
==== Front
Int J Clin Oncol
Int J Clin Oncol
International Journal of Clinical Oncology
1341-9625
1437-7772
Springer Nature Singapore Singapore

39017806
2583
10.1007/s10147-024-02583-3
Original Article
Phase 3 THOR Japanese subgroup analysis: erdafitinib in advanced or metastatic urothelial cancer and fibroblast growth factor receptor alterations
Matsubara Nobuaki nmatsuba@east.ncc.go.jp

1
Miura Yuji 2
Nishiyama Hiroyuki 3
Taoka Rikiya 4
Kojima Takahiro 5
Shimizu Nobuaki 6
Hwang Jason 7
Ote Tatsuya 8
Oyama Ryo 9
Toyoizumi Kiichiro 10
Mukhopadhyay Sutapa 11
Triantos Spyros 12
Deprince Kris 13
Loriot Yohann 14
1 https://ror.org/03rm3gk43 grid.497282.2 Department of Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577 Japan
2 https://ror.org/05rkz5e28 grid.410813.f 0000 0004 1764 6940 Department of Medical Oncology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470 Japan
3 https://ror.org/02956yf07 grid.20515.33 0000 0001 2369 4728 Department of Urology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575 Japan
4 https://ror.org/04j7mzp05 grid.258331.e 0000 0000 8662 309X Department of Urology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793 Japan
5 https://ror.org/03kfmm080 grid.410800.d 0000 0001 0722 8444 Department of Urology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi 464-8681 Japan
6 grid.517686.b 0000 0004 1763 6849 Department of Urology, Gunma Prefectural Cancer Center, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511 Japan
7 grid.519059.1 Department of Medical Affairs, Janssen Pharmaceutical K.K, 5-2-3 Nishikanda, Chiyoda-ku, Tokyo, 101-0065 Japan
8 grid.519059.1 Oncology Clinical Development Department, Clinical Science Division, Research and Development, Janssen Pharmaceutical K.K, 5-2-3 Nishikanda, Chiyoda-ku, Tokyo, 101-0065 Japan
9 grid.519059.1 Research and Development, Janssen Pharmaceutical K.K, 5-2-3 Nishikanda, Chiyoda-ku, Tokyo, 101-0065 Japan
10 grid.519059.1 Statistics and Decision Sciences, Research and Development, Janssen Pharmaceutical K. K, 5-2-3 Nishikanda, Chiyoda-ku, Tokyo, 101-0065 Japan
11 grid.497530.c 0000 0004 0389 4927 Janssen Research and Development, 920 US Highway 202 S, Raritan, NJ 08807 USA
12 grid.497530.c 0000 0004 0389 4927 Janssen Research and Development, 1400 McKean Road, Spring House, PA 19477 USA
13 grid.419619.2 0000 0004 0623 0341 Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse Anterwerpen, Belgium
14 https://ror.org/03xjwb503 grid.460789.4 0000 0004 4910 6535 Department of Cancer Medicine, INSERM U981, Gustave Roussy, Universite Paris-Saclay, 94800 Villejuif, France
17 7 2024
17 7 2024
2024
29 10 15161527
22 5 2024
2 7 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Background

In the THOR trial (NCT03390504) Cohort 1, erdafitinib demonstrated significantly prolonged overall survival (OS) (median 12.1 versus 7.8 months) and reduced risk of death by 36% (hazard ratio 0.64, P = 0.005) compared with chemotherapy in metastatic urothelial carcinoma (mUC) patients with FGFR alterations who progressed after ≥ 1 prior treatments, including anti-PD-(L)1. There have been no reports of the Japanese subgroup results yet.

Methods

THOR Cohort 1 randomized patients to erdafitinib once daily or docetaxel/vinflunine once every 3 weeks. Primary endpoint was OS. Secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). No specific statistical power was set for this Japanese subgroup analysis.

Results

Of 266 patients randomized, 27 (14 erdafitinib; 13 chemotherapy) were Japanese. Baseline characteristics were generally similar between treatments and to the overall population, except for more males, lower body weight, and more upper tract primary tumors among Japanese patients. Compared with chemotherapy, erdafitinib showed improved OS (median 25.4 versus 12.4 months), PFS (median 8.4 versus 2.9 months) and ORR (57.1% versus 15.4%). Any grade treatment-related adverse events (AEs) occurred in all patients from both arms but Grade 3/4 AEs and AEs leading to discontinuation were lower in the erdafitinib arm. No new safety signals were observed in the Japanese subgroup.

Conclusion

In the Japanese subgroup, erdafitinib showed improved survival and response compared to chemotherapy, with no new safety concerns. These results support erdafitinib as a treatment option for Japanese mUC patients with FGFR alterations, and early FGFR testing after diagnosis of mUC should be considered.

Supplementary Information

The online version contains supplementary material available at 10.1007/s10147-024-02583-3.

Keywords

Erdafitinib
Fibroblast growth factor receptor
Japanese subgroup
Oral tyrosine kinase inhibitor
Metastatic urothelial carcinoma
Janssen Pharmaceutical K.K.issue-copyright-statement© Japan Society of Clinical Oncology 2024
==== Body
pmcIntroduction

Urothelial carcinoma, also known as transitional cell carcinoma, is the predominant type of bladder, renal pelvis and ureter cancer [1]. Urothelial carcinoma is common, especially in white people, men, smokers, and the elderly [2]. According to a structured literature search from 2001 to 2017, the incidence of locally advanced or metastatic urothelial cancer (mUC) was 3.8, 3.8 and 2.8 per 100,000 in the US, Europe, and Japan, respectively [3]. In Japan, a total of 1,162 new in-hospital cases were reported in 2021 to be locally advanced or metastatic urothelial carcinoma, which represented 3.4% of all urothelial carcinoma cases [4]. The prognosis of locally advanced or mUC is still poor [5], with an analysis of in-hospital cases in Japan reporting a 5-year survival rate of approximately 17% [6].

In Japan, first-line treatment generally follows the principles of international guidelines in recommending platinum-based chemotherapy with or without avelumab maintenance depending on disease progression during chemotherapy [7]. Second-line treatment with pembrolizumab is recommended for anti-PD-(L)1 checkpoint inhibitor-naïve patients [8], whereas either single-agent chemotherapy or enfortumab vedotin [9], are recommended in patients who have previously received chemotherapy and an anti-PD-(L)1 checkpoint inhibitor. Although anti-PD-(L)1 checkpoint inhibitors are used for both first- and second-line treatment, only approximately one-third of patients respond and treatment options following anti-PD-(L)1 checkpoint inhibitor therapy are limited.

