BALVERSA®

(erdafitinib)

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BALVERSA® (erdafitinib)

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BALVERSA - NORSE Study

Last Updated: 05/17/2024

Click on the following links to related sections within the document: Study Design/Methods and Results.
Note: For information regarding this ongoing clinical trial, including a detailed listing of eligibility criteria, please visit https://clinicaltrials.gov/ct2/show/NCT03473743.
Abbreviations: CI, confidence interval; DCR, disease control rate; DL, dose level; DLT, dose-limiting toxicity; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; FGFR, fibroblast growth factor receptor; IV, intravenous; mUC, metastatic urothelial carcinoma; ORR, overall response rate; OS, overall survival; PD-1, programmed cell death receptor-1; PD-L1, programmed cell death ligand-1; PFS, progression-free survival; PK, pharmacokinetics; PO, orally; PO₄, phosphate; Q2W, every 2 weeks; QD, daily; RP2D, recommended phase 2 dose; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event; UC, urothelial carcinoma.
^aClinicalTrials.gov (NCT03473743).¹ ^bSiefker-Radtke (2020).² ^cMoreno (2020).³ ^dPowles (2021).⁴ ^eSiefker-Radtke (2023).⁵^fPer serum phosphate levels.^gOf the total 87 patients, 1 in the erdafitinib arm (n=43) and 5 in the erdafitinib plus cetrelimab arm (n=44) were inevaluable.

CLINICAL STUDY

NORSE Study

The NORSE study (BLC2002; NCT03473743) is evaluating the recommended phase 2 dose (RP2D), pharmacokinetics (PK), efficacy, and safety of BALVERSA plus cetrelimab, and for BALVERSA in combination with cetrelimab and platinum (cisplatin and carboplatin) chemotherapy, in patients with locally advanced or metastatic urothelial carcinoma (mUC) and selected fibroblast growth factor receptor (FGFR) alteration.¹^-⁵

Study Design/Methods

Phase 1b/2, open-label, multicenter study
Patients with metastatic or locally advanced urothelial carcinoma (UC) and selected FGFR alterations were enrolled (N=125):
- The phase 1b dose-escalation study evaluated 3 dosing levels of BALVERSA orally (PO) daily with a fixed dose of cetrelimab 240 mg intravenous (IV) every 2 weeks (Q2W) in patients who had received ≥1 prior therapy to identify the RP2D for further evaluation in the phase 2 dose-expansion study (see Figure: NORSE Study Design - BALVERSA Combination With Cetrelimab Cohorts).

NORSE Study Design - BALVERSA Combination With Cetrelimab Cohorts¹^-⁵

Abbreviations: AE, adverse event; CrCL, creatinine clearance; CV, cardiovascular; DCR, disease control rate; DL, dose level; DLT, dose-limiting toxicity; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; FGFR, fibroblast growth factor receptor; HIV, human immunodeficiency virus; IV, intravenous; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; ORR, overall response rate; OS, overall survival; PD, progressive disease; PD-1, programmed cell death receptor-1; PD-L1, programmed cell death ligand-1; PFS, progression-free survival; PK, pharmacokinetics; PO, orally; Q2W, every 2 weeks; Q6W, every 6 weeks; Q12W, every 12 weeks; QD, daily; RECIST, Response Evaluation Criteria in Solid Tumors; UC, urothelial carcinoma.
^aPer serum phosphate levels.

An estimated 90 patients with mUC and selected FGFR alterations are planned for enrollment in the phase 2 study. Patients with no prior treatment for metastatic disease and those ineligible for cisplatin are included in the preliminary analysis.⁴
Patients are randomized 1:1 to receive⁴^,⁵:
- BALVERSA 8 mg PO daily with pharmacodynamically guided uptitration to 9 mg PO daily alone or
- BALVERSA 8 mg PO daily in combination with cetrelimab 240 mg IV Q2W for cycles 1-4, then 480 mg IV every 4 weeks (Q4W) thereafter

Results

Baseline Characteristics

Phase 1b: Baseline Disease Characteristics, Demographics, and Treatment Exposure²

