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BALVERSA® (erdafitinib)

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BALVERSA - THOR Study

Last Updated: 06/03/2024

Click on the following links to related sections within the document: Study Overview and Study Design

Abbreviations: AE, adverse event; C1D1, cycle 1 day 1; CNS, central nervous system; CrCl, creatinine clearance; CV, cardiovascular; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EQ-5D-5L, European Quality of Life-5 Dimensions-5 Levels Questionnaire; FACT-B1, Functional Assessment of Cancer Therapy-Bladder Cancer; FGFR, fibroblast growth factor receptor; HIV, human immunodeficiency virus; IV, intravenous; ORR, objective response rate; OS, overall survival; PD-[L]1, programmed death-ligand 1 or programmed death-1; PFS, progression-free survival; PGIS, Patient-Global Impression of Severity; PO4, phosphate; Q3W, every 3 weeks; UC, urothelial carcinoma; ULN, upper limit of normal.
aLoriot (2023){Siefker-Radtke,  #9}.1
bClinicalTrials.gov. NCT03390504 (2022).2
cRandomization stratified by region (North America vs European Union vs rest of the world), ECOG PS (0 vs 1 vs 2), and disease distribution (presence or absence of visceral metastases: lung, liver, or bone).

SUMMARY  

  • THOR (BLC-3001/NCT03390504) 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 urothelial carcinoma (UC) and selected fibroblast growth factor receptor (FGFR) gene alterations that has progressed during or after 1 or 2 prior lines of therapy. The primary endpoint is overall survival (OS).1,2
  • Loriot et al (2023)1 presented results from cohort 1 (n=266) after a median follow-up of 15.9 months. The median OS was 12.1 months for patients receiving BALVERSA vs 7.8 months for patients receiving chemotherapy. A 36% reduction in risk of death was observed in patients receiving BALVERSA (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.47-0.88; P=0.005). Median progression free survival (PFS) was 5.6 months for patients receiving BALVERSA vs 2.7 months for patients receiving chemotherapy. Objective response rate (ORR) was 45.6% for patients receiving BALVERSA vs 11.5% for patients receiving chemotherapy. The safety profiles were consistent with the known safety profiles of BALVERSA and chemotherapy.
    • Matsubara et al (2023)3 presented efficacy and safety results in the Asian subgroup of THOR cohort 1 (n=76 randomized). The median OS was 23.3 months for patients receiving BALVERSA vs 11.3 months for patients receiving chemotherapy (HR, 0.47; 95% CI, 0.23-0.96; P=0.0327). Median PFS was 5.6 months for patients receiving BALVERSA vs 2.7 months for patients receiving chemotherapy (HR, 0.49; 95% CI, 0.27-0.88; P=0.0144). ORR was 48.6% (n=18) for patients receiving BALVERSA vs 7.7% (n=3) for patients receiving chemotherapy. Disease control rate (DCR) was 86.5% (n=32) for patients receiving BALVERSA vs 43.6% (n=17) for patients receiving chemotherapy. Median duration of response (DOR) was 6.7 months for patients receiving BALVERSA vs 4.9 months for patients receiving chemotherapy. The safety profiles were consistent with the known profiles of BALVERSA and chemotherapy in the Asian and overall populations.
  • Siefker-Radtke et al (2023)4 presented results from cohort 2 (n=351) of the THOR study. The median OS was 10.9 months for patients receiving BALVERSA vs 11.1 months for patients receiving pembrolizumab (HR, 1.18; 95% CI, 0.9-1.5; P=0.18). Median PFS was 4.4 months for patients receiving BALVERSA vs 2.7 months for patients receiving pembrolizumab (HR, 0.88; 95% CI, 0.70-1.10). ORR was 40% for patients receiving BALVERSA vs 21.6% for patients receiving pembrolizumab. Median DOR was 4.3 months for patients receiving BALVERSA vs 14.4 months for patients receiving pembrolizumab. Safety profiles were consistent with the known safety profiles of BALVERSA and pembrolizumab.
  • Siefker-Radtke et al (2024)5 conducted an analysis of tumors from THOR cohort 2 to evaluate the association of molecular subtype with clinical outcomes in patients receiving BALVERSA (n=65) vs pembrolizumab (n=87). Within the luminal-papillary (LumP) subtype, ORR (41.7 vs 19.7%; P=0.0129), median PFS (5.52 vs 2.73 months), and median OS (10.94 vs 12.94 months) were reported with patients receiving BALVERSA vs pembrolizumab.
  • For information regarding this ongoing clinical trial, please visit https://clinicaltrials.gov.

CLINICAL STUDY

THOR Study

THOR is an ongoing study evaluating the efficacy and safety of BALVERSA vs standard of care chemotherapy (docetaxel or vinflunine) or pembrolizumab in patients with metastatic or unresectable UC and selected FGFR gene alterations that has progressed during or after  1 or 2 prior lines of therapy.1,2

