SUMMARY  

• THOR (BLC-3001/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 selected fibroblast growth factor receptor (FGFR) gene alterations that has progressed during or after 1 or 2 prior lines of therapy. The primary endpoint is overall survival (OS).^1,2
  • Siefker-Radtke et al (2023)³ presented results from cohort 2 (n=351) of the THOR study. The median OS was 10.9 months for patients receiving BALVERSA vs 11.1 months for patients receiving pembrolizumab (hazard ratio [HR], 1.18; 95% confidence interval [CI], 0.9-1.5; P=0.18). Median progression-free survival (PFS) was 4.4 months for patients receiving BALVERSA vs 2.7 months for patients receiving pembrolizumab (HR, 0.88; 95% CI, 0.70-1.10). Objective response rate (ORR) was 40% for patients receiving BALVERSA vs 21.6% for patients receiving pembrolizumab. Median duration of response (DOR) was 4.3 months for patients receiving BALVERSA vs 14.4 months for patients receiving pembrolizumab. Safety profiles were consistent with the known safety profiles of BALVERSA and pembrolizumab.
  • Siefker-Radtke et al (2024)⁴ conducted an analysis of tumors from THOR cohort 2 to evaluate the association of molecular subtype with clinical outcomes in patients receiving BALVERSA (n=65) vs pembrolizumab (n=87). Within the luminal-papillary (LumP) subtype, ORR (41.7 vs 19.7%; P=0.0129), median PFS (5.52 vs 2.73 months), and median OS (10.94 vs 12.94 months) were reported with patients receiving BALVERSA vs pembrolizumab.
• A matching adjusted indirect comparison (MAIC) evaluated individual patient data (IPD) from the BLC2001 study⁵ for BALVERSA compared to aggregated data from published randomized controlled trials (RCTs) for existing second-line treatments, including pembrolizumab. The HR for PFS favored BALVERSA compared to pembrolizumab (HR, 0.773; 95% CI, 0.579-1.032; P=0.0805) in patients with metastatic UC (mUC). Safety data were not reported.⁶

Clinical Data

THOR Study

THOR is an ongoing study evaluating the efficacy and safety of BALVERSA vs standard of care chemotherapy (docetaxel or vinflunine) or pembrolizumab in patients with metastatic or unresectable UC and selected FGFR gene alterations that has progressed during or after  1 or 2 prior lines of therapy.^1,2

Study Design/Methods

• Phase 3, randomized, open-label, multicenter study
• A total of 629 patients from 345 study locations were screened for the presence of FGFR gene alterations and assigned to 2 cohorts based on prior treatment with anti-PD-(L)1 agent:
  • Cohort 1 (n=266): prior chemotherapy with anti-PD-(L)1 treatment in combination or maintenance setting (anti-PD-[L]1 alone in cisplatin-ineligible patients only)^1,7
    • Patients were randomized 1:1 to receive:
      • BALVERSA at a starting dose of 8 mg once daily, with uptitration to 9 mg once daily based on day 14 serum phosphate levels (≤9.0 mg/dL and no associated adverse events [AEs]).⁷
      • Chemotherapy (docetaxel 75 mg/m² as a 1-hour intravenous [IV] infusion every 3 weeks [Q3W] or vinflunine 320 mg/m² as a 20-minute IV infusion once Q3W)
  • Cohort 2 (n=351): prior chemotherapy without anti-PD-(L)1 treatment³
    • Patients were randomized 1:1 to receive:
      • BALVERSA at a starting dose of 8 mg once daily, with uptitration to 9 mg once daily based on day 14 serum phosphate levels (≤9.0 mg/dL and no associated AEs).⁷
      • Pembrolizumab 200 mg as a 30-minute IV infusion once Q3W
• Randomization will be stratified by region (North America vs European Union vs rest of the world), Eastern Cooperative Oncology Group performance status (ECOG PS; 0 vs 1 vs 2), and disease distribution (presence or absence of visceral metastases: lung, liver, or bone).
• Treatment will continue until disease progression, intolerable toxicity, withdrawal of consent, or decision by the investigator to discontinue treatment.
• Disease assessments by computed tomography (CT) or magnetic resonance imaging (MRI) will be performed every 6 weeks for 6 months followed by every 12 weeks for the next 6 months and then as clinically indicated.
• Tumor responses will be evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
• Select inclusion criteria: adult patients with stage 4 carcinoma of the urothelium and documented progression; only 1 line of prior systemic treatment for metastatic UC (cohort 1: prior treatment with an anti-PD-(L)1 agent as monotherapy or as combination therapy; ≤2 prior lines of systemic treatment; cohort 2: prior chemotherapy [no prior treatment with an anti-PD-(L)1 agent; only 1 line of prior systemic treatment])²; patients who received neoadjuvant or adjuvant chemotherapy and showed disease progression within 12 months of the last dose are considered to have received systemic chemotherapy in the metastatic setting); tumors with ≥1 select FGFR3 or FGFR2 fusion or mutation determined by central laboratory screening; ECOG PS ≤2; adequate bone marrow, liver, and renal function (creatinine clearance >30 mL/min/1.73 m²); phosphate levels <upper limit of normal (ULN) within 14 days of treatment and prior to first day of cycle 1 day 1 (C1D1).
• Select exclusion criteria: treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 30 days before randomization; active malignancies (ie, requiring treatment change in the last 24 months) other than UC (except skin cancer within the last 24 months that is considered completely cured); symptomatic central nervous system (CNS) metastases; prior FGFR inhibitor treatment; corneal or retinal abnormality including central serous retinopathy (CSR) or retinal pigment epithelial detachment (RPED) of any grade; history of uncontrolled cardiovascular disease or known active human immunodeficiency virus, hepatitis B or C infection
• Primary endpoint: OS
• Secondary endpoints: PFS, ORR, DOR, patient-reported outcomes (Functional Assessment of Cancer Therapy-Bladder Cancer [FACT-B1], Patient-Global Impression of Severity [PGIS], European Quality of Life-5 Dimensions-5 Levels Questionnaire [EQ-5D-5L]), safety, and pharmacokinetics (PK)

Results

In order to provide the most relevant information, results reported are limited to cohort 2.

