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BALVERSA® (erdafitinib)

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BALVERSA - Nail Disorders

Last Updated: 11/22/2024

Follow dose modification guidelines for adverse reactions within product labeling.
Click on the following links to related sections within the document: THOR Study, BLC2001 Study, and Guidelines for Management of Nail Toxicity.
Abbreviations: AE, adverse event; FGFR, fibroblast growth factor receptor; TEAE, treatment-emergent adverse event; UC, urothelial carcinoma; UpT, uptitration.
^aLoriot (2023).¹ ^bClinicalTrials.gov. NCT03390504 (2023).² ^cNail disorders: nail bed bleeding, nail discoloration, nail disorder, nail dystrophy, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, paronychia, and onychomadesis.^dSiefker-Radtke (2022).³ ^eSiefker-Radtke (2022).⁴ ^fDeutsch (2020).⁵ ^gMonteiro (2021).⁶

CLINICAL Data

To provide the most relevant information, the summary below is limited to information from the pivotal phase 3 (THOR/BLC3001; cohort 1) and phase 2 (BLC2001) studies in patients with locally advanced or metastatic urothelial carcinoma (UC) and selected fibroblast growth factor receptor (FGFR) alterations.

THOR Study

THOR is an ongoing, phase 3, randomized, open-label, multicenter 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 who had disease progression during or after 1 or 2 prior lines of therapy.¹^,²

In cohort 1, 266 patients were randomized 1:1 to receive an uptitration regimen of BALVERSA 8 mg once daily or chemotherapy (docetaxel 75 mg/m² intravenous [IV] every 3 weeks [Q3W] or vinflunine 320 mg/m² IV Q3W).¹^,²

Cohort 1 Analysis

In cohort 1, after a median of 15.9 months follow-up for efficacy and median duration of BALVERSA exposure of 4.8 months (range, 0.2-38.2), 136 patients received BALVERSA 8 mg once daily. The safety profiles in both arms were consistent with the known safety profiles of BALVERSA and chemotherapy.¹

The incidence of nail disorders in the safety population is summarized in the Table: THOR Cohort 1 Safety Population: Incidence of Nail Disorders and Table: THOR Cohort 1 Safety Population: Incidence of Nail Disorders Leading to Treatment Discontinuation.

THOR Cohort 1 Safety Population: Incidence of Nail Disorders¹^,⁷

AEs, n (%)^a	BALVERSA (n=135)		Chemotherapy (n=112)
AEs, n (%)^a	Any Grade	Grade ≥3	Any Grade	Grade ≥3
Onycholysis	31 (23.0)	8 (5.9)	1 (0.9)	0
Onychomadesis	28 (20.7)	2 (1.5)	2 (1.8)	0
Nail discoloration	24 (17.8)	1 (0.7)	2 (1.8)	0
AEs of interest
Nail disorders^b	90 (66.7)	15 (11.1)	6 (5.4)	0
Abbreviation: AE, adverse event. ^aAEs (of any cause) that emerged or worsened during treatment, according to preferred term and highest grade, and that were reported in >15% of the patients in either treatment group.^bNail disorders: nail bed bleeding, nail discoloration, nail disorder, nail dystrophy, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, paronychia, and onychomadesis.

THOR Cohort 1 Safety Population: Incidence of Nail Disorders Leading to Treatment Discontinuation⁷

AEs, n (%)^a	BALVERSA (n=135)	Chemotherapy (n=112)
Onycholysis	2 (1.5)	0
Nail discoloration	1 (0.7)	0
Nail dystrophy	1 (0.7)	0
Paronychia	1 (0.7)	0
Abbreviation: AE, adverse event. ^aAEs (of any cause) that emerged or worsened during treatment, according to preferred term and highest grade, and that were reported in >2% of the patients in either treatment group.