Fibroblast growth factor receptors (FGFR) regulate several cellular processes such as migration, proliferation, differentiation, and survival especially during embryonic development, as well as inflammation and wound healing in adults [10], FGFR gene alterations, especially FGFR2/3 mutations and fusions, are noted in many malignancies, including urothelial carcinoma, and may function as oncogenic drivers to promote carcinogenesis [11–13]. Approximately 20% of patients with advanced urothelial carcinoma have FGFR alterations [11], which are almost twice as frequent in patients with upper tract urothelial carcinoma [14]. Therefore, addressing FGFR alterations in advanced urothelial carcinoma as a treatment target is a suitable strategy to improve survival outcomes in these patients.

Erdafitinib, an oral, selective small-molecule pan-FGFR tyrosine kinase inhibitor, has been shown to inhibit downstream FGFR signal transduction and signaling, and possess potent antiproliferative activity on FGFR-altered cancer cell lines [10]. In an open-label, phase 2 study (BLC2001), erdafitinib was associated with an objective tumor response in 40% of previously treated patients who had locally advanced and unresectable or mUC with selected FGFR3/2 alterations [15]. Accordingly, erdafitinib was granted accelerated approval by the US Food and Drug Administration [16]. Erdafitinib has also been approved in 17 other countries for treating adults with locally advanced or mUC with susceptible FGFR3/2 alterations but has not yet received approval in Japan.

Based on this background, the THOR study was conducted as a confirmatory study of the Phase 2 BLC2001 study and led to full US FDA approval. There have been no reports of the THOR Cohort 1 Japanese subgroup at present, so this subgroup analysis aims at clarifying the efficacy and safety results of Japanese patients enrolled in the study [17].

Methods

Study design and participants

THOR was an open-label, randomized, phase 3 study of erdafitinib versus chemotherapy conducted in 121 clinical sites globally, including 26 sites in Japan (ClinicalTrials.gov, NCT03390504) [17]. The study assigned patients into two cohorts based on prior treatment with an anti-PD-(L)1 checkpoint inhibitor, which compared erdafitinib with either choice of chemotherapy (docetaxel or vinflunine; Cohort 1) or with pembrolizumab (Cohort 2).

Inclusion and exclusion criteria have been published previously for the overall population. Patients with metastatic or surgically unresectable urothelial cancer with confirmed disease progression after one or two previous treatments that included an anti-PD-(L)1 checkpoint inhibitor were also required to meet molecular eligibility criteria. Molecular eligibility was confirmed using either central or local historical FGFR test results, with tumors having at least 1 of the following alterations: FGFR2-BICC1, FGFR2-CASP7, FGFR3-TACC3, FGFR3-BAIAP2L1; or 1 of the following FGFR3 gene mutations: R248C, S249C, G370C, Y373C. Eligible patients also had ECOG performance status of 0–2.

The final study protocol and related documents were approved by the institutional review board or independent ethics committee at each centre, and the trial was done in compliance with Good Clinical Practice, the International Conference on Harmonisation, the Declaration of Helsinki, and any local regulatory requirements. All enrolled patients provided written, informed consent.

Randomization and treatment

Patients in Cohort 1 were randomized 1:1 to erdafitinib or chemotherapy. Erdafitinib 8 mg once daily was administered orally for 21 days in a 21-day cycle with an option to up-titrate to 9 mg daily based on phosphate level measured at Cycle 1 Day 14 and in the absence of significant toxicity. Patients assigned to chemotherapy received either vinflunine or docetaxel determined by the investigator at each site. Randomization was stratified according to the ECOG performance-status score (0 or 1 versus 2), disease distribution (presence versus absence of visceral [lung, liver, or bone] metastases), and geographic region (North America versus Europe versus the rest of the world).

Treatment with erdafitinib or chemotherapy was continued until disease progression, intolerable toxicity, withdrawal of consent or decision by the investigator to discontinue treatment, whichever occurs first. Erdafitinib dose interruptions and reductions were permitted for the management of adverse events (AEs). Guidelines for the management of specific erdafitinib toxicities such as elevated phosphate levels, dry mouth and mucositis, dry skin and skin toxicity, nail toxicity (onycholysis, onychodystrophy, paronychia), eye toxicity associated with visual changes, and dry eye can be found in the protocol of previous publication [17].

Endpoints and evaluation

The intention-to-treat (ITT) population, consisting of all randomised patients, was used for analysis of efficacy endpoints. The safety population, defined as patients who received at least one dose of study drug, was used for analysis of safety endpoints.

The primary endpoint was OS, defined as the time from randomization to death from any cause. The secondary endpoints of interest for this subgroup analysis were PFS (duration from randomization to disease progression or death), ORR (proportion of patients who achieved complete response or partial response), and safety. Tumor response was assessed according to RECIST version 1.1 by investigator. Adverse events were graded according to the NCI-CTCAE version 4.03.

Analysis method and statistical methods

Details of the sample size and power calculations for the overall population have been published previously [17]. No tests of statistical power were applied to this analysis of the Japanese subgroup. Descriptive statistics were used to summarize the data with Kaplan–Meier (KM) estimates calculated for time-to-event variables. The Cox proportional hazard model was used to compare survival curves of OS and PFS between the 2 treatment arms.

