Oral Selective FGFR3 Inhibition in Urothelial Carcinoma: Opportunities in Intermediate Risk Non-Muscle Invasive Bladder Cancer and Low Grade Upper Tract Urothelial Carcinoma

Disease Burden in Early-Stage Urothelial Carcinoma

Recent progress in the treatment of advanced urothelial carcinoma (UC) has improved the outlook for patients with metastatic disease. However, UC in the earlier stages remains a major source of morbidity worldwide and the available therapies continue to have limitations related to tolerability, treatment burden, and long-term disease control. The majority of patients with UC first present with non-muscle invasive bladder cancer (NMIBC), which represents 75% of UC diagnoses,¹ yet there is a particular need for innovative, patient-friendly therapies in this setting.

NMIBC is staged according to depth of penetration into the bladder wall and graded by tumor differentiation following transurethral resection of bladder tumor (TURBT).² These parameters classify patients as low, intermediate, or high risk for recurrence and/or progression per the AUA 2024 Risk Stratification criteria (Figure 1).²

Intermediate risk NMIBC (IR-NMIBC) encompasses tumors with features between low and high risk, such as low grade (LG) recurrence within 1-year, LG multifocal disease, larger LG solitary tumors, and smaller Ta high-grade tumors (Figure 1).² Disease recurrence is as high as 61% in IR-NMIBC, with many patients experiencing multiple recurrences.³ While the rate of progression is low in IR-NMIBC, the morbidity associated with repeated TURBTs and intravesical chemotherapy has a substantial impact on quality of life, including the physical and emotional burdens.⁴ One such burden of care is the time required for frequent intravesical therapy treatment office visits.

Similarly, significant unmet need remains in treating patients with low-risk, low-grade, upper tract urothelial carcinoma (UTUC). The structure of the upper tract, including ureter length, diameter, orientation, and intra-renal anatomy, presents challenges with diagnosis and treatment. Repetitive kidney-sparing surgeries are the favored standard of care but will miss up to 25% of UTUC tumors due to challenging anatomy and frequent multifocality.^5,6 These surgeries carry additional risks of repeat general anesthesia and intra- and post-operative complications. From 35–48% of all low grade UTUC tumors will recur within 3 years,⁷ with an even higher rate for large tumors.⁸ Clinical guidelines indicate that persistent or recurrent disease often necessitates radical nephroureterectomy⁹, which can result in chronic dialysis and increased cardiovascular morbidity and mortality.

Currently, non-surgical treatment options for UTUC are limited. Jelmyto, mitomycin hydrogel, is approved for renal pelvis tumors 5–15 mm in size. However uptake appears limited with modest efficacy (58% complete response and 56% 12-month duration of response) as well as associated adverse events (AEs) including ureteric obstruction (58%), urinary tract infection (34%) and renal dysfunction (25%).¹⁰

Both patients with IR-NMIBC and patients with UTUC would benefit from novel non-surgical and non-intravesical treatment options that reduce the risk of recurrence and mitigate long-term toxicity.

FGFR3 Biology: A Frequent Driver of Early-Stage Disease

The fibroblast growth factor (FGF) family of receptor tyrosine kinases is composed of four highly conserved transmembrane proteins (i.e., FGFR1, FGFR2, FGFR3, FGFR4) that function as key regulators of cellular growth, differentiation, and homeostasis.¹¹ FGFR gene alterations have been implicated in the pathogenesis of many cancers, including breast cancer, gynecological, hematological, and gastrointestinal malignancies.¹¹ FGFR3 gain-of-function alterations leading to malignant cell proliferation are particularly frequent in early-stage, low-grade UC: present in up to 80% of NMIBC^12,13 and up to 96% of LG-UTUC (Figure 2).^14-16 In contrast, such alterations are only present in up to 20% of advanced or metastatic UC.^15,16 Targeting the underlying biological driver of early-stage, low-grade disease may provide an improved therapeutic strategy to delay recurrence and reduce the need for repeated invasive procedures.

