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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

Key Ongoing Clinical Trials and Future Directions

Phase III THOR: Study Design

The ongoing phase III THOR study is evaluating the efficacy of erdafitinib vs chemotherapy or pembrolizumab in patients with advanced UC harboring selected FGFR aberrations (N = 631). Cohort 1 included patients who had received previous anti–PD-1 or anti–PD-L1 and not more than 2 previous lines of systemic therapy. Patients were randomized to receive 8 mg of erdafitinib daily or to investigator's choice of treatment (vinflunine 320 mg/m2 IV or docetaxel 75 mg/m2 IV every 3 weeks). Cohort 2 patients with 1 previous line of systemic treatment and no prior anti–PD-1 or anti–PD-L1 therapy were randomized to erdafitinib (8 mg/day) or pembrolizumab (200 mg IV every 3 weeks). The primary endpoint is OS and secondary endpoints are PFS, ORR, DoR, patient-reported outcomes, and safety. The results of this study will further determine the role of erdafitinib in the treatment paradigm for metastatic UC. 

FGFR Alterations Common in Multiple Tumor Types

There is ongoing intense clinical development with FGFR inhibitors in other malignancies as FGFR alterations have been detected across many tumor types. Clinical trials have shown that patients with cancers other than UC and that have FGFR2/FGFR3 gene fusions also show clinical outcome benefits when treated with FGFR inhibitors.[18]

Areas of Research in the Near Future

I think the 4 areas of future research related to FGFR therapy include: 1) combining FGFR inhibition with other treatment approaches; 2) moving to earlier settings, for example, in the context of non-muscle-invasive bladder cancer and first-line therapies for those patients with bladder cancer who are not cisplatin eligible; 3) the development of assays optimized for use with circulating tumor DNA with real-time detection where just a blood sample will allow us to ascertain whether patients have genetic abnormalities that make them eligible for a specific treatment; and 4) increasing knowledge of the role of tumor-extrinsic mechanisms that may explain acquired resistance.[18]  

Combinations: Phase I/II NORSE: Study Design

Regarding therapy combinations, the phase I/II NORSE study evaluated the combination of erdafitinib with cetrelimab (an anti–PD-1 mAb), in patients with advanced UC with FGFR alteration and who had progressed on or after ≥1 previous lines of systemic therapy (N = 160). The study found that the safety profile was acceptable, and of the 16 evaluable patients, 50% achieved a confirmed ORR with 94% disease control rate.[43-45] The results of the NORSE trial presented in 2020 have shifted the development of PD-1 therapy as an advanced line of treatment to a combination therapy with erdafitinib for patients with earlier-stage cancer. This combination is currently being evaluated in first-line treatment for cisplatin-ineligible patients.

Erdafitinib vs Investigator’s Choice of Therapy for BCG-Resistant Non-Muscle-Invasive Bladder Cancer

FGFR inhibitors are also being tested in non-muscle-invasive bladder cancer and currently a randomized phase II study of erdafitinib compared with intravesical chemotherapy (gemcitabine or mitomycin C/hyperthermic mitomycin C) in patients with high-risk non-muscle-invasive bladder cancer that have FGFR mutations or fusions and that recurred after BCG therapy (N = 280) is underway. The primary endpoint is recurrence-free survival2.[46]

Summary

In summary, for the first time, we have precision medicine and a new window of opportunity available in bladder cancer. We are identifying patients who can receive a targeted therapy based on genetic abnormalities in FGFR. We have learned that the FGF-FGFR pathway is critical for carcinogenesis in many tumors, including bladder cancer. We have learned that erdafitinib works in this population of patients with bladder cancer, with an approximately 40% response rate in previously treated patients with negative prognostic factors such as visceral disease. We should look for FGFR abnormalities in our patients and incorporate this treatment strategy in our treatment armamentarium for patients with bladder cancer, cholangiocarcinoma, and other cancers on trials as available.

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