Characteristic	DL1^a(n=4)	DL2A^b(n=3)	DL2B^c(n=3)	DL2^d(n=12)	Total (N=22)
Median treatment exposure, months (range)	5.3 (3-7)	8.3 (0-9)	5.1 (5-5)	5.5 (0-9)	5.5 (0-9)
Median age, years (range)	74 (64-79)	68 (57-75)	58 (51-65)	67 (31-73)	67 (31-79)
Sex, n (%)
Male	4 (100)	2 (67)	3 (100)	7 (58)	16 (73)
ECOG PS, n (%)
0	2 (50)	1 (33)	3 (100)	8 (67)	14 (64)
1	2 (50)	2 (67)	0	4 (33)	8 (36)
Presence of visceral metastases,^e n (%)	2 (50)	3 (100)	2 (67)	5 (42)	12 (55)
Number of prior systemic therapy lines,^f n (%)
0	0	0	0	1 (8)	1 (5)
1	4 (100)	2 (67)	3 (100)	7 (58)	16 (73)
2	0	1 (33)	0	4 (33)	5 (23)
Primary tumor location, n (%)
Lower tract	3 (75)	3 (100)	2 (67)	6 (50)	14 (64)
Upper tract	1 (25)	0	1 (33)	6 (50)	8 (36)
PD-L1 positive status,^g n (%)
Yes	0	0	0	4 (33)	4 (18)
No	1 (25)	1 (33)	0	2 (17)	4 (18)
Not available	3 (75)	2 (67)	3 (100)	6 (50)	14 (64)
Any FGFR alteration,^h n (%)	4 (100)	2 (67)	1 (33)	10 (83)	17 (77)
FGFR mutations (excluding fusions)	3 (75)	2 (67)	1 (33)	9 (75)	15 (68)
FGFR fusions (excluding mutations)	1 (25)	0	0	1 (8)	2 (9)
Abbreviations: DL, dose level; ECOG PS, Eastern Cooperative Oncology Group performance status; FGFR, fibroblast growth factor receptor; PD-L1, programmed cell death ligand-1; PO₄, phosphate. ^aDL1=BALVERSA 6 mg plus cetrelimab 240 mg. ^bDL2A=BALVERSA 8 mg (no uptitration) plus cetrelimab 240 mg. ^cDL2B=BALVERSA 8 mg with uptitration to 9 mg based on serum PO₄ levels plus cetrelimab 240 mg (cetrelimab started at cycle 2 day 1). ^dDL2=BALVERSA 8 mg with uptitration to 9 mg based on serum PO₄ levels plus cetrelimab 240 mg. ^eLung, liver, and bone. ^fIn phase 2, prior lines were for neo/adjuvant therapy. ^gPD-L1 expression level was assessed by immunohistochemistry (Dako 28.8) in tumor tissue provided at screening (PD-L1 positivity if Tumor Proportion Score ≥1%). ^hBased on central laboratory tissue testing, FGFR alteration status was not available for 3 patients at the time of this analysis; 2 patients enrolled using local and blood-based testing, respectively, but did not have FGFR alterations according to central laboratory tissue testing.

Phase 2 Interim Analysis: Baseline Disease Characteristics and Demographics⁴

Characteristic	BALVERSA (n=26)	BALVERSA + Cetrelimab (n=27)
Median age, years (range)	75 (45-92)	69 (56-91)
Male, n (%)	19 (73)	20 (74)
ECOG PS,^a n (%)
0-1	20 (77)	17 (63)
2	6 (23)	9 (33)
Presence of visceral metastases,^b n (%)	14 (54)	14 (52)
Primary tumor location, n (%)
Lower tract	19 (76)	22 (85)
Upper tract	6 (24)	4 (15)
PD-L1 positive status,^c n (%)
Yes	2 (8)	2 (7)
No	10 (39)	7 (26)
Unknown^d	14 (54)	18 (67)
Any FGFR alteration,^e n (%)
FGFR mutations	23 (88)	18 (67)
FGFR fusions	3 (12)	7 (26)
Mutations and fusions	0	1 (4)
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; FGFR, fibroblast growth factor receptor; PD-L1, programmed cell death ligand-1. ^aECOG PS was not reported for 1 patient in the BALVERSA + cetrelimab arm. ^bLung, liver, or bone. ^cPD-L1 expression level was assessed by immunohistochemistry (Dako 28.8) in tumor tissue provided at screening (PD-L1 positivity if combined positive score ≥10). ^dIncludes insufficient biopsy tissue, results pending, and test failed. ^eFGFR alterations were reported in 26 patients in the BALVERSA + cetrelimab arm.