Current Landscape of FGFR Inhibition

The first generation of FGFR inhibitors provided clinical proof-of-concept and also highlighted significant limitations. Erdafitinib (Balversa^®) is the only FDA approved pan-FGFR inhibitor for FGFR3-altered, locally advanced or metastatic urothelial carcinoma.¹⁷ Erdafitinib demonstrated a confirmed objective response rate (ORR) of 35.3% and a median DOR of 4.9 months in patients with metastatic UC and FGFR3 gene alterations.¹⁸

However, due to lack of FGFR selectivity, toxicities associated with the inhibition of FGFR1, 2, and 4 were observed. Hyperphosphatemia, a result of excessive FGFR1 inhibition,¹¹was the dose-limiting toxicity (DLT) and was reported in over 70% of patients in a Phase 2 clinical study of erdafitinib¹⁹, and was also identified in 76% of patients in the Phase 3 trial.¹⁷ FGFR2-mediated toxicities^20,21 have also been reported in erdafitinib clinical trials.¹⁷ These primarily involve epithelial and ocular tissues including nail disorders (70%), stomatitis (56%), and dry mouth (39%).¹⁷ Together, toxicities contributed to dose reductions in 69% of patients,¹⁷ which may ultimately limit target engagement and efficacy. A similarly high rate of FGFR-related toxicities has been reported in clinical studies of other pan-FGFR inhibitors including pemigatinib, infigratinib and futibatinib.^22-25

The limitations of pan-FGFR inhibition became more apparent when oral erdafitinib was investigated at a dose of 6 mg in the IR-NMIBC setting. Erdafitinib demonstrated a complete response rate of 89% with a median duration of response not reached (95% CI, 13.4 months to not estimable).²⁶ Notably, the 12-month duration of response for those who remained on study drug was 100%, although 61% and 78% of patients experienced dose reductions and interruptions, respectively.²⁶ A high rate of associated toxicities was observed, including hyperphosphatemia and ocular toxicities, and there are no additional studies of oral erdafitinib in NMIBC.²⁶ As a result, there remains a clear unmet need for FGFR3-selective oral therapies in this space, particularly agents that balance efficacy, tolerability, and ease of administration.

FGFR3-Selective Inhibition

Dabogratinib (TYRA-300) was designed using a structure based approach to maximize potency for FGFR3 while minimizing its activity against FGFR1, 2 and 4.²⁷ In preclinical studies, dabogratinib demonstrated in vitro potency against FGFR3-driven cancer cell lines, an engineered Ba/F3 cell line dependent on FGFR3, and cell lines containing resistance mutations.²⁷ Dabogratinib also demonstrated in vivo efficacy against urothelial cancer xenograft models driven by an FGFR3 fusion or mutation.^27,28 In studies comparing engineered Ba/F3 cells driven by the different FGFR isoforms, dabogratinib exhibits 25-fold selectivity for FGFR3 over FGFR1 while erdafitinib demonstrates a 2-fold difference. Dabogratinib exhibits 14-fold selectivity for FGFR2 over FGFR3, while erdafitinib demonstrates a 1.5-fold difference, and 37-fold selectivity for FGFR4 over FGFR3, while erdafitinib demonstrates 4.2-fold (Table 1).²⁷

FGFR3 selectivity demonstrated by dabogratinib has the potential to translate to increased efficacy while reducing off-target toxicities.²⁷ As FGFR inhibitors progress into earlier-stage disease settings such as NMIBC, where patients are generally healthier and may be treated for longer, reducing the potential for off-target toxicities becomes increasingly important.

Dabogratinib Lessons from Metastatic Urothelial Cancer (mUC) Development

The first dabogratinib clinical trial, SURF301 (TYR300-101; NCT05544552) in adults with advanced solid tumors and activating FGFR3 mutations/fusions, is no longer enrolling patients. Promising early clinical results in the first 41 patients with bladder and other solid tumors were reported at the 2024 EORTC-NCI-AACR (ENA) symposium.²⁹ Heavily pre-treated patients with mUC and FGFR3 alterations who received dabogratinib 90 mg once daily demonstrated a preliminary overall response rate of 50% and a 100% disease control rate (SD + confirmed PR).²⁹ Six confirmed partial responses were observed among 11 evaluable patients at doses of 90 mg or higher, with three responses ongoing at the time of reporting (Figure 3).²⁹ In terms of safety, most of the dabogratinib adverse events (AEs) were low grade (grade 1 and 2).²⁹ The most frequent (>20%) treatment-related AEs were alanine aminotransferase increase (24%), diarrhea (22%), dry mouth (22%), and aspartate aminotransferase increase (20%). Grade 3 TRAEs occurred in 20%of patients, which included ALT increase (5%), diarrhea (2%), and AST increase (2%). No grade 4 or 5 toxicities were observed.²⁹

