Summary Basis of Decision for Balversa

Clinical Pharmacology

The medicinal ingredient in Balversa, erdafitinib, is an oral pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor that binds to and inhibits all FGFR family members, FGFR 1, 2, 3 and 4.

Erdafitinib demonstrated dose-independent pharmacokinetic properties across the dose range of 0.5 to 12 mg. According to a population pharmacokinetic model, the typical volume of distribution was estimated to be 18.9 L, demonstrating limited distribution outside the extravascular space. As erdafitinib is a drug with low extraction ratio, its clearance is dependent on plasma protein binding influences, and the total apparent oral clearance was approximately 0.2 L/h. The mean effective half-life was 76.4 hours. Steady state is expected to be achieved after approximately 16 days. At steady state, erdafitinib demonstrated approximately 5.1-fold accumulation in plasma area under the concentration-time curve from time 0 to 24 hours (AUC_0-24).

No clinically meaningful differences in the pharmacokinetics of erdafitinib were observed based on age, sex, race, body weight, mild or moderate renal impairment or mild hepatic impairment.

In a population pharmacokinetic/pharmacodynamic model, a slope model with power exponent to link free erdafitinib concentrations at biophase with serum phosphate concentrations was demonstrated. This model was used to demonstrate that erdafitinib-induced serum phosphate increase is a surrogate of clinical efficacy, as patients with serum phosphate concentrations in the target window (5.5-7.0 mg/dL) have a significant likelihood of achieving a clinical response.

Based on evaluation of QTc interval in an open-label, dose-escalation and dose-expansion study in 187 patients with cancer, erdafitinib had no large effect (i.e., >20 ms) on the QTc interval.

For further details, please refer to the Balversa Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Balversa for the treatment of locally advanced or metastatic urothelial carcinoma was based on evaluation of data from a multicentre, open-label, single-arm Phase II study (BLC2001). The study enrolled 210 patients, whose tumours had specific FGFR genetic alterations (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, as determined by a clinical trial assay performed at a central laboratory).

The key efficacy conclusions were based on data derived from 87 patients who had disease progression during or following at least one line of prior chemotherapy. These patients received Balversa at a starting dose of 8 mg once daily, with a dose increase to 9 mg once daily, based on tolerability, in patients whose serum phosphate levels, measured between days 14 and 17, were below the target of 5.5 mg/dL. A dose increase occurred in 41% of patients. Balversa was administered until disease progression or unacceptable toxicity.

The median duration of treatment was 5.3 months, and the median duration of efficacy follow-up was 11.3 months. The follow-up duration was considered reasonable for efficacy assessment in order to establish promising evidence of efficacy of Balversa in the target patient population, as patients with relapsed/refractory metastatic urothelial carcinoma have a poor prognosis, with a five-year survival rate of only approximately 5%.

The primary efficacy endpoint was objective response rate assessed by the investigator using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Additionally, if the primary objective (objective response rate higher than 25%) was achieved as per investigator assessment, independent radiologic review committee (IRRC) assessment was also to be performed.

The investigator-assessed objective response rate was determined to be 40.2% (95% CI: 29.9%, 50.5%), including three complete responses. The objective response rate as determined by the IRRC was 32.2% (95% CI: 22.4%, 42%), including two complete responses. Of note, for urothelial cancer there are known limitations and challenges with treatment response assessment based only on RECIST criteria, as only the longest tumour diameter is measured. Measurement of bladder wall lesions and infiltrative bladder lesions can lead to large inter- and intraobserver variations, especially for tumours with irregular shape. Accordingly, the discordance observed between the investigator assessment and the IRRC assessment of the objective response rate is considered acceptable. The results from both assessments have been included in the Balversa Product Monograph.