Study Design/Methods

  • Phase 3, randomized, open-label, multicenter study
  • A total of 629 patients from 345 study locations were screened for the presence of FGFR gene alterations and assigned to 2 cohorts based on prior treatment with anti-PD-(L)1 agent:
    • Cohort 1 (n=266): prior chemotherapy with anti-PD-(L)1 treatment in combination or maintenance setting (anti-PD-[L]1 alone in cisplatin-ineligible patients only)1,6
      • Patients were randomized 1:1 to receive:
        • BALVERSA at a starting dose of 8 mg once daily, with uptitration to 9 mg once daily based on day 14 serum phosphate levels (≤9.0 mg/dL and no associated adverse events [AEs]).6
        • Chemotherapy (docetaxel 75 mg/m2 as a 1-hour intravenous [IV] infusion every 3 weeks [Q3W] or vinflunine 320 mg/m2 as a 20-minute IV infusion once Q3W)
    • Cohort 2 (n=351): prior chemotherapy without anti-PD-(L)1 treatment4
      • Patients were randomized 1:1 to receive:
        • BALVERSA at a starting dose of 8 mg once daily, with uptitration to 9 mg once daily based on day 14 serum phosphate levels (≤9.0 mg/dL and no associated AEs).6
        • Pembrolizumab 200 mg as a 30-minute IV infusion once Q3W
  • Randomization will be stratified by region (North America vs European Union vs rest of the world), Eastern Cooperative Oncology Group performance status (ECOG PS; 0 vs 1 vs 2), and disease distribution (presence or absence of visceral metastases: lung, liver, or bone).
  • Treatment will continue until disease progression, intolerable toxicity, withdrawal of consent, or decision by the investigator to discontinue treatment.
  • Disease assessments by computed tomography (CT) or magnetic resonance imaging (MRI) will be performed every 6 weeks for 6 months followed by every 12 weeks for the next 6 months and then as clinically indicated.
  • Tumor responses will be evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
  • Select inclusion criteria: adult patients with stage 4 carcinoma of the urothelium and documented progression; only 1 line of prior systemic treatment for metastatic UC (cohort 1: prior treatment with an anti-PD-(L)1 agent as monotherapy or as combination therapy; ≤2 prior lines of systemic treatment; cohort 2: prior chemotherapy [no prior treatment with an anti-PD-(L)1 agent; only 1 line of prior systemic treatment])2; patients who received neoadjuvant or adjuvant chemotherapy and showed disease progression within 12 months of the last dose are considered to have received systemic chemotherapy in the metastatic setting); tumors with ≥1 select FGFR3 or FGFR2 fusion or mutation determined by central laboratory screening; ECOG PS ≤2; adequate bone marrow, liver, and renal function (creatinine clearance >30 mL/min/1.73 m2); phosphate levels <upper limit of normal (ULN) within 14 days of treatment and prior to first day of cycle 1 day 1 (C1D1).
  • Select exclusion criteria: treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 30 days before randomization; active malignancies (ie, requiring treatment change in the last 24 months) other than UC (except skin cancer within the last 24 months that is considered completely cured); symptomatic central nervous system (CNS) metastases; prior FGFR inhibitor treatment; corneal or retinal abnormality including central serous retinopathy (CSR) or retinal pigment epithelial detachment (RPED) of any grade; history of uncontrolled cardiovascular disease or known active human immunodeficiency virus, hepatitis B or C infection
  • Primary endpoint: OS
  • Secondary endpoints: PFS, ORR, DOR, patient-reported outcomes (Functional Assessment of Cancer Therapy-Bladder Cancer [FACT-B1], Patient-Global Impression of Severity [PGIS], European Quality of Life-5 Dimensions-5 Levels Questionnaire [EQ-5D-5L]), safety, and pharmacokinetics (PK)

Results

Cohort 1

Loriot et al (2023)1 reported interim results from cohort 1 of the THOR study (n=266).

Patient Characteristics

Cohort 1 Select Baseline Demographics and Disease Characteristics1
BALVERSA (n=136)
Chemotherapy (n=130)
Median age (range), years
66 (32-85)
69 (35-86)
Male, n (%)
96 (70.6)
94 (72.3)
Race, n (%)
White
81 (59.6)
63 (48.5)
Asian
37 (27.2)
40 (30.8)
Black or African American
0
1 (0.8)
Multiple
0
1 (0.8)
Not reported
18 (13.2)
25 (19.2)
Geographic region, n (%)
North America
8 (5.9)
5 (3.8)
Europe
82 (60.3)
80 (61.5)
Rest of the world
46 (33.8)
45 (34.6)
Visceral metastasis, n (%)
Present (lung, liver, or bone)
101 (74.3)
97 (74.6)
Absent
35 (25.7)
33 (25.4)
ECOG PS score, n (%)
0
63 (46.3)
51 (39.2)
1
61 (44.9)
66 (50.8)
2
12 (8.8)
13 (10)
Primary tumor location, n (%)
Upper tract
41 (30.1)
48 (36.9)
Lower tract
95 (69.9)
82 (63.1)
PD-(L)1 status, n/total (%)a
CPS <10
89/96 (93)
68/79 (86)
CPS ≥10
7/96 (7)
11/79 (14)
FGFR alterations, n (%)
Mutation
108 (79.4)
107 (82.3)
Fusion
25 (18.4)
19 (14.6)
Mutation and fusion
2 (1.5)
3 (2.3)

False positive result
1 (0.7)
1 (0.8)
Prior lines of systemic therapy,n (%)
1 line
45 (33.1)
33 (25.4)
2 lines
90 (66.2)
97 (74.6)
3 lines
1 (0.7)
0
Abbreviations: CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; FGFR, fibroblast growth factor receptor; PD-(L)1, programmed death-ligand 1.
aThe CPS is the number of PD-(L)1-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.