Results

Between August 6, 2018, and January 15, 2023, a total of 266 patients were randomized (erdafitinib, n = 136; chemotherapy, n = 130), of whom 27 patients (erdafitinib, n = 14; chemotherapy, n = 13) were Japanese. All Japanese patients assigned to the chemotherapy arm received docetaxel. Patient disposition is shown in Fig. 1.Fig. 1 Patient disposition

Demographic and clinical characteristics

Baseline characteristics of the Japanese patients were generally similar between the erdafitinib and chemotherapy arms, except for a greater proportion of patients with upper tract as primary site (Table 1, Supplementary Table 1). Compared with the overall population, Japanese patients had a higher proportion of males (88.9% vs 71.4%), and lower median body weight (62.0 kg vs 70.9 kg). Furthermore, Japanese patients treated with erdafitinib had a higher proportion of patients with upper tract tumors (71.4% vs 30.1%) and ECOG PS 0 (92.9 vs 46.3%) than the overall population [17].Table 1 Baseline demographic and clinical characteristicsa

Characteristics	Japanese subpopulation	Overall population	
Erdafitinib
(N = 14)	Chemotherapy
(N = 13)	Erdafitinib
(N = 136)	Chemotherapy
(N = 130)	
Age, years, median (range)	68.5 (50, 81)	70.0 (51, 84)	66.0 (32, 85)	69.0 (35, 86)	
  < 65 years	5 (35.7%)	2 (15.4%)	59 (43.4%)	45 (34.6%)	
 65–69 years	2 (14.3%)	3 (23.1%)	30 (22.1%)	23 (17.7%)	
 70–74 years	4 (28.6%)	5 (38.5%)	21 (15.4%)	32 (24.6%)	
  ≥ 75 years	3 (21.4%)	3 (23.1%)	26 (19.1%)	30 (23.1%)	
Sex, n (%)	
 Male	12 (85.7%)	12 (92.3%)	96 (70.6%)	94 (72.3%)	
 Female	2 (14.3%)	1 (7.7%)	40 (29.4%)	36 (27.7%)	
Weight, kg, median (range)	62.2

(42.0, 84.6)

	62.0

(46.0, 72.0)

	71.0

(41.0, 166.0)

	70.3

(44.0, 113.0)

	
Primary tumor location, n (%)	
 Upper tract	10 (71.4%)	6 (46.2%)	41 (30.1%)	48 (36.9%)	
 Lower tract	4 (28.6%)	7 (53.8%)	95 (69.9%)	82 (63.1%)	
Baseline ECOGb, n (%)	
 0	13 (92.9%)	8 (61.5%)	63 (46.3%)	51 (39.2%)	
 1	1 (7.1%)	5 (38.5%)	61 (44.9%)	66 (50.8%)	
 2	0	0	12 (8.8%)	13 (10.0%)	
Visceral metastasis, n (%)	10 (71.4%)	9 (69.2%)	101 (74.3%)	97 (74.6%)	
PD-(L)1 Status, n (%)	
 CPSc ≥ 10	0	1 (16.7%)	7 (7.3%)	11 (13.9%)	
 CPSc < 10	9 (100.0%)	5 (83.3%)	89 (92.7%)	68 (86.1%)	
FGFR alterations, n (%)	
 Mutation	11 (78.6%)	10 (76.9%)	108 (79.4%)	107 (82.3%)	
 Fusion	3 (21.4%)	1 (7.7%)	25 (18.4%)	19 (14.6%)	
 Mutation and fusion	0	2 (15.4%)	2 (1.5%)	3 (2.3%)	
Number of prior systemic therapy lines, n (%)	
 1	4 (28.6%)	1 (7.7%)	45 (33.1%)	33 (25.4%)	
 2	10 (71.4%)	12 (92.3%)	90 (66.2%)	97 (74.6%)	
 3	0	0	1 (0.7%)	0	
CPS combined positive score, ECOG eastern cooperative oncology group

aPercentages may not total 100 because of rounding

bScores on the Eastern Cooperative Oncology Group (ECOG) scale range from 0 (no disability) to 5 (death)

cCPS is the number of PD-L1–staining tumor cells, lymphocytes, and macrophages, divided by the total number of viable tumor cells, multiplied by 100. Results are for patients with available data

Results of the FGFR genetic alterations analysis found that approximately 80% of Japanese patients had mutations (mostly FGFR3-Y373C and FGFR3-S249C) and a higher proportion of patients treated with erdafitinib had FGFR3 fusions (21.4% versus 7.7% in the chemotherapy arm) (Supplementary Table 2). This is similar to the pattern seen in the overall population, in which mutations (also mostly FGFR3-Y373C and FGFR3-S249C) occurred in approximately 80% of patients. Prior anti-cancer therapy consisted mainly of platinum-based chemotherapy, received by 85.2% of Japanese patients (Supplementary Table 3). Anti-PD-(L)1 therapy, most commonly pembrolizumab, was administered to all Japanese patients. Overall, the pattern of prior anti-cancer therapy use was similar between the Japanese subgroup and the overall population in Cohort 1.

As shown in Supplementary Table 4, 13 (92.9%) erdafitinib-treated patients had a serum phosphate concentration < 7.0 mg/dL at Cycle 1 Day 14 and 9 (64.3%) patients underwent up-titration. Overall, 12 (85.7%) of Japanese patients underwent at least one dose reduction, which was considerably higher than that observed in the overall population (51.1%). The extent of exposure was longer in erdafitinib-treated patients compared with chemotherapy-treated patients in the overall population and in Japanese patients in both arms compared with the overall population.

Subsequent anti-cancer therapy is shown in Supplementary Table 5. Compared with the chemotherapy arm, patients who received erdafitinib were treated with enfortumab vedotin as subsequent therapy more frequently in both the overall population and Japanese subgroup. Compared with the overall population, Japanese patients received 1–2 lines of subsequent therapy and enfortumab vedotin as subsequent therapy more frequently.

Efficacy

The median follow-up period was 19.0 months. Median OS was numerically greater in the erdafitinib arm (25.4 [95% CI 10.1, NE] months) compared with the chemotherapy arm (12.4 [4.4, NE] months) corresponding to a hazard ratio (HR) of 0.23 (0.06, 0.88; Fig. 2). OS in both arms as well as the OS difference was greater in the Japanese subgroup compared with the overall population in which the median OS in the erdafitinib arm (12.1 [95% CI 10.3, 16.4] months) and the chemotherapy arm (7.8 [6.5, 11.1] months) corresponded to a HR of 0.64 (0.47, 0.88; P = 0.005).Fig. 2 Kaplan–Meier plot of OS (primary endpoint) in Japanese patients

Median PFS in the erdafitinib arm (8.4 [95% CI 4.1, 11.1] months) was also greater than in the chemotherapy arm (2.9 [95% CI 1.3, 7.7] months; HR = 0.56 [95% CI 0.24, 1.31]; Fig. 3). In the overall population, the difference in PFS between the erdafitinib arm (5.6 [95% CI 4.4, 5.7] months) and chemotherapy arm (2.7 [95% CI 1.8, 3.7] months) was similar (HR = 0.58 [95% CI 0.44, 0.78]) to that observed in the Japanese subgroup.Fig. 3 Kaplan–Meier plot of PFS (secondary endpoint) in Japanese patients

