CLINICAL DATA

THOR Study

THOR (BLC3001/NCT03390504) is an ongoing, phase 3, open-label, multicenter study evaluating the efficacy and safety of BALVERSA vs standard of care (SOC) 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.^1,10

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- programmed death ligand 1 (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)^1,11
    • 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]).¹¹
      • 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 treatment¹²
    • 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).¹¹
      • 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) version 1.1.
• Select inclusion criteria:
  • Patients (age ≥18 years) had stage 4 carcinoma of the urothelium and documented progression.
  • Patients had 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])¹⁰; patients who received neoadjuvant or adjuvant chemotherapy and showed disease progression within 12 months of the last dose were considered to have received systemic chemotherapy in the metastatic setting.
  • Patients had tumors with ≥1 select FGFR3 or FGFR2 fusion or mutation determined by central laboratory screening.
  • An ECOG PS of ≤2 was required.
  • Patients had adequate bone marrow, liver, and renal function (creatinine clearance >30 mL/min/1.73 m²).
  • Patients had 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:
  • Patients treated with any other investigational agent or having participated in another clinical study with therapeutic intent within 30 days before randomization were excluded.
  • Patients with 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) were excluded.
  • Patients with symptomatic central nervous system (CNS) metastases were excluded.
  • Patients with prior FGFR inhibitor treatment were excluded.
  • Patient with corneal or retinal abnormality including central serous retinopathy (CSR) or retinal pigment epithelial detachment (RPED) of any grade were excluded.
  • Patients with history of uncontrolled cardiovascular disease or known active human immunodeficiency virus (HIV), hepatitis B or C infection were excluded.
• Primary endpoint: Overall survival (OS)
• Secondary endpoints: Progression‑free survival (PFS), objective response rate (ORR), duration of response (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).

Patient Characteristics

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

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.
  • Hazard ratio (HR), 0.64 (95% confidence interval [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.¹³
  • 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.¹³
  • 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: Cohort 1 Efficacy Analysis: HR for OS Across Clinically Relevant Subgroups.

Safety: Cohort 1¹

• In the BALVERSA treatment arm (n=135), 62 (45.9%) patients had grade 3-4 treatment-related adverse events (TRAEs; most frequent grade 3-4 TRAEs were palmar-plantar erythrodysesthesia syndrome [13 patients, 9.6%], stomatitis [11 patients, 8.1%], onycholysis [8 patients, 5.9%], and hyperphosphatemia [7 patients, 5.2%]), 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%), CSR (2.2%), and other eye disorders (2.2%).
  • In 16 of 23 patients (70%) with CSR 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 (most frequent grade 3-4 TRAEs were neutropenia [15 patients, 13.4%] and anemia [7 patients, 6.2%]), 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.

BLC2001 Study

BLC2001 (NCT02365597) is a phase 2, multicenter, open-label study in adult patients with locally advanced and unresectable or metastatic UC and prespecified FGFR genetic alterations (FGFR3 mutation or FGFR2/3 fusion) with disease progression during or following ≥1 line of prior systemic chemotherapy or within 12 months of receiving neoadjuvant or adjuvant chemotherapy, or were chemotherapy-naïve due to cisplatin ineligibility. Efficacy and safety results are described for patients who received a starting dose of BALVERSA 8 mg orally (PO) once daily (N=99).^3,4