Cohort 2

Siefker-Radtke et al (2023)³ reported interim results from cohort 2 of the THOR study (n=351).

Patient Characteristics

• The demographics and baseline characteristics of patients in the fully enrolled cohort 2 are included in Table: Cohort 2 Select Baseline Demographics and Disease Characteristics.

Efficacy: Cohort 2³

• The median OS was 10.9 months for patients receiving BALVERSA (95% CI, 9.2-12.6) vs 11.1 months for patients receiving pembrolizumab (95% CI, 9.7-13.6).
  • HR, 1.18 (95% CI, 0.9-1.5; P=0.18).
• Median PFS was 4.4 months for patients receiving BALVERSA (95% CI, 4.1-5.5) vs 2.7 months for patients receiving pembrolizumab (95% CI, 1.6-3).
  • HR, 0.88 (95% CI, 0.7-1.1).
• Patients receiving BALVERSA (n=175) had an ORR of 40% (95% CI, 32.7-47.7), 11 (6.3%) patients had a CR, and 59 (33.7%) patients had a PR. Patients receiving pembrolizumab (n=176) had an ORR of 21.6% (95% CI, 15.8-28.4), 8 (4.5%) patients had a CR, and 30 (17%) patients had a PR.
  • Relative risk (RR), 1.85 (95% CI, 1.32-2.59).
• Median DOR was 4.3 months (95% CI, 3.7-6.9) for BALVERSA vs 14.4 months (95% CI, 7.4-27.8) for pembrolizumab.
• OS across clinically relevant subgroups was evaluated, please refer to Table: Cohort 2 Efficacy Analysis: HR for OS Across Clinically Relevant Subgroups.

Safety: Cohort 2³

• In the BALVERSA treatment arm (n=173), 23 (13.3%) patients had serious TRAEs and 26 (15%) patients discontinued treatment due to TRAEs (most frequent TRAEs leading to discontinuation were gastrointestinal disorders [n=9], eye disorders [n=9], and skin and subcutaneous tissue disorders [n=6]).⁸ TRAEs were mostly manageable with dose modifications and supportive care. No deaths due to TRAEs occurred.
• In the pembrolizumab treatment arm (n=173), 18 (10.4%) patients had serious TRAEs and 8 (4.6%) patients discontinued treatment due to TRAEs (most frequent TRAEs leading to discontinuation were renal and urinary disorders [n=2], respiratory and thoracic and mediastinal disorders [n=2]).⁸ Three treatment-related deaths occurred.
  • TRAEs leading to death in the pembrolizumab group included respiratory failure, pulmonary embolism, and urinary tract infection (1 patient each).

THOR Molecular Subgroup Analysis

Siefker-Radtke et al (2024)⁴ conducted an analysis of tumors from THOR cohort 2 to evaluate the association of molecular subtype with clinical outcomes in patients receiving BALVERSA (n=65) vs pembrolizumab (n=87).

Study Design/Methods

• All available FGFR-altered tumor samples from patients in THOR cohort 2 (n=201) and a subset of tumor samples from patients with wildtype (WT) FGFR (n=116), who were anti-PD(L)1/PD1-naïve, were used to perform whole transcriptome RNA sequencing (RNAseq).
• Consensus single-sample classifier was applied to the RNAseq data to determine the molecular subtype of each tumor.
• Outcomes: Correlation between tumor subtypes and clinical outcomes of BALVERSA vs pembrolizumab including ORR, PFS, and OS

Results

Patient Characteristics

• The demographics and baseline characteristics of patients are included in Table: Molecular Analysis: Baseline Demographics and Disease Characteristics.

Efficacy

• Of 236 tumor samples screened via whole transcriptome RNAseq, 152 FGFR-altered and 84 FGFR WT tumors passed quality control.
• Molecular classification of tumors identified a significant proportion of LumP subtype in FGFR-altered vs FGFR WT tumors (78.3% vs 36.9%; P<0.001).
  • Numeric differences between FGFR-altered and FGFR WT tumors were also identified in basal/squamous, stroma-rich, luminal unstable, luminal non-specified, and neuroendocrine-like tumor subtypes.
• Clinical outcomes by tumor subtype are summarized in Table: Molecular Analysis: Clinical Outcomes by Tumor Subtype.

Indirect Comparison Study

Loriot et al (2019)⁶ conducted a MAIC study to compare the efficacy of BALVERSA with existing second-line treatments, including pembrolizumab, for the treatment of mUC. The study evaluated overall response rate (total number of patients with complete or partial response), OS, and PFS utilizing IPD from the BLC2001 study for BALVERSA and aggregated data from published RCTs for comparators.

The matching adjusted odds ratios (OR) for overall response rate was statistically significant for BALVERSA compared to pembrolizumab (OR, 2.259; 95% CI, 1.113-4.585; P=0.0240). The matching adjusted HR for OS showed significant improvement with BALVERSA compared to pembrolizumab (HR, 0.605; 95% CI, 0.369-0.991; P=0.0458). In addition, the matching adjusted HR for PFS was in favor of BALVERSA compared to pembrolizumab (HR, 0.773; 95% CI, 0.579-1.032; P=0.0805). Safety data were not reported.

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 27 May 2024.