CLINICAL DATA

BLC2001 Subgroup Analysis in Patients With Locally Advanced or Metastatic UC

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 (QD) 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 (AEs). 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 QD.
  • 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 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 QD 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 QD:
  • 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 mUC and selected FGFR gene alterations are planned for enrollment in the phase 2 study. Patients with no prior treatment for metastatic disease and ineligible for cisplatin are included in the preliminary analysis.²
• 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
• Patients are randomized 1:1 to receive:²
  • BALVERSA 8 mg PO QD with pharmacodynamically-guided uptitration to 9 mg PO QD alone or
  • BALVERSA 8 mg PO QD in combination with cetrelimab 240 mg IV Q2W for cycles 1-4, then 480 mg IV every 4 weeks (Q4W) thereafter.

Results

Baseline Characteristics

Efficacy

• In the phase 2 interim analysis, patients in both treatment arms had a durable reduction in the sum of target lesion diameters over time.³
  • Median of the maximum reduction in the sum of target lesion diameters was 28% in the BALVERSA arm and 51% in the BALVERSA plus cetrelimab arm.
  • Responses were observed in patients with both FGFR mutations and fusions.
  • In patients with programmed cell death ligand-1 (PD-L1) low status, responses were observed in 50% of patients in the BALVERSA arm (5 of 10) and in 71% of patients in the BALVERSA plus cetrelimab arm (5 of 7); few patients with PD-L1 positive status had available data at the time of this analysis.
• Please see Table: Phase 2 Interim Analysis: Summary of Best Overall Response for the Response-Evaluable Set.

• In the phase 2 final analysis⁴:
  • Patients receiving BALVERSA monotherapy had an ORR of 44.2% (95% CI, 29.1-60.1), 1 patient had a confirmed complete response (CR), and 18 patients had a confirmed partial response (PR). Patients receiving BALVERSA plus cetrelimab combination therapy had an ORR of 54.5% (95% CI, 38.8-69.6), 6 patients had a confirmed CR, and 18 patients had a confirmed PR.
  • In patients with a combined positive score (CPS) <10, ORR was 46.4% in the BALVERSA monotherapy arm and 50% in the BALVERSA plus cetrelimab combination therapy arm. Data is limited in patients with PD-L1 high status (CPS ≥10).
• Please see Table: Phase 2 Final Analysis: Efficacy Results.

Safety

• The safety profile of BALVERSA plus cetrelimab was generally similar to that of BALVERSA alone, see Table: Phase 2 Interim Analysis: Most Common TEAEs Occurring in ≥25% of Patients.³
• Grade 3-4 TEAEs occurred in 9 patients (38%) in the BALVERSA arm and in 12 patients (50%) in the BALVERSA plus cetrelimab arm; most frequent were³:
  • BALVERSA arm: anemia (n=3 patients [12.5%]) and general physical health deterioration (n=3 [12.5%])
  • BALVERSA plus cetrelimab arm: stomatitis (n=3 [12.5%]), lipase increased (n=3 [12.5%]), and fatigue (n=2 [8.3%])
• 1 death in the BALVERSA plus cetrelimab arm was determined to be related to cetrelimab (respiratory failure).³
• The frequency of TEAEs of interest was mostly similar between arms, with the exception of immune-related TEAEs, as summarized in Table: Phase 2 Interim Analysis: TEAEs of Interest for BALVERSA or BALVERSA and Cetrelimab.

• In the BALVERSA monotherapy treatment arm, 6 patients (14%) discontinued therapy due to TRAEs. No treatment-related deaths occurred.⁴
  • The most frequent drug-related AE leading to discontinuation was stomatitis (n=2).
• In the BALVERSA plus cetrelimab combination therapy arm, 9 patients (20.5%) discontinued BALVERSA, and 6 patients (13.6%) discontinued cetrelimab. One treatment-related death occurred due to pulmonary failure, determined to be related to cetrelimab.⁴
  • Three patients (6.8%) discontinued both BALVERSA and cetrelimab due to treatment-related AEs.
  • The most frequent drug-related AEs leading to discontinuation of BALVERSA were stomatitis (n=2) and nail dystrophy (n=2). No AE that led to discontinuation of cetrelimab occurred in >1 patient.

SOGUG-NEOWIN Study

The SOGUG-NEOWIN study (EudraCT 2022-002586-15) 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-Ta N0/1 M0) and FGFR alterations.⁸

Study Design/Methods

• Phase 2, prospective, non-comparative, open-label, multicenter, international study⁸
• Select eligibility criteria included patients who declined or were ineligible for cisplatin-based chemotherapy.⁸
• 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.⁸
• A total of 45 patients will be randomized to each arm by a centralized system.⁸
• Co-primary endpoints are pathological CR rate and percentage of pathological downstaging response.⁸
• Results have not yet been published.⁸

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 20 May 2024.