METASTATIC UROTHELIAL CARCINOMA
Systemic second-line therapy: The platinum-refractory setting
Alfonso Gómez de Liaño Lista, MD
Medical Oncology Department
Complejo Hospitalario Universitario Insular-Materno Infantil
Las Palmas de Gran Canaria, Spain
Ignacio Durán, MD, PhD
Medical Oncology Department,
Hospital Universitario Marqués de Valdecilla, IDIVAL
Santander, Spain
LEARNING OBJECTIVES
To become familiar with the current state-of-the-art in platinum-refractory metastatic urothelial carcinoma therapeutics
To specifically review the role of chemotherapy and immune checkpoint inhibitors in this setting
To understand the evolving scenario with the development of many novel promising drugs
OUTLINE
Introduction
General overview
Chemotherapy in second-line
Maintenance studies (early second-line)
Immuno-oncology: Checkpoint inhibition
Targeted therapy
◆ FGFR inhibitors
◆ Antibody Drug Conjugates
A glimpse into the future
Conclusions
THE SECOND-LINE SETTING:
AN UNMET NEED
First-line platinum-based chemotherapy has remained the standard of care for >30 years1,2
All patients virtually progress to first-line chemotherapy despite an initial response
Until recently, second-line options have remained scarce3,4
1. Sternberg CN, et al. J Urol 1985;133:403–7; 2. von der Maase H, et al. J Clin Oncol 2005;23:4602–8; 3. Bellmunt J, et al. J Clin Oncol 2009;2:4454–61; 4. McCaffrey JA, et al. J Clin Oncol 1997;15:1853–7
THE SECOND-LINE SETTING:
A GENERAL OVERVIEW
The “old” era1,2 Randomised era and early
targeted-therapy approaches3-6
Immuno-oncology (IO)
irruption7 The near future8,9
◆ No randomised data until 2006
◆ Vinflunine: First agent to
demonstrate in a randomised
controlled trial (RCT) OS
advantage (against best
supportive care)
◆ Failure of targeted therapies in
biomarker unselected
population
◆ Maintenance concept after first-
line response (early second-line
treatment)
◆ PD-1 and PDL-1 inhibitors
leading to encouraging results
(long-term durable responses)
in a subset of patients
◆ Development and “success” of
Phase 3 RCT – from hype to
cautiousness
◆ Molecular understanding leads
to novel targeted therapies in
biomarker selected patients
◆ Fibroblast Growth Factor
Receptor 3 (FGFR3) inhibitors
◆ Antibody drug conjugates
◆ IO-targeted treatment combos
◆ Hypothetical scenario: second-
line setting after front-line IO
◆ Mostly single-agent cytotoxic
chemotherapy
◆ Taxanes introduction
◆ Non-randomised data
◆ Small size trials
◆ Heterogenic population
◆ Limited efficacy
1. McCaffrey JA, et al. J Clin Oncol 1997;15:1853–7; 2. Papamichael D, et al. Br J Cancer 1997;75:606–7; 3. Fechner G, et al. Int J Clin Pract 2006;60:27–3; 4. Bellmunt J, et al. J Clin Oncol 2009:27;4454–61;
5. Ghosh M, et al. Curr Opin Oncol 2014;26:305–20; 6. Garcia-Donas J, et al. Lancet Oncol 2017;18:672–81; 7. Powles T, et al. Clin Genitourin Cancer 2018;16(2):117–29; 8. Loriot Y, et al. N Engl J Med 2019 (In press);
9. Petrylak DP, et al. Oral presentation at ASCO 2019.
SECOND-LINE:
NON-RANDOMISED CHEMOTHERAPY TRIALS
Gomez De Liaño A, Duran I. Ther Adv Urol 2018;10(12):455–80. Reproduced under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/.
Accessed Sept 2019)
Difficult setting (ill defined, mixed
populations, prognostic factors)
Multiple undersized single-agent
studies with scarce success (N less
than 50 in most of them)
ORR ranging from 0–28%
OS around 7–8 months
Few small combination studies with
poor outcomes in general
Author [Year] Chemotherapy Phase n ORR (%)PFS/TTP* (months)
OS/CSS**(months)
Single-agent chemotherapy
McCaffrey [1997] Docetaxel (3 weekly) 2 30 13.3 4 9
Kim [2016] Docetaxel (weekly) 2 31 6 1.4 8.3
Papamichael [1997] Paclitaxel (3 weekly) 2 14 7 NR NR
Vaughn [2002] Paclitaxel (weekly) 2 31 10 2.2 7.2
Joly [2009] Paclitaxel (weekly) 2 55 9 3 7
Ko [2013] Nab-Paclitaxel 2 48 28 6 9.8
Hoffman-Censits [2014] Cabazitaxel 2 14 0 NR NR
Arranz [2015] Cabazitaxel 2 71 5 2.1 4.3
Culine [2006] Vinflunine 2 51 18 3 6.6
Vaughn [2009] Vinflunine 2 175 15 2.8 8.2
Lorusso [1998] Gemcitabine 2 35 23 3.8* 5
Gebbia [1999] Gemcitabine 2 24 29 NR 13
Albers [2002] Gemcitabine 2 30 11 4.9* 8.7**
Akaza [2007] Gemcitabine 2 46 25 3.1 12.6
Sweeney [2006] Pemetrexed 2 47 28 2.9* 9.6
Galsky [2007] Pemetrexed 2 13 8 NR NR
Winquist [2005] Oxaliplatin 2 20 5 1.4* 6.9
Dreicer [2007] Ixabepilone 2 45 12 2.7 8
Chemotherapy combinations
Krege [2001] Docetaxel-Ifosfamide 2 22 25 NR 4
Sweeney [1999] Paclitaxel-Ifosfamide 2 13 15 NR 8
Sternberg [2001] Paclitaxel-Gemc 2 41 60 6.4 14.4
Bellmunt [2018] Docetaxel+ B-701 1b 19 16 3.2 6.9
CSS, cancer-specific survival; NR, not reported; ORR, overall response rate;
OS, overall survival; PFS, progression-free survival; TTP, time to progression.