Cohort 1 Patients with Prior Systemic Therapy1,7
Patients Receiving Prior Therapy, n (%)
BALVERSA (n=136)a
Chemotherapy
(n=130)
1 line of prior systemic therapy
45 (33.1)
33 (25.4)
Chemotherapy + anti-PD-(L)1b
33 (24.3)
15 (11.5)
Anti-PD-(L)1c
11 (8.1)
16 (12.3)
Chemotherapy
1 (0.7)
2 (1.5)
2 lines of prior systemic therapy
90 (66.2)
97 (74.6)

First line of therapy

Chemotherapy
77 (56.6)
76 (58.5)
Chemotherapy + anti-PD-(L)1
6 (4.4)
10 (7.7)

Other
7 (5.1)
11 (8.5)

Second line of therapy
Anti-PD-(L)1
76 (55.9)
76 (58.5)
Chemotherapy
10 (7.4)
14 (10.8)
Other
4 (2.9)
7 (5.4)
Abbreviation: PD-(L)1, programmed death-ligand 1.
aOne patient in the BALVERSA group had 3 prior lines of systemic therapy.
bIncludes patients who received other therapy in addition to chemotherapy + anti-PD(L)1.
cIncludes patients who received other therapy in addition to anti-PD-(L)1.
Efficacy: Cohort 11
  • At a median follow-up of 15.9 months, the median OS was 12.1 months for patients receiving BALVERSA vs 7.8 months for patients receiving chemotherapy. BALVERSA reduced the risk of death by 36% vs chemotherapy.
    • HR, 0.64 (95% CI, 0.47-0.88; P=0.005).
  • Median PFS was 5.6 months for patients receiving BALVERSA vs 2.7 months for patients receiving chemotherapy. BALVERSA reduced the risk of progression or death by 42% vs chemotherapy.7
    • HR, 0.58 (95% CI, 0.44-0.78; P<0.001).
  • Patients receiving BALVERSA (n=136) had an ORR of 45.6%, 9 (6.6%) patients had a complete response (CR), and 53 (39%) patients had a partial response (PR). Patients receiving chemotherapy (n=130) had an ORR of 11.5%, 1 (0.8%) patient had a CR, and 14 (10.8%) patients had a PR.7
    • Relative risk (RR), 3.94 (95% CI, 2.37-6.57; P<0.001).
  • OS across clinically relevant subgroups was evaluated, please refer to Table: Cohort 1 Efficacy Analysis: HR for OS Across Clinically Relevant Subgroups.

Cohort 1 Efficacy Analysis: HR for OS Across Clinically Relevant Subgroups8
Subgroups
BALVERSA n/Na
Median OS, mo
Chemotherapy n/Na
Median OS, mo
HR (95%, CI)
Overall
77/136
12.1
78/130
7.8
0.64 (0.47-0.88)
Age group
<65 years
36/59
14
25/45
8.7
0.46 (0.27-0.79)
≥65 years
41/77
10.9
53/85
7.6
0.71 (0.47-1.07)
Gender
Female
24/40
10.6
24/36
7.3
0.71 (0.4-1.26)
Male
53/96
14
54/94
8.7
0.61 (0.41-0.89)
FGFR alterations
Translocation
13/25
16.4
15/19
8
0.49 (0.23-1.03)
Mutation
63/108
10.9
60/107
7.7
0.67 (0.47-0.95)
Baseline ECOG PS
0-1
70/125
12.2
71/119
8.7
0.65 (0.46-0.9)
2
7/11
6.1
7/11
2.8
0.47 (0.16-1.35)
Baseline creatinine clearance
30-≤60 mL/min
30/57
11.6
47/73
7.3
0.55 (0.34-0.87)
≥60 mL/min
46/77
13.2
31/56
9.6
0.73 (0.46-1.15)
PD-(L)1 status
CPS ≥10
5/7
10.2
8/11
19.6
1.98 (0.57-6.91)
CPS <10
53/89
12.1
40/68
8.8
0.58 (0.38-0.89)
Primary tumor location
Upper tract
16/41
23.3
27/48
7.2
0.34 (0.18-0.64)
Lower tract
61/95
10.5
51/82
9.6
0.82 (0.56-1.18)
Lines of prior treatment
1 line
27/45
14
21/33
7.8
0.61 (0.35-1.09)
2 lines
49/90
11.6
57/97
7.7
0.67 (0.45-0.98)
Prior anticancer therapy
PBC
70/122
11.6
64/111
7.7
0.67 (0.48-0.94)
No PBC
7/14
20.5
14/19
8.7
0.43 (0.17-1.06)
Anti PD-(L)1 therapy
First line
35/57
14.3
29/50
8.7
0.61 (0.37-1.01)
Second line
42/78
10.8
49/80
7.7
0.71 (0.47-1.07)
Chemotherapy
Docetaxel
77/136
12.1
40/69
10.6
0.76 (0.52-1.11)
Vinflunine
77/136
12.1
30/43
7.7
0.6 (0.39-0.92)
Visceral metastasis
Presence
59/103
12.2
57/101
7.7
0.65 (0.45-0.93)
Absence
18/33
10.6
21/29
8.8
0.61 (0.32-1.14)
Bone metastasis
Presence
25/36
10.3
28/39
6.3
0.57 (0.33-0.99)
Absence
52/100
14.7
50/91
10.3
0.68 (0.46-1)
Liver metastasis
Presence
24/31
8.5
26/38
6.5
0.76 (0.43-1.32)
Absence
53/105
15.7
52/92
10.6
0.6 (0.41-0.89)
Lung metastasis
Presence
38/71
14.7
39/67
7.5
0.59 (0.37-0.92)
Absence
39/65
10.6
39/63
9.6
0.73 (0.47-1.13)
Abbreviations: CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; FGFR, fibroblast growth factor receptor; HR, hazard ration; mo, months; PBC, platinum based chemotherapy; PD-(L)1, programmed death-ligand 1.
aNumber of events/patients
Safety: Cohort 11
  • In the BALVERSA treatment arm (n=135), 62 (45.9%) patients had grade
  • 3-4 treatment-related adverse events (TRAEs; most frequent grade 3-4 TRAEs were palmar-plantar erythrodysesthesia syndrome [13 patients, 9.6%], stomatitis [11 patients, 8.1%], onycholysis [8 patients, 5.9%], and hyperphosphatemia [7 patients, 5.2%]), 18 (13.3%) patients had treatment-related serious AEs, and 1 treatment-related death occurred (reported as sudden death).
    • The median duration of exposure in the BALVERSA treatment arm was 4.8 months (range, 0.2 to 38.2).
    • In the BALVERSA group, AEs of any cause led to treatment discontinuation in 19 (14.1%) patients and TRAEs that led to treatment discontinuation occurred in 8.1% of patients.
    • Grade 3/4 AEs of interest based on the known safety profile of BALVERSA included skin disorders (11.9%), nail disorders (11.1%), central serous retinopathy (CSR; 2.2%), and other eye disorders (2.2%).
    • In 16 of 23 patients (70%) with central serous retinopathy of any grade, events were resolved by the clinical cutoff date. Among the 7 patients with ongoing events, the events in 5 patients were grade 1.
  • In the chemotherapy treatment arm (n=112), 52 (46.4%) patients had grade 3-4 TRAEs (most frequent grade 3-4 TRAEs were neutropenia [15 patients, 13.4%] and anemia [7 patients, 6.2%]), 27 (24.1%) patients had treatment-related serious AEs, and 6 treatment-related deaths occurred (reported as 2 each with febrile bone marrow aplasia and septic shock, 1 each with atypical pneumonia and febrile neutropenia).
    • The median duration of exposure in the chemotherapy treatment arm was 1.4 months (range, 0.03 to 27.0).
    • In the chemotherapy group, AEs of any cause led to treatment discontinuation in 20 (17.9%) patients and TRAEs that led to treatment discontinuation occurred in 13.4% of patients.

