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 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
  • Loriot et al (2023)¹ presented results from cohort 1 (n=266) after a median follow-up of 15.9 months. The median OS was 12.1 months for patients receiving BALVERSA vs 7.8 months for patients receiving chemotherapy. The safety profiles were consistent with the known safety profiles of BALVERSA and chemotherapy.
  • In the cohort 1 chemotherapy arm, 69 patients received docetaxel. Results were reported for the BALVERSA and chemotherapy arms. Results were not specifically reported for patients who received docetaxel.¹
• A matching adjusted indirect comparison (MAIC) evaluated individual patient data (IPD) from the BLC2001 study³ for BALVERSA compared to aggregated data from published randomized controlled trials (RCTs) for existing second-line treatments, including docetaxel. Treatment with BALVERSA in patients with metastatic UC (mUC) resulted in a significant improvement in overall response rate. Matching adjusted HRs for OS showed a significant benefit for BALVERSA and matching adjusted HRs for PFS were also in favor of BALVERSA with significant results for 2 of 4 docetaxel studies. Safety data were not reported.⁴

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.^1,2

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)^1,5
    • 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]).⁵
      • 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 treatment⁶
    • 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).⁵
      • 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

Cohort 1

Loriot et al (2023)¹ reported interim results from cohort 1 of the THOR study (n=266).

In the cohort 1 chemotherapy arm, 69 patients received docetaxel. Results were reported for the BALVERSA and chemotherapy arms. Results were not specifically reported for patients who received docetaxel.¹

Patient Characteristics

• The demographics and baseline characteristics of patients in cohort 1 are included in Table: THOR Cohort 1 Select Baseline Demographics and Disease Characteristics.

• Patients in cohort 1 with prior systemic therapy are included in Table: THOR Cohort 1 Patients with Prior Systemic Therapy.

Efficacy: Cohort 1¹

• At a median follow-up of 15.9 months, the median OS was 12.1 months for patients receiving BALVERSA vs 7.8 months for patients receiving chemotherapy. BALVERSA reduced the risk of death by 36% vs chemotherapy.
  • HR, 0.64 (95% CI, 0.47-0.88; P=0.005).
• Median PFS was 5.6 months for patients receiving BALVERSA vs 2.7 months for patients receiving chemotherapy. BALVERSA reduced the risk of progression or death by 42% vs chemotherapy.⁷
  • HR, 0.58 (95% CI, 0.44-0.78; P<0.001).
• Patients receiving BALVERSA (n=136) had an ORR of 45.6%, 9 (6.6%) patients had a complete response (CR), and 53 (39%) patients had a partial response (PR). Patients receiving chemotherapy (n=130) had an ORR of 11.5%, 1 (0.8%) patient had a CR, and 14 (10.8%) patients had a PR.⁷
  • Relative risk (RR), 3.94 (95% CI, 2.37-6.57; P<0.001).
• OS across clinically relevant subgroups was evaluated, please refer to Table: THOR Cohort 1 Efficacy Analysis: HR for OS Across Clinically Relevant Subgroups.

Safety: Cohort 1¹

• Treatment-related adverse events (TRAEs) and adverse events interest in the safety population of cohort 1 are reported in tables: THOR Cohort 1 TRAEs in the Safety Population and THOR Cohort 1 AEs of Interest in the Safety Population.
• In the BALVERSA treatment arm (n=135), 62 (45.9%) patients had grade 3-4 TRAEs, 18 (13.3%) patients had treatment-related serious AEs, and 1 treatment-related death occurred (reported as sudden death).
  • The median duration of exposure in the BALVERSA treatment arm was 4.8 months (range, 0.2 to 38.2).
  • In the BALVERSA group, AEs of any cause led to treatment discontinuation in 19 (14.1%) patients and TRAEs that led to treatment discontinuation occurred in 8.1% of patients.
  • Grade 3/4 AEs of interest based on the known safety profile of BALVERSA included skin disorders (11.9%), nail disorders (11.1%), central serous retinopathy (CSR; 2.2%), and other eye disorders (2.2%).
  • In 16 of 23 patients (70%) with central serous retinopathy of any grade, events were resolved by the clinical cutoff date. Among the 7 patients with ongoing events, the events in 5 patients were grade 1.
• In the chemotherapy treatment arm (n=112), 52 (46.4%) patients had grade 3-4 TRAEs, 27 (24.1%) patients had treatment-related serious AEs, and 6 treatment-related deaths occurred (reported as 2 each with febrile bone marrow aplasia and septic shock, 1 each with atypical pneumonia and febrile neutropenia).
  • The median duration of exposure in the chemotherapy treatment arm was 1.4 months (range, 0.03 to 27.0).
  • In the chemotherapy group, AEs of any cause led to treatment discontinuation in 20 (17.9%) patients and TRAEs that led to treatment discontinuation occurred in 13.4% of patients.

Indirect Comparison Study

Loriot et al (2019)⁴ conducted a MAIC study to compare the efficacy of BALVERSA with existing second-line treatments, including docetaxel, 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 ratio (OR) for overall response rate were statistically significant for BALVERSA compared to docetaxel (all studies) as shown in the Table: Matching Adjusted ORs for Overall Response Rate for BALVERSA vs Docetaxel. Safety data were not reported.

The matching adjusted HRs for OS and PFS are shown in the Table: Matching Adjusted HRs for OS and PFS for BALVERSA vs Docetaxel.

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 04 December 2024.