*TTP reported when PFS data is not available.
**CSS reported when OS not available.
VINFLUNINE PHASE 3 TRIAL
Second-line
T4bN0M0 or TxN2-3 or M1
Progression after first-line platinum
treatment
Stratify:
- Centre
- Refractory vs. non-refractory
VINFLUNINE + BSC
(PS0: 320 mg/m2 q3w; PS 0 with previous
pelvic irradiation and PS1: 280 mg/m2)
BSC with treatment upon progression
permitted
R
N=370 n=253
n=117
Primary endpoint: OS
Secondary endpoints: ORR, PFS, DCR, QoL, CB
Bellmunt J, et al. J Clin Oncol 2009;27(27):4454–61.
HB <10: 86%
Liver metastases: 29%
VINFLUNINE PHASE 3 TRIAL:
PATIENT CHARACTERISTICS
Bellmunt J, et al. J Clin Oncol 2009;27(27):4454–61.
Patient demographics and clinical characteristicsVFL + BSC (n=253) BSC (n=117)
No. of patients % No. of patients %
All treated patients* 248 98.0 117 100
Eligible population† 249 98.4 108 92.3
Age, years
<65
≥65
135
118
53.4
46.6
60
57
51.3
48.7
ECOG PS
0
1
72
181
28.5
71.5
45
72
38.5
61.5
Creatinine clearance in the treated population, mL/min
<60
40–60
<40
Missing
134
104
10
0
54.0
41.9
4.0
0
69
41
4
3
59.0
35.0
3.4
2.6
No. organs involved
1
2
≥3
62
87
104
24.5
34.4
41.4
31
39
47
26.5
33.3
40.2
Visceral involvement 187 73.9 87 74.4
Patients experiencing relapse or progression within
6 months after the prior chemotherapy‡ 82.4 86.1
Prior pelvic/abdominal irradiation 22.5 22.2
Prior therapy with platinum-based regimen
Cisplatin and no other platinum
Carboplatin and no other platinum
Other platinum combination
164
75
14
64.8
29.6
5.6
85
23
9
72.6
19.7
7.7
VFL, vinflunine; BSC, best supportive care; ECOG PS,
Eastern Cooperative Oncology Group performance status.
*Used for safety analysis.†Excludes patients presenting at baseline with ≥1 of four
significant protocol deviations (>1 previous chemotherapy
regimen, no locally advanced or metastatic histologically
proven transitional cell carcinoma of urothelial tract at study
entry, no progression after first-line platinum-containing
chemotherapy for advanced disease, and patients having
received a neoadjuvant or adjuvant chemotherapy).‡Percentages based on 250 patients in BSC + VFL arm and
108 patients in BSC arm.
VINFLUNINE: OVERALL SURVIVAL RESULTS
Bellmunt J, et al. J Clin Oncol 27(27), 2009: 4454–61. Reprinted with permission. © (2009) American Society of Clinical Oncology. All rights reserved
Bellmunt J, et al. Ann Oncol 2013;24(6):1466–72.
VINFLUNINE: SECONDARY ENDPOINTS
ORR (%, p) DCR (%, p) PFS (months, p) DoR (months)
Vinflunine 8.6p=0.0063
41.1p=0.0024
3.0p=0.0012
7.4
BSC 0 24.8 1.5 NA
VFL BSC
Fatigue/asthenia 19.3 17.9
Nausea 2.4 0.9
Vomiting 2.8 0
Mucositis 1.6 0
Constipation 16.1 0.9
Myalgia 3.2 0
Sens. neuropathy 1.2 0
SAFETY PROFILE: Most common Grade 3/4 events (%)
VFL BSC
Anaemia 19.1 8.1
Neutropenia 50 0.9
Febrile neutropenia 6 0
Thrombocytopenia 5.7 0.9
Bellmunt J, et al. J Clin Oncol 2009;27(27):4454–61
RANGE (NCT02426125) TRIAL DESIGN
*Docetaxel 60 mg/m2 in East Asia. #Docetaxel was limited to 6 cycles; up to 4 additional cycles could be given after sponsor approval.De Wit R, et al. Presented at 2019 Genitourinary Cancers Symposium. Reproduced with permission from Dr R. De Wit
Key inclusion criteria:
Locally advanced, unresectable or
metastatic UC
Progression ≤14 mo after platinum regimen
Prior immune checkpoint inhibitor allowed
ECOG PS 0 or 1
Ramucirumab 10 mg/kg +
docetaxel 75 mg/m2 (RAM+DOC) IV*#
Day 1 of a 21-day cycle, N=263
Placebo 10 mg/kg +
docetaxel 75 mg/m2 (P+DOC) IV*#
Day 1 of a 21-day cycle, N=267
R
1:1
Disease
progression
or other
withdrawal
criteria met
Primary endpoint:
PFS (investigator assessment)
Secondary endpoints:
OS, ORR, DCR, DOR, safety, PRO, PK and
immunogenicity
Stratification factors:
◆ Geography (North America vs. East Asia vs. Europe/other)
◆ ECOG PS (0 vs. 1)
◆ Visceral metastasis (Yes vs. No), defined as liver, lung or bone
RANGE PRIMARY AND SECONDARY EFFICACY
OUTCOMES
De Wit R, et al. Presented at 2019 Genitourinary Cancers Symposium. Reproduced with permission from Dr Ronald De Wit
1. Reprinted from The Lancet, 390(10109):, Petrylak DP, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy
(RANGE): a randomised, double-blind, phase 3 trial, 2266–77. Copyright 2017, with permission from Elsevier;
2. Petrylak DP, et al. Ann Oncol 2018;29(suppl_8):viii303-viii331. Presented at ESMO 2018. By permission of Dr DP Petrylak.