Cohort 1 TRAEs in the Safety Population7
TRAEs, n (%)
BALVERSA (n=135)
Chemotherapy (n=112)
Any Grade
Grade ≥3
Any Grade
Grade ≥3
Hyperphosphatemia
106 (78.5)
7 (5.2)
0
0
Diarrhea
74 (54.8)
4 (3.0)
12 (10.7)
3 (2.7)
Stomatitis
62 (45.9)
11 (8.1)
13 (11.6)
2 (1.8)
Dry mouth
52 (38.5)
0
3 (2.7)
0
Palmar-plantar erythrodysesthesia syndrome
41 (30.4)
13 (9.6)
1 (0.9)
0
Dysgeusia
34 (25.2)
1 (0.7)
7 (6.3)
0
Alopecia
32 (23.7)
1 (0.7)
24 (21.4)
0
Onycholysis
31 (23.0)
8 (5.9)
1 (0.9)
0
Dry skin
30 (22.2)
2 (1.5)
4 (3.6)
0
ALT increased
29 (21.5)
4 (3.0)
3 (2.7)
1 (0.9)
Decreased appetite
28 (20.7)
3 (2.2)
20 (17.9)
3 (2.7)
Onychomadesis
27 (20.0)
2 (1.5)
2 (1.8)
0
AST increased
25 (18.5)
2 (1.5)
1 (0.9)
0
Nail discoloration
24 (17.8)
1 (0.7)
2 (1.8)
0
Dry eye
22 (16.3)
0
2 (1.8)
0
Anemia
16 (11.9)
4 (3.0)
31 (27.7)
7 (6.3)
Nausea
14 (10.4)
1 (0.7)
22 (19.6)
2 (1.8)
Asthenia
11 (8.1)
0
21 (18.8)
2 (1.8)
Constipation
12 (8.9)
0
21 (18.8)
2 (1.8)
Neutropenia
0
0
21 (18.8)
15 (13.4)
Fatigue
18 (13.3)
0
17 (15.2)
4 (3.6)
Abbreviations: TRAE, treatment-related adverse event.
aListed are all TRAEs by preferred term and worst toxicity grade that were reported in >15% of patients in either treatment group.

Cohort 1 AEs of Interest in the Safety Population7
AEs of Interest, n (%)
BALVERSA (n=135)
Chemotherapy (n=112)
Any Grade
Grade ≥3
Any Grade
Grade ≥3
Nail disordersb
90 (66.7)
15 (11.1)
6 (5.4)
0
Skin disordersc
74 (54.8)
16 (11.9)
14 (12.5)
0
Eye disorders (excluding central serous retinopathy)d
57 (42.2)
3 (2.2)
6 (5.4)
0
Central serous retinopathy
23 (17.0)
3 (2.2)
0
0
Chorioretinopathy
8 (5.9)
0
0
0
Detachment of retinal pigment epithelium
7 (5.2)
2 (1.5)
0
0
Subretinal fluid
5 (3.7)
0
0
0
Macular detachment
2 (1.5)
0
0
0
Retinopathy
2 (1.5)
0
0
0
Detachment of macular retinal pigment epithelium
1 (0.7)
1 (0.7)
0
0
Abbreviation: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase.aListed are all adverse events of any cause by preferred term and worse toxicity grade that were reported in >2% of the patients.
bNail disorders: nail bed bleeding, nail discoloration, nail disorder, nail dystrophy, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, paronychia, onychomadesis.
cSkin disorders: blister, dry skin, erythema, hyperkeratosis, palmar erythema, palmar-plantar erythrodysesthesia syndrome, plantar erythema, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, skin atrophy, skin exfoliation, skin fissures, skin lesion, skin ulcer, toxic skin eruption, xeroderma.
dEye disorders (excluding central serous retinopathy): blepharitis, cataract, cataract subcapsular, conjunctival hemorrhage, conjunctival hyperemia, conjunctival irritation, corneal erosion, corneal infiltrates, dry eye, eye inflammation, eye irritation, eye pain, foreign body sensation in eyes, keratitis, lacrimation increased, night blindness, ocular hyperemia, photophobia, vision blurred, visual acuity reduced, visual impairment, xanthopsia, xerophthalmia, chorioretinitis, conjunctivitis, ulcerative keratitis.