The pharmacokinetic coverage of dabogratinib at 60 mg reached the IC₉₀ target for FGFR3 pS249C mUC.³⁰ This is comparable to the 6 mg dose level of erdafitinib that previously demonstrated efficacy in the IR-NMIBC setting.^26,31 Importantly, no grade 3 or higher AEs, no hyperphosphatemia, or dose reductions/discontinuations were observed in patients treated with dabogratinib at this ≤60 mg dose. In a pre-clinical mass balance study in rats, the radioactivity concentration of dabogratinib in urinary bladder was approximately 6-fold higher than that in plasma at peak. This, along with the efficacy observed with erdafitinib at the 6 mg dose in NMIBC,²⁶ suggests that a lower dose of dabogratinib will be sufficient for tumors confined to the bladder wall versus metastatic tumors.

Early-UC: NMIBC, UTUC, and The Next Wave of Precision Oncology

Early-stage urothelial carcinoma needs precision oncology treatment that reduces the rate of recurrence and improves tolerability. For IR-NMIBC, TURBT combined with intravesical chemotherapy provides disease control but does not adequately reduce recurrence.³² Patients must undergo repeated TURBT procedures, and intravesical chemotherapy such as gemcitabine or Zusduri^TM (mitomycin) introduce further logistical challenges, including frequency of clinic visits, prolonged chair time, urine alkalization, local urinary symptoms, urinary retention, reliance on caregivers, and household precautions such as toilet and laundry hygiene.^4,33,34

Upper tract UC occurs in the renal pelvis or ureters and represents 5%-10% of all UC cases.³⁵ Patients with LG-UTUC also experience recurrent disease with the limited available therapies and ultimately may require radical nephroureterectomy.⁹ Given the high frequency of FGFR3 alterations across both NMIBC and UTUC,¹² there is a compelling opportunity to improve the treatment paradigm with a precision agent. Dabogratinib offers the potential for an oral therapy that could treat, prevent, or delay recurrence and the need for TURBT and intravesical chemotherapy.

Dabogratinib Clinical Trials in NMIBC (SURF302) and UTUC (SURF303)

Currently, dabogratinib is being evaluated in the SURF302 trial (NCT06995677),³⁶ which is an open-label, multi-center study to determine the safety, efficacy, and tolerability in participants harboring FGFR3 alterations with LG-IR-NMIBC (Figure 4). Approximately 90 evaluable participants may be enrolled (up to 30 participants per dose cohort) to determine the appropriate dose of dabogratinib. Initially, 2 doses will be explored in a parallel study design and enrolled by 1:1 randomization. A third dose (Dose Cohort C) may be introduced if needed based on efficacy and safety data from the first two cohorts. The primary endpoint for this marker lesion study is CR rate at 3 months.

Dabogratinib is also being studied in SURF303 (NCT07265947³⁷), which is an open-label, Phase 2A/B, multi-center study to determine the safety, efficacy, and tolerability in participants with low-grade upper tract urothelial carcinoma (LG-UTUC) (Figure 5). Initially, 2 doses will be explored in a parallel study design and enrolled by 1:1 randomization. Up to 130 evaluable participants may be enrolled (including up to 25 participants per dose cohort) in Phase 2A to determine the appropriate dose of dabogratinib; Phase 2B will utilize the identified dose from Phase 2A to confirm efficacy and safety.A third dose (Dose Cohort C) may be introduced if needed based on efficacy and safety data from the first two cohorts. The primary endpoint for this marker lesion study is complete response (CR) rate within 6 months.

Conclusion

Dabogratinib represents the next wave of precision oncology in urology, with early clinical data demonstrating promising activity and a tolerable safety profile.^28,29 As an oral, highly selective FGFR3 inhibitor, dabogratinib aims to maximize potency against FGFR3 while minimizing off-target toxicities which have limited the use of pan-FGFR inhibitors. This selectivity may translate into improved patient tolerability and broader utilization in earlier-stage disease. Ongoing clinical trials across urothelial carcinoma will determine the full potential of dabogratinib, but selective FGFR3 inhibition has the potential to reshape the treatment paradigm in LG-IR-NMIBC and LG-UTUC.

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