Progression-free survival1 Overall survival2 Best overall response1
Median PFS (months)
Ramucirumab + docetaxel (n=216) 4.07
PBO + docetaxel (n=221) 2.76
Prognostic factors
Cabazitaxel
(n=35)
Vinflunine
(n=35)
0 n (%) 13 (37) 13 (37)
1 n (%) 22 (63) 22 (63)
Age (median) 64 66
Gender, male n (%) 28 (80) 28 (80)
Race, caucasian n (%) 34 (97) 35 (100)
Previous surgery n (%) 26 (74) 33 (94)
Prior chemotherapy
Carbo-gemcitabine n (%) 6 (17) 14 (40)
Cisplatin-gemcitabine 28 (80) 20 (57)
Other n (%) 9 (26) 6 (17)
Cabazitaxel Vinflunine p HR
ORR (%) 13 30 0.26
OS (mo) 5.5 7.6 0.342 1.4004
PFS (mo) 1.9 2.9 0.0391 2.0360
Bellmunt J, et al. Ann Oncol 2017;28(7):1517–22
A RANDOMISED PHASE 2/3 STUDY OF CABAZITAXEL
VS. VINFLUNINE
In metastatic or locally advanced transitional cell
carcinoma of the urothelium (SECAVIN)
Primary endpoints:
◆ Phase 2 → ORR
◆ Phase 3 → OS
Randomised Phase 2/3
Population: locally advanced/metastatic UC who have failed
a first-line platinum-based chemotherapy
Stratification factors: PS 0-1, Hb <10 g/dL, liver metastases
Hypothesis: Cabazitaxel has sufficient activity (≥15% ORR)
to test in a Phase 3 trial against vinflunine
N=70
Eligible
patients
Cabazitaxel 25 mg/m2 every 21 days
Vinflunine 250–320 mg/m2 every 21 days
R
1:1
SECOND-LINE CHEMOTHERAPY:
THE RANDOMISED DATA
†Significant in eligible population, not in ITT
*Time to progression (TTP) is reported when PFS is not available
**Cancer specific survival (CSS) is reported when OS is not available
Adapted from Gomez De Liaño A, Duran I. Ther Adv Urol 2018;10(12):455–80.
Author [Year] Experimental arm Control arm Phase n ORR (%) PFS/TTP* (months)OS/CSS**
(months)
Ch
emo
ther
apy
(CT
) al
on
e Fechner [2006] Gem-Paclitaxel q2w cont Gem-Paclitaxel q3w x6 2 30 39 vs. 50 6 vs. 11 (NS) 9 vs. 13 (NS)
Albers [2010] Gem-Paclitaxel q3w cont Gem-Paclitaxel q3w x6 3 10241.5 vs. 37.5
(NS)3.1 vs. 4 (NS) 8 vs. 7.8 (NS)
Bellmunt [2009, 2013] Vinflunine BSC 3 370 8.6 vs. 0 3 vs. 1.56.9 vs. 4.3†
(HR 0.78)
Bellmunt [2017] Cabazitaxel Vinflunine 2 70 13 vs. 30 (NS) 1.9 vs. 2.9 5.5 vs. 7.6 (NS)
Sridhar [2018] Nab-Paclitaxel Paclitaxel 2 160 22 vs. 25 3.35 vs. 3.02 (NS)7.46 vs. 8.77
(NS)
CT
+ t
arg
eted
th
erap
y
Choueiri [2012] Docetaxel-Vandetanib Docetaxel 2 142 7 vs. 11 2.56 vs. 1.58 (NS)5.85 vs. 7.03
(NS)
Petrylak [2017] Docetaxel-Ramucirumab Docetaxel 3 530 24.5 vs. 14 4.07 vs. 2.76 9.4 vs. 7.85 (NS)
Choueiri [2017] Docetaxel-Apatorsen Docetaxel 2 99 16 vs. 11 (NS) 1.8 vs. 1.6 (NS) 6.4 vs. 5.9 (NS)
EARLY SECOND-LINE CHEMOTHERAPY:
THE MAINTENANCE CONCEPT
MAJA trial
Design: Randomised, open-label,
Phase 2 trial
Population: mUC patients who
have not progressed during first-line
Gem-Cisplatin (4–6 cycles)
PFS 6.5 mo (95% CI 2.0, 11.1)
PFS 4.2 mo (95% CI 2.1, 6.3)
HR 0.59; 95% CI 0.37, 0.96; p=0.031G3/4 events of interest %
Neutropenia 18%
Febrile neutropenia 2%
Ashtenia 16%
Constipation 14%
Abdominal pain 5%
Patients
characteristics
Vinflunine
(n=45)
BSC
(n=43)
ECOG 0 21 (47%) 23 (53%)
Age (median) 63.7 65.0
Gender, male 37 (82%) 40 (93%)
Primary site, bladder 36 (80%) 37 (86%)
Pure TCC histology 38 (84%) 37 (86%)
Prognostic factors
0
1
2
3
20 (44%)
19 (42%)
6 (13%)
0
17 (40%)
20 (47%)
5 (12%)
1 (2%)
Liver metastasis 5 (11%) 13 (30%)
GemCis response
CR
PR
SD
7 (16%)
28 (63%)
10 (22%)
7 (16%)
23 (54%)
13 (30%)
Reprinted from The Lancet, 18(5), Garcia-Donas J, et al. Maintenance therapy with vinflunine plus best supportive care versus best supportive care alone in patients with advanced urothelial carcinoma with a response after
first-line chemotherapy (MAJA; SOGUG 2011/02): a multicentre, randomised, controlled, open-label, phase 2 trial, 672-681a Copyright 2017, with permission from Elsevier.
