CLINICAL DATA

To provide the most relevant information, the summary below is limited to information from the pivotal phase 3 (THOR; cohort 1) and phase 2 (BLC2001) studies in patients with locally advanced or metastatic urothelial carcinoma (UC).

Phase 3 Study in Patients With Locally Advanced or Metastatic UC (THOR)

Interim Analysis

Interim results from cohort 1 (n=266) were presented after a median follow-up of 15.9 months. The median overall survival (OS) was 12.1 months for patients receiving BALVERSA vs 7.8 months for patients receiving chemotherapy. A 36% reduction in risk of death was observed in patients receiving BALVERSA (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.47-0.88; P=0.005). Median progression-free survival (PFS) was 5.6 months for patients receiving BALVERSA vs 2.7 months for patients receiving chemotherapy. Objective response rate (ORR) was 45.6% for patients receiving BALVERSA vs 11.5% for patients receiving chemotherapy. The safety profiles were consistent with the known safety profiles of BALVERSA and chemotherapy.¹

• In the BALVERSA treatment arm (n=135), 62 (45.9%) patients had grade 3-4 treatment-related adverse events (TRAEs; most frequent grade 3-4 TRAEs were palmar-plantar erythrodysesthesia syndrome [13 patients; 9.6%], stomatitis [11 patients; 8.1%], onycholysis [8 patients; 5.9%], and hyperphosphatemia [7 patients; 5.2%]), 18 (13.3%) patients had treatment-related serious adverse events (AEs), and 1 treatment-related death occurred (reported as sudden death).
• The median duration of exposure in the BALVERSA treatment arm was 4.8 months (range, 0.2-38.2).
• In the BALVERSA group, AEs of any cause led to treatment discontinuation in 19 (14.1%) patients, and TRAEs that led to treatment discontinuation occurred in 8.1% of patients.
• Grade 3/4 AEs of interest based on the known safety profile of BALVERSA included central serous retinopathy (CSR; 2.2%). The incidence of CSR AEs of interest is summarized in Table: THOR: Cohort 1 CSR AEs of Interest: BALVERSA.
  • In 16 of 23 patients (70%) with any-grade CSR, events were resolved by the clinical cutoff date. Of the 7 patients with ongoing events, 5 experienced grade 1 events.

Phase 2 Study in Patients With Locally Advanced or Metastatic UC (BLC2001)

Final Analysis

In the final analysis, after a median 24-month follow-up for efficacy (interquartile range [IQR], 22.7-26.6) and median treatment duration of 5.4 months (IQR, 2.8-9), 101 patients were treated with an uptitration regimen of BALVERSA 8 mg daily (2 patients enrolled after the clinical cutoff date for the primary analysis). Overall, 60 patients received BALVERSA 8 mg daily and 41 were uptitrated to BALVERSA 9 mg daily.^6,7

• The safety profile of BALVERSA remained consistent with that reported in the primary analysis.⁶
• No grade 4 AEs were considered related to BALVERSA, and no new TRAEs were observed with a longer follow-up.⁶
• A post hoc analysis was conducted to determine the cumulative incidence of first-onset CSR by grade.⁶
  • The median time to first onset of all-grade and grade 3 CSR events was 53 days (IQR, 32-100 days) and 94 days (IQR, 72-154 days), respectively.
  • Overall, 27 of 101 patients (27%) reported CSR (BALVERSA 8 mg daily, n=15/60 [25%]; BALVERSA uptitration to 9 mg daily, n=12/41 [29%]).
    • At data cutoff, 17 CSR events resolved, with a median time to resolution of 27 days (range, 9-299 days). The 10 unresolved events were grade 1-2.
• Treatment-emergent CSR events and their outcomes are presented in Table: BLC2001: TreatmentEmergent CSR Events and Outcomes for Grade ≥3 Events.

• The incidence of treatment-emergent CSR events is summarized in Table: BLC2001: TreatmentEmergent CSR Events.

An exploratory analysis was conducted for 2 dosing regimens in the BLC2001 study to investigate the relationship between selected efficacy and safety endpoints and phosphate (PO₄) concentrations. Exposure analyses supported the use of pharmacodynamically (PD)-guided dose titration to optimize therapeutic benefit/risk ratio.⁸

csr Screening

Screening of CSR in the THOR Study¹⁰:

• The Amsler grid was used to screen for CSR at screening, at the beginning of every new cycle from cycle 2 onwards, and at the end-of-treatment visit.
• Screening was performed by the study physician or nurse.
• Observation of wavy, broken or distorted lines, or a blurred/missing area of vision was considered positive.
• Referral for a comprehensive ophthalmological examination was made within 7 days for a positive Amsler grid test.

csr MANAGEMENT

• Follow ophthalmological monitoring and dose modification guidelines for ocular adverse reactions as described within product labeling to include dosing interruption and discontinuation. The interventions investigators in the THOR study were instructed to perform to manage CSR-suspected ocular disorders included¹⁰:
  • A consultation with a retina specialist
  • Performing an optical coherence tomography (OCT), and obtaining color fundus photos or OCT images for future reference
  • Consideration of fluorescein angiography in conditions such as suspected retinal vein occlusion (RVO)

case reports

• The occurrence and management of individual CSR and retinal pigment epithelial detachment (RPED) events in patients receiving BALVERSA have been reported.^11-16

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 02 October 2024.