ORR was higher in the erdafitinib arm than in the chemotherapy arm (57.1% vs 15.4%; relative benefit 3.71; 95% CI 0.96–14.37) (Fig. 4). These results were consistent with that of the overall population, although the ORR among Japanese patients treated with erdafitinib was higher than in the overall population (45.6%). The disease control rate was higher between the Japanese subgroup treatment arms (erdafitinib, 92.9%; chemotherapy, 76.9%; relative risk: 1.21 [95% CI 0.87, 1.68]) as well as in the overall population (erdafitinib, 82.4%; chemotherapy, 43.1%; relative risk: 1.91 [95% CI 1.55, 2.35]).Fig. 4 Objective response rate by investigator assessment

Safety

Treatment-related AEs occurred in 100% of patients in both the erdafitinib and chemotherapy arms and most were Grade 1–2 severity (Table 2). The most common treatment-related AEs in the erdafitinib arm were dysgeusia and hyperphosphatemia (71.4% each); onychomadesis (64.3%); dry mouth, diarrhea, and stomatitis (57.1% each; Table 3). The most common treatment-related AEs in the chemotherapy arm were alopecia (46.2%); neutropenia, leukopenia, and pyrexia (30.8% each); anemia, peripheral sensory neuropathy, and febrile neutropenia (23.1% each; Table 3). Grade 3–4 treatment-related AEs occurred in 6 patients (42.9%) in the erdafitinib arm and 8 patients (61.5%) in the chemotherapy arm. Treatment-related AEs leading to treatment discontinuation were not observed in the erdafitinib arm but noted in 2 patients (15.4%) in the chemotherapy arm. In contrast, treatment-related AEs leading to dose reduction or interruption were higher in the erdafitinib arm. There were no deaths related to AEs or treatment-related AEs in either treatment arm in the Japanese subgroup (Table 2). More specifically, the most common AEs leading to dose reduction (Supplementary Table 6) in the erdafitinib arm were onychomadesis (28.6%); chorioretinopathy, keratitis, and nausea (14.3% each). Similarly, the most common AEs leading to dose interruption (Supplementary Table 7) in the erdafitinib arm were onychomadesis (35.7%); paronychia (21.4%); nail discoloration, onycholysis, corneal disorder, and decreased appetite (14.3% each). AEs of clinical importance/ special interest such as nail, skin and eye toxicity including central serous retinopathy are also shown in Supplementary Table 8, where most of these toxicities were observed as Grade 1–2 severity in Japanese patients except for one case of Grade 3 skin toxicity (dry skin).Table 2 Overall safety summary

Adverse events, n (%)	Japanese subpopulation	Overall population	
Erdafitinib
(N = 14)	Chemotherapy
(N = 13)	Erdafitinib
(N = 135)	Chemotherapy
(N = 112)	
Any AE	14 (100.0%)	13 (100.0%)	133 (98.5%)	109 (97.3%)	
 Related AEsa	14 (100.0%)	13 (100.0%)	131 (97.0%)	97 (86.6%)	
AEs leading to deathb	0	0	6 (4.4%)	7 (6.3%)	
 Related AEsa leading to deathb	0	0	1 (0.7%)	6 (5.4%)	
Serious AEs	6 (42.9%)	3 (23.1%)	56 (41.5%)	47 (42.0%)	
 Related serious AEs	2 (14.3%)	1 (7.7%)	18 (13.3%)	27 (24.1%)	
AEs leading to discontinuation of study agent	0	3 (23.1%)	19 (14.1%)	20 (17.9%)	
 Related AEsa leading to discontinuation of study agent	0	2 (15.4%)	11 (8.1%)	15 (13.4%)	
AEs leading to dose reduction of study agent	12 (85.7%)	5 (38.5%)	93 (68.9%)	27 (24.1%)	
 Related AEsa leading to dose reduction of study agent	11 (78.6%)	4 (30.8%)	89 (65.9%)	24 (21.4%)	
AEs leading to dose interruption of study agent	12 (85.7%)	7 (53.8%)	97 (71.9%)	35 (31.3%)	
 Related AEsa leading to dose interruption of study agent	12 (85.7%)	6 (46.2%)	89 (65.9%)	22 (19.6%)	
Grade 3–4 AEs	8 (57.1%)	9 (69.2%)	85 (63.0%)	72 (64.3%)	
 Grade 3–4 related AEsa	6 (42.9%)	8 (61.5%)	62 (45.9%)	52 (46.4%)	
Grade 3–4 serious AEs	6 (42.9%)	2 (15.4%)	52 (38.5%)	41 (36.6%)	
 Grade 3–4 related serious AEsa	1 (7.1%)	0	16 (11.9%)	23 (20.5%)	
aAE is categorized as related if assessed by the investigator as possibly, probably, or very likely related to study agent

bAEs leading to death are based on AE outcome of Fatal

Table 3 Treatment-related AEs with frequency ≥ 15% in either treatment arm in the Japanese subpopulation and overall population

Event	Japanese subpopulation	Overall population	
Erdafitinib (N = 14)	Chemotherapy (N = 13)	Erdafitinib (N = 135)	Chemotherapy (N = 112)	
Grade	Grade	Grade	Grade	
All	1	2	 ≥ 3	All	1	2	 ≥ 3	All	1	2	 ≥ 3	All	1	2	 ≥ 3	
Dysgeusia	10

(71.4%)

	8

(57.1%)

	1

(7.1%)

	1

(7.1%)

	0	0	0	0	34 (25.2%)	25 (18.5%)	8

(5.9%)

	1

(0.7%)

	7

(6.3%)

	4

(3.6%)

	3

(2.7%)

	0	
Hyperphosphatemia	10

(71.4%)

	9

(64.3%)

	0	1

(7.1%)

	0	0	0	0	106

(78.5%)

	70

(51.9%)

	29

(21.5%)

	777

(5.2%)

	0	0	0	0	
Onychomadesis	9

(64.3%)

	3

(21.4%)

	6

(42.9%)

	0	2 (15.4%)	1

(7.7%)

	1

(7.7%)

	0	27

(20.0%)

	8

(5.9%)

	17

(12.6%)

	2

(1.5%)

	2

(1.8%)

	1

(0.9%)

	1

(0.9%)

	0	
Dry mouth	8

(57.1%)

	8

(57.1%)

	0	0	1

(7.7%)

	1

(7.7%)

