Use of BALVERSA as First-Line Therapy in Cisplatin-Ineligible Patients With Locally Advanced or Metastatic Urothelial Carcinoma

CLINICAL DATA

BLC2001 Subgroup Analysis in Patients With Locally Advanced or Metastatic Urothelial Carcinoma

Loriot et al (2019)¹ reported the efficacy and safety of BALVERSA in adults with locally advanced or metastatic urothelial carcinoma (UC) and prespecified fibroblast growth factor receptor (FGFR) genetic alterations (FGFR3 mutation or FGFR2/3 fusion) who received prior chemotherapy or who were chemotherapy-naïve due to cisplatin-ineligibility.

Study Design/Methods

• Multicenter, open-label phase 2 study (NCT02365597)
• Patients were initially randomized 1:1 to 28-day cycles of oral BALVERSA according to either an intermittent regimen or a continuous regimen. Based on interim analysis and pharmacokinetic-pharmacodynamic (PK-PD) modeling of serum phosphate levels, the protocol was amended to evaluate a starting dose of continuous BALVERSA 8 mg per day (regimen 3) with a recommended dose escalation to 9 mg once daily for patients who did not reach target serum phosphate level of 5.5 mg/dL on day 14 and were without treatment-related adverse events (TRAEs). Patients whose serum phosphate levels on day 14 were within the target range of 5.5 to <7.0 mg/dL continued to receive BALVERSA 8 mg once daily.
  • Randomization was stratified according to performance status (0 to 1 vs 2), hemoglobin value, FGFR alteration type, prior treatment status, and presence vs absence of liver, lung, or bone metastases.
  • Treatment was continued until disease progression or unacceptable adverse events (AEs).
  • Patients who experienced investigator-assessed disease progression were permitted to continue BALVERSA at discretion of the investigator and sponsor.
• A preplanned subgroup analysis investigated response by prior lines of systemic therapy.

Results

Efficacy in Subgroup of Cisplatin-Ineligible Patients Who Received First-Line BALVERSA

• Among 99 patients treated with BALVERSA 8 mg daily, 11 cisplatin-ineligible, chemo-naive patients received BALVERSA as first-line therapy.
• In this subgroup of cisplatin-ineligible patients who received first-line BALVERSA therapy, the objective response rate (ORR) per investigator assessment was 36% (4 of
  11 patients; 95% confidence interval [CI], 8-65).

Safety

• Safety results were not delineated for the subset of cisplatin-ineligible patients who received first-line BALVERSA.
• All patients in the overall population treated with BALVERSA 8 mg once daily experienced an AE of any cause during treatment, of which 67% were grade 3 or 4.
• The most common AEs of any cause in the overall population are summarized in the table below.
• Thirteen patients experienced AEs leading to treatment discontinuation, including detachment of retinal pigment epithelium, hand-foot syndrome, dry mouth, and skin or nail events.
• Dose reductions were required in 55 patients, most commonly due to stomatitis (n=16) and hyperphosphatemia (n=9).
• Among the 41 patients who had a dose escalation to 9 mg once daily:
  • 24 (59%) required ≥1 dose reduction
  • 68% experienced grade ≥3 treatment-emergent AEs
• Safety outcomes after a median follow-up of 24 months were consistent with the primary analysis.⁵

NORSE Study

The NORSE study (BLC2002; NCT03473743) is evaluating the recommended phase 2 dose (RP2D), PK, efficacy, and safety of BALVERSA plus cetrelimab, and for BALVERSA in combination with cetrelimab and platinum (cisplatin and carboplatin) chemotherapy, in patients with locally advanced or metastatic UC and selected FGFR gene alterations.^2-4,6,7

