Balversa (Erdafitinib)

BALVERSA is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC) with susceptible

Select patients for therapy based on an FDA-approved companion diagnostic for BALVERSA

[see

2.1 Patient Selection

Select patients for the treatment of locally advanced or metastatic urothelial carcinoma with BALVERSA based on the presence of susceptible

FGFR3

genetic alterations in tumor specimens as detected by an FDA-approved companion diagnostic

[see Clinical Studies (14.1)]

.

Information on FDA-approved tests for the detection of

FGFR3

genetic alterations in urothelial cancer is available at: http://www.fda.gov/CompanionDiagnostics.

and

14.1 Urothelial Carcinoma with Susceptible

FGFR3

Genetic Alterations

The efficacy of BALVERSA was evaluated in Study BLC3001 (NCT03390504) Cohort 1, a randomized, open-label, multicenter study in which 266 patients with advanced urothelial cancer harboring selected

FGFR3

alterations were randomized 1:1 to receive BALVERSA (8 mg with titration up to 9 mg) versus chemotherapy (docetaxel 75 mg/m²once every 3 weeks or vinflunine 320 mg/m²once every 3 weeks) until unacceptable toxicity or progression. Randomization was stratified by region (North America vs. Europe vs. rest of world), Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 vs. 2) and visceral or bone metastases (yes vs. no). All patients needed to have had disease progression after 1 or 2 prior treatments, at least 1 of which included a PD-1 or PD-L1 inhibitor.

FGFR3

genetic alterations were identified from tumor tissue in a central laboratory by the QIAGEN

therascreen

^®

FGFR

RGQ RT-Polymerase Chain Reaction (PCR) kit in 75% of patients while the remainder (25%) were identified by local next generation sequencing (NGS) assays.

The major efficacy outcome measures were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) assessed by investigator using RECIST (Response Evaluation Criteria in Solid Tumors) Version 1.1.

The median age was 67 years (range: 32 to 86 years) and 71% were male; 54% were White, 29% Asian, 0.4% Black, 0.4% multiple races, 16% not reported; 2% were Hispanic/Latino; and baseline ECOG performance status was 0 (43%), 1 (48%), or 2 (9%). Eighty-one percent of patients had

FGFR3

mutations, 17% had fusions, and 2% had both mutations and fusions. Ninety-five percent of patients had pure transitional cell carcinoma (TCC) and 5% had TCC with other histologic variants. The primary tumor location was the upper tract for 33% of subjects and lower tract for 67%; 74% of patients had visceral or bone metastases. Eighty-eight percent of patients received platinum-containing chemotherapy previously. PD-1 or PD-L1 inhibitor therapy was received only in the neoadjuvant or adjuvant setting in 7% of patients.

Statistically significant improvements in OS, PFS, and ORR were demonstrated for BALVERSA compared with chemotherapy.

Table 9 and Figures 1 and 2 summarize the efficacy results for BLC3001 Cohort 1.

Table 9: Efficacy Results for Study BLC3001 Cohort 1

	BALVERSA N=136	Chemotherapy N=130
All p-values reported are 2-sided and compared with 0.019 of the allocated alpha for the interim analysis. ORR = confirmed objective response (CR + PR) CI = Confidence Interval
Overall Survival (OS)
Number of events (%)	77 (56.6%)	78 (60.0%)
MedianBased on Kaplan-Meier estimates, months (95% CI)	12.1 (10.3, 16.4)	7.8 (6.5, 11.1)
Hazard ratioBased on an unstratified Cox proportional hazard model(95% CI)	0.64 (0.47, 0.88)
p-valueBased on an unstratified log-rank test	0.0050
Progression-free survival (PFS)
Number of events (%)	101 (74.3%)	90 (69.2%)
Median , months (95% CI)	5.6 (4.4, 5.7)	2.7 (1.8, 3.7)
Hazard ratio (95% CI)	0.58 (0.44, 0.78)
p-value	0.0002
Objective response rate (ORR)
ORR (95% CI)	35.3% (27.3, 43.9)	8.5% (4.3, 14.6)
p-valuep-value is estimated using Cochran-Haenszel (CMH) test with ECOG performance status (0 or 1 vs 2) as a stratification factor.	<0.001
Complete response, CR (%)	5.1%	0.8%
Partial response, PR (%)	30.1%	7.7%

Figure 1: Kaplan-Meier Plot of Overall Survival (Study BLC3001 Cohort 1)

Figure 2: Kaplan-Meier Plot of Progression-free Survival (Study BLC3001 Cohort 1)