	0	0	52

(38.5%)

	44

(32.6%)

	8

(5.9%)

	0	3

(2.7%)

	3

(2.7%)

	0	0	
Diarrhea	8

(57.1%)

	5

(35.7%)

	3

(21.4%)

	0	3 (23.1%)	0	3

(23.1%)

	0	74 (54.8%)	43

(31.9%)

	27

(20.0%)

	4

(3.0%)

	12

(10.7%)

	3

(2.7%)

	6

(5.4%)

	3

(2.7%)

	
Stomatitis	8

(57.1%)

	4

(28.6%)

	4

(28.6%)

	0	1

(7.7%)

	0	1

(7.7%)

	0	62 (45.9%)	20

(14.8%)

	31

(23.0%)

	11

(8.1%)

	13

(11.6%)

	4

(3.6%)

	7

(6.3%)

	2

(1.8%)

	
Alopecia	6

(42.9%)

	6

(42.9%)

	0	0	6

(46.2%)

	4

(30.8%)

	2

(15.4%)

	0	32 (23.7%)	27

(20.0%)

	4

(3.0%)

	1

(0.7%)

	24

(21.4%)

	15

(13.4%)

	9

(8.0%)

	0	
Paronychia	6

(42.9%)

	3

(21.4%)

	3

(21.4%)

	0	0	0	0	0	16

(11.9%)

	6

(4.4%)

	9

(6.7%)

	1

(0.7%)

	0	0	0	0	
Nail discoloration	5

(35.7%)

	4

(28.6%)

	1

(7.1%)

	0	1

(7.7%)

	0	1

(7.7%)

	0	24 (17.8%)	16

(11.9%)

	7

(5.2%)

	1

(0.7%)

	2

(1.8%)

	1

(0.9%)

	1

(0.9%)

	0	
Decreased appetite	5

(35.7%)

	2

(14.3%)

	1

(7.1%)

	2

(14.3%)

	2

(15.4%)

	2

(15.4%)

	0	0	28

(20.7%)

	15

(11.1%)

	10

(7.4%)

	3

(2.2%)

	20

(17.9%)

	8

(7.1%)

	9

(8.0%)

	3

(2.7%)

	
Dry skin	4

(28.6%)

	3

(21.4%)

	0	1

(7.1%)

	2

(15.4%)

	2

(15.4%)

	0	0	30

(22.2%)

	22

(16.3%)

	6

(4.4%)

	2

(1.5%)

	4

(3.6%)

	3

(2.7%)

	1

(0.9%)

	0	
Angular cheilitis	4

(28.6%)

	1

(7.1%)

	3

(21.4%)

	0	0	0	0	0	5

(3.7%)

	2

(1.5%)

	3

(2.2%)

	0	0	0	0	0	
Epistaxis	4

(28.6%)

	4

(28.6%)

	0	0	0	0	0	0	12

(8.9%)

	11

(8.9%)

	1

(0.7%)

	0	2

(1.8%)

	2

(1.8%)

	0	0	
Onycholysis	3

(21.4%)

	0	3

(21.4%)

	0	0	0	0	0	31

(23.0%)

	9

(6.7%)

	14

(10.4%)

	8

(5.9%)

	1

(0.9%)

	0	1

(0.9%)

	0	
Nausea	3

(21.4%)

	0	3

(21.4%)

	0	1

(7.7%)

	1

(7.7%)

	0	0	14

(10.4%)

	6

(4.4%)

	7

(5.2%)

	1

(0.7%)

	22

(19.6%)

	12

(10.7%)

	8

(7.1%)

	2

(1.8%)

	
Aspartate aminotransferase increased	3

(21.4%)

	2

(14.3%)

	1

(7.1%)

	0	0	0	0	0	25

(18.5%)

	18

(13.3%)

	5

(3.7%)

	2

(1.5%)

	1

(0.9%)

	1

(0.9%)

	0	0	
Anaemia	3

(21.4%)

	1

(7.1%)

	1

(7.1%)

	1

(7.1%)

	3

(23.1%)

	0	1

(7.7%)

	2

(15.4%)

	16 (11.9%)	8

(5.9%)

	4

(3.0%)

	4

(3.0%)

	31

(27.7%)

	6

(5.4%)

	18

(16.1%)

	7

(6.3%)

	
Constipation	1

(7.1%)

	1

(7.1%)

	0	0	2

(15.4%)

	2

(15.4%)

	0	0	12

(8.9%)

	8

(5.9%)

	4

(3.0%)

	0	21

(18.8%)

	9

(8.0%)

	10

(8.9%)

	2

(1.8%)

	
Fatigue	1

(7.1%)

	0	1

(7.1%)

	0	4

(30.8%)

	4

(30.8%)

	0	0	18

(13.3%)

	12

(8.9%)

	6

(4.4%)

	0	17

(15.2%)

	10

(8.9%)

	3

(2.7%)

	2

(1.8%)

	
Peripheral sensory neuropathy	0	0	0	0	3

(23.1%)

	2

(15.4%)

	1

(7.7%)

	0	4

(3.0%)

	3

(2.2%)

	1

(0.7%)

	0	6

(5.4%)

	2

(1.8%)

	3

(2.7%)

	1

(0.9%)

	
Pneumonitis	0	0	0	0	2

(15.4%)

	0	2

(15.4%)

	0	0	0	0	0	2

(1.8%)

	0	2

(1.8%)

	0	
Leukopenia	0	0	0	0	4

(30.8%)

	0	1

(7.7%)

	3

(23.1%)

	0	0	0	0	13 (11.6%)	3

(2.7%)

	1

(0.9%)

	9

(8.0%)

	
Neutropenia	0	0	0	0	4

(30.8%)

	0	0	4

(30.8%)

	0	0	0	0	21 (18.8%)	1

(0.9%)

	5

(4.5%)

	15

(13.4%)

	
Febrile neutropenia	0	0	0	0	3

(23.1%)

	0	1

(7.7%)

	2

(15.4%)

	0	0	0	0	9

(8.0%)

	0	1

(0.9%)

	8

(7.1%)

	
Pyrexia	0	0	0	0	4

(30.8%)

	4

(30.8%)

	0	0	3

(2.2%)

	1

(0.7%)

	2

(1.5%)

	0	7

(6.3%)

	7

(6.3%)

	0	0	
Oedema peripheral	0	0	0	0	3

(23.1%)

	1

(7.7%)