Study Design Methods^3,4

• Phase 2, multicenter, open-label study
• Patients were initially randomized 1:1 to 28-day cycles of BALVERSA PO according to either an intermittent regimen or a continuous regimen. Based on interim analysis and PK-pharmacodynamic (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 for patients who did not reach target serum phosphate level of 5.5 mg/dL on day 14 and were without 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 ECOG PS (0-1 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.
• Select inclusion criteria:
  • Patients had locally advanced and unresectable or metastatic UC with measurable disease according to the RECIST version 1.1.
  • Patients had tumor tissues with 1 of the following FGFR3 gene mutations: R248C, S249C, G370C, Y373C OR 1 of the following FGFR gene fusions: FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7.¹⁵
  • Patients had disease progression during or following ≥1 line of prior systemic chemotherapy or ≤12 months of neoadjuvant or adjuvant chemotherapy.
  • Chemotherapy-naïve patients who were ineligible for cisplatin-based chemotherapy were also enrolled.
  • Prior immunotherapy (eg, immune checkpoint inhibitor) was permitted.
  • An ECOG PS of 0-2 was required.
• Select exclusion criteria:
  • Patients with persistently elevated phosphate levels above the ULN despite medical management, uncontrolled cardiovascular disease, brain metastases, or known HIV or hepatitis B or C infection were excluded.
• Primary endpoint: confirmed response rate according to RECIST version 1.1 among patients receiving selected regimen of BALVERSA 8 mg daily
  • Responses were assessed by both investigators and independent radiological review committee
• Secondary endpoints: PFS, response duration, OS, safety, response rate in biomarker-specific subgroups, and PK

Results in Patients Receiving BALVERSA 8 mg Once Daily

Patient Characteristics

Final Analysis⁴

• The final analysis included 101 patients; 2 patients were enrolled into the 8 mg once daily regimen after the clinical cutoff date for the primary analysis.
  • There were no notable changes in patient and disease baseline characteristics in the final analysis compared to the primary analysis.

Efficacy

Final Analysis⁴

• Final efficacy results for 101 patients enrolled in the 8 mg once daily regimen are described in the table below.

• 12-month and 24-month OS rates were 49% and 31%, respectively.
• OS was not impacted by age, sex, and most baseline disease characteristics (eg, hemoglobin level and renal function) whereas ECOG PS had a significant impact on OS (see table below).

Safety

Final Analysis^4,16

• The safety profile of BALVERSA after a median efficacy follow-up of 24 months (IQR [interquartile range]: 22.7-26.6) and a median treatment duration of 5.4 months (IQR: 2.8-9) remained consistent with the primary analysis as described above.
• Longer follow-up did not result in any new treatment-related AEs.
• Grade 3-4 treatment-emergent AEs (TEAEs) of any causality occurred in 71% (72/101) of patients; 53% (53/101) had events that were considered related to BALVERSA.
• 45% (45/101) of patients had serious AEs; 11% were related to BALVERSA, and no grade 4 TRAEs and no treatment-related deaths occurred.
• 16% (16/101) of patients had AEs leading to treatment discontinuation that were considered related to BALVERSA.
• 27% (27/101) of patients had CSR events; 85% (23/27) were grade 1 or 2.
  • At data cutoff, 63% (17/27) of CSR events had resolved; all 10 unresolved events were grade 1 or 2.
  • Median time to first incidence of CSR was 53 days (IQR: 32-100) for any-grade events and 94 days (IQR:72-154) for grade 3 events; 2/27 (7%) events occurred after 6 months.
  • Dose reduction, interruption, and discontinuation due to CSR occurred in 13% (13/101), 8% (8/101), and 3% (3/101) of patients, respectively.
    • Three patients had grade 3 CSR events that resolved or lessened in severity to grade 1 following dose reduction or interruption (n=2); or no dose modification (n=1).
    • One patient had grade 3 RPED, which initially resolved, but then recurred as a grade 2 event following dose reduction. BALVERSA was discontinued.

Additional Analyses

• Post hoc and additional analyses of the BLC2001 study have been published.^17-19

