SUMMARY

THOR-2/BLC-2003 (NCT04172675) is an ongoing, phase 2, randomized, open-label, multicenter study evaluating the efficacy and safety of BALVERSA compared to investigator’s choice of therapy in patients with recurrent high-risk non-muscle-invasive bladder cancer (HR-NMIBC) and fibroblast growth factor receptor (FGFR) mutations or fusions; and who have received prior Bacillus Calmette-Guérin (BCG) therapy. The primary endpoint is recurrence-free survival (RFS). Efficacy and safety results for cohorts 2 and 3 (exploratory cohorts) have been published.^1,2

• Catto et al (2023)³ presented outcomes for patients with BCG-unresponsive HR-NMIBC with FGFR3/2 alterations who refused or were ineligible for cystectomy in THOR-2 exploratory cohort 2 after a median study follow-up of 14.8 months (n=16). Complete response (CR) rate was 93.8% (15/16 evaluable patients) (95% confidence interval [CI], 70-100) at 8 weeks, and 72.7% (8/11 evaluable patients) (95% CI, 39-94) at 32 weeks. The most common grade 1-2 treatment-emergent adverse events (TEAEs) included dry mouth, hyperphosphatemia, diarrhea, stomatitis, dysgeusia, and dry skin.
• Daneshmand et al (2023)⁴ presented outcomes from exploratory cohort 3 of the THOR-2 study after a median 10-month follow-up in patients with intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC) and FGFR alterations (n=18). CR was observed in 15 patients (83.3%), partial response (PR) was observed in 2 patients (11.1%), median time to response was 1.15 months, and 1 patient (5.6%) had high grade recurrence. In 17 responders, median duration of response (DOR) was 12.8 months, with 12 responses ongoing, 3 censored, and 2 ending with recurrence. The most common TEAEs included hyperphosphatemia, diarrhea, dry mouth, dry skin, and dysgeusia.
• Catto et al (2023)¹ presented efficacy and safety outcomes from THOR-2 cohort 1 (n=73) in patients with recurrent BCG-treated, papillary-only high-risk NMIBC (high-grade Ta/T1) and select FGFR alterations refusing or ineligible for radical cystectomy. Patients were randomized to receive either BALVERSA 6 mg once daily (QD) or chemotherapy (mitomycin C or gemcitabine). Median follow-up for RFS was 13.4 months for both treatment groups. Median RFS was not reached (NR) for BALVERSA (95% CI, 16.9 months-not estimable [NE]) and was 11.6 months (95% CI, 6.4-20.1) for chemotherapy, hazard ratio (HR) 0.28 (95% CI, 0.1-0.6). The 6-month and 12-month RFS rates (95% CI) were 96% (83.7-98.9) and 77% (60-87.4) for BALVERSA vs 73% (50.1-87.1) and 41% (18.9-61.7) for chemotherapy, respectively. Safety results were generally consistent with known profiles for BALVERSA and chemotherapy.

CLINICAL STUDY

Catto et al (2023)¹ presented efficacy and safety outcomes from THOR-2 cohort 1 (n=73) in patients with recurrent BCG-treated, papillary-only high-risk NMIBC (high-grade Ta/T1) and select FGFR alterations refusing or ineligible for radical cystectomy.

Patient Characteristics

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

Efficacy

• Median follow-up for RFS was 13.4 months in both BALVERSA and chemotherapy treatment groups.
• Efficacy outcomes from cohort 1 are summarized in Table: Cohort 1 RFS.
• At clinical cutoff, 25 RFS events had occurred (BALVERSA, n=11; chemotherapy, n=14).
• Median RFS was NR for patients receiving BALVERSA (95% CI, 16.9 months-NE) and 11.6 months (95% CI, 6.4-20.1) for patients receiving chemotherapy (HR, 0.28 [95% CI, 0.1-0.6]).
• The 6-month and 12-month RFS rates (95% CI) were 96% (83.7-98.9) and 77% (60‑87.4) for BALVERSA vs 73% (50.1-87.1) and 41% (18.9-61.7) for chemotherapy, respectively.
• RFS benefit for BALVERSA was generally consistent across subgroups of prior BCG therapy (experienced vs unresponsive) and tumor stage (Ta vs T1).
• Nine (38%) patients crossed over from chemotherapy to receive BALVERSA.

Safety

• The median duration of exposure was 9 months (range, 1-23.1) with BALVERSA and 6.4 months (range, 1.1-14.2) with chemotherapy.
• The most frequent grade ≥3 treatment-related adverse events (AEs) were:
  • Stomatitis (10%), nail dystrophy (4%), and glossitis (4%) in the BALVERSA group.
  • Elevated alanine aminotransferase (4%) in the chemotherapy group.
• Serious AEs occurred in 11 (22%) and 3 (13%) patients in the BALVERSA and chemotherapy groups, respectively.
• No TEAEs leading to death were reported.
  • After treatment discontinuation, 3 deaths occurred in the BALVERSA group (disease progression, n=2; secondary malignancy, n=1). All 3 were deemed unrelated to treatment.
• Any-cause AEs led to treatment discontinuation in 14 (29%) patients in the BALVERSA group (the most frequent AE leading to discontinuation was stomatitis [6%]) and no patients in the chemotherapy group.
• AEs based on the known safety profile of BALVERSA included:
  • Nail disorders (78%), hyperphosphatemia (74%), eye disorders (excluding central serous retinopathy, 59%), skin disorders (51%), dry mouth (47%), mucositis (41%), and central serous retinopathy (39%).
    • Most central serous retinopathy AEs were grade 1/2; 2 patients in the BALVERSA group reported grade 3 events (at clinical cutoff, events had resolved in 1 patient and were resolving in the other patient).
    • Central serous retinopathy AEs (central serous retinopathy, detachment of macular retinal pigment epithelium, maculopathy, and macular detachment) led to treatment discontinuation in 6 patients.
• Any-cause AEs are listed by preferred term and worst toxicity grade that was reported in >15% of the patients in either treatment group in Table: Cohort 1 TEAEs. For patients who crossed over from chemotherapy to BALVERSA treatment, this table summarizes AEs before crossover.