Study BLC3001 Cohort 2

Study BLC3001 (NCT03390504) Cohort 2 was a multicenter, open-label, randomized study in 351 patients with locally advanced or metastatic urothelial carcinoma with selected

FGFR3

alterations who received 1 prior line of systemic therapy and no prior PD-1 or PD-L1 inhibitor. Patients were randomized 1:1 to receive BALVERSA (8 mg with titration up to 9 mg) or pembrolizumab 200 mg every 3 weeks. The study did not meet its major efficacy outcome measure for superiority of OS at the pre-specified final analysis. The OS hazard ratio (HR) was 1.18 (95% CI: 0.92, 1.51; p=0.18), median 10.9 (95% CI: 9.2, 12.6) months for BALVERSA versus 11.1 (95% CI: 9.7, 13.6) months for pembrolizumab

[see Indications and Usage (1)]

.

Study BLC2001

Study BLC2001 (NCT02365597) was a multicenter, open-label, single-arm study to evaluate the efficacy and safety of BALVERSA in patients with locally advanced or metastatic urothelial carcinoma (mUC).

FGFR

mutation status for screening and enrollment of patients was determined by a clinical trial assay (CTA). The efficacy population consists of a cohort of eighty-seven patients who were enrolled in this study with disease that had progressed on or after at least one prior chemotherapy and that had at least 1 of the following genetic alterations:

FGFR3

gene mutations (

R248C

,

S249C

,

G370C

,

Y373C

) or

FGFR

gene fusions (

FGFR3-TACC3

,

FGFR3-BAIAP2L1

,

FGFR2-BICC1

,

FGFR2-CASP7

), as determined by the CTA performed at a central laboratory. Tumor samples from 69 patients were tested retrospectively by the QIAGEN

therascreen

^®

FGFR

RGQ RT-PCR Kit, which is the FDA-approved test for selection of patients with mUC for BALVERSA.

Patients received a starting dose of BALVERSA at 8 mg once daily with a dose increase to 9 mg once daily in patients whose serum phosphate levels were below the target of 5.5 mg/dL between days 14 and 17; a dose increase occurred in 41% of patients. BALVERSA was administered until disease progression or unacceptable toxicity. The major efficacy outcome measures were ORR and duration of response (DoR), as determined by blinded independent review committee (BIRC) according to RECIST v1.1.

The median age was 67 years (range: 36 to 87 years), 79% were male, and 74% were Caucasian. Most patients (92%) had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Sixty-six percent of patients had visceral metastases. Eighty-four (97%) patients received at least one of cisplatin or carboplatin previously. Fifty-six percent of patients only received prior cisplatin-based regimens, 29% received only prior carboplatin-based regimens, and 10% received both cisplatin and carboplatin-based regimens. Three (3%) patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy only. Twenty-four percent of patients had been treated with prior anti PD-L1/PD-1 therapy.

Efficacy results are summarized in Table 10 and Table 11. ORR was 32.2%. Responders included patients who had previously not responded to anti PD-L1/PD-1 therapy.

Table 10: Efficacy Results

Endpoint	BIRCBIRC: Blinded Independent Review CommitteeAssessment
	N=87
ORR = CR + PR CI = Confidence Interval
ORR (95% CI)	32.2% (22.4, 42.0)
Complete response (CR)	2.3%
Partial response (PR)	29.9%
Median DoR in months (95% CI)	5.4 (4.2, 6.9)

Table 11: Efficacy Results by FGFR Genetic Alteration

	BIRCBIRC: Blinded Independent Review CommitteeAssessment
ORR = CR + PR CI = Confidence Interval
FGFR3 Point Mutation	N=64
ORR (95% CI)	40.6% (28.6, 52.7)
FGFR3 FusionBoth responders had FGFR3-TACC3_V1 fusion,One patient with a FGFR2-CASP7/FGFR3-TACC3_V3 fusion is reported in both FGFR2 fusion and FGFR3 fusion above	N=18
ORR (95% CI)	11.1% (0, 25.6)
FGFR2 Fusion	N=6
ORR	0

]

• Confirm the presence of
  
  FGFR3
  genetic alterations in tumor specimens prior to initiation of treatment with BALVERSA. (
  
  2.1 Patient Selection

  Select patients for the treatment of locally advanced or metastatic urothelial carcinoma with BALVERSA based on the presence of susceptible

  FGFR3

  genetic alterations in tumor specimens as detected by an FDA-approved companion diagnostic

  [see Clinical Studies (14.1)]

  .

