SUMMARY

• THOR (BLC3001/NCT03390504) is an ongoing, phase 3, randomized, open-label, multicenter study evaluating the efficacy and safety of BALVERSA vs chemotherapy (docetaxel or vinflunine) or pembrolizumab in patients with metastatic or unresectable urothelial carcinoma (UC) and select FGFR alterations who had disease progression during or after 1 or 2 prior lines of therapy.^1,2
  • In the interim analysis of cohort 1 (n=266), treatment-related skin adverse events (AEs) of any grade reported in the safety population included palmar-plantar erythrodysesthesia syndrome (30.4%), alopecia (23.7%), and dry skin (22.2%).³
• BLC2001 (NCT02365597) is an ongoing, phase 2, open-label, multicenter study of BALVERSA in patients with locally advanced and unresectable or metastatic UC and prespecified FGFR alterations (FGFR3 mutation or FGFR2/3 fusion).^4,5
  • In the final analysis (n=101), the safety profile remained similar to that in the primary analysis, with no new safety signals reported with a longer follow-up. The most common treatment-related skin AEs, of any grade, included dry skin (33.7%), alopecia (29.7%), and palmar-plantar erythrodysesthesia syndrome (24.8%). Grade 3 palmar-plantar erythrodysesthesia syndrome was reported (5%), and there were no reports of grade 3 dry skin or alopecia.⁴
• Follow dose modification guidelines for adverse reactions within product labeling. For the medical management of dry skin during the THOR study, refer to Table: Guidelines for the Management of Dry Skin in the THOR Study.⁵
• A case of BALVERSA-induced grade 3 dermatologic toxicities was reported. The patient experienced abrupt relief of his urinary symptoms and cancer-related pain, but complained of nail, skin, and hair changes 8 weeks after therapy initiation. Onycholysis, nail bed superinfection, paronychia, and painful macular erythema on the palmar and dorsal surfaces of bilateral hands and feet, in addition to eyelash trichomegaly and eyebrow hypertrichosis, required temporary drug discontinuation, medical management, and subsequent dose reduction.⁶

CLINICAL DATA

To provide the most relevant information, the summary below is limited to information from the pivotal phase 3 (THOR/BLC3001; cohort 1) and phase 2 (BLC2001) studies in patients with locally advanced or metastatic UC and selected FGFR alterations.

Phase 3 Study in Patients With Locally Advanced or Metastatic UC (THOR/BLC3001)

Interim Cohort 1 Analysis

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

• In cohort 1, 266 patients were randomized 1:1 to receive an uptitration regimen of BALVERSA 8 mg orally once daily or chemotherapy (docetaxel 75 mg/m² intravenous [IV] every 3 weeks [Q3W] or vinflunine 320 mg/m² IV Q3W).¹
• Interim results from cohort 1 (n=266) were presented after a median follow-up of 15.9 months. The safety profiles were consistent with the known safety profiles of BALVERSA and chemotherapy.¹
• Median duration of exposure was longer for the BALVERSA group at 4.8 months (range, 0.2-38.2) compared to the chemotherapy group at 1.4 months (range, 0.03-27.0).¹
• Among AEs of any cause in the safety population, palmar-plantar erythrodysesthesia syndrome occurred in 41 (30.4%) patients in the BALVERSA group and 1 (0.9%) patient in the chemotherapy group. Alopecia occurred in 34 (25.2%) and 27 (24.1%) and dry skin occurred in 31 (23.0%) and 5 (4.5%) patients in the BALVERSA and chemotherapy groups, respectively.¹
  • TRAEs related to skin disorders are reported in Table: THOR Cohort 1 Safety Population: Treatment-Related Skin AEs.
• Grade 3/4 AEs of interest based on the known safety profile of BALVERSA included skin disorders which occurred in 11.9% patients in the BALVERSA group.¹ Skin disorders included blister, dry skin, erythema, hyperkeratosis, palmar erythema, palmar-plantar erythrodysesthesia syndrome, plantar erythema, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, skin atrophy, skin exfoliation, skin fissures, skin lesion, skin ulcer, toxic skin eruption, and xeroderma.³
• Grade 3/4 TRAEs occurred in 45.9% patients in the BALVERSA group and 46.4% patients in the chemotherapy group.¹
  • The most common grade ≥3 TRAE in the BALVERSA group was palmar-plantar erythrodysesthesia syndrome (9.6%).
• AEs of any cause led to treatment discontinuation in 19 (14.1%) patients in the BALVERSA group and 20 (17.9%) patients in the chemotherapy group. Dry skin led to treatment discontinuation in 1 (0.7%) patient in the BALVERSA arm.³

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

Final Analysis

BLC2001 is an ongoing, phase 2, open-label, multicenter study evaluating the use of BALVERSA in patients with locally advanced and unresectable or metastatic UC who had prespecified FGFR alterations (FGFR3 mutation or FGFR2/3 fusion) and disease progression during or following ≥1 line of prior systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy or were chemotherapy-naïve due to cisplatin ineligibility. Patients had tumor tissues with one of the following FGFR3 mutations: R248C, S249C, G370C, Y373C or one of the following FGFR fusions: FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7.^5,7

• 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 once daily (2 patients were 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.^4,8
• The safety profile of BALVERSA remained consistent with that of the primary analysis.⁴
• The most common treatment-related skin events (grade 1-3) are presented in the Table: BLC2001: Most Common Treatment-Related Skin AEs. Grade 4/5 events of dry skin, alopecia, or palmar-plantar erythrodysesthesia syndrome were not reported in patients treated with BALVERSA.⁸
• Treatment-related skin AEs that led to treatment discontinuation were palmar-plantar erythrodysesthesia syndrome (n=2) and skin ulcer (n=1).⁸
• A total of 55 (54.5%) patients treated with BALVERSA 8 mg daily reported treatment-emergent skin AEs.⁸
  • The most frequently occurring treatment-emergent skin AEs were dry skin (33.7%), palmar-plantar erythrodysesthesia syndrome (24.8%), and erythema (7.9%).

• The incidence of treatment-emergent skin events is summarized in the Table: BLC2001: Treatment-Emergent Skin Adverse Events.

GUIDELINES FOR the MANAGEMENT OF DRY SKIN AND SKIN TOXIcity IN THE thor AND BLC2001 STUDIES

Guidelines and interventions that investigators were instructed to perform to manage dry skin (Table: Guidelines for the Management of Dry Skin in the THOR and BLC2001 Studies) and skin toxicity are summarized in this section. These are not recommendations. Interventions should be based on patient presentation and the clinical judgment of the treating physician for dry skin and skin toxicity.^7,10

• General prophylaxis^7,10:
  • Avoid unnecessary exposure to sunlight and excessive use of soap.
  • Avoid bathing in excess; use tepid rather than hot water.
  • Use moisturizers regularly; apply thick, alcohol-free and oil-in-water based emollient cream on exposed and dry areas of the body.
  • Avoid perfumed products, bubble bath, perfumed soaps, and take breaks from shaving.
  • Use broad spectrum sunscreen with a skin protection factor (SPF) ≥15.
  • Wear cotton clothes next to skin rather than wool, synthetic fibers, or rough clothing.
  • Use occlusive alcohol-free emollient creams (jar or tub) for treatment of mild/moderate xerosis.
  • For scaly areas, use exfoliants (ammonium lactate 12% or lactic acid cream 12%).

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 04 November 2024. Study data and case reports of BALVERSA monotherapy for the treatment of advanced and metastatic UC are included in this response.