n=43
Gem/platinum
chemotherapy
Vinflunine
Best SC
Disease
control
n=45
Primary endpoint: PFS
SECOND-LINE CHEMOTHERAPY: CONCLUSIONS
Vinflunine is the only cytotoxic agent to prove OS improvement in platinum refractory patients1
Docetaxel–ramucirumab increases PFS but not OS against docetaxel
Single-agent chemotherapy tested (mainly taxanes) has shown limited efficacy, ORR ranges 0–28% and data from
single-arm trials → should not be standard of care
Vinflunine has superior outcomes than cabazitaxel
Nabpaclitaxel is not superior to paclitaxel
Maintenance chemotherapy may have a role in mUC but needs to be proven (and may be hard in the current era)
1. Not in the intention-to-treat population, only in the per-protocol analysis.
IMMUNE CHECKPOINT INHIBITION AS SECOND-LINE TREATMENT
IMMUNO-THERAPY: SINGLE-ARM DATA
Atezolizumab1 Pembrolizumab2 Nivolumab3 Avelumab4,5 Durvalumab6
Phase Phase 2 Phase 1 Phase 2 Phase 1b Phase 1/2
Patients, N 310 33 265249
(161 post-plat)
191
(182 post-plat)
Dosing 1200 mg q3w 10 mg/kg/q2w 3 mg/kg/q3w 10 mg/kg q2w 10 mg/kg q2w
ORR, % 15 26 19.6 17 17.8
Duration of
response
84% after median f-u of
11.7 mo. Median NRMedian 10 months
77% after median f-u of
7 mo. Median NR
64% at data cut,
median NR
76.5% at data cut,
median NR
OS, months 7.9 13 8.7 7.7 18.2
PFS, months 2.1 2.0 2.0 1.5 1.5
G3/4 TRAEs, % 16 15 (G3) 18 10.8 (G3-5) 6.8
f-u, follow-up; TRAEs, treatment-related adverse events1. Rosenberg JE, et al. Lancet 2016; 2. Plimack E, et al. Lancet Oncol 2017; 3. Sharma P, et al. Lancet Oncol 2017; 4. Patel MR, et al. Lancet Oncol 2018;
5. Apolo AB, et al. J Clin Oncol 2017; 6. Powles T, et al. JAMA Oncol 2017
KEYNOTE-045 STUDY DESIGN (NCT02256436)
aIn total ITT population and in patients with combined positive score ≥10%.Bellmunt J, et al. N Engl J Med 2017;376(11):1015–26
Key eligibility criteria:
Urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra
Transitional cell predominant
PD after 1–2 lines of platinum-based chemotherapy or recurrence <12 months after perioperative platinum-based therapy
ECOG performance status 0–2
Provision of tumour sample for biomarker assessment
Pembrolizumab 200 mg IV q3w
Paclitaxel 175 mg/m2 q3w
OR
Docetaxel 75 mg/m2 q3w
OR
Vinflunine 320 mg/m2 q3w
R
1:1
N=542
n=270
n=272
◆ Dual primary endpoints: OS and PFS
◆ Key secondary endpoints: ORR, DOR, safety
◆ Response: RECIST v1.1 by blinded, independent central review
◆ Both unselected and biomarker-selected patients
Stratification factors:
◆ ECOG performance status (0/1 vs. 2)
◆ Hemoglobin level (<10 vs. ≥10 g/dL)
◆ Liver metastases (Yes vs. No)
◆ Time from last chemotherapy dose (<3 vs. ≥3 months)
BASELINE CHARACTERISTICS
aMissing for 5 patients in pembrolizumab arm and 4 patients in chemotherapy arm. bMissing for 7 patients in pembrolizumab arm and 4 patients in chemotherapy arm.cRisk factors include Bellmunt risk factors of ECOG performance-status score >0, Hb concentration <10 g/dL, and presence of liver metastases, plus a time since completion or
discontinuation of previous therapy <3 months.
Data cut-off date: October 26, 2017.Bellmunt J, et al. N Engl J Med 2017;376(11):1015–26
n (%)
Pembro
(n=270)
Chemo
(n=272)
Age, median
(range), y67 (29-88) 65 (26-84)
Men 200 (74.1) 202 (74.3)
Upper tract
disease38 (14.1) 37 (13.6)
Lower tract
disease232 (85.9) 235 (86.4)
ECOG PSa
0
1
2
120 (44.4)
142 (52.6)
3 (1.1)
106 (39.0
158 (58.1)
4 (1.5)
Visceral disease 241 (89.3) 235 (86.4)
Disease in lymph
node only28 (10.4) 37 (13.6)
n (%)
Pembro
(n=270)
Chemo
(n=272)
Liver metastases 91 (33.7) 95 (34.9)
Hemoglobin <10
g/dLb 43 (15.9) 44 (16.2)
Time since completion of most recent prior therapy
≥3 months 167 (61.9) 168 (61.8)
<3 months 103 (38.1) 104 (38.2)
Setting of most recent prior therapy
Neoadjuvant 19 (7.0) 22 (8.1)
Adjuvant 12 (4.4) 3 (11.4)
First line 184 (68.1) 158 (58.1)
Second line 55 (20.4) 59 (21.7)
Third line 0 2 (0.7)
n (%)
Pembro
(n=270)
Chemo
(n=272)
Risk factorsc
0
1
2
3–4
54 (20.0)
96 (35.6)
66 (24.4)
45 (16.7)
45 (16.5)
97 (35.7)
80 (29.4)
45 (16.5)
Prior platinum therapy
Cisplatin
Carboplatin
Othera
199 (73.7)
70 (25.9)
1 (0.4)
214 (78.7)
56 (20.6)
2 (0.7)
Smoking statusb
Never
Former
Current
104 (38.5)
136 (50.4)
29 (10.7)
83 (30.5)
148 (54.4)
38 (14.0)
PD-L1 CPS ≥10% 74 (27.4) 90 (33.1)
OVERALL SURVIVAL
At 24 months, 60% of chemotherapy arm patients had
received an IO agent (including pembro at crossover)
Bellmunt J, et al. N Engl J Med 2017;376(11):1015–26. Updated results presented at ASCO GU 2018. Reproduced with permission from Dr J Bellmunt.