The detected responses appeared durable, with a median duration of response of 5.6 months (95% CI: 4.2 months, 7.0 months), as assessed by the investigator. Subgroup analyses for the different FGFR genetic alterations demonstrated clinical responses in patients with tumours harbouring FGFR3 point mutations and FGFR3 fusions, whereas no responses were observed in patients whose tumours had FGFR2 fusions. However, there were too few of these patients enrolled in Study BLC2001 to conclude that Balversa lacks efficacy in these rare molecular subsets. Based on the totality of evidence, including biological feasibility, data from in vitro studies, and results from study patients with other FGFR genetic alterations, it was considered reasonable to conclude there is promising evidence of efficacy for the recommended Balversa indication to encompass all of the genetic alterations harboured by patients enrolled in Study BLC2001.

The promising efficacy results remain to be confirmed in the ongoing, randomized Phase III confirmatory trial, which enrolled patients based on the same molecular eligibility criteria used for Study BLC2001.

Indication

The New Drug Submission for Balversa was filed by the sponsor with the following indication:

• Balversa is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma, whose tumours have certain fibroblast growth factor receptor (FGFR) genetic alterations, who have disease progression during or following at least one line of prior chemotherapy including within 12 months of neoadjuvant or adjuvant chemotherapy.

Upon review of the submission, Health Canada revised the proposed indication to reflect the FGFR genetic alterations from Study BLC2001. Furthermore, the revised indication included a caveat statement to summarize the limitations of the clinical effectiveness data derived from a single-arm Phase II trial and highlighted the recommendation for confirmation of a susceptible FGFR genetic alteration prior to initiating treatment. Accordingly, Health Canada approved the following indication:

• Balversa is indicated for the treatment of adult 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.
• Clinical effectiveness of Balversa is based on objective response rates and duration of response from a single-arm Phase II trial in patients with specific genetic alterations in FGFR2 or FGFR3.
• Treatment with Balversa should be initiated following confirmation of a susceptible FGFR genetic alteration using a validated test.

For more information, refer to the Balversa Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety of Balversa was evaluated in 87 patients from the Phase II Study BLC2001 (described in the Clinical Efficacy section).

All patients experienced at least one treatment-emergent adverse event. Dose interruptions and dose reductions due to treatment-emergent adverse events occurred in 68% and 53% of patients, respectively. The treatment-emergent events most commonly leading to dose modifications (interruptions and/or reductions) included hyperphosphatemia, stomatitis, eye disorders, and palmar-plantar erythrodysaesthesia syndrome (PPES).

Grade 3-4 adverse events were reported in 67% of patients, and serious adverse events were reported in 41% of patients. There was a fatal adverse event (acute myocardial infarction) in one patient.

Hyperphosphatemia was the treatment-emergent adverse event reported with the highest frequency (76%). Other common treatment-emergent adverse events reported with a frequency higher than 20% were stomatitis, diarrhea, dry mouth, decreased appetite, dysgeusia, dry skin, fatigue, constipation, alopecia, PPES, asthenia, nausea, onycholysis, dry eye, and anemia.

The most common Grade 3-4 adverse events were stomatitis, nail dystrophy, PPES, paronychia, nail disorder, keratitis, onycholysis, and hyperphosphatemia.

Central serous retinopathy (CSR) adverse events were reported in 25% of patients. The most commonly reported CSR events were chorioretinopathy, retinal detachment, and detachment of retinal pigment epithelium.

The safety database was considered sufficiently large to characterize the overall safety profile of single-agent Balversa in the target patient population, although the number of patients enrolled in the study was not large enough to allow detection of rare adverse events. Additionally, due to the single-arm study design, a causal association between single-agent Balversa and reported adverse events could not be established.

Overall, the safety profile of Balversa is considered acceptable. The adverse events can be adequately managed by dose reduction, temporary treatment discontinuation and/or standard medical care. The Balversa Product Monograph includes recommendations regarding adverse event monitoring and dose modifications, as well as reference to physician educational materials pertaining to the diagnosis and management of CSR.

For more information, refer to the Balversa Product Monograph, approved by Health Canada and available through the Drug Product Database.