	1

(7.7%)

	1

(7.7%)

	1

(0.7%)

	1

(0.7%)

	0	0	7

(6.3%)

	3

(2.7%)

	2

(1.8%)

	2

(1.8%)

	
Malaise	0	0	0	0	2

(15.4%)

	2

(15.4%)

	0	0	0	0	0	0	3

(2.7%)

	2

(1.8%)

	1

(0.9%)

	0	
Palmar-plantar erythrodysaesthesia syndrome	2

(14.3%)

	0	2

(14.3%)

	0	0	0	0	0	41

(30.4%)

	6

(4.4%)

	22

(16.3%)

	13

(9.6%)

	1

(0.9%)

	0	1

(0.9%)

	0	
Alanine aminotransferase increased	2

(14.3%)

	2

(14.3%)

	0	0	0	0	0	0	29

(21.5%)

	18

(13.3%)

	7

(5.2%)

	4

(3.0%)

	3

(2.7%)

	2

(1.8%)

	0	1

(0.9%)

	
Asthenia	0	0	0	0	0	0	0	0	11

(8.1%)

	4

(3.0%)

	6

(4.4%)

	1

(0.7%)

	21

(18.8%)

	8

(7.1%)

	11

(9.8%)

	2

(1.8%)

	
Patients were counted only once for any given event, regardless of the number of times they actually experienced the event. The event experienced by the patient with the worst toxicity was used. If a patient had missing toxicity for a specific adverse event, the patient is only counted in the total column for that adverse event. AEs were coded using MedDRA Version 24.1

Discussion

This subgroup analysis of the THOR Cohort 1 study confirmed that the results observed in the Japanese subgroup are consistent with those of the overall population. No notable differences were found between Japanese subgroup and overall population in the analysis of FGFR genetic alterations and prior anti-cancer therapy. Consistent efficacy of erdafitinib was observed in Japanese patients in terms of the primary endpoint of OS as well as secondary endpoints. Specifically, median OS was 25.4 months with erdafitinib compared with 12.4 months with chemotherapy. Erdafitinib also provided longer PFS (8.4 vs 2.9 months) and greater ORR (57.1% vs 15.4%) compared with chemotherapy.

The median OS and PFS, as well as ORR in Japanese patients receiving erdafitinib compared with chemotherapy were numerically greater than in the overall population. However, the small patient numbers and lack of ability to assess for statistical significance, make it difficult to conclude erdafitinib is more effective in Japanese patients. More frequent dose reductions and lower discontinuation rate due to erdafitinib-related AEs in the Japanese subgroup might also contribute to these efficacy results. In this subgroup analysis, there were notable differences in the proportion of males, patients with upper tract tumors as primary site, and better performance status (ECOG PS 0) as well as lower body weight between the Japanese subgroup and the overall population. These discrepancies may have led to the differences in survival noted between the Japanese and overall populations. In particular, a possible survival benefit in patients with upper tract tumors was noted previously in the published results for the overall population [17]. The greater proportion of patients with upper tract tumors and better performance status in the Japanese subgroup receiving erdafitinib may, therefore, have influenced better survival compared with the overall population although this should be considered cautiously given the limitations of this subgroup analysis. Better baseline performance status among Japanese patients may also have translated to improved survival compared with the overall population.

This analysis also confirmed that the safety profile of erdafitinib in Japanese patients is consistent with that observed for the overall population with no new safety signals. Treatment-related AEs leading to treatment discontinuation were not observed in the erdafitinib arm, which contrasts with the results for the overall population in which treatment discontinuation occurred in 8.1% of patients who received erdafitinib. However, treatment-related events leading to dose reduction and interruption of erdafitinib occurred in a higher proportion of Japanese patients (78.6% and 85.7%, respectively) compared with the overall population (65.9% for both outcomes) [17].

Results of this study can help clinicians further understand the potential treatment sequence of erdafitinib as therapy after anti-PD(L)1 checkpoint inhibitor in locally advanced or mUC. Other recently investigated options include enfortumab vedotin, for which the results of the phase 3 EV-301 study found that OS was longer in the enfortumab vedotin group than in the chemotherapy group in a similar setting, including among Japanese patients [9, 18]. Therefore, erdafitinib provides an alternative effective option to enfortumab vedotin but with a different safety profile to consider, most notably in relation to the potential occurrence of central serous retinopathy. In the overall population, central serous retinopathy generally resolved or was of Grade 1 severity if ongoing after the clinical cutoff date but there was no specific follow-up observation of these AEs for Japanese patients. This consideration contrasts with those of other options, such as enfortumab vedotin, in which case cutaneous reactions and peripheral neuropathy are the most frequent treatment-related AEs of special interest. Erdafitinib also has the obvious advantage of being an oral formulation that is less burdensome and more convenient for patients, involving fewer and shorter hospital visits, and which allows physicians to adjust doses more conveniently to achieve a balance between efficacy and tolerability.

Definitive data on the prevalence of FGFR alterations in Japanese patients with urothelial cancer are lacking. In a large-scale cross-sectional study, the percentage of patients in the United States with urothelial cancer and FGFR alterations was estimated to be 23.0% [19]. Another study that characterized the molecular profile of patients with urothelial cancer found FGFR3 alteration occurred in 20% of patients [20]. It is reasonable to expect that the prevalence of FGFR alterations in Japanese patients with urothelial cancer would be similar to those noted elsewhere and affect approximately one in five patients. This highlights the importance of testing for FGFR2/3 alterations, ideally at first diagnosis, to appropriately plan treatment among FGFR-positive patients. In a US healthcare claims database cohort study, uptake of erdafitinib was limited despite it being the first gene-targeted therapy for urothelial carcinoma with real-world survival outcomes similar to that of clinical trials [21]. Inadequate FGFR testing likely underlies this, and expansion of FGFRalt2/3 blood-based testing, which captures susceptible alterations at a rate similar to that of tissue testing, has the potential to improve uptake of erdafitinib in suitable patients. Such FGFR testing performed early after diagnosis of mUC should be considered to determine which patients might derive benefit from this treatment option.

This subgroup analysis is limited by various factors, including the relatively small number of patients leading to a lack of statistical power to allow for formal statistical testing. The ad hoc nature of the analysis also limits the ability of the analysis to be confirmatory.