Matsubara et al (2023)3 reported results from the cohort 1 Asian subgroup of the THOR study (n=76).

Patient Characteristics

Cohort 1 Asian Subgroup Select Baseline Demographics and Disease Characteristics3
BALVERSA (n=37)
Chemotherapye (n=39)
Age, median (range), years
62 (32-81)
67 (51-86)
Men, n (%)
24 (64.9)
31 (79.5)
Weight, mean (SD), kg
63.9 (12.6)
64.8 (9.9)
ECOG PS 0-1, n (%)a
35 (94.6)
37 (94.9)
FGFR alterations, n (%)b
Mutations
25 (67.6)
33 (84.6)
Fusions
11 (29.7)
3 (7.7)
Mutations and fusions
1 (2.7)
2 (5.1)
PD-(L)1 status, n (%)c
n=20
 n=17

CPS<10
18 (90)
15 (88.2)
Prior systemic therapy, n(%)d
1 line
11 (29.7)
12 (30.8)
2 lines
25 (67.6)
27 (69.2)
Primary tumor location
Upper tract, n (%)
21 (56.8)
18 (46.2)
Lower tract, n (%)
16 (43.2)
21 (53.8)
Abbreviations: CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; FGFR, fibroblast growth factor receptor; PD-(L)1, programmed death-ligand 1; SD, standard deviation.
aScores on the ECOG scale ranged from 0 (no disability) to 5 (death).
bAll patients had FGFR3 alterations; no patients had FGFR2 alterations.
cBased on data available.
dOne Asian patient in the BALVERSA group had 3 lines of prior systemic therapy.
eAll patients received docetaxel, and none received vinflunine.

Cohort 1 Asian Subgroup Dosing Information3
Study Agent Administration
Asian Population
Overall Population
BALVERSA (n=37)
Chemotherapy (n=33)
BALVERSA (n=135)
Chemotherapy (n=112)
Extent of exposure, median (range), days
179 (25-1162)
43 (1-421)
146 (5-1162)
43 (1-820)
Relative dosing intensity,a median (range), %
62.6 (27-100)
100.0 (100-103)
67.4 (14-100)
100.0 (4-117)
Subjects with dose reduction, n (%)
32 (86.5)
NA
93 (68.9)
NA
Subjects with uptitration, n (%)
27 (73.0)
NA
104 (77.0)
NA
Abbreviation: NA, not applicable.
aRelative dose intensity was defined as cumulative total dose divided by cumulative planned total dose which is based on initial planned dose (displayed as percentages).

Efficacy: Cohort 1 Asian Subgroup3

  • At a median follow-up of 15.7 months, the median OS was 23.2 months for patients receiving BALVERSA (95% CI, 10.1, NE) and 11.3 months for patients receiving chemotherapy (95% CI, 5, 15.5).
    • HR, 0.47 (95% CI, 0.23, 0.96; P=0.0327).
  • Median PFS was 5.6 months for patients receiving BALVERSA (95% CI, 4.9, 8.5) and 2.7 months for patients receiving chemotherapy (95% CI, 1.5, 3.1).
    • HR, 0.49 (95% CI, 0.27, 0.88; P=0.0144).

Cohort 1 Asian Subgroup Efficacy Results: Secondary Endpoints3
Secondary Endpoints
Asian Population
Overall Population
BALVERSA (n=37)
Chemotherapy (n=39)
BALVERSA (n=136)
Chemotherapy (n=130)
ORR (confirmed), n (%)
18 (48.6)
3 (7.7)
48 (35.3)
11 (8.5)

RR (95% CI)a
6.33 (2.03, 19.76), P<0.001
4.16 (2.27, 7.64), P<0.001
DCR, n (%)
32 (86.5)
17 (43.6)
100 (73.5)
51 (39.2)

RR (95% CI)a
1.99 (1.37, 2.89), P<0.001
1.87 (1.48, 2.35), P<0.001
DOR, monthsb
n=20
n=5
n=62
n=15

Median (95% CI)c
6.7 (2.9, 12)
4.9 (1, NE)
4.9 (3.8, 7.5)
5.6(2.1, 6.0)

HR (95% CI)d
0.69 (0.19, 2.5), P=0.54
0.85 (0.43, 1.66), P=0.62
Abbreviations: CI, confidence interval; DCR, disease control rate (complete response + partial response + stable disease); DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; NE, non-estimable; ORR, objective response rate (complete response + partial response); RR, relative risk.
aRelative risk, 95% CI and P-value were estimated using Cochran-Mantel-Haenszel test with ECOG PS (0 or 1 vs 2) as a stratification factor.
bDOR in months was defined as time from the date of initial documentation of CR or PR to the date of disease progression. DOR is only calculated for the subgroup of subjects with an overall response of CR or PR.
cKaplan-Meier estimates of median DOR.
dHR and 95% CI were estimated using a Cox proportional hazards regression model with treatment as the explanatory variable, and chemotherapy as the reference group.