BLC2001 Study

BLC2001 is an ongoing, phase 2, open-label, multicenter study evaluating the use of BALVERSA in patients with locally advanced and unresectable or metastatic UC who had prespecified FGFR alterations (FGFR3 mutation or FGFR2/3 fusion) and 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 mutations: R248C, S249C, G370C, and Y373C or one of the following FGFR fusions: FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7.⁸

Final Analysis

In the final analysis, after a median 24-month follow-up for efficacy (interquartile range [IQR], 22.7-26.6) and median treatment duration of 5.4 months (IQR, 2.8-9), 101 patients were treated with an uptitration regimen of BALVERSA 8 mg daily (2 patients were enrolled after the clinical cutoff date for the primary analysis). Overall, 60 patients received BALVERSA 8 mg daily and 41 were uptitrated to BALVERSA 9 mg daily.³^,⁴

The safety profile of BALVERSA remained consistent with that of the primary analysis.³
No grade 4 adverse events (AEs) were considered related to BALVERSA, and no new treatment-emergent adverse events (TEAEs) were observed with longer follow-up.³
A total of 60 (59.4%) patients treated with BALVERSA 8 mg daily reported nail TEAEs.⁴
- The most frequently occurring nail TEAEs were onycholysis (18.8%), paronychia (18.8%), and nail dystrophy (16.8%).
The most common treatment-related nail AEs are presented in the Table: BLC2001: Most Common Treatment-Related Nail AEs.
A treatment-related nail AE that led to treatment discontinuation was nail dystrophy (n=1).⁴

BLC2001: Most Common Treatment-Related Nail AEs⁴

AEs, n (%)	BALVERSA 8 mg Daily UpT (N=101)
AEs, n (%)	Any Grade	Grade 1	Grade 2	Grade 3
Nail dystrophy	17 (16.8)	6 (5.9)	5 (5.0)	6 (5.9)
Onycholysis	17 (16.8)	5 (5.0)	10 (9.9)	2 (2.0)
Paronychia	15 (14.9)	1 (1.0)	11 (10.9)	3 (3.0)
Nail discoloration	12 (11.9)	9 (8.9)	3 (3.0)	0
Abbreviations: AE, adverse event; UpT, potential for uptitration to 9 mg daily.

The incidence of nail TEAEs is summarized in the Table: BLC2001: Incidence of Nail TEAEs.

BLC2001: Incidence of Nail TEAEs⁹

Adverse Event	Data Values
Developed nail events, n/N with ≥ 1 TEAE (%)	60/101 (59)
Median (range) time to onset of nail events, days	69 (16-281)
Had dose modification for nail events, n/N with nail events (%)
Dose reduction	20/60 (33)
Dose interruption	17/60 (28)
Discontinuation	1/60 (2)
Received treatment for nail events, n^a/N with nail event (%)	34/60 (57)
Most common nail event: onycholysis	(n=19)
Median (range) time treatment was withheld for onycholysis, days	14 (14-14)
Resolution of ≥1 onycholysis by data cutoff, n^b/N with onycholysis (%)	6/19 (32)
Median (range) time to resolution of onycholysis, days	122 (14-385)
Most common nail event: paronychia	(n=19)
Median (range) time treatment was withheld for paronychia, days	18 (7-40)
Resolution of ≥1 paronychia event by data cut-off, n^b/N with paronychia (%)	11/19 (58)
Median (range) time to resolution of paronychia, days	75 (8-329)
Abbreviation: TEAE, treatment-emergent adverse event. ^aAmong the 34 patients receiving concomitant medications, the most common therapies were systemic antibacterials (38%) and dermatological antifungals (35%). ^bAmong patients with onycholysis and paronychia, ≥ 1 event resolved in 2 of 5 and 4 of 6 patients with dose reduction and 2 of 3 and 5 of 6 with dose interruption, respectively (none had onycholysis or paronychia leading to treatment discontinuation).

An exploratory analysis was conducted for 2 dosing regimens in the BLC2001 study to investigate the relationship between selected efficacy and safety endpoints and phosphate (PO₄) concentrations. Exposure analyses supported the use of pharmacodynamically-guided dose titration to optimize therapeutic benefit/risk ratio.¹⁰

GUIDELINES FOR MANAGEMENT OF NAIL TOXICITY (ONYCHOLYSIS, ONYCHODYSTROPHY, and Paronychia) IN THE THOR AND BLC2001 STUDies

Table: Guidelines for Management of Nail Discoloration/Loss/Ridging (Onycholysis/ Onychodystrophy) in the THOR and BLC2001 Studies and Table: Guidelines for Management of Paronychia in the THOR and BLC2001 Studies summarizes interventions investigators in the BLC2001 study were instructed to perform to manage nail toxicity. These are not recommendations. Interventions should be based on patient presentation and the clinical judgment of the treating physician.⁸ For management of other nail toxicities, follow standard clinical practice. Nail events (onycholysis, nail dystrophy, and paronychia) were included among the treatment.