Phase 2 Final Analysis: Baseline Disease Characteristics and Demographics⁵

Characteristic	BALVERSA (n=43)	BALVERSA + Cetrelimab (n=44)
Median age, years (range)	72 (45-92)	69 (51-91)
Male, n (%)	33 (76.7)	33 (75)
Race, n (%)
White	36 (83.7)	36 (81.8)
Asian	3 (7)	2 (4.5)
Not reported	4 (9.3)	6 (13.6)
ECOG PS, n (%)
0-1	31 (72.1)	28 (63.6)
2	12 (27.9)	16 (36.4)
Presence of visceral metastases,^a n (%)	27 (62.8)	26 (59.1)
Liver	8 (18.6)	6 (13.6)
Primary tumor location, n (%)
Lower tract	31 (72.1)	38 (86.4)
Upper tract	12 (27.9)	6 (13.6)
PD-L1 status, n (%)
CPS ≥10 (high)	4 (9.3)	4 (9.1)
CPS <10 (low)	28 (65.1)	28 (63.6)
Not available	11 (25.6)	12 (27.3)
FGFR alterations, n (%)
Mutations	36 (83.7)	31 (70.5)
Fusions	6 (14)	11 (25)
Mutations and fusions	0	2 (4.5)
FGFR gene with alteration, n (%)
FGFR3	43 (100)	44 (100)
FGFR2	0	0
Abbreviations: CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; FGFR, fibroblast growth factor receptor; PD-L1, programmed cell death ligand-1. ^aLung, liver, or bone.

Efficacy

In phase 1b response-evaluable patients (n=21), the confirmed overall response rate (ORR) was 52%. The confirmed ORR in 11 evaluable patients treated at the RP2D was 55%.²
- The disease control rate (DCR), which included unconfirmed complete responses (CRs) and partial responses (PRs), as well as stable disease (SD), was 91% overall and 100% at the RP2D.
Please see Table: Phase 1b: Summary of Best Overall Response for the Response-Evaluable Set.

Phase 1b: Summary of Best Overall Response for the Response-Evaluable Set²^,a

Patients with response, n (%)	DL1^a(n=4)	DL2A^b(n=3)	DL2B^c(n=3)	DL2^d(n=11)	Total (N=21)
ORR^e	2 (50)	2 (67)	1 (33)	6 (55)	11 (52)
DCR^f	4 (100)	2 (67)	2 (67)	11 (100)	19 (91)
Best overall response
PR (confirmed)	2 (50)	2 (67)	1 (33)	6 (55)	11 (52)
uPR	0	0	0	2 (18)	2 (10)
SD	2 (50)	0	1 (33)	3 (27)	6 (29)
PD	0	1 (33)	0	0	1 (5)
Not evaluable	0	0	1 (33)	0	1 (5)
Abbreviations: CR, complete response; DCR, disease control rate; DL, dose level; ORR, overall response rate; PD, progressive disease; PO₄, phosphate; PR, partial response; SD, stable disease; uPR, unconfirmed partial response. ^aIncludes all patients in the safety analysis set who have had a baseline and ≥1 adequate posttreatment disease evaluation, have had clinical signs or symptoms of disease progression, or died before the first posttreatment disease evaluation; 1 patient was not response-evaluable, as they did not have measurable disease at baseline; therefore, they were excluded from the analysis for response. ^aDL1=BALVERSA 6 mg plus cetrelimab 240 mg. ^bDL2A=BALVERSA 8 mg (no uptitration) plus cetrelimab 240 mg. ^cDL2B=BALVERSA 8 mg with uptitration to 9 mg based on serum PO₄ levels plus cetrelimab 240 mg (cetrelimab started at cycle 2 day 1). ^dDL2=BALVERSA 8 mg with uptitration to 9 mg based on serum PO₄ levels plus cetrelimab 240 mg. ^eIncludes only confirmed responses (CR + PR). ^fCR + PR + unconfirmed CR + unconfirmed PR + SD.