Safety: Cohort 1 Asian Subgroup3


Cohort 1 Asian Subgroup Safety Analysis: Treatment Toxicity Profile3
Patients with ≥1 AE, n (%)
Asian Population
Overall Population
BALVERSA (n=37)
Chemotherapy (n=33)
BALVERSA (n=135)
Chemotherapy (n=112)
TRAEsa
37 (100)
31 (93.9)
131 (97)
97 (86.6)
Leading to deathb
0
2 (6.1)c
1 (0.7)d
6 (5.4)e
Serious AEs
2 (5.4)f
7 (21.2)
18 (13.3)
27 (24.1)
Leading to discontinuation of study agent
1 (2.7)g
4 (12.1)
11 (8.1)
15 (13.4)
Leading to dose reductions
30 (81.1)
11 (33.3)
89 (65.9)
24 (21.4)
Grade 3-4
15 (40.5)
19 (57.6)
62 (45.9)
52 (46.4)
Grade 3-4 serious AEs
1 (2.7)h
5 (15.2)
16 (11.9)
(20.5)
Abbreviations: AE, adverse event; TRAE, treatment-related adverse event.
aAn AE is categorized as related if assessed by the investigator as possibly, probably, or very likely related to the study agent.
bAEs leading to death are based on AE outcome of fatal.
cIncluded atypical pneumonia (1 patient), septic shock (1 patient).
dSudden death (1 patient).
eIncluded febrile bone marrow aplasia (2 patients), febrile neutropenia (1 patient), septic shock (2 patients), and atypical pneumonia (1 patient).
fIncluded vomiting (1 patient) and decreased appetite (1 patient).
g1 patient with mouth ulceration and skin disorders.
h1 patient had grade 3 vomiting that was serious.

Cohort 1 Asian Subgroup Safety Analysis: BALVERSA AEs3
Patients with ≥1 AE, n (%)
BALVERSA
Asia (n=37)
Overall (n=135)
Any Grade
Grade 3-4
Any Grade
Grade 3-4
TRAEs, n (%)a
Hyperphosphatemia
32 (86.5)
4 (10.8)
106 (78.5)
7 (5.1)
Diarrhea
17 (45.9)
0
74 (54.8)
4 (3.0)
Onychomadesis
15 (40.5)
1 (2.7)
27 (20.0)
2 (1.5)
Stomatitis
14 (37.8)
0
62 (45.9)
11 (8.1)
Dry mouth
13 (35.1)
0
52 (38.5)
0
AEs of clinical importance, n (%)
Hyperphosphatemia
32 (86.5)
4 (10.8)
108 (80.0)
7 (5.1)
Gastrointestinal toxicity
27 (73.0)
0
98 (72.6)
12 (8.9)
Nail toxicity
27 (73.0)
2 (5.4)
90 (66.7)
15 (11.1)
Skin toxicity
21 (56.8)
6 (16.2)
74 (54.8)
16 (11.9)
Eye toxicity
14 (37.8)
1 (2.7)
57 (42.2)
3 (2.2)
Abbreviations: AE, adverse event; TRAE, treatment-related adverse event.
aTop 5 most common TRAEs (by preferred term) of any grade in the Asian subgroup are listed.

Cohort 1 Asian Subgroup Safety Analysis: Chemotherapy AEs3
Chemotherapy
Asia (n=33)
Overall (n=112)
Any Grade
Grade 3-4
Any Grade
Grade 3-4
TRAEs, n (%)a
Alopecia
14 (42.4)
0
24 (21.4)
0
Anemia
9 (27.3)
2 (6.1)
31 (27.7)
7 (6.3)
Neutropenia
9 (27.3)
8 (24.3)
21 (18.8)
15 (13.4)
Leukopenia
8 (24.2)
6 (18.2)
13 (11.6)
9 (8.1)
Nausea
6 (18.2)
0
22 (19.6)
2 (1.8)
Abbreviations: AE, adverse event; TRAE, treatment-related adverse event.
aTop 5 most common TRAEs (by preferred term) of any grade in the Asian subgroup are listed.

Cohort 2

Siefker-Radtke et al (2023)4 reported interim results from cohort 2 of the THOR study (n=351).

Patient Characteristics

Cohort 2 Select Baseline Demographics and Disease Characteristics4
BALVERSA (n=175)
Pembrolizumab (n=176)
Age, median (range), years
67 (44-86)
66 (31-87)
Men, n (%)
142 (81.1)
132 (75)
Race, n (%)
White
95 (54.3)
111 (63.1)
Asian
37 (21.1)
36 (20.5)
Black or African American
4 (2.3)
0
Multiple
0
1 (0.6)
Not reported
39 (22.3)
28 (15.9)
Geographic region, n (%)
North America
8 (4.6)
6 (3.4)
Europe
118 (67.4)
119 (67.6)
Rest of the world
49 (28)
51 (29)
ECOG PS, n (%)
0-1
164 (93.7)
164 (93.1)
2
11 (6.3)
12 (6.8)
Primary tumor upper tract, n (%)
42 (24)
44 (25.1)
Presence of visceral metastases, n (%)
118 (67.4)
133 (75.6)
Lung
76 (43.4)
84 (47.7)
Liver
42 (24)
42 (23.9)
Bone
51 (29.1)
54 (30.7)
PD-(L)1 low, n (%)a
CPS <10
121 (90.3)
121 (91)
CPS <1
67 (50)
70 (52.6)
Creatinine clearance, n (%)
<30 mL/min
1 (0.6)
3 (1.7)
30-<60 mL/min
72 (41.1)
76 (43.2)
≥60 mL/min
102 (58.3)
97 (55.1)
FGFR alterations
175 (100)
176 (100)
FGFR3 mutations only
142 (81.1)
142 (80.7)
FGFR3 fusions only
30 (17.1)b
30 (17)
FGFR3 fusions and FGFR3 mutations
3 (1.7)
4 (2.3)
FGFR2 fusion and FGFR3 fusion
1 (0.6)
0
Abbreviations: CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; FGFR, fibroblast growth factor receptor; PD-(L)1, programmed death-ligand 1.
aFor PD-(L)1 status, percentage is based on patients with available data (n=134 for BALVERSA and n=133 for pembrolizumab).
bInclusive of one patient with FGFR2-BICC1 and FGFR3-TACC3 V1 fusions.
Efficacy: Cohort 24
  • The median OS was 10.9 months for patients receiving BALVERSA (95% CI, 9.2-12.6) vs 11.1 months for patients receiving pembrolizumab (95% CI, 9.7-13.6).
    • HR, 1.18 (95% CI, 0.9-1.5; P=0.18).
  • Median PFS was 4.4 months for patients receiving BALVERSA (95% CI, 4.1-5.5) vs 2.7 months for patients receiving pembrolizumab (95% CI, 1.6-3).
    • HR, 0.88 (95% CI, 0.7-1.1).
  • Patients receiving BALVERSA (n=175) had an ORR of 40% (95% CI, 32.7-47.7), 11 (6.3%) patients had a CR, and 59 (33.7%) patients had a PR. Patients receiving pembrolizumab (n=176) had an ORR of 21.6% (95% CI, 15.8-28.4), 8 (4.5%) patients had a CR, and 30 (17%) patients had a PR.
    • Relative risk (RR), 1.85 (95% CI, 1.32-2.59).
  • Median DOR was 4.3 months (95% CI, 3.7-6.9) for BALVERSA vs 14.4 months (95% CI, 7.4-27.8) for pembrolizumab.
  • OS across clinically relevant subgroups was evaluated, please refer to Table: Cohort 2 Efficacy Analysis: HR for OS Across Clinically Relevant Subgroups.