A: Based on Cox regression model with treatment as a covariate stratified by ECOG performance status (0/1 vs 2). Liver metastases (yes vs no), hemoglobin (<10 vs >10 gr/dL) and time from completion of chemotherapy (<3
vs. > or = 3months)
B: One-sided P value based on stratified log-rank test
Events, n HR (95% CI)a p-valueb
Pembro 155 0.73
(0.59, 0.91)0.0022
Chemo 179
14.1 months of follow-up1
Events, n HR (95% CI)a p-valueb
Pembro 199 0.70
(0.57, 0.85)0.00017
Chemo 218
27.7 months of follow-up
OVERALL SURVIVAL: SUBGROUPS
aIncludes Bellmunt risk factors of ECOG performance status >0, haemoglobin level <10 g/dL, and liver metastases (J Clin Oncol. 2010;27:1850–5) and time from prior chemotherapy
<3 months (Eur Urol 2013;63:717-723). bN is shown for the chemotherapy arm only. All comparisons were to all patients in the pembrolizumab arm.
Data cut-off date: October 26, 2017.Bellmunt J, et al. N Engl J Med 2017;376(11):1015–26. Updated results presented at ASCO GU 2018. Reproduced with permission from Dr J Bellmunt.
PROGRESSION-FREE SURVIVAL
Bellmunt J, et al. N Engl J Med 2017;376(11):1015–26. Updated results presented at ASCO GU 2018. Reproduced with permission from Dr J Bellmunt.
OBJECTIVE RESPONSE BY PD-L1 STATUS
Data cut-off date: October 26, 2017.Bellmunt J, et al. N Engl J Med 2017;376(11):1015–26. Updated results presented at ASCO GU 2018. Reproduced with permission from Dr J Bellmunt.
CPS ≥10 CPS <10
TREATMENT-RELATED AEs OCCURRING IN ≥10% OF
PATIENTS*
*Of patients in either treatment arm. 7.5% febrile neutropenia in the chemotherapy arm. Data cut-off date: October 26, 2017.Bellmunt J, et al. N Engl J Med 2017;376(11):1015–26. Updated results presented at ASCO GU 2018. Reproduced with permission from Dr J Bellmunt.
Pembrolizumab Chemotherapy
IMMVIGOR 211: TRIAL DESIGN
Powles T, et al. Lancet 2018;391(10122):748–57
Atezolizumab vs. chemotherapy in platinum refractory PD-L1 positive disease
n=464
Key eligibility criteria
• Urothelial carcinoma of the renal pelvis,
ureter, bladder, or urethra
• Transitional cell predominant
• PD after 1–2 lines of platinum-based
chemo or recurrence within 12 months of
perioperative platinum-based therapy
• ECOG PS 0-1
• Provision of tumour sample for biomarker
assessment
Atezolizumab
1200 mg IV q3w
Paclitaxel 175 mg/m2 q3w
OR
Docetaxel 75 mg/m2 q3w
OR
Vinflunine 320 mg/m2 q3w
R(1:1)
N=931
n=467
Key endpoints:
Primary: OS in PD-L1 +ve population
Hierarchical analysis: OS in ITT population
WHY CHOOSING THE BIOMARKER AS THE
PRIMARY ENDPOINT?
Summary of Phase 1 and 2 atezolizumab data
◆ PD-L1 positive was defined as ≥5 % of immune cells with SP142Ab
Phase 1 Study PCD4989g Phase 2 Study IMvigor210 (Cohort 2)
◆ The biomarker positive patients did better than historical chemotherapy controls
◆ The biomarker negative patients had similar outcomes to historical chemotherapy controls
Powles T, et al. Presented at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care. Reproduced with permission from Dr T. Powles.
IMMVIGOR 211: PATIENTS CHARACTERISTICS
Baseline characteristics
ITT population
Atezolizumab
(n=467)
Chemotherapy
(n=464)
Age, median (range) 67 (33–88) years 67 (31–84) years
Gender, male 76% 78%
ECOG 0 | 1 47% | 53% 45% | 55%
Smoker: current | past | never 13% | 57% | 30% 13% | 61% | 26%
Hemoglobin ≤10 g/dL 14% 16%
Bellmunt Risk factors 0 | 1 | 2 | 3 31% | 46% | 18% | 5% 30% | 45% | 21% | 4%
Primary site:
Lower tract bladder | urethra 69% | 2% 73% | 2%
Upper tract (renal pelvis| ureter | other) 14% | 13% | 2% 11% | 13% | 2%
Metastatic disease 91% 93%
Metastatic sites:
Only lymph nodes| visceral | liver 12% | 77% | 30% 14% | 77% | 28%
Prior cystectomy 43% 43%
Previous chemotherapy <3 mo 34% 35%
No. of previous lines (metastatic setting): 0 | 1 | 2 | ≥3 28% | 53% | 17% | 2% 26% | 56% | 16% | 2%
PD-L1 score: IC2/3 | IC1 | IC0 25% | 43% | 32% 25% | 41% | 33%
Powles T, et al. Lancet 2018;391(10122):748–57
ATEZOLIZUMAB VS. CHEMOTHERAPY IN BIOMARKER-
POSITIVE PLATINUM REFRACTORY UBC
HR, hazard ratio.Reprinted from The Lancet, 391(10122) Powles T, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3
randomised controlled trial, 748-757, Copyright 2018, with permission from Elsevier.
The biomarker was prognostic and not predictive (SP142 >5% in IC)
OS ANALYSIS: ITT POPULATION (N=931)
Reprinted from The Lancet, 391(10122) Powles T, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3
randomised controlled trial, 748-757, Copyright (2018, with permission from Elsevier.