  Information on FDA-approved tests for the detection of

  FGFR3

  genetic alterations in urothelial cancer is available at: http://www.fda.gov/CompanionDiagnostics.
  )
  
• Recommended initial dosage: 8 mg orally once daily with a dose increase to 9 mg daily if criteria are met. (
  
  2.2 Recommended Dosage and Schedule

  The recommended starting dose of BALVERSA is 8 mg (two 4 mg tablets) orally once daily, with a dose increase to 9 mg (three 3 mg tablets) once daily based on tolerability, including hyperphosphatemia, at 14 to 21 days

  [see Dosage and Administration (2.3)].

  Swallow tablets whole with or without food. If vomiting occurs any time after taking BALVERSA, the next dose should be taken the next day. Treatment should continue until disease progression or unacceptable toxicity occurs.

  If a dose of BALVERSA is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule for BALVERSA the next day. Extra tablets should not be taken to make up for the missed dose.

  Dose Increase based on Serum Phosphate Levels

  Assess serum phosphate levels 14 to 21 days after initiating treatment. Increase the dose of BALVERSA to 9 mg once daily if serum phosphate level is < 9.0 mg/dL and there are no ocular disorders or Grade 2 or greater adverse reactions. If the phosphate level is 9.0 mg/dL or higher follow the relevant dose modifications in Table 2. Monitor phosphate levels monthly for hyperphosphatemia

  [see Pharmacodynamics (12.2)]

  .
  )
  
• Swallow whole with or without food. (
  
  2.2 Recommended Dosage and Schedule

  The recommended starting dose of BALVERSA is 8 mg (two 4 mg tablets) orally once daily, with a dose increase to 9 mg (three 3 mg tablets) once daily based on tolerability, including hyperphosphatemia, at 14 to 21 days

  [see Dosage and Administration (2.3)].

  Swallow tablets whole with or without food. If vomiting occurs any time after taking BALVERSA, the next dose should be taken the next day. Treatment should continue until disease progression or unacceptable toxicity occurs.

  If a dose of BALVERSA is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule for BALVERSA the next day. Extra tablets should not be taken to make up for the missed dose.

  Dose Increase based on Serum Phosphate Levels

  Assess serum phosphate levels 14 to 21 days after initiating treatment. Increase the dose of BALVERSA to 9 mg once daily if serum phosphate level is < 9.0 mg/dL and there are no ocular disorders or Grade 2 or greater adverse reactions. If the phosphate level is 9.0 mg/dL or higher follow the relevant dose modifications in Table 2. Monitor phosphate levels monthly for hyperphosphatemia

  [see Pharmacodynamics (12.2)]

  .
  )
  

Tablets: 3 mg, 4 mg, and 5 mg. (

• Lactation: Advise not to breastfeed. (
  
  
  8.2 Lactation

  Risk Summary

  There are no data on the presence of erdafitinib in human milk, or the effects of erdafitinib on the breastfed child, or on milk production. Because of the potential for serious adverse reactions from erdafitinib in a breastfed child, advise lactating women not to breastfeed during treatment with BALVERSA and for one month following the last dose.
  )
  

• Ocular disorders: BALVERSA can cause central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED). Perform monthly ophthalmological examinations during the first four months of treatment, every 3 months afterwards, and at any time for visual symptoms. Withhold BALVERSA when CSR/RPED occurs and permanently discontinue if it does not resolve within 4 weeks or if Grade 4 in severity. (
  
  
  2.3 Dose Modifications for Adverse Reactions

  The recommended dose modifications for adverse reactions are listed in Table 1.

  Table 1: BALVERSA Dose Reduction Schedule

  Dose	1stdose reduction	2nddose reduction	3rddose reduction	4thdose reduction	5thdose reduction
  9 mg ➞ (three 3 mg tablets)	8 mg (two 4 mg tablets)	6 mg (two 3 mg tablets)	5 mg (one 5 mg tablet)	4 mg (one 4 mg tablet)	Stop
  8 mg ➞ (two 4 mg tablets)	6 mg (two 3 mg tablets)	5 mg (one 5 mg tablet)	4 mg (one 4 mg tablet)	Stop

  Table 2 summarizes recommendations for dose interruption, reduction, or discontinuation of BALVERSA in the management of specific adverse reactions.