Additional Studies

NORSE Study

• NORSE (BLC2002; NCT03473743) is an ongoing, phase 1b/2, open-label, multicenter dose escalation and dose expansion study of BALVERSA plus cetrelimab (JNJ-63723283), an anti-programmed death 1 (PD-1) monoclonal antibody, in patients with metastatic or locally advanced UC and selected FGFR gene alterations. The primary endpoints for the phase 1b dose escalation portion are dose-limiting toxicity (DLT) and safety. The primary endpoints for the phase 2 dose expansion portion are overall response rate and safety. The study is expected to enroll 150 patients.⁵
• DLTs were not observed at any dose level in the phase 1b dose escalation study.²⁰ Evaluations of both BALVERSA and cetrelimab PK also indicated no drug interactions with the other drug.²¹ The most common TEAEs in the phase 1b evaluable patients (n=22) across all dose levels included stomatitis (73%), diarrhea and dry mouth (55% each), and hyperphosphatemia (46%).²⁰
• The recommended phase 2 dose (RP2D) was BALVERSA 8 mg PO daily, with uptitration to 9 mg based on serum phosphate levels, plus cetrelimab 240 mg IV every 2 weeks (Q2W).²⁰ Patients in the dose expansion (phase 2) study are randomized 1:1 to receive either BALVERSA alone or in combination with cetrelimab.⁶
• Preliminary findings from the phase 2 study in 37 efficacy-evaluable patients with newly diagnosed metastatic UC and FGFR alterations who were ineligible for cisplatin-based therapy suggest that BALVERSA plus cetrelimab may improve overall response rate compared to BALVERSA alone. The overall response rate was 68% (95% CI: 43-87) vs 33% (95% CI:13-59), respectively. Clinical activity was observed in both patients with high and low PD-(L)1 status.⁶
• Overall safety of BALVERSA plus cetrelimab in this phase 2 analysis was generally consistent with BALVERSA alone and aligned with the known safety profile of approved anti-PD-1 therapies; however, discontinuation of one or both therapies occurred more frequently in the BALVERSA plus cetrelimab arm than in the BALVERSA alone arm. Grade 3-4 TEAEs in 48 safety-evaluable patients occurred in 9 patients (38%) in the BALVERSA alone arm and in 12 patients (50%) in the BALVERSA plus cetrelimab arm.⁶

Phase 1b Study 

• Jain et al (2025; NCT04963153) reported interim results of an ongoing, phase 1b, single arm, multicenter, dose escalation and expansion study of BALVERSA plus enfortumab vedotin (EV), a monoclonal antibody, in patients with metastatic UC harboring somatic FGFR3/2 genetic alterations who have progressed after platinum and/or PD1/L1 inhibitor therapies.^7,8 
• The primary endpoints of the study are to identify the maximum tolerated dose (MTD), the recommended phase II dose (RP2D) of EV in combination with BALVERSA at 8 mg/day, and safety. The secondary endpoints are overall response rate, duration of response, progression free survival and overall survival. The study is expected to enroll 30 patients.⁷ 
• The following dose escalation was evaluated to identify the MTD and RP2D, please refer to Table: Dose Escalation of EV in combination with BALVERSA.

• The RP2D of EV was 1.25 mg/kg in combination with BALVERSA at 8 mg/day.⁸ 
• At the data cutoff, 9 patients were enrolled and finished DLT period. There were 6 patients who were enrolled in Dose Level 1 with 1 DLT (skin rash) and 3 in Dose Level 2 (no DLT).
• The most common (TRAEs) included hyperphosphatemia (88%), mucositis (88%), hypercalcemia (75%), high AST (75%), hand foot syndrome (75%), peripheral neuropathy (75%), alopecia (63%), diarrhea (63%), hypoalbuminemia (63%) and hypomagnesemia (63%).⁸ 
• Grade 3 TRAEs included hand foot syndrome (50%), anemia (17%), rash (17%), anorexia (17%) and paronychia (17%). Grade 4 Stevens-Johnson syndrome related to EV occurred in 1 patient.⁸ 
• Nine patients were evaluated for response and exhibited objective responses (100%), including 8 partial responses (PRs) and 1 complete response (CR).⁸ 
  • The mOS was not reported (NR) (95% CI, 17.1 months-NR) and mPFS 7.52 months (95% CI, 5.55-NR) with median follow up of 22.7 months. The mDOR is 5.49 months and median time to progression is 7.52 months.
• For information regarding ongoing clinical trials, please visit www.clinicaltrials.gov.

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 04 February 2025.