Median follow-up duration in ITT population: 17.3 mo (range, 0 to 24.5 mo)
IMVIGOR 211: PFS, ORR, DOR
Powles T, et al. Lancet 2018;391(10122):748–57
IC2/3 population ITT population
Atezolizumab group
(n=116)
Chemotherapy group
(n=118)
Atezolizumab group
(n=467)
Chemotherapy group
(n=464)
Progression-free survival
Patients with event, n (%) 93 (80) 105 (89) 407 (87) 410 (88)
Median, months (95% CI) 2.4 (2.1, 4.2) 4.2 (3.7, 5.0) 2.1 (2.1, 2.2) 4.0 (3.4, 4.2)
Objective response
Evaluable patients, n 113 116 462 461
Patients with response, n (%; 95% CI) 26 (23.0; 15.6, 31.9) 25 (21.6; 14.5, 30.2) 62 (13.4; 10.5, 16.9) 62 (13.4; 10.5, 16.9)
Best overall response, n (%)
Complete response 8 (7) 8 (7) 16 (3) 16 (3)
Partial response 18 (16) 17 (15) 46 (10) 46 (10)
Stable disease 23 (20) 37 (32) 92 (20) 162 (35)
Progressive disease 47 (42) 30 (26) 240 (52) 150 (32)
Missing or unevaluable 17 (15) 24 (21) 68 (15) 87 (19)
Duration of response
Patients with event, n/N (%) 10/26 (38) 20/25 (80) 23/62 (37) 49/62 (79)
Median, months (95% CI) 15.9 (10.4, NE) 8.3 (5.6, 13.2) 21.7 (13.0, 21.7) 7.4 (6.1, 10.3)
IMVIGOR 211: DURATION OF RESPONSE
21.7 months
7.4 months
Reprinted from The Lancet, 391,(10122) Powles T, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3
randomised controlled trial, 748–57, Copyright 2018, with permission from Elsevier.
Duration of response*
*Duration of response determined by Investigator using RECIST v1.1; defined as time from first occurrence of complete response or partial response, whichever came first, to first
documented progression of disease or death, whichever occurred first.
ATEZOLIZUMAB: TOXICITY PROFILE
Atezolizumab Chemotherapy
All grades
Grades 3-4
Nausea
Constipation
Alopecia
Fatigue
Anaemia
Decreased appetite
Asthenia
Diarrhoea
Neutropenia
Vomiting
Peripheral neuropathy
Myalgia
Mucosal inflammation
Neutrophil count decreased
Febrile neutropenia
Pruritus
Proportion of patients
Adapted from Powles T, et al. Lancet. 2018;391(10122):748–57
ATEZOLIZUMAB REAL-WORLD DATA:
SAUL PHASE 3B TRIAL
Between 30 Nov 2016 and 16 March 2018, 1004 patients
were enrolled (997 treated) from sites in 32 countries
worldwide
Sternberg C, et al. Eur Urol 2019;76(1):73-81; Merseburger AS, et al. Presented at EAU 2019. Reproduced with permission from Dr AS Merseburger.
bIC2/3 = expression on ≥5% of tumour-infiltrating immune cells; denominator = 928 patients with known PD-L1 status. cOther non-urothelial/mixed in 6 patients (1%). dOther in 24 (2%).
Adverse events
aDefined as the SAUL ITT population MINUS populations excluded from IMvigor211
Sternberg C, et al. Eur Urol 2019;76(1):73-81; figures reproduced under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License (CC BY NC ND). https://creativecommons.org/licenses/by-nc-
nd/4.0/. Accessed Sep 2019; Merseburger AS, et al. Presented at EAU 2019. Reproduced with permission from Dr AS Merseburger.
OVERALL SURVIVAL ANALYSIS IN THE DIFFERENT POPULATIONS
IN SAUL STUDY
IMMUNE CHECKPOINT INHIBITORS IN PLATINUM
REFRACTORY PATIENTS – SUMMARY
IO agents have superseded chemotherapy in the second-line setting as the preferred option, based on duration of
response and safety
Nevertheless, there is a lack of predictive biomarkers to help us selecting those patients [15–25%] most likely to
benefit from CPI
Pembrolizumab has the highest level of evidence in a randomised setting. Atezolizumab seems a reasonable option
based on Phase 3 and 3b results. The SAUL trial demonstrates that the efficacy of atezolizumab is consistent with
previous pivotal anti-PD-L1/PD-1 mUC trials
Other ICI agents (avelumab, durvalumab, and nivolumab) seem to achieve similar benefit, although randomised data
are lacking
TARGETED THERAPY: FROM FAILURE TO SUCCESS?
High somatic mutation frequencies in bladder cancer
Multiple failed attempts (mainly single-arm trials) in unselected populations over the last decade
Main agents tested: VEGF-targeted therapy (TKIs, mABs), EGFR/HER2 inhibitors, mTOR inhibitors
Randomised trials are scarce and have failed (LAMB trial) or demonstrated little benefit (RANGE trial)
Better understanding of mUC molecular behaviour has led to the design of novel trials, testing targeted therapies in
biomarker-selected patients
TARGETED THERAPY: BACKGROUND IN A SNAPSHOT
*Low predicted likelihood of response based on preliminary data. **Low response rate.Reprinted from Cell, 171(3), Robertson AG, et al. Comprehensive Molecular Characterisation of Muscle-Invasive Bladder Cancer, 540–56.e25. Copyright 2017, with permission from Elsevier.
Reprinted by permission from Springer Nature: Nature, Mutational heterogeneity in cancer and
the search for new cancer-associated genes, Lawrence MS, et al. Copyright 2013
Eligibility criteria for randomisation
1. Metastatic or advanced UBC
2. HER1 or 2 positive transitional cell
histology
3. Clinical benefit with first-line
chemotherapy
4. Normal ejection fractionCommonest reason for
screen failure: n=214
1. Disease progression (24%)
2. Biomarker –ve (20%)
3. Low LVEF (19%)
4. Patient choice (9%)
Endpoints
Primary: PFS
Secondary: OS / adverse events
Exploratory: Subset analysis
Stratification: Chemotherapy
response and PS
EGFR/HER2 INHIBITION: LAMB TRIAL
R=232
Lapatinib 1500 mg OD
Placebo
Chemotherapy
Screening phase
HER1/2 testing
(N=446)
Powles T, et al. J Clin Oncol 2017;35(1):48–55
LAMB TRIAL
0
10
20
30
40
T0 T1 T2 T3 T4
%
% of T Stage ExpressionHER1 +ve
HER2 +ve
HER1 Whole Pop. Trial Pop. HER2 Whole Pop. Trial Pop.