  Table 2: Dose Modifications for Adverse Reactions

  Adverse Reaction	BALVERSA Dose Modification
  Hyperphosphatemia
  In all patients, restrict phosphate intake to 600–800 mg daily.
  <6.99 mg/dL	Continue BALVERSA at current dose.
  7–8.99 mg/dL	Continue BALVERSA at current dose. Start phosphate binder with food until phosphate level is <7 mg/dL. Reduce the dose if serum phosphate remains ≥7 mg/dL for a period of 2 months or if clinically necessary.
  9–10 mg/dL	Withhold BALVERSA with weekly reassessments until level returns to <7 mg/dL. Then restart BALVERSA at the same dose level. Start phosphate binder with food until serum phosphate level returns to <7 mg/dL. Reduce the dose if serum phosphate remains ≥9 mg/dL for a period of 1 month or if clinically necessary.
  >10 mg/dL	Withhold BALVERSA with weekly reassessments until level returns to <7 mg/dL. Then may restart BALVERSA at the first reduced dose level. If hyperphosphatemia (≥10 mg/dL) for >2 weeks, discontinue BALVERSA permanently. Medical management of symptoms as clinically relevant.
  Serum phosphate with life-threatening consequences; urgent intervention indicated (e.g., dialysis)	Discontinue BALVERSA permanently.
  Central Serous Retinopathy (CSR)
  Any	Withhold BALVERSA and perform an ophthalmic evaluation within 2 weeks: If improving within 14 days, restart BALVERSA at the current dose. If not improving within 14 days, withhold BALVERSA until improving; once improving, may resume at the next lower dose level. Upon restarting BALVERSA, monitor for recurrence every 1 to 2 weeks for a month. If recurs or has not improved after 4 weeks of withholding BALVERSA, consider permanent discontinuation.
  Other Adverse Reactions Dose adjustment graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAEv5.0).
  Grade 3	Withhold BALVERSA until resolves to Grade 1 or baseline, then may resume dose level lower.
  Grade 4	Permanently discontinue.
  ,
  
  
  5.1 Ocular Disorders

  BALVERSA can cause ocular disorders, including central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED) resulting in visual field defect.

  In the pooled safety population

  [see Adverse Reactions (6)]

  , CSR/RPED occurred in 22% of patients treated with BALVERSA, with a median time to first onset of 46 days. In 104 patients with CSR, 40% required dose interruptions and 56% required dose reductions; 2.9% of BALVERSA-treated patients required permanent discontinuation for CSR. Of the 24 patients who restarted BALVERSA after dose interruption with or without dose reduction, 67% had recurrence and/or worsening of CSR after restarting. CSR was ongoing in 41% of the 104 patients at the time of last evaluation.

  Dry eye symptoms occurred in 26% of BALVERSA-treated patients. All patients should receive dry eye prophylaxis with ocular demulcents as needed.

  Perform monthly ophthalmological examinations during the first 4 months of treatment and every 3 months afterwards, and urgently at any time for visual symptoms. Ophthalmological examination should include assessment of visual acuity, slit lamp examination, fundoscopy, and optical coherence tomography.

  Withhold or permanently discontinue BALVERSA based on severity and/or ophthalmology exam findings

  [see Dosage and Administration (2.3)]

  .
  )
  
• Hyperphosphatemia: Increases in phosphate levels are a pharmacodynamic effect of BALVERSA. Monitor for hyperphosphatemia and manage with dose modifications when required. (
  
  
  2.3 Dose Modifications for Adverse Reactions

  The recommended dose modifications for adverse reactions are listed in Table 1.

  Table 1: BALVERSA Dose Reduction Schedule

  Dose	1stdose reduction	2nddose reduction	3rddose reduction	4thdose reduction	5thdose reduction
  9 mg ➞ (three 3 mg tablets)	8 mg (two 4 mg tablets)	6 mg (two 3 mg tablets)	5 mg (one 5 mg tablet)	4 mg (one 4 mg tablet)	Stop
  8 mg ➞ (two 4 mg tablets)	6 mg (two 3 mg tablets)	5 mg (one 5 mg tablet)	4 mg (one 4 mg tablet)	Stop

  Table 2 summarizes recommendations for dose interruption, reduction, or discontinuation of BALVERSA in the management of specific adverse reactions.