In the phase 2 interim analysis, patients in both treatment arms had a durable reduction in the sum of target lesion diameters over time.⁴
- Median of the maximum reduction in the sum of target lesion diameters was 28% in the BALVERSA arm and 51% in the BALVERSA plus cetrelimab arm.
- Responses were observed in patients with both FGFR mutations and fusions.
- In patients with programmed cell death ligand-1 (PD-L1) low status, responses were observed in 50% of patients in the BALVERSA arm (5 of 10) and 71% of patients in the BALVERSA plus cetrelimab arm (5 of 7); few patients with PD-L1 positive status had available data at the time of this analysis.
Please see Table: Phase 2 Interim Analysis: Summary of Best Overall Response for the Response-Evaluable Set.

Phase 2 Interim Analysis: Summary of Best Overall Response for the Response-Evaluable Set⁴

Response	BALVERSA (n=18)	BALVERSA + Cetrelimab (n=19)
ORR,^a n (%) [95% CI]	6 (33) [13-59]	13 (68) [43-87]
CR, n (%)	1 (6)	4 (21)
PR, n (%)	5 (28)	9 (47)
Median DOR, months (95% CI)	NE [4.4-NE]	6.9 [1.6-NE]
Responses ongoing, n (%)	5 (28)	10 (53)
Median time to response, months (range)	2.3 (1-6)	1.8 (1-4)
DCR, n (%) (95% CI)	18 (100) [82-100]	17 (90) [67-99]
Abbreviations: CI, confidence interval; CR, complete response; DCR, disease control rate; DOR, duration of response; NE, not evaluable; ORR, overall response rate; PR, partial response. ^aAll responses included in ORR are confirmed responses.

In the phase 2 final analysis⁵:
- Patients receiving BALVERSA monotherapy had an ORR of 44.2% (95% CI, 29.1-60.1), 1 patient had a confirmed CR, and 18 patients had a confirmed PR. Patients receiving BALVERSA plus cetrelimab combination therapy had an ORR of 54.5% (95% CI, 38.8-69.6), 6 patients had a confirmed CR, and 18 patients had a confirmed PR.
- In patients with a combined positive score (CPS) <10, ORR was 46.4% in the BALVERSA monotherapy arm and 50% in the BALVERSA plus cetrelimab combination therapy arm. Data are limited in patients with PD-L1 high status (CPS ≥10).
Please see Table: Phase 2 Final Analysis: Efficacy Results.

Phase 2 Final Analysis: Efficacy Results⁵

Response	BALVERSA (n=43)^a	BALVERSA + Cetrelimab (n=44)^a
ORR,^a % (95% CI)	44.2 (29.1-60.1)	54.5 (38.8-69.6)
Confirmed CR, n	1	6
Confirmed PR, n	18	18
Median DCR, % (95% CI)	88.4 (74.9-96.1)	79.5 (64.7-90.2)
Median DOR, months (95% CI)	9.72 (4.6-NE)	11.10 (8.8-NE)
Median time to response, months (range)	1.5 (1-6)	2.4 (1-14)
Ongoing treatment, %	25.6	36.4
Median PFS, months (95% CI)	5.6 (4.3-7.4)	11.0 (5.5-13.6)
Median OS, months (95% CI)	16.2 (8.3-NE)	20.8 (12.0-NE)
Abbreviations: CI, confidence interval; CR, complete response; DCR, disease control rate; DOR, duration of response; NE, not evaluable; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response. ^aOne patient in the BALVERSA arm and 5 patients in the BALVERSA plus cetrelimab arm were inevaluable.

Safety

A total of 22 patients (dose level [DL]1, n=4; DL2A, n=3; DL2B, n=3; DL2, n=12) were evaluated in the phase 1b dose-escalation study, all of whom experienced adverse events (AEs; see Table: Phase 1b: Overall Summary of Adverse Events).²
- 41% (n=9) experienced grade 3-4 treatment-related adverse events (TRAEs)
- 14% (n=3) experienced serious TRAEs
- 18% (n=4) experienced TRAEs leading to discontinuation of study drug
Dose-limiting toxicities (DLTs) were not observed at any DL; BALVERSA 8 mg with uptitration to 9 mg plus cetrelimab (DL2) was established as the RP2D.²
All patients reported AEs at the RP2D (n=12); 42% (n=5) experienced grade 3-4 TRAEs and 25% (n=3) experienced serious TRAEs (pneumonia and diarrhea [n=1], serous retinal detachment [n=1], and herpetic keratitis [n=1]).²
Overall, stomatitis was the most common treatment-emergent adverse event (TEAE), occurring in 73% of patients; grade 3 treatment-related stomatitis occurred in 14% of patients overall and 17% of patients at the RP2D.²
- A total of 2 patients died due to TEAEs: 1 patient due to large intestinal obstruction and 1 patient due to urinary tract infection (both were in the DL1 cohort).
Three patients had central serous retinopathy (CSR) events, a TEAE of special interest (grade 3 [n=1] and grade 2 [n=2]); all CSR events improved to grade 1 or resolved.²

