SUMMARY

• THOR (BLC-3001/NCT03390504) is an ongoing, phase 3, randomized, open-label, multicenter study evaluating the efficacy and safety of BALVERSA vs the checkpoint inhibitor pembrolizumab or chemotherapy (docetaxel or vinflunine) 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). Key secondary endpoints include progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and safety.^1-3
  • To provide the most relevant information, the summary below is limited to results from cohort 2 of the THOR study in anti-programmed death-ligand 1 (PD-(L)1)-naïve patients with metastatic UC between BALVERSA vs pembrolizumab.³
  • Siefker-Radtke et al (2024)³ reported 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). Safety profiles were consistent with the known safety profiles of BALVERSA and pembrolizumab.
• A matching-adjusted indirect comparison (MAIC) evaluating individual patient data (IPD) from the BLC2001 study⁴ for BALVERSA compared to aggregated data from published randomized controlled trials (RCTs) for existing second-line treatments, including checkpoint inhibitors (pembrolizumab and atezolizumab), suggest that treatment with BALVERSA results in improved clinical benefit as compared to pembrolizumab and atezolizumab.⁵

Clinical Data

THOR Study

THOR is an ongoing 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 gene alterations that has progressed during or after 1 or 2 prior lines of therapy.^1-3

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)^1,6
    • 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]).⁶
      • 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).⁶
      • 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 or magnetic resonance imaging 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 version 1.1.
• 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 within 14 days of treatment and prior to first day of cycle 1 day 1.
• 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 metastases; prior FGFR inhibitor treatment; corneal or retinal abnormality including central serous retinopathy or retinal pigment epithelial detachment 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, Patient-Global Impression of Severity, European Quality of Life-5 Dimensions-5 Levels Questionnaire), safety, and pharmacokinetics

Results

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

Cohort 2

Siefker-Radtke et al (2024)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: THOR Cohort 2 Select Baseline Demographics and Disease Characteristics.

Efficacy: Cohort 2

• 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, 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: THOR Cohort 2 Efficacy Analysis: HR for OS Across Clinically Relevant Subgroups.

Safety: Cohort 2

• The overall safety summary is included in Table: THOR Cohort 2: Overall Safety Summary.

• Treatment-emergent AEs are included in Table: THOR Cohort 2: Treatment-Emergent AEs.

• AEs of interest in the safety population are included in Table: THOR Cohort 2: AEs of Interest in the Safety Population.

Indirect Comparison Study

Loriot et al (2019)⁵ conducted a MAIC study to compare the efficacy of BALVERSA with existing second-line treatments, including pembrolizumab and atezolizumab for the treatment of metastatic UC. 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 (ORs) for overall response rate were statistically significant for BALVERSA compared to pembrolizumab (OR, 2.259; 95% CI, 1.113-4.585; P=0.0240) and atezolizumab (OR, 6.798; 95% CI, 3.549-13.022; P<0.0001) as shown in Table: Matching Adjusted ORs for Overall Response Rate for BALVERSA vs Comparators.

The matching adjusted HRs for OS showed improvement with BALVERSA compared to pembrolizumab (HR, 0.605; 95% CI, 0.369-0.991; P=0.0458) and atezolizumab (HR, 0.582; 95% CI, 0.366-0.924; P=0.0217). 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) as shown in Table: Matching Adjusted HRs for OS and PFS for BALVERSA vs Comparators. Safety data were not reported.

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 05 December 2024.