Study Design/Methods

• Phase 1b/2, open-label, multicenter study
  • The phase 1b dose escalation study evaluated 3 dosing levels of BALVERSA orally (PO) daily with a fixed dose of cetrelimab 240 mg intravenous (IV) every 2 weeks (Q2W) in patients who had received ≥1 prior therapy to identify the RP2D for further evaluation in the phase 2 dose expansion study.^4,5
• An estimated 90 patients with metastatic (mUC) or locally advanced UC and selected FGFR gene alterations are planned for enrollment in the phase 2 study.²
  • Key inclusion criteria included patients with no prior treatment for metastatic disease and those who are cisplatin-ineligible.
  • Cisplatin-ineligible is defined as Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 plus ≥1 of the following criteria: renal function defined as creatinine clearance (CrCl) ˂60 mL/min, grade ≥2 peripheral neuropathy, grade ≥2 hearing loss, or ECOG PS 2.^2,3
• In the phase 2 study, patients are randomized 1:1 to receive:^2,4
  • BALVERSA 8 mg PO once daily with pharmacodynamically-guided uptitration to 9 mg PO once daily alone or
  • BALVERSA 8 mg PO once daily (without uptitration) in combination with cetrelimab 240 mg IV Q2W for cycles 1-4, then 480 mg IV every 4 weeks (Q4W) thereafter.
• Randomization was stratified by Eastern Cooperative Oncology Group performance status (ECOG PS; 0-1 vs 2).⁴ 
• The primary analysis was the end of the study, and no additional efficacy data were collected.⁴ 
• Patients continued to receive the study treatment and were allowed to continue in a long-term extension phase. Only serious AE data were collected during this time.⁴ 

Results

Baseline Characteristics

• There were 132 patients who met full study eligibility (for both parts 1 and 2 of the study), including those who were FGFR-positive.²
• A total of 89 patients were randomly assigned in part 2 of the study (BALVERSA, n=44; BALVERSA plus cetrelimab, n=45). One patient from each group was not randomly assigned and not included in the treated analysis set.⁴ 
• Baseline characteristics of the patients from the phase 2 study are summarized in Table: Phase 2 Final Analysis: Baseline Disease Characteristics and Demographics.

Efficacy

• Final efficacy results are summarized in Table: Phase 2 Final Analysis: Efficacy Results.

• Among 4 patients treated with BALVERSA with PD-L1 high status (combined positive score [CPS] ≥10), none responded (0/4); while among 4 patients treated with BALVERSA plus cetrelimab, 75% (3/4) responded.⁴ 

Safety

• The median durations of BALVERSA exposure were 5.6 months (range, 0.3-31.6) and 7.5 months (range, 0.5-23.1) in the BALVERSA and BALVERSA plus cetrelimab groups, respectively. The median duration of cetrelimab exposure was 7.8 months (range, 0-33).⁴ 
• The overall safety summary is presented in Table: Phase 2 Final Analysis: Overall Safety Summary.

• Common (occurring in ≥15% of patients) TRAEs are summarized in Table: Phase 2 Final Analysis: TRAEs Occurring in the Safety Population.

• AEs of interest on the basis of the known BALVERSA safety profile included hyperphosphatemia, gastrointestinal disorders, nail disorders, skin disorders, eye disorders (excluding central serous retinopathy [CSR]), and CSR.⁸ See Table: Phase 2 Final Analysis: AEs of Special Interest Occurring in the Safety Population.

SOGUG-NEOWIN Study

The SOGUG-NEOWIN study (EU CT Number 2024-512573-27-01; NCT06511648) is evaluating the efficacy of 9 or 12 weeks of neoadjuvant BALVERSA (cohort 1) or BALVERSA plus cetrelimab (cohort 2) in patients with muscle-invasive bladder cancer (MIBC) (cT2-T4a N0/1 M0) and FGFR alterations.^9-11

Study Design/Methods

• Phase 2, prospective, non-comparative, open-label, multicenter, international study.
• Select eligibility criteria included patients who declined or were ineligible for cisplatin-based chemotherapy.
• Cisplatin-ineligible is defined as 1 of the following criteria: impaired renal function (glomerular filtration rate ˂60 mL/min), grade ≥2 peripheral neuropathy, or grade ≥2 hearing loss.
• A total of 45 patients will be randomized to each arm by a centralized system.
• Co-primary endpoints are pathological CR rate and percentage of pathological downstaging response (<ypT2).
• The first patient was pre-screened on January 31, 2024.
• As of March 31, 2025, 91 patients were pre-screened, 9 were FGFR2/3 positive, and 5 were enrolled.
• Results have not yet been published.

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 14 May 2026.