Cohort 2 Efficacy Analysis: HR for OS Across Clinically Relevant Subgroups4
Subgroups
BALVERSA n/Na
Median OS, mo
Pembrolizumab n/Na
Median OS, mo
HR (95%, CI)
Overall
136/175
10.9
121/76
11.1
1.16 (0.91-1.48)
Age
<65 years
48/67
11.7
43/70
12.9
1.13 (0.75-1.71)
≥65 years
88/108
10.4
78/106
10.8
1.17 (0.86-1.59)
Gender
Female
22/33
13.9
28/44
10.6
0.95 (0.54-1.65)
Male
114/142
10.3
93/132
11.1
1.20 (0.91-1.57)
Primary tumor location
Upper tract
34/42
11.5
26/44
12.9
1.52 (0.91-2.54)
Lower tract
102/133
10.8
94/131
11
1.07 (0.81-1.42)
FGFR alterations
Translocation
22/30
12.3
20/30
11.7
1.13 (0.61-2.07)
Mutation
112/142
10.5
98/142
11.1
1.18 (0.9-1.54)
PD-(L)1 status
CPS <1
56/67
10.8
54/70
10.5
1.05 (0.72-1.53)
CPS ≥1
49/67
12.6
40/63
10.8
1.1 (0.72-1.67)
CPS <10
95/121
11.4
86/121
10.6
1.08 (0.8-1.44)
CPS ≥10
10/13
12.4
8/12
9.2
0.87 (0.34-2.22)
Visceral metastasis
Presence
104/129
9.7
90/126
10.5
1.15 (0.87-1.52)
Absence
32/46
19.3
31/50
14.2
1.14 (0.7-1.88)
Bone metastasis
Presence
46/51
9.7
45/54
5.9
0.84 (0.56-1.27)
Absence
90/124
11.6
76/122
15.8
1.31 (0.97-1.79)
Liver metastasis
Presence
37/42
6.5
38/42
4.7
0.93 (0.59-1.46)
Absence
99/133
12.6
83/134
15
1.26 (0.94-1.69)
Abbreviations: CPS, combined positive score; FGFR, fibroblast growth factor receptor; HR, hazard ratio; mo, months; OS, overall survival; PD-(L)1, programmed death-ligand 1. aNumber of events/patients in subgroups
Safety: Cohort 24
  • In the BALVERSA treatment arm (n=173), 23 (13.3%) patients had serious TRAEs and 26 (15%) patients discontinued treatment due to TRAEs (most frequent TRAEs leading to discontinuation were gastrointestinal disorders [n=9], eye disorders [n=9], and skin and subcutaneous tissue disorders [n=6]).8 TRAEs were mostly manageable with dose modifications and supportive care. No deaths due to TRAEs occurred.
  • In the pembrolizumab treatment arm (n=173), 18 (10.4%) patients had serious TRAEs and 8 (4.6%) patients discontinued treatment due to TRAEs (most frequent TRAEs leading to discontinuation were renal and urinary disorders [n=2], respiratory and thoracic and mediastinal disorders [n=2]).8 Three treatment-related deaths occurred.
    • TRAEs leading to death in the pembrolizumab group included respiratory failure, pulmonary embolism, and urinary tract infection (1 patient each).

Cohort 2 TRAEs: BALVERSA9
Patients With TRAEs, n (%)a
BALVERSA (n=173)
Any Grade
Grade 3-4
≥1 TRAE
169 (97.7)
75 (43.9)
Hyperphosphatemia
126 (72.8)
1 (0.6)
Stomatitis
78 (45.1)
15 (8.7)
Diarrhea
77 (44.5)
6 (3.5)
Dry mouth
61 (35.3)
1 (0.6)
Dry skin
43 (24.9)
3 (1.7)
Onycholysis
41 (23.7)
10 (5.8)
PPE syndrome
38 (22)
16 (9.2)
Abbreviations: PPE, palmar-plantar erythrodysesthesia; TRAE, treatment-related adverse event.
aAEs by preferred term are listed if events of any grade occurred in ≥25% of patients in the BALVERSA group or if events of grade 3-4 occurred in ≥5% of patients.