Conclusions

This Japanese subgroup analysis of the THOR study shows that erdafitinib improved survival and response compared to chemotherapy, with no new safety concerns. The survival benefits of erdafitinib in the Japanese subgroup supports early FGFR testing after diagnosis of mUC.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 54 KB)

Acknowledgements

The authors thank all patients, researchers, volunteers, and staff who participated in this study. The authors also thank Mark Snape, MB BS, of inScience Communications, Springer Healthcare, for providing medical writing assistance, which was funded by Janssen Pharmaceutical K.K. Erdafitinib (JNJ-42756493) was discovered in collaboration with Astex Pharmaceuticals. This subgroup analysis and medical writing assistance was supported by Janssen Pharmaceutical K.K.

Author contributions

NM was involved in conception or design, and data acquisition and interpretation. YM, HN, RT, TK, and NS were involved in data acquisition and interpretation. JH, TO, and RO were involved in data interpretation. KT was involved in data analysis and interpretation. SM, ST, KD, and YL were involved in conception or design, and data interpretation. All authors were involved in writing or reviewing the manuscript and approved the final version of the manuscript.

Data availability

Janssen Pharmaceutical Companies of Johnson & Johnson’s data sharing policy is available at https://www.janssen.com/clinicaltrials/transparency. As noted on this site, requests for study data access can be submitted through the Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.

Declarations

Conflict of interest

Nobuaki Matsubara has received grants or contracts from Janssen Pharmaceutical K.K., MSD K.K., Bayer Yakuhin, Ltd., Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., Astellas Pharma Inc., Bayer AG, Amgen K.K., Takeda Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Eisai Co. Ltd., Roche/Genentech, Seagen, Novartis Pharma K.K., and AbbVie Inc.; consulting fees from Sanofi K.K., Janssen Pharmaceutical K.K., AstraZeneca K.K., Eli Lilly Japan K.K., Amgen K.K., Seagen, and Pfizer Japan Inc.; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Sanofi K.K.. Yuji Miura has received grants or contracts from MSD and Ono Pharmaceutical Co., Ltd.; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Takeda Pharmaceutical Co., Ltd., Bristol-Myers Squibb K.K., Eisai Co. Ltd., Ono Pharmaceutical Co., Ltd., and MSD. Hiroyuki Nishiyama has received grants or contracts from Ono Pharmaceutical Co., Ltd., and Chugai Pharmaceutical Co., Ltd.; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MSD, Astellas Pharma Inc., Merck Biopharma Co. Ltd., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb K.K., and Nippon Fine Chemical Co., Ltd..; other financial or non-financial interests from Bayer Yakuhin, Ltd Rikiya Taoka and Nobuaki Shimizu report no conflicts of interest. Takahiro Kojima has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas Pharma Inc. Jason Hwang reports employment and employee stock ownership from Janssen Pharmaceutical K.K.; Tatsuya Ote reports employment from Janssen Pharmaceutical K.K., and employee stock ownership from Janssen Pharmaceutical K.K., and Johnson & Johnson. Ryo Oyama reports employment and employee stock ownership from Janssen Pharmaceutical K.K. Kiichiro Toyoizumi reports employment from Janssen Pharmaceutical K.K., and employee stock ownership from Johnson & Johnson. Sutapa Mukhopadhyay, Spyros Triantos, and Kris Deprince report employment from Janssen Research & Development, and employee stock ownership from Johnson & Johnson. Yohann Loriot has received grants or contracts from Janssen Oncology, MSD Oncology, AstraZeneca, Exelixis, Incyte, Pfizer Japan Inc., Sanofi K.K., Seagen, Astellas Pharma Inc., Gilead Sciences Inc., Merck KGaA, Taiho Pharmaceutical Co., Ltd., Bristol-Myers Squibb, Roche, and Tyra Biosciences; consulting fees from Janssen Pharmaceutical Co. Ltd., Astellas Pharma Inc., Roche, AstraZeneca, MSD Oncology, Seagen, Bristol-Myers Squibb, Taiho Pharmaceutical Co., Ltd., Loxo/Lilly, Pfizer/EMD Serono, Merck KGaA, Gilead Sciences, Pfizer Japan Inc., Roche, MSD Oncology; support for attending meetings and/or travel from Astellas Pharma, Janssen Oncology, Roche, MSD Oncology, AstraZeneca, and Seagen.