Catto et al (2023)³ reported efficacy and safety results from cohort 2 of the THOR-2 study in patients with BCG-unresponsive carcinoma in situ (CIS) and FGFR alterations, with or without papillary disease (n=16).

Patient Characteristics

• At data cutoff (June 2023; median study follow-up 14.8 months), 16 patients (median age: 68.5 years [range, 35-83]; tumor stage: 100% CIS) received BALVERSA 6 mg orally (PO) QD for a median duration of 6.7 months (range, 1.9-18.6).
• The demographics and baseline characteristics of patients in cohort 2 are included in Table: Expansion Cohort 2 Select Demographics and Baseline Characteristics.

Efficacy

• CR rate in disease-evaluable patients at 8 weeks was seen in 15 out of 16 (93.8%) patients (95% CI, 70-100).
  • Disease-evaluable at 8 weeks includes only patients that have met any of the following criteria:
    • A disease evaluation on or after the week 8 window.
    • Reports recurrence, progression, death, or study withdrawal at any time.
    • Starts subsequent anticancer therapy at any time.
• CR rate in disease-evaluable patients at 32 weeks was seen in 8 out of 11 (72.7%) patients (95% CI, 39-94).
  • Disease-evaluable at 32 weeks includes only patients that have met any of the following criteria:
    • A disease evaluation on or after the 32-week window.
    • Reports recurrence, progression, death, or study withdrawal at any time.
    • Starts subsequent anticancer therapy at any time.
• Median DOR was NR, with 12 responses ongoing.

Safety

• The incidence of cohort 2 TEAEs is summarized in Table: Cohort 2 TEAEs.
• Common TEAEs were mostly grade 1/2:
  • Dry mouth (56.3%; n=9), hyperphosphatemia (56.3%; n=9), diarrhea (56.3%; n=9), stomatitis (43.8%; n=7), dysgeusia (43.8%; n=7), dry skin (43.8%; n=7).
• One (6.3%) patient reported grade 2 treatment-related retinal detachment which led to treatment discontinuation and 1 (6.3%) patient had grade 1 treatment-related subretinal fluid; both resolved.
• Six (37.5%) patients had grade ≥3 treatment-related TEAEs (onychomadesis, acute kidney injury, elevated alanine aminotransferase, chronic kidney disease, dry mouth, hypotension, nail disorders, stomatitis, and sepsis).
• One (6.3%) patient discontinued treatment due to treatment-related TEAE.
• No treatment-related deaths occurred.
• The most common cohort 2 treatment related TEAEs are presented in Table: Cohort 2 Most Common Treatment-Related TEAEs.

Daneshmand et al (2023)⁴ reported efficacy and safety results from cohort 3 of the THOR-2 study for patients with IR-NMIBC with FGFR alterations treated with BALVERSA.

Patient Characteristics

• At data cutoff (June 2023; median follow-up 10 months), 18 patients were enrolled (median age: 63.5 years [range, 47-77]; tumor stage: n=13 Ta, n=5 not staged) and received BALVERSA 6 mg PO QD for median duration 7.1 months (range, 0.7-17.4).
• The demographics and baseline characteristics of patients in cohort 3 are included in Table: Expansion Cohort 3 Select Demographics and Baseline Characteristics.

Efficacy

• Fifteen (83.3%) patients had CR (95% CI, 59-96); 2 (11.1%) patients had PR; 1 (5.6%) patient had high grade recurrence.
  • Median time to response was 1.15 months.
• In 17 responders, median DOR was 12.8 months, with 12 responses ongoing, 3 censored, and 2 ending with recurrence (1 low-grade; 1 high-grade).

Safety

• The incidence of cohort 3 TEAEs is summarized in Table: Cohort 3 Safety Summary.
• Most common TEAEs:
  • Hyperphosphatemia (100%; n=18), diarrhea (83.3%; n=15), dry mouth (72.2%; n=13), dry skin (50%, n=9), dysgeusia (50%; n=9).
• Grade 3 TEAEs:
  • Abdominal pain (n=1), diarrhea (n=1), dysuria (n=1), and gastritis (n=1).
• Seven grade 1 treatment-related central serous retinopathy events were reported in 3 (16.7%) patients.
  • The event resolved in 1 patient and was ongoing in 2 patients.
• Three (16.7%) patients discontinued BALVERSA due to treatment-related TEAEs.
• No deaths were reported.
• The most common cohort 3 treatment related TEAEs are presented in Table: Cohort 3 Most Common Treatment-Related TEAEs.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, DERWENT Drug File (and/or other resources, including internal/external databases) was conducted on 07 November 2024.