Phase 1b: Overall Summary of Adverse Events²

Patients With Adverse Events, n (%)	DL1^a(n=4)	DL2A^b(n=3)	DL2B^c(n=3)	DL2^d(n=12)	Total (N=22)
Any TEAEs	4 (100)	3 (100)	2 (67)	11 (92)	20 (91)
Any TRAEs^e	4 (100)	3 (100)	2 (67)	11 (92)	20 (91)
Grade 3-4 TEAEs	3 (75)	2 (67)	1 (33)	5 (42)	11 (50)
Grade 3-4 TRAEs^e	1 (25)	2 (67)	1 (33)	5 (42)	9 (41)
Serious TEAEs	3 (75)	0	0	4 (33)	7 (32)
Serious TRAEs^e	0	0	0	3 (25)	3 (14)
TRAEs leading to discontinuation	0	1 (33)	0	3 (25)	4 (18)
Most common grade 3-4 TRAE, ie, stomatitis^f	1 (25)	0	0	2 (17)	3 (14)
TEAE of special interest, ie, CSR^f	0	1 (33)	0	2 (17)	3 (14)
Abbreviations: CSR, central serous retinopathy; DL, dose level; MedDRA, Medical Dictionary for Regulatory Activities; PO₄, phosphate; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event. ^aDL1=BALVERSA 6 mg plus cetrelimab 240 mg. ^bDL2A=BALVERSA 8 mg (no uptitration) plus cetrelimab 240 mg. ^cDL2B=BALVERSA 8 mg with uptitration to 9 mg based on serum PO₄ levels plus cetrelimab 240 mg (cetrelimab started at cycle 2 day 1). ^dDL2=BALVERSA 8 mg with uptitration to 9 mg based on serum PO₄ levels plus cetrelimab 240 mg. ^eAn adverse event was categorized as related if assessed by the investigator as possibly, probably, or very likely related to the study drug. ^fAdverse events were coded using MedDRA v22.1.

The most common TEAEs and grade ≥3 TRAEs across all DLs in the phase 1b study are summarized in Tables: Phase 1b: Most Common TEAEs Occurring in >20% of Patients and Phase 1b: Grade ≥3 TRAEs, respectively.²

Phase 1b: Most Common TEAEs Occurring in >20% of Patients²

Adverse Event, n (%)	DL1^a(n=4)	DL2A^b(n=3)	DL2B^c(n=3)	DL2^d(n=12)	Total (N=22)
Stomatitis	3 (75)	3 (100)	1 (33)	9 (75)	16 (73)
Diarrhea	1 (25)	1 (33)	1 (33)	9 (75)	12 (55)
Dry mouth	2 (50)	2 (67)	1 (33)	7 (58)	12 (55)
Hyperphosphatemia	1 (25)	2 (67)	0	7 (58)	10 (46)
Dysgeusia	2 (50)	2 (67)	0	4 (33)	8 (36)
Dry skin	1 (25)	2 (67)	0	4 (33)	7 (32)
Alopecia	0	2 (67)	0	4 (33)	6 (27)
Asthenia	0	1 (33)	0	7 (58)	8 (36)
Decreased appetite	2 (50)	0	0	4 (33)	6 (27)
PPE	0	2 (67)	1 (33)	2 (17)	5 (23)
Pyrexia	2 (50)	0	0	3 (25)	5 (23)
Pruritus	1 (25)	1 (33)	0	3 (25)	5 (23)
Onycholysis	0	1 (33)	1 (33)	3 (25)	5 (23)
Abbreviations: DL, dose level; PO₄, phosphate; PPE, palmar-plantar erythrodysesthesia syndrome. ^aDL1=BALVERSA 6 mg plus cetrelimab 240 mg. ^bDL2A=BALVERSA 8 mg (no uptitration) plus cetrelimab 240 mg. ^cDL2B=BALVERSA 8 mg with uptitration to 9 mg based on serum PO₄ levels plus cetrelimab 240 mg (cetrelimab started at cycle 2 day 1). ^dDL2=BALVERSA 8 mg with uptitration to 9 mg based on serum PO₄ levels plus cetrelimab 240 mg.