General Prophylaxis¹¹^,¹²:
- Good hygienic practices, keep fingers and toes clean
- Keep nails trimmed but avoid aggressive manicuring
- Use gloves for housecleaning and gardening to minimize damage and prevent infection
- Nail polish and imitation fingernails should not be worn until the nails have grown out and returned to normal
- Wearing comfortable shoes (wide-sized shoes with room for the toes)

Guidelines for Management of Nail Discoloration/Loss/Ridging (Onycholysis/ Onychodystrophy) in the THOR and BLC2001 Studies¹¹^,¹²

Grade and Definition	Drug Management	Medical Management
Grade 1: Asymptomatic; clinical or diagnostic observations only, intervention not indicated	Continue BALVERSA at current dose	OTC nail strengthener OR poly-urea urethane nail lacquer OR diethylene glycol monoethylether nail lacquer daily
Grade 2: Symptomatic separation of the nail bed from the nail plate or nail loss, limiting IADLs	Continue BALVERSA at current dose Consider holding BALVERSA if there is no improvement in 12 weeks When the AE resolves to ≤grade 1 or baseline, restart at same or 1 dose level below in consultation with the medical monitor	For signs of infection (periungal edema/erythema/tenderness and/or discharge), obtain bacterial cultures, and then start the following: Treatment with oral antibiotic for 2 weeks (cefadroxil 500 mg BID, ciprofloxacin 500 mg BID, or sulfamethoxazole/trimethoprim BID) AND Topical antifungal lacquer daily for 6+ weeks (ciclopirox olamine 8% OR efinaconazole 10% OR amorolfine 5% weekly OR bifonazole/urea ointment daily)
Grade 3: Severe nail tip pain, symptomatic separation of the nail bed from the nail plate or nail loss, significantly limiting IADLs	Hold BALVERSA (for up to 28 days), with weekly reassessments of clinical condition When the AE resolves to ≤grade 1 or baseline, restart at 1 dose level below in consultation with the medical monitor	Silver nitrate application weekly AND topical antibiotics^a AND vinegar soaks^b For signs of infection (periungal edema/erythema/tenderness and/or discharge), obtain bacterial cultures, and then start the following: treatment with oral antibiotic for 2 weeks (cefadroxil 500 mg BID, ciprofloxacin 500 mg BID, or sulfamethoxazole/trimethoprim BID) For severe/refractory infection consider IV antibiotics Consider dermatological and/or surgical evaluation
Grade 4: Life-threatening consequences, urgent intervention indicated	Discontinue BALVERSA	Evaluation and therapy as clinically indicated
Abbreviations: AE, adverse event; BID, twice daily; IADL, instrumental activities of daily living; IV, intravenous; OTC, over-the-counter. ^aExamples of topical antibiotic ointments: mupirocin 2%, gentamycin, bacitracin zinc/polymixin B. ^bVinegar soaks consist of soaking fingers or toes in a solution of white vinegar in water 1:1 for 15 minutes every day.