  Table 2: Dose Modifications for Adverse Reactions

  Adverse Reaction	BALVERSA Dose Modification
  Hyperphosphatemia
  In all patients, restrict phosphate intake to 600–800 mg daily.
  <6.99 mg/dL	Continue BALVERSA at current dose.
  7–8.99 mg/dL	Continue BALVERSA at current dose. Start phosphate binder with food until phosphate level is <7 mg/dL. Reduce the dose if serum phosphate remains ≥7 mg/dL for a period of 2 months or if clinically necessary.
  9–10 mg/dL	Withhold BALVERSA with weekly reassessments until level returns to <7 mg/dL. Then restart BALVERSA at the same dose level. Start phosphate binder with food until serum phosphate level returns to <7 mg/dL. Reduce the dose if serum phosphate remains ≥9 mg/dL for a period of 1 month or if clinically necessary.
  >10 mg/dL	Withhold BALVERSA with weekly reassessments until level returns to <7 mg/dL. Then may restart BALVERSA at the first reduced dose level. If hyperphosphatemia (≥10 mg/dL) for >2 weeks, discontinue BALVERSA permanently. Medical management of symptoms as clinically relevant.
  Serum phosphate with life-threatening consequences; urgent intervention indicated (e.g., dialysis)	Discontinue BALVERSA permanently.
  Central Serous Retinopathy (CSR)
  Any	Withhold BALVERSA and perform an ophthalmic evaluation within 2 weeks: If improving within 14 days, restart BALVERSA at the current dose. If not improving within 14 days, withhold BALVERSA until improving; once improving, may resume at the next lower dose level. Upon restarting BALVERSA, monitor for recurrence every 1 to 2 weeks for a month. If recurs or has not improved after 4 weeks of withholding BALVERSA, consider permanent discontinuation.
  Other Adverse Reactions Dose adjustment graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAEv5.0).
  Grade 3	Withhold BALVERSA until resolves to Grade 1 or baseline, then may resume dose level lower.
  Grade 4	Permanently discontinue.
  ,
  
  
  5.2 Hyperphosphatemia and Soft Tissue Mineralization

  BALVERSA can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcinosis, non-uremic calciphylaxis and vascular calcification. Increases in phosphate levels are a pharmacodynamic effect of BALVERSA

  [see Pharmacodynamics (12.2)].

  In the pooled safety population

  [see Adverse Reactions (6)],

  increased phosphate occurred in 73% of BALVERSA-treated patients. The median onset time of increased phosphate was 16 days (range: 8–421) after initiating BALVERSA. Twenty-four percent of patients received phosphate binders during treatment with BALVERSA. Vascular calcification was observed in 0.2% of patients treated with BALVERSA.

  Monitor for hyperphosphatemia throughout treatment. Restrict dietary phosphate intake (600–800 mg daily) and avoid concomitant use of agents that may increase serum phosphate levels.

  If serum phosphate is above 7.0 mg/dL, consider adding an oral phosphate binder until serum phosphate level returns to <7.0 mg/dL. Withhold, dose reduce, or permanently discontinue BALVERSA based on duration and severity of hyperphosphatemia according to Table 2

  [see Dosage and Administration (2.3)].
  )
  
• Embryo-fetal toxicity: Can cause fetal harm. Advise patients of the potential risk to the fetus and to use effective contraception (
  
  
  5.3 Embryo-Fetal Toxicity

  Based on the mechanism of action and findings in animal reproduction studies, BALVERSA can cause fetal harm when administered to a pregnant woman. In an embryo-fetal toxicity study, oral administration of erdafitinib to pregnant rats during the period of organogenesis caused malformations and embryo-fetal death at maternal exposures that were less than the human exposures at the maximum human recommended dose based on area under the curve (AUC). Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose

  [see Use in Specific Populations (8.1, 8.3)and Clinical Pharmacology (12.1)]

  .
  ,
  
  
  8.1 Pregnancy

  Risk Summary

  Based on the mechanism of action and findings in animal reproduction studies, BALVERSA can cause fetal harm when administered to a pregnant woman

  [see Clinical Pharmacology (12.1)]

  . There are no available data on BALVERSA use in pregnant women to inform a drug-associated risk. Oral administration of erdafitinib to pregnant rats during organogenesis caused malformations and embryo-fetal death at maternal exposures that were less than the human exposures at the maximum recommended human dose based on AUC

  (see Data)

  . Advise pregnant women and females of reproductive potential of the potential risk to the fetus.

  The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

  Data

  Animal Data

  In an embryo-fetal toxicity study, erdafitinib was orally administered to pregnant rats during the period of organogenesis. Doses ≥4 mg/kg/day (at total maternal exposures <0.1% of total human exposures at the maximum recommended human dose based on AUC) produced embryo-fetal death, major blood vessel malformations and other vascular anomalies, limb malformations (ectrodactyly, absent or misshapen long bones), an increased incidence of skeletal anomalies in multiple bones (vertebrae, sternebrae, ribs), and decreased fetal weight.
  ,
  
  
  8.3 Females and Males of Reproductive Potential

  BALVERSA can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations (8.1)]

  .

  Pregnancy Testing

  Verify pregnancy status in females of reproductive potential prior to initiating treatment with BALVERSA.

  Contraception

  Females

  Advise females of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose.

  Males

  Advise male patients with female partners of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose.

  Infertility

  Females

  Based on findings from animal studies, BALVERSA may impair fertility in females of reproductive potential

  [see Nonclinical Toxicology (13.1)]

  .