SUMMARY

• No clinical studies designed to prospectively evaluate sequencing strategies for BALVERSA and checkpoint inhibitors in the treatment of urothelial carcinoma (UC) were identified in the published literature.
• 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 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.^1,2
  • To provide the most relevant information, the summary below is limited to results from cohort 1 of the THOR study in patients who received prior chemotherapy with anti-programmed death ligand-1 (anti-PD-[L]1) in a combination or maintenance setting and were subsequently randomized to receive BALVERSA or chemotherapy.^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.
• BLC2001 (NCT02365597) is an ongoing, phase 2, open-label, multicenter study of BALVERSA in patients with locally advanced and unresectable or metastatic UC and prespecified FGFR genetic alterations (FGFR3 mutation or FGFR2/3 fusion). Of the 99 patients in the study, 22 received prior immunotherapy (eg, checkpoint inhibitors).³
• A retrospective analysis of data collected from patients who were randomized to receive BALVERSA 8 mg once daily in the BLC2001 study evaluated clinical responses to prior and subsequent therapies in FGFR-positive patients with metastatic UC, including checkpoint inhibitors. Patients who received immunotherapy after BALVERSA treatment had a higher ORR and disease control rate (DCR) than patients who received chemotherapy after BALVERSA.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 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 (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 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 (CSR) 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 [FACT-B1], Patient-Global Impression of Severity [PGIS], European Quality of Life-5 Dimensions-5 Levels Questionnaire [EQ-5D-5L]), safety, and pharmacokinetics

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: THOR Cohort 1 Select Baseline Demographics and Disease Characteristics.

• Details of prior systemic therapies of patients in cohort 1 are included in Table: THOR Cohort 1 Patients with Prior Systemic Therapy.

Efficacy: Cohort 1

• 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.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, 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 1

• Treatment-related adverse events (TRAEs) and AEs of interest from the safety population of cohort 1 are reported in Table: THOR Cohort 1 TRAEs in the Safety Population and Table: THOR Cohort 1 AEs of Interest in the Safety Population, respectively.
• 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, 0.2-38.2).
  • 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, 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, 0.03-27.0).
  • 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.

Phase 2 Study in Patients with Locally Advanced or Metastatic UC (BLC2001)

BLC2001 is an ongoing, phase 2, open-label, multicenter study evaluating the use of BALVERSA in patients with locally advanced and unresectable metastatic UC who had prespecified FGFR genetic alterations (FGFR3 mutation or FGFR2/3 fusion) and experienced disease progression during or following ≥1 line of prior systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy, or were chemotherapy-naïve due to cisplatin ineligibility. Patients had tumor tissues with one of the following FGFR3 gene mutations: R248C, S249C, G370C, Y373C or one of the following FGFR gene fusions: FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7.³

• Of the 99 patients in the BLC2001 study, 22 patients received prior immunotherapy (eg, checkpoint inhibitors).
• The efficacy and safety analyses were described in patients who received initial BALVERSA dosing of 8 mg once daily, with uptitration to 9 mg once daily if serum phosphate levels assessed by day 14 were below a target of 5.5 mg/dL and there were no TRAEs. Efficacy and safety results were not reported separately for patients who received prior immunotherapy.

Retrospective Analysis

Siefker-Radtke et al (2019)⁴ conducted a retrospective analysis of data collected from patients who were randomized to receive BALVERSA 8 mg once daily in the BLC2001 study to evaluate clinical responses to prior and subsequent therapies in FGFR-positive patients with metastatic UC, including checkpoint inhibitors.

Study Design/Methods

• Prior systemic therapies received for metastatic or surgically unresectable UC and subsequent lines of treatment to BALVERSA were reported by the investigator.
• Study endpoints: duration of prior treatment, time to disease progression (TTP); response to prior and subsequent therapies (ORR and DCR [defined as the percentage of patients with complete, partial, and stable disease responses]); PFS; and OS

Results

Patient Characteristics

• Of 210 eligible patients, 99 were enrolled in the BALVERSA 8 mg (uptitration to 9 mg) once daily group.
• A total of 88/99 (88.9%) patients had received prior systemic therapies, including 22 patients who received prior immunotherapy: pembrolizumab or nivolumab, n=4 (4%); and atezolizumab, durvalumab, or avelumab, n=18 (18.2%).
  • Of these patients, 1 patient received durvalumab+tremelimumab and 1 received atezolizumab+anti-CSF1R.
• A total of 34/99 (34.3%) patients received subsequent systemic therapies following treatment with BALVERSA, including 15 (15.2%) who received subsequent immunotherapy: atezolizumab (n=2), pembrolizumab (n=3), nivolumab (n=5), durvalumab (n=3), and ipilimumab (n=2).

Efficacy

• The median duration of BALVERSA treatment in the BLC2001 study was 5.3 months.
• Treatment with BALVERSA showed a confirmed ORR of 40% (95% CI, 30.7-50.1) per investigator-assessment.³

Outcomes for Prior Therapies

• The median duration of prior immunotherapy was 8.43 months (95% CI, 4.63-14.46).
• Median TTP (calculated for patients with an available date of progression prior to study entry) on prior immunotherapy (n=20) was 5.55 months (95% CI, 2.30-11.53).
• ORR and DCR for the 22 patients who received any prior immunotherapy was 5% and 50%, respectively.

Outcomes for Subsequent Therapies

• Patients who received immunotherapy after BALVERSA treatment had higher ORR and DCR than patients who received chemotherapy after BALVERSA. Response rates with subsequent immunotherapies are included in Table: Response Rates with Subsequent Immunotherapies.

• The median PFS and OS in the BLC2001 study, respectively, were 5.5 months (95% CI, 4.2-6.0) and 13.8 months (95% CI, 9.8-not reached).
• Patients who received subsequent anticancer therapy after BALVERSA treatment had a median PFS of 2.27 months (95% CI, 0.79-2.86) and median OS of 3.52 months (95% CI, 2.04-8.90 months). Data were not delineated for immunotherapy.

Safety

• 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.