0 15% 6% 0 23% 14%
1+ 15% 12% 1+ 31% 30%
2+ 38% 44% 2+ 34% 40%
3+ 32% 38% 3+ 12% 16%
% of HER expression
Randomly assigned (n=232), n (%) Total, n (%)
Lapatinib Placebo
116 116 445
HER status
HER1 positive 53 (45.7) 49 (42.2) 175 (39.2)
HER2 positive 21 (18.1) 21 (18.1) 60 (13.5)
Both positive 42 (36.2) 46 (39.7) 145 (32.5)
HER negative 0 (0.0) 0 (0.0) 66 (14.8)
Powles T, et al. J Clin Oncol 2017;35(1):48–55
HR 1.1
(95% CI: 0.8, 1.4); p=0.62
Median PFS
Lapatinib 4.6 months (95% CI: 2.8, 5.4)
Placebo 5.1 months (95% CI: 3.0, 5.8)
Response rate
Lapatinib 14%
Placebo 8%
p=0.14
LAMB TRIAL
Randomised population: PFS for lapatinib vs. placebo (primary endpoint)
Powles T, et al. J Clin Oncol 35(1), 2017: 48–55. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.
FGFR3 INHIBITORS: LESSONS LEARNED IN MUC
“Old” trials tested these agents in unselected population
The Cancer Genome Atlas Research Network. Nature 2014;507:315–22. Reproduced under the Creative Commons CC-BY-NC-SA license. https://creativecommons.org/licenses/by-nc-nd/4.0/. Accessed Sept 2019;
Milowsky MI, et al. Phase 2 trial of dovitinib in patients with progressive FGFR3-mutated or FGFR3 wild-type advanced urothelial carcinoma. Eur J Cancer 2014;50(18):3145–52.
Clinical response FGFR3MUT (n=12) FGFR3WT (n=31)
Investigator review, n (%)
CR
PR
SD
PD
UNK
ORR (CR+PR)
DCRa
95% CI for ORR
95% CI for DCR
0
0
5 (42)
5 (42)
2 (17)
0
3 (25)
(0.0, 26.5)
(5.5, 57.2)
0
1 (3)
10 (32)
12 (39)
8 (26)
1 (3)
8 (26)
(0.1 ,16.7)
(11.9, 44.6)
Central radiology review, n (%)
CR
PR
SD
PD
UNK
ORR (CR+PR)
DCRa
95% CI for ORR
95% CI for DCR
0
1 (8)
3 (25)
6 (50)
2 (17)
1 (8)
2 (17)
(0.2, 38.5)
(2.1, 48.4)
0
0
12 (39)
9 (29)
10 (32)
0
9 (29)
(0.0, 11.2)
(14.2, 48.0)
Best overall tumour response by FGFR3 mutation status,
as determined by investigator and central radiology review
FGFR3 alterations in mUC ≈20% and ≈35% in UTUC
A: Defined as the proportion of patients with best overall response of CR or PR, or a response of SD lasting P16 weeks
after the start of dovitinib treatment.
PHASE 2 BLC2001: ERDAFITINIB IN PATIENTS WITH
MUC AND FGFR3 ALTERATIONS
Siefker-Radtke A, et al. J Clin Oncol 36, 2018 (suppl; abstr 4503). Presented at ASCO 2018 Annual Meeting. Reproduced with permission from Dr A Siefker-Radtke.
ERDAFITINIB ACTIVITY
Siefker-Radtke A, et al. J Clin Oncol 36, 2018 (suppl; abstr 4503). Presented at ASCO 2018 Annual Meeting; Updated at ASCO 2019 by SH Park et al. J Clin Oncol 37, 2019 (suppl; abstr 4543). Presented at ASCO 2019
Annual Meeting. Reproduced with permission from Dr A Siefker-Radtke.
REGULATORY APPROVAL
FDA grants accelerated approval to erdafitinib for metastatic urothelial carcinoma
On April 12, 2019, the Food and Drug Administration granted accelerated approval to erdafitinib (BALVERSA,
Janssen Pharmaceutical Companies) for patients with locally advanced or metastatic urothelial carcinoma, with
susceptible FGFR3 or FGFR2 genetic alterations, that has progressed during or following platinum-containing
chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.
Patients should be selected for therapy based on an FDA-approved companion diagnostic for erdafitinib.
Today, the FDA also approved the therascreen® FGFR RGQ RT-PCR Kit, developed by QIAGEN, for use as a
companion diagnostic for this therapeutic indication.
Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-erdafitinib-metastatic-urothelial-carcinoma. Accessed Sept 2019
ERDAFITINIB: TOXICITY
Majority of events were Grade 1/2
Serious TRAEs in 9 patients (9%)
Only 7 patients discontinued because of AEs of special interest
CSR rarely led to discontinuation (n=3), no retinal vein or artery occlusion
Treatment-related Adverse Events (TRAEs) TRAEs of special interest
Siefker-Radtke A, et al. J Clin Oncol 36, 2018 (suppl; abstr 4503). Presented at ASCO 2018 Annual Meeting. Reproduced with permission from Dr A Siefker-Radtke.
BGJ398 (INFIGRATINIB) IN MUC WITH
FGFR3 MUTATIONS
Most common AEs:
◆ Hyperphosphatemia (46%)
◆ ↑ creatinine (42%)
◆ Constipation (37%)
◆ Anaemia (36%)
◆ ↓ appetite
Most common G3/4 AEs:
◆ ↑ Lipase (10%)
◆ Fatigue (7.5%)
◆ Anaemia (7.5%)
◆ Hypophosphatemia (7.5%)
◆ Palmar-plantar
erythrodysthesia (7.5%)◆ Median PFS: 3.75 months
◆ Median OS 7.75 months
◆ Median DoR: 5.06 months
67 patients with mUC and FGFR3 mutations
ORR: 25.4%
SD: 38.8%
Reprinted from Cancer Discovery, Copyright 2018, 8(7), Pal SK, et al. Author, Efficacy of BGJ398, a Fibroblast Growth Factor Receptor 1–3 Inhibitor, in Patients with Previously Treated Advanced Urothelial Carcinoma with
FGFR3 Alterations, with permission from AACR.