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References

1. Kaseb H, Aeddula N Bladder Cancer. [Updated 2022 Oct 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK536923/. Accessed 19 Oct 2023
2. Cumberbatch MGK Jubber I Black PC Epidemiology of bladder cancer: A systematic review and contemporary update of risk factors in 2018 Eur Urol 2018 74 6 784 795 10.1016/j.eururo.2018.09.001 30268659
Cumberbatch MGK, Jubber I, Black PC et al (2018) Epidemiology of bladder cancer: A systematic review and contemporary update of risk factors in 2018. Eur Urol 74(6):784–795. 10.1016/j.eururo.2018.09.00130268659
3. Bharmal M Guenther S Kearney M Epidemiology of locally advanced or metastatic urothelial cancer in the US Europe and Japan Value Health 2017 20 9 A419 10.1016/j.jval.2017.08.127
Bharmal M, Guenther S, Kearney M (2017) Epidemiology of locally advanced or metastatic urothelial cancer in the US Europe and Japan. Value Health 20(9):A419. 10.1016/j.jval.2017.08.127
4. National cancer center in-hospital cancer registries nationwide tally [In Japanese]. Available at: https://ganjoho.jp/public/qa_links/report/hosp_c/hosp_c_registry.html. Accessed 21 Nov 2023
5. Fischer C Hofmann R Hegele A Chemotherapy of locally advanced or metastatic urothelial cell carcinoma: monocentric real-life data Cancer Manag Res 2020 12 5077 5084 10.2147/cmar.S231508 32636673
Fischer C, Hofmann R, Hegele A (2020) Chemotherapy of locally advanced or metastatic urothelial cell carcinoma: monocentric real-life data. Cancer Manag Res 12:5077–5084. 10.2147/cmar.S23150832636673
6. National cancer center in-hospital cancer registry survival rate aggregation. Available at: https://ganjoho.jp/public/qa_links/report/hosp_c/hosp_c_reg_surv/index.html. Accessed 21 Nov 2023
7. The Japanese urological association (Bladder cancer treatment guidelines (2019 edn). Available at: https://www.urol.or.jp/lib/files/other/guideline/39_bladder_cancer_2019_rev2021_info.pdf. Accessed 21 Nov 2023
8. Bellmunt J de Wit R Vaughn DJ Pembrolizumab as second-line therapy for advanced urothelial carcinoma New Engl J Med 2017 376 11 1015 1026 10.1056/NEJMoa1613683 28212060
Bellmunt J, de Wit R, Vaughn DJ et al (2017) Pembrolizumab as second-line therapy for advanced urothelial carcinoma. New Engl J Med 376(11):1015–1026. 10.1056/NEJMoa161368328212060
9. Powles T Rosenberg JE Sonpavde GP Enfortumab vedotin in previously treated advanced urothelial carcinoma New Engl J Med 2021 384 12 1125 1135 10.1056/NEJMoa2035807 33577729
Powles T, Rosenberg JE, Sonpavde GP et al (2021) Enfortumab vedotin in previously treated advanced urothelial carcinoma. New Engl J Med 384(12):1125–1135. 10.1056/NEJMoa203580733577729
10. Perera TPS Jovcheva E Mevellec L Discovery and pharmacological characterization of JNJ-42756493 (erdafitinib), a functionally selective small-molecule FGFR family inhibitor Mole Cancer Ther 2017 16 6 1010 1020 10.1158/1535-7163.Mct-16-0589
Perera TPS, Jovcheva E, Mevellec L et al (2017) Discovery and pharmacological characterization of JNJ-42756493 (erdafitinib), a functionally selective small-molecule FGFR family inhibitor. Mole Cancer Ther 16(6):1010–1020. 10.1158/1535-7163.Mct-16-0589
11. Haugsten EM Wiedlocha A Olsnes S Roles of fibroblast growth factor receptors in carcinogenesis Mole Cancer Res: MCR 2010 8 11 1439 1452 10.1158/1541-7786.Mcr-10-0168
Haugsten EM, Wiedlocha A, Olsnes S et al (2010) Roles of fibroblast growth factor receptors in carcinogenesis. Mole Cancer Res: MCR 8(11):1439–1452. 10.1158/1541-7786.Mcr-10-0168
12. Knowles MA Novel therapeutic targets in bladder cancer: mutation and expression of FGF receptors Future Oncol (London, England) 2008 4 1 71 83 10.2217/14796694.4.1.71
Knowles MA (2008) Novel therapeutic targets in bladder cancer: mutation and expression of FGF receptors. Future Oncol (London, England) 4(1):71–83. 10.2217/14796694.4.1.71
13. Turo R Harnden P Thygesen H FGFR3 expression in primary invasive bladder cancers and matched lymph node metastases J Urol 2015 193 1 325 330 10.1016/j.juro.2014.06.026 24933362
Turo R, Harnden P, Thygesen H et al (2015) FGFR3 expression in primary invasive bladder cancers and matched lymph node metastases. J Urol 193(1):325–330. 10.1016/j.juro.2014.06.02624933362
14. Li Q Bagrodia A Cha EK Prognostic genetic signatures in upper tract urothelial carcinoma Curr Urol Rep 2016 17 2 12 10.1007/s11934-015-0566-y 26757906
Li Q, Bagrodia A, Cha EK et al (2016) Prognostic genetic signatures in upper tract urothelial carcinoma. Curr Urol Rep 17(2):12. 10.1007/s11934-015-0566-y26757906
15. Loriot Y Necchi A Park SH Erdafitinib in locally advanced or metastatic urothelial carcinoma New Engl J Med 2019 381 4 338 348 10.1056/NEJMoa1817323 31340094
Loriot Y, Necchi A, Park SH et al (2019) Erdafitinib in locally advanced or metastatic urothelial carcinoma. New Engl J Med 381(4):338–348. 10.1056/NEJMoa181732331340094
16. U.S. Food and Drug Administration FDA grants accelerated approval to erdafitinib for metastatic urothelial carcinoma. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-erdafitinib-metastatic-urothelial-carcinoma. Accessed 17 Oct 2023
17. Loriot Y Matsubara N Park SH Erdafitinib or chemotherapy in advanced or metastatic urothelial carcinoma New Engl J Med 2023 10.1056/NEJMoa2308849 37870920
Loriot Y, Matsubara N, Park SH et al (2023) Erdafitinib or chemotherapy in advanced or metastatic urothelial carcinoma. New Engl J Med. 10.1056/NEJMoa230884937870920
18. Matsubara N Yonese J Kojima T Japanese subgroup analysis of EV-301: An open-label, randomized phase 3 study to evaluate enfortumab vedotin versus chemotherapy in subjects with previously treated locally advanced or metastatic urothelial carcinoma Cancer Med 2023 12 3 2761 2771 10.1002/cam4.5165 36052536
Matsubara N, Yonese J, Kojima T et al (2023) Japanese subgroup analysis of EV-301: An open-label, randomized phase 3 study to evaluate enfortumab vedotin versus chemotherapy in subjects with previously treated locally advanced or metastatic urothelial carcinoma. Cancer Med 12(3):2761–2771. 10.1002/cam4.516536052536
19. de Almeida CLM de Oliveira SAS Haslam A Estimation of percentage of patients with fibroblast growth factor receptor alterations eligible for off-label use of erdafitinib JAMA Netw Open 2019 2 11 e1916091 e1916091 10.1001/jamanetworkopen.2019.16091 31755953
de Almeida CLM, de Oliveira SAS, Haslam A et al (2019) Estimation of percentage of patients with fibroblast growth factor receptor alterations eligible for off-label use of erdafitinib. JAMA Netw Open 2(11):e1916091–e1916091. 10.1001/jamanetworkopen.2019.1609131755953
20. Knowles MA Hurst CD Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity Nat Rev Cancer 2015 15 1 25 41 10.1038/nrc3817 25533674
Knowles MA, Hurst CD (2015) Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer 15(1):25–41. 10.1038/nrc381725533674
21. Nimgaonkar V Hubbard RA Carpenter EL Biomarker testing, treatment uptake, and survival among patients with urothelial cancer receiving gene-targeted therapy JAMA Oncol 2022 8 7 1070 1072 10.1001/jamaoncol.2022.1167 35551582
Nimgaonkar V, Hubbard RA, Carpenter EL et al (2022) Biomarker testing, treatment uptake, and survival among patients with urothelial cancer receiving gene-targeted therapy. JAMA Oncol 8(7):1070–1072. 10.1001/jamaoncol.2022.116735551582
