Regulatory Decision Summary for Balversa

One single-arm Phase 2 trial, performed in the target patient population, provided the primary efficacy and safety data for the proposed indication of Balversa. The study enrolled 87 patients with locally advanced or metastatic urothelial carcinoma who had disease progression during or following at least one prior chemotherapy regimen. Patients were treated at a daily dose of 8 mg, uptitrated to 9 mg, based on serum phosphate levels below the target of 5.5-7.0 mg/dL when assessed between days 14 and 17 of therapy.

Erdafitinib was administered until disease progression or unacceptable toxicity. After a median duration of treatment of 5.3 months, and a median duration of follow-up of 11 months, investigator-assessed Overall Response Rate (ORR) was determined to be 40.2% (95% Confidence Interval (CI): 29.9%, 50.5%), including 3 Complete Responses (CRs). The ORR as determined by an independent committee was supportive of the investigator assessment.

The detected responses appeared durable, with a median duration of response (DoR) of 5.6 months (95% CI: 4.2 months, 7.0 months), as assessed by the investigator. Subgroup analyses of patients in various risk categories (including those with liver metastases) indicated a consistently favourable ORR, and suggested a clinically meaningful benefit for the general patient population in the clinical setting. Subgroup analyses for the different FGFR genetic alterations demonstrated clinical responses in patients harboring FGFR3 point mutations and FGFR3 fusions but no responses in patients with FGFR2 fusions. However, there were too few of these patients enrolled in Study BLC2001 (N = 6) to conclude that erdafitinib has a lack of efficacy in these (rare) molecular subsets. Based on the totality of evidence, including biological plausibility, data from in vitro studies and non-clinical xenograft models, as well as reports of prolonged stable disease (SD), and partial responses in other doses and/or cancer types, it is reasonable and acceptable to conclude there is promising evidence of efficacy for the recommended Balversa indication to include all genetic alterations harboured by patients enrolled in Study BLC2001.

The primary safety data from the Phase 2 Study BL2001 (N = 87), and integrated safety data from across the studies in this submission (N = 164), revealed a consistent safety profile. Only the data from the 87 patients from Study BLC2001 were included in the safety labelling in the final Balversa Product Monograph. In the pivotal Study BLC2001, the most common adverse events were hyperphosphatemia, stomatitis, dry mouth, decreased appetite, dry skin, alopecia, palmar-plantar erythrodysaesthesia syndrome (PPES), dry eye, onycholysis, paronychia, and nail dystrophy. Serious adverse reactions occurred in 41% of patients, including eye disorders in 10% of patients. Grade 3-4 TEAEs were experienced by 67% of patients, most commonly stomatitis, nail dystrophy, PPES, paronychia, nail disorder, keratitis, onycholysis, and hyperphosphatemia. Dose interruptions and dose reductions due to adverse events occurred in 68% and 53% of patients, respectively, most commonly due to hyperphosphatemia, stomatitis, eye disorders, and PPES. Myocardial infarction was the only adverse event with a fatal outcome (1 patient). The most common Treatment-emergent adverse event (TEAE) was hyperphosphatemia, in 77% of patients, which was managed by dose interruption (23%), dose reduction (9%), and phosphate binders (34%) when necessary. Phosphate elevations were not associated with any clinical sequelae (no cardiovascular, musculoskeletal, renal, or metabolic dysfunction).

Central serous retinopathy (CSR) occurred in 25% of patients in Study BLC2001 at the 8 mg daily dose. The most commonly reported CSR events were chorioretinopathy, retinal detachment, and detachment of retinal pigment epithelium. It was primarily managed with dose interruption (9%) and dose reduction (14%), and 3% of patients permanently discontinued treatment due to CSR. Baseline ophthalmological exams and monthly monitoring for eye disorders were also important risk mitigation measures in the pivotal study, and will be included as recommendations in the final Product Monograph.

Overall, the safety profile of erdafitinib is considered acceptable, with adverse events typically manageable through the use of erdafitinib dose reduction, temporary treatment discontinuation and/or standard medical care. Appropriate labelling in the final Balversa Product Monograph, including recommendations regarding adverse event monitoring and dose modifications, as well as reference to physician educational materials pertaining to the diagnosis and management of CSR, is required to adequately manage the risks associated with Balversa therapy.

Together, the data from Study BLC2001 are concluded to provide promising evidence of clinical effectiveness and demonstrate a favourable benefit-risk profile for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose tumours have susceptible fibroblast growth factor receptor (FGFR)2 or FGFR3 genetic alterations and who have disease progression during or following at least one line of prior chemotherapy, including within 12 months of neoadjuvant or adjuvant chemotherapy. These data must be confirmed in the ongoing randomized Phase 3 Study BLC3001.