SUMMARY  

• BALVERSA can cause ocular disorders, including central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED).¹
• At the interim analysis of the THOR study, an ongoing phase 3, randomized, open-label, multicenter study evaluating the efficacy and safety of BALVERSA vs chemotherapy in patients with metastatic or unresectable urothelial carcinoma (UC) and selected fibroblast growth factor receptor (FGFR) gene alterations, grade 3/4 adverse events (AEs) of interest based on the known safety profile of BALVERSA included other non-CSR eye disorders (2.2%) summarized in Table: THOR Cohort 1 Non-CSR AEs of Interest: BALVERSA.²
• In the final analysis of the BLC2001 study, a phase 2, multicenter, open-label study of BALVERSA in 99 patients with locally advanced and unresectable or metastatic urothelial carcinoma (UC) and prespecified FGFR genetic alterations (FGFR3 mutation or FGFR2/3 fusion), the safety profile remained similar to that in the primary analysis, with no new safety signal reported with longer follow-up.³
  • The most frequently occurring non-CSR ocular treatment-emergent adverse events (TEAEs) (any grade) were dry eye (27.7%), blurred vision (17.8%), and conjunctivitis (12.9%).⁴
  • The most common non-CSR ocular treatment-related adverse events (TRAEs) (any grade) were dry eye (25.7%), blurred vision (15.8%), and increased lacrimation (10.9%).⁴
• TRAEs and TEAEs of special interest or clinical importance in the primary and final analyses of BLC2001 included non-CSR eye disorders (any grade), which were reported in 52% and 56% of patients treated with BALVERSA, respectively.^5,6
• A retrospective case series of 3 patients with severe dry eye syndrome while receiving BALVERSA was reported. One patient had bilateral corneal thinning and 1 had bilateral neurosensory retinal detachment, unilateral corneal thinning, and white cataracts in both eyes. A third patient had bilateral corneal thinning, a corneal ulcer of the left eye and acute-onset white cataracts in both eyes, causing angle-closure glaucoma in the left eye. Corneal thinning resolved in all three cases within four months following dose modifications. Acute-onset cataracts were treated urgently by surgery, with no complications. In one patient, although the corneal ulcer healed, corneal transparency was lost without return to his initial vision.⁷
• Another case report of pseudovitelliform maculopathy in an 84-year-old man who had presented with bilateral visual disturbances 1 week after starting BALVERSA for metastatic UC was published. Spontaneous regression of the subretinal fluid was observed despite drug continuation.⁸
• Follow monitoring and dose modification guidelines for adverse reactions as described within product labeling. The interventions that investigators in the THOR study were instructed to perform to manage non-CSR ocular disorders are summarized in the section entitled Non-CSR Ocular Disorder Management below.

CLINICAL STUDIES

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 UC.

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

Interim Analysis

THOR is an ongoing, phase 3, randomized, open-label, multicenter study evaluating the efficacy and safety of BALVERSA vs chemotherapy (docetaxel or vinflunine) in patients with metastatic or unresectable urothelial carcinoma (UC) and selected FGFR gene alterations that have progressed during or after 1 or 2 prior lines of therapy. The primary endpoint is overall survival (OS).¹

• Interim results from cohort 1 (n=266) were presented after a median follow-up of 15.9 months. The median 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.
• The median duration of exposure in the BALVERSA treatment arm was 4.8 months (range, 0.2 to 38.2).
• The most common non-CSR AEs of interest are summarized in THOR Cohort 1: Non-CSR AEs of Interest for BALVERSA.
• In the BALVERSA treatment arm (n=135), 62 (45.9%) patients had grade 3-4 treatment-related adverse events (TRAEs).
• In the BALVERSA treatment arm, 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 other non-CSR eye disorders (2.2%).

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

Final Analysis

BLC2001 is a multicenter, open-label phase 2 study evaluating the use of BALVERSA in 99 patients with locally advanced and unresectable or metastatic UC who had prespecified FGFR genetic alterations (FGFR3 mutation or FGFR2/3 fusion) and who had progressed during or following ≥1 line of prior systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy (n=87), or were chemotherapy-naïve due to cisplatin ineligibility (n=12).³ Patients had tumor tissues with 1 of the following FGFR3 gene mutations: R248C, S249C, G370C, Y373C OR 1 of the following FGFR gene fusions: FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7.¹⁰

• In the final analysis, 101 patients were treated with an up-titration regimen of BALVERSA 8 mg daily (2 patients enrolled after the clinical cutoff date for the primary analysis) after a median follow-up of 24 months for efficacy (interquartile range [IQR], 22.7-26.6 months) and a median treatment duration of 5.4 months (IQR, 2.89.0 months). Overall, 60 patients received BALVERSA 8 mg daily, and 41 were up-titrated to BALVERSA 9 mg daily.³
• The safety profile of BALVERSA in the final analysis remained consistent with that in the primary analysis.³
• No grade 4 adverse event was considered related to BALVERSA, and no new TRAE was observed with longer follow-up.³
• No incidence of grade 4 or 5 non-CSR ocular TRAE or TEAE was reported.^3,4
• The incidence of non-CSR ocular TEAEs is summarized in Table: BLC2001: Non-CSR Ocular TEAEs.
• The most frequently occurring non-CSR ocular TEAEs (any grade) were dry eye (27.7%), blurred vision (17.8%), and conjunctivitis (12.9%).⁴
• The most common serious non-CSR ocular TEAEs were cataract and keratitis (n=2 [2%], each).⁴
• The most common non-CSR ocular TRAEs are presented in Table: BLC2001: Most Common Treatment-Related Non-CSR Ocular Adverse Events.
• Non-CSR ocular TRAEs that led to treatment discontinuation were chorioretinopathy, corneal erosion, keratitis, keratopathy, maculopathy, optic atrophy, reduced visual acuity, and visual impairment (n=1 [1%], each).⁴
• The median time to onset of ocular events other than CSR was 50 days for any-grade event and 162 days for grade ≥3 events.⁶

non-csr ocular DISORDER MANAGEMENT

• Follow ophthalmological monitoring and dose modification guidelines for adverse reactions as described within product labeling to include dosing interruption and discontinuation. The interventions that investigators in the THOR study were instructed to perform to manage non-CSR ocular disorders included the following¹¹:
  • Avoidance of unnecessary exposure to sunlight and use of sunglasses in bright light.
  • Use of artificial tear substitutes for the prophylactic management of dry eye.
  • Withholding BALVERSA (for grade 3 toxicity), use of artificial tear substitutes every  4 to 6 hours, and/or use of hydrating/lubricating eye gels and ointments for the reactive management of dry eye.
  • Evaluation by an ophthalmologist for cases of severe treatment-related dry eye.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug Files (and/or other resources, including internal/external databases) was conducted on 09 October 2024.