Phase 1b: Grade ≥3 TRAEs²^,a

Patients With TRAEs, n (%)	DL1^b(n=4)	DL2A^c(n=3)	DL2B^d(n=3)	DL2^e(n=12)	Total (N=22)
Stomatitis	1 (25)	0	0	2 (17)	3 (14)
Nail discoloration	0	0	1 (33)	0	1 (5)
Nail dystrophy	0	1 (33)	0	0	1 (5)
Onycholysis	0	1 (33)	0	0	1 (5)
Hypothyroidism	0	0	0	1 (8)	1 (5)
Serous retinal detachment	0	0	0	1 (8)	1 (5)
Autoimmune hepatitis	0	0	0	1 (8)	1 (5)
Pneumonia	0	0	0	1 (8)	1 (5)
GGT increased	0	0	0	1 (8)	1 (5)
Hyperphosphatemia	0	1 (33)	0	0	1 (5)
Abbreviations: DL, dose level; GGT, gamma-glutamyl transferase; PO₄, phosphate; TRAE, treatment-related adverse event. ^aNo grade 4 or 5 TRAEs were reported. ^bDL1=BALVERSA 6 mg plus cetrelimab 240 mg. ^cDL2A=BALVERSA 8 mg (no uptitration) plus cetrelimab 240 mg. ^dDL2B=BALVERSA 8 mg with uptitration to 9 mg based on serum PO₄ levels plus cetrelimab 240 mg (cetrelimab started at cycle 2 day 1). ^eDL2=BALVERSA 8 mg with uptitration to 9 mg based on serum PO₄ levels plus cetrelimab 240 mg.

The safety profile of BALVERSA plus cetrelimab was generally similar to that of BALVERSA alone, see Table: Phase 2 Interim Analysis: Most Common TEAEs Occurring in ≥25% of Patients.⁴
Grade 3-4 TEAEs occurred in 9 patients (38%) in the BALVERSA arm and 12 patients (50%) in the BALVERSA plus cetrelimab arm; the most frequent were as follows⁴:
- BALVERSA arm: anemia (n=3 patients [12.5%]) and general physical health deterioration (n=3 [12.5%])
- BALVERSA plus cetrelimab arm: stomatitis (n=3 [12.5%]), lipase increased (n=3 [12.5%]), and fatigue (n=2 [8.3%]).
One death in the BALVERSA plus cetrelimab arm was determined to be related to cetrelimab (respiratory failure).⁴
The frequency of TEAEs of interest was mostly similar between arms, with the exception of immune-related TEAEs as summarized in Table: Phase 2 Interim Analysis: TEAEs of Interest for BALVERSA or Cetrelimab.

Phase 2 Interim Analysis: Most Common TEAEs Occurring in ≥25% of Patients⁴

Patients with TEAEs, n (%)	BALVERSA (n=24)	BALVERSA + Cetrelimab (n=24)
TEAE of any grade	23 (96)	23 (96)
Most frequent (≥25% of patients)
Hyperphosphatemia	14 (58)	14 (58)
Stomatitis	15 (63)	13 (54)
Diarrhea	12 (50)	10 (42)
Dry mouth	5 (21)	14 (58)
Dry skin	5 (21)	9 (38)
Anemia	6 (25)	6 (25)
Drug-related TEAEs leading to treatment discontinuation^a	2 (8)	BALVERSA and/or cetrelimab: 7 (29)^bBoth BALVERSA and cetrelimab: 2 (8)
Abbreviation: TEAE, treatment-emergent adverse event. ^aNo drug-related TEAE of the same type led to discontinuation in >1 patient. ^bFour patients discontinued only BALVERSA, 1 discontinued only cetrelimab, and 2 discontinued both.

