectomy. Some patients may be candidates for bladder preservation strategies where instead of removing the whole bladder, the patient is treated with radiation along with chemotherapy as a radiosensitizer.

But the reality is that approximately 40% to 50% of the patients with muscle-invasive bladder cancer—despite receiving the best treatment—may relapse into the third scenario, advanced metastatic disease, joining the approximately 5% of patients with bladder cancer who have already presented with this disease. This discussion focuses on this group of patients.

This slide also summarizes the different clinical contexts: first-line patients who have not received treatment for metastatic disease; second-line patients who have received platinum chemotherapy; and the third line after receiving platinum chemotherapy and a checkpoint inhibitor. I will briefly summarize what we do in each one of these contexts that will help us to understand the role of FGFR inhibitors in this disease.

In our clinic, we divide first-line patients (patients who have never received any systemic treatment) into 2 groups. First are those who are cisplatin eligible because they lack the characteristics described in the Galsky criteria and do not have, for instance, problems with renal function, have an Eastern Cooperative Oncology Group performance status ≤2, no neuropathy or hearing disability of grade ≥2, and no severe heart function impairment.[2] Cisplatin-eligible patients are most often treated with a cisplatin and gemcitabine combination. The results of the phase III JAVELIN 100 trial showed that in patients with unresectable locally advanced or metastatic UC, maintenance avelumab significantly prolonged the overall survival (OS) in the overall population (21.4 months with avelumab plus best supportive care [BSC] vs 14.3 months with BSC alone; HR: 0.69; 95% CI: 0.56-0.86; P <.001) and in the PD-L1–positive population (not estimable with avelumab plus BSC vs 17.1 months with BSC; HR: 0.56; 95% CI: 0.40-0.79; P <.001) in patients with a response or stable disease after previous first-line platinum chemotherapy.

Cisplatin-ineligible patients are those 40% to 50% of patients who are not healthy enough to receive cisplatin and, therefore, would be treated with a carboplatin-based combination such as carboplatin/gemcitabine.[3] Patients who benefit from carboplatin-based therapy will receive avelumab maintenance. If patients are not healthy enough to receive these combination therapies, we would treat them with either single-agent chemotherapy or sometimes with checkpoint inhibitors.

Initial Systemic Therapy for Metastatic UC

Until recently, patients who progressed on cisplatin were treated with checkpoint inhibitors, such as pembrolizumab, nivolumab, atezolizumab, avelumab, or durvalumab.[4] This treatment strategy is based on phase III trial results with pembrolizumab having the highest level of evidence and has been the standard of care for patients who progress on platinum chemotherapy. The phase III KEYNOTE-045 trial looked at pembrolizumab vs paclitaxel, docetaxel, or vinflunine in patients with advanced UC. The results showed a median OS of 10.3 months for pembrolizumab vs 7.4 months with chemotherapy (P = .0004). In this clinical context, erdafitinib, an FGFR2/FGFR3-targeted therapy was developed, and it is an approved option to treat patients after progression on platinum-based therapies.

Patients who have received both chemotherapy and immunotherapy, can be treated with either the ADCs enfortumab vedotin and sacituzumab govitecan or erdafitinib, which is approved for patients with certain FGFR3 mutations or FGFR2 or FGFR3 fusions. Chemotherapy is an alternative option, but there are little supportive data.

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