Guidelines for Management of Paronychia in the THOR and BLC2001 Studies¹¹^,¹²

Grade and Definition	Drug Management	Medical Management
Grade 1: Nail fold edema or erythema; disruption of the cuticle	Continue BALVERSA at current dose	Topical antibiotics^a AND vinegar soaks^b
Grade 2: Nail fold edema or erythema with pain; associated with discharge or nail plate separation; limiting IADL	Continue BALVERSA at current dose Consider holding BALVERSA if there is no improvement in 1 to 2 weeks When the AE resolves to ≤grade 1 or baseline, restart at same or 1 dose level below	Topical antibiotics^a AND vinegar soaks^bAND topical antifungal lacquer daily for 6+ weeks (ciclopirox olamine 8% OR efinaconazole 10% OR amorolfine 5% weekly OR bifonazole/urea ointment daily) For signs of infection (periungal edema/erythema/tenderness and/or discharge), obtain bacterial cultures, and then start the following: treatment with oral antibiotic for 2 weeks (cefadroxil 500 mg BID, ciprofloxacin 500 mg BID, or sulfamethoxazole/trimethoprim BID)
Grade 3: Limiting self-care ADLs, surgical intervention, or IV antibiotics indicated	Hold BALVERSA (for up to 28 days), with weekly reassessments of clinical condition When the AE resolves to ≤grade 1 or baseline, restart at 1 dose level below	Vinegar soaks^b AND consider nail avulsion For signs of infection (periungal edema/erythema/tenderness and/or discharge), obtain bacterial cultures, and then start the following: treatment with oral antibiotic for 2 weeks (cefadroxil 500 mg BID, ciprofloxacin 500 mg BID, or sulfamethoxazole/trimethoprim BID) For cases of severe/refractory infection consider IV antibiotics Consider dermatological and/or surgical evaluation
Grade 4: Life-threatening consequences, urgent intervention indicated	Discontinue BALVERSA	Evaluation and therapy as clinically indicated
Abbreviations: ADL, activities of daily living; AE, adverse event; BID, twice daily; IADL, instrumental activities of daily living; IV, intravenous. ^aExamples of topical antibiotic ointments: Mupirocin 2%, gentamycin, bacitracin zinc/polymixin B. ^bVinegar soaks consist of soaking fingers or toes in a solution of white vinegar in water 1:1 for 15 minutes every day.

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 04 November 2024. Study data and case reports of BALVERSA use as monotherapy are included in this response.

References

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1	Loriot Y, Matsubara N, Park SH, et al. Erdafitinib or chemotherapy in advanced or metastatic urothelial carcinoma. N Engl J Med. 2023;389(21):1961-1971.
2	Janssen Research & Development, LLC. A phase 3 study of erdafitinib compared with vinflunine or docetaxel or pembrolizumab in subjects with advanced urothelial cancer and selected FGFR gene aberrations. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2024 November 04]. Available from: https://clinicaltrials.gov/ct2/show/NCT03390504 NLM Identifier: NCT03390504.
3	Siefker-Radtke AO, Necchi A, Park SH, et al. Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study. Lancet Oncol. 2022;23(2):248-258.
4	Siefker-Radtke AO, Necchi A, Park SH, et al. Supplement for: Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study. Lancet Oncol. 2022;23(2):248-258.
5	Deutsch A, McLellan BN. Severe onycholysis and eyelash trichomegaly in a patient treated with erdafitinib. JAAD Case Rep. 2020;6(6):569-571.
6	Monteiro FSM, Silva AGE, Gomes AJPS, et al. Erdafitinib treatment in Brazilian patients with metastatic urothelial carcinoma (mUC): real-world evidence from an Expanded Access Program. Ther Adv Méd Oncol. 2021;13:17588359211015500.
7	Loriot Y, Matsubara N, Park SH, et al. Supplement for: Erdafitinib or chemotherapy in advanced or metastatic urothelial carcinoma. N Engl J Med. 2023;389(21):1961-1971.
8	Loriot Y, Necchi A, Park SH, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019;381(4):338-348.
9	Siefker-Radtke AO, Necchi A, Park SH, et al. Management of fibroblast growth factor receptor inhibitor treatment-emergent adverse events of interest in patients with locally advanced or metastatic urothelial carcinoma. Poster presented at: American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium; February 11-13, 2021; Virtual.
10	Dosne A, Valade E, Goeyvaerts N, et al. Exposure-response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma. Cancer Chemother Pharmacol. 2022;89(2):151-164.
11	Loriot Y, Necchi A, Park SH, et al. Protocol for: Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019;381(4):338-348.
12	Loriot Y, Matsubara N, Park SH, et al. Protocol for: Erdafitinib or chemotherapy in advanced or metastatic urothelial carcinoma. N Engl J Med. 2023;389(21):1961-1971.