Phase 2 Interim Analysis: TEAEs of Interest for BALVERSA or Cetrelimab⁴

Patients With TEAEs, n (%)	BALVERSA (n=24)		BALVERSA + Cetrelimab (n=24)
Patients With TEAEs, n (%)	Any Grade	Grade 3-4	Any Grade	Grade 3-4
TEAEs of interest
Nail toxicity	12 (50)	1 (4)	8 (33)	1 (4)
Skin toxicity	9 (38)	0	11 (46)	0
Eye toxicity (excluding CSR)	6 (25)	1 (4)	8 (33)	0
CSR	4 (17)	0	4 (17)	0
Immune-related TEAEs^a	1 (4)^b	0	12 (50)	4 (17)
Diarrhea	0	0	3 (13)	0
Lipase increased	0	0	3 (13)	2 (8)
Stomatitis	0	0	2 (8)	0
Anemia	0	0	2 (8)	0
Abbreviations: CSR, central serous retinopathy; TEAE, treatment-emergent adverse event. ^aImmune-related TEAEs (as reported by the investigator) in ≥2 patients are listed by preferred term. ^bNail toxicity reported as immune-related by investigator.

In the BALVERSA monotherapy treatment arm, 6 patients (14%) discontinued therapy due to TRAEs. No treatment-related deaths occurred.⁵
- The most frequent drug-related AE leading to discontinuation was stomatitis (n=2).
In the BALVERSA plus cetrelimab combination therapy arm, 9 patients (20.5%) discontinued BALVERSA, and 6 patients (13.6%) discontinued cetrelimab. One treatment-related death occurred due to pulmonary failure, determined to be related to cetrelimab.⁵
- Three patients (6.8%) discontinued both BALVERSA and cetrelimab due to treatment-related AEs.
- The most frequent drug-related AEs leading to discontinuation of BALVERSA were stomatitis (n=2) and nail dystrophy (n=2). No AE that led to discontinuation of cetrelimab occurred in >1 patient.

Phase 2 Final Analysis: Most Common TRAEs Occurring in ≥25% of Patients⁵

Patients With TRAEs, n (%)	BALVERSA (n=43)		BALVERSA + Cetrelimab (n=44)
Patients With TRAEs, n (%)	Any Grade	Grade 3-4	Any Grade	Grade 3-4
≥1 TRAE	41 (95.3)	20 (46.5)	43 (97.7)	20 (45.5)
Hyperphosphatemia	36 (83.7)	3 (7)	30 (68.2)	0
Stomatitis	30 (69.8)	7 (16.3)	25 (56.8)	4 (9.1)
Dry mouth	16 (37.2)	0	25 (56.8)	1 (2.3)
Diarrhea	18 (41.9)	2 (4.7)	13 (29.5)	1 (2.3)
Dry skin	14 (32.6)	0	16 (36.4)	0
Abbreviation: TRAE, treatment-related adverse event.

Phase 2 Final Analysis: TEAEs of Interest for BALVERSA or Cetrelimab⁵

Patients With TEAEs, n (%)	BALVERSA (n=43)		BALVERSA + Cetrelimab (n=44)
Patients With TEAEs, n (%)	Any Grade	Grade 3-4	Any Grade	Grade 3-4
Nail disorders	27 (62.8)	5 (11.6)	26 (59.1)	2 (4.5)
Skin disorders	25 (58.1)	1 (2.3)	24 (54.5)	4 (9.1)
Eye disorders (excluding CSR)	16 (37.2)	2 (4.7)	18 (40.9)	1 (2.3)
CSR^a	9 (20.9)	1 (2.3)	9 (20.5)	0
Immune-related TEAEs^b	0	0	16 (36.4)	6 (13.7)
Hypothyroidism	0	0	3 (6.8)	0
Lipase increased	0	0	3 (6.8)	1 (2.3)
Dry mouth	0	0	2 (4.5)	0
Alanine aminotransferase increased	0	0	2 (4.5)	2 (4.5)
Aspartate aminotransferase increased	0	0	2 (4.5)	2 (4.5)
Anemia	0	0	2 (4.5)	0
Abbreviations: CSR, central serous retinopathy; TEAE, treatment-emergent adverse event. ^aIncludes events with the following preferred terms: serous retinal detachment, chorioretinopathy, retinal detachment, detachment of retinal pigment epithelium, maculopathy, retinopathy, and subretinal fluid. ^bImmune-related TEAEs in ≥2 patients are listed by preferred term.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, DERWENT Drug File (and/or other resources, including internal/external databases) was conducted on 24 April 2024.

References

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