Cohort 2 TRAEs: Pembrolizumab9
Patients With TRAEs, n (%)a
Pembrolizumab (n=173)
Any Grade
Grade 3-4
≥1 TRAE
105 (60.7)
21 (12.1)
Pruritus
21 (12.1)
1 (0.6)
Asthenia
18 (10.4)
0
Hypothyroidism
18 (10.4)
0
Fatigue
17 (9.8)
1 (0.6)
Diarrhea
10 (5.8)
0
Rash
10 (5.8)
1 (0.6)
AST increased
8 (4.6)
2 (1.2)
Abbreviation: AST, aspartate aminotransferase; TRAE, treatment-related adverse event.
aAEs by preferred term are listed if events of any grade occurred in ≥6% of patients in the BALVERSA group or if events of grade 3-4 occurred in ≥1% of patients.

Cohort 2 AEs of Interest: BALVERSA9
Patients With AEs of Interest, n (%)
BALVERSA (n=173)
Any Grade
Grade 3-4
Hyperphosphatemia
134 (77.5)
1 (0.6)
Gastrointestinal disorders
117 (67.6)
17 (9.8)
Nail disordersa
102 (59)
24 (13.9)
Skin disordersb
94 (54.3)
20 (11.6)
Eye disorders (excluding central serous retinopathy)c
66 (38.2)
3 (1.7)
Central serous retinopathyd
39 (22.5)
2 (1.2)
Abbreviation: AE, adverse event.
aNail disorders: nail bed bleeding, nail discoloration, nail disorder, nail dystrophy, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, paronychia, onychomadesis.
bSkin disorders: blister, dry skin, erythema, hyperkeratosis, palmar erythema, palmar-plantar erythrodysesthesia syndrome, plantar erythema, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, skin atrophy, skin exfoliation, skin fissures, skin lesion, skin ulcer, toxic skin eruption, xeroderma.
cEye disorders (excluding central serous retinopathy): blepharitis, cataract, cataract subcapsular, conjunctival hemorrhage, conjunctival hyperemia, conjunctival irritation, corneal erosion, corneal infiltrates, dry eye, eye inflammation, eye irritation, eye pain, foreign body sensation in eyes, keratitis, lacrimation increased, night blindness, ocular hyperemia, photophobia, vision blurred, visual acuity reduced, visual impairment, xanthopsia, xerophthalmia, chorioretinitis, conjunctivitis, ulcerative keratitis.
dCentral serous retinopathy: retinal detachment, vitreous detachment, retinal edema, retinopathy, chorioretinopathy, detachment of retinal pigment epithelium, detachment of macular retinal pigment epithelium, macular detachment, serous retinal detachment, subretinal fluid, retinal thickening, chorioretinitis, serous retinopathy, maculopathy, choroidal effusion.

Cohort 2 AEs of Interest: Pembrolizumab9
Patients With AEs of Interest, n (%)a
Pembrolizumab (n=173)
Any Grade
Grade 3-4
Hypothyroidism
19 (11)
0
Hyperthyroidism
9 (5.2)
1 (0.6)
Pneumonitis
6 (3.5)
2 (1.2)
Thyroid disorder
4 (2.3)
0
Blood thyroid stimulating hormone increased
3 (1.7)
0
Adrenal insufficiency
1 (0.6)
1 (0.6)
Autoimmune thyroiditis
1 (0.6)
0
Colitis
0
0
Infusion reactionb
0
0
Nephritis
0
0
Myositis
0
0
Severe skin reactionc
0
0
Abbreviation: AE, adverse event.
aAEs of interest are based on those reported in KEYNOTE-045, including both treatment-related and unrelated AEs.
bIncludes anaphylaxis and hypersensitivity.
cIncludes Stevens-Johnson syndrome or toxic epidermal necrolysis.

Literature Search

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 28 May 2024.

References

Show
1 Loriot Y, Matsubara N, Park SH, et al. Erdafitinib or chemotherapy in advanced or metastatic urothelial carcinoma. N Engl J Med. 2023;389:1961-1971.  
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 May 28]. Available from: https://clinicaltrials.gov/ct2/show/NCT03390504. NLM Identifier: NCT03390504.  
3 Matsubara N, Loriot Y, Burgess E, et al. Asian subgroup analysis of the THOR phase 3 study: erdafitinib versus chemotherapy in patients with advanced or metastatic urothelial cancer and selected fibroblast growth factor receptor alterations. Oral presentation presented at: European Society for Medical Oncology (ESMO) Asia Congress; December 1-3, 2023; Singapore.  
4 Siefker-Radtke AO, Matsubara N, Park SH, et al. Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial. Ann Oncol. 2023;35(1):107-117.  
5 Siefker-Radtke AO, Loriot Y, Matsubara N, et al. FGFR3 alterations (FGFRalt) in patients (pts) who develop locally advanced or metastatic urothelial cancer (mUC), and their association with tumor subtype and clinical outcomes in patients treated with erdafitinib (erda) vs. pembrolizumab (pembro). Poster presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; May 31-June 4, 2024; Chicago, IL.  
6 Loriot Y, Matsubara N, Park SH, et al. Protocol for: Erdafitinib or chemotherapy in advanced or metastatic urothelial carcinoma. N Engl J Med. 2023;389:1961-1971.  
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;389:1961-1971.  
8 Loriot Y, Matsubara N, Huddart R, et al. Erdafitinib versus chemotherapy in patients with advanced or metastatic urothelial cancer with select fibroblast growth factor receptor alterations: subgroup from the phase 3 THOR study. Oral presentation presented at: European Society of Medical Oncology (ESMO) Annual Meeting; October 20-24, 2023; Madrid, Spain and online.  
9 Siefker-Radtke AO, Matsubara N, Park SH, et al. Phase 3 THOR study: results of erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select fibroblast growth factor receptor alterations. Oral presentation presented at: European Society of Medical Oncology (ESMO) Annual Meeting; October 20-24, 2023; Madrid, Spain and online.