Baseline patient and disease characteristics
Variable, n (%)Participants
(N=67)
Age group <65 years≥65 years
29 (43.3)38 (56.7)
Sex MaleFemale
46 (68.7)21 (31.3)
WHO performance status
012Missing
20 (29.9)36 (53.7)10 (14.9)
1 (1.5)
Bellmunt criteriaa Risk group 0Risk group 1Risk group 2Risk group 3
12 (17.9)27 (40.3)25 (37.3)
3 (4.5)
Visceral disease LungLiver
41 (61.2)25 (37.3)
Lymph node metastases
YesNoMissing
19 (28.4)46 (68.7)
2 (3)
Bony metastases YesNoMissing
25 (37.3)40 (59.7)
2 (3)
Prior immunotherapy at last medication 11 (16.4)
FGFR3 status Not mutatedMutatedb
Exon 7 R248CExon 7 S249CExon 10 Y375CExon 15 K625E/QOtherb
067 (100)11 (16.4)38 (56.7)
3 (4.5)0
15 (22.4)
INFIGRATINIB: SUBGROUP OF UPPER TRACT (UTUC)
Patients with UTUC vs. different molecular profile and better outcomes than bladder carcinoma patients
Dizman N, et al. J Clin Oncol 37, 2019:(suppl; abstr 4510). Presented at ASCO 2019.
Reproduced with permission from Dr N Dizman
Progression-free survival
Overall survival
ORR 24%
SD 49%
PD 27%
Analysis in 51 patients with FGFR1-3 mRNA overexpression
Joerger M, et al. J Clin Oncol 36, 2018:(suppl; abstr 4513). Presented at ASCO 2019. Reproduced with permission from Dr M Joerger.
ROGARATINIB IN PATIENTS WITH ADVANCED
UROTHELIAL CARCINOMAS
Pre-screened for tumour FGFR mRNA expression and effects of mutations in FGFR signalling pathway
◆ In line with TCGA research, 133 UC
tumours treated with rogaratinib showed
that samples with high FGFR3 mRNA
levels expressed los PD-L1 mRNA levels
◆ 10 patients had prior IO treatment (6 anti-
PD-L1 treatment)
◆ 9/10 (90%) showed PD as best response
to IO therapy, 1 had SD for 9 months
TEAEs observed in >20% patients with UC (n=51) by
Common Terminology Criteria for AEs grade
The Cancer
Genome
Atlas (n=408)
Rogaratinib
trial (n=133)
Necchi A, et al. J Clin Oncol 37, 2019 (suppl 7S; abstr 409). Presented at ASCO GU 2019.
Reproduced with permission from Dr A Necchi.
FIERCE 22: PRELIMINARY ANALYSIS OF VOFATAMAB +
PEMBROLIZUMAB
Siefker-Radtke A, et al. J Clin Oncol 37, 2019 (suppl; abstr 4511). Presented at ASCO 2019 Annual Meeting. Reproduced with permission from Dr A Siefker-Radtke.
FGFR3 INHIBITORS: SELECTED ONGOING TRIALS
Trial Phase N (estimated) Investigational arm Comparative arm Target population
NORSE 1/2 102 Erdafitinib + JNJ-63723283 (anti-PD1) Erdafitinib Platinum refractory
FIERCE-22 1/2 74 Vofatamab + Pembrolizumab None Platinum refractory
FORT-2 1/2 190 Rogaratinib + Atezolizumab PBO + Rogaratinib First-line unfit
Fight-2015 2 372 Pemigatinib + Pembrolizumab Pemigatinib First-line unfit
Selected ICI+FGFR3i combination trials
THOR: Ongoing Phase 3 Study (N=630) of erdafitinib compared with chemotherapy or pembrolizumab
FORT-1: Phase 2/3 trial of rogaratinib compared with chemotherapy (NCT03410693)
• FGRR1 or 3 positive
tumours determined by
mRNA expression
• mUC with prior platinum
treatment
• ≤2 prior lines
Arm 1: Rogaratinib
Arm 2: Comparator
Taxane (docetaxel or
paclitaxel) or vinflunine
R(1:1)
Primary outcome
measure: OS
N=400Molecular
screening of
patients with
advanced UC
for FGFR
alterations
Erdafitinib
Chemotherapy
R(1:1)Prior
treatment with
PD-(L)1
inhibitor?
YES
Erdafitinib
Pembrolizumab
R(1:1)
NO
TARGETED THERAPY AND FGFR3 INHIBITORS –
CONCLUSIONS
Erdafitinib, vofatamab, infigratinib, and rogaratinib show encouraging activity in FGFR3-altered tumours
Preliminary data suggests tumours with FGFR alterations are less likely to respond to ICIs
Multiple FGFR3 inhibitors are currently being tested, either as single-agent or combined with ICIs, in randomised trials
FGRF3 inhibitors are safe, but need to be aware about MAPK class effect toxicity (CSR, hyperphosphatemia, …)
mUC is a heterogeneous disease. Targeted agents should be designed along with a biomarker, unlikely to be effective
in unselected population
ANTIBODY DRUG CONJUGATES (ADCs) IN MUC
New generation of cancer therapeutics: monoclonal antibodies (mAbs) connected by a specified linkage to
antitumour cytotoxic molecules
ADC binds to tumour target cell surface antigens (B)
leading to triggering of a specific receptor-mediated
internalisation (C). The internalised ADCs are
decomposed, releasing their cytotoxic payloads inside
the tumour cell, either through its linkage/linker
sensitivity to protease, acidic, reductive agents or by
lysosomal process, leading to cell death (D)
Targeted Ag Payload Linkage
Enfortumab Vedotin1,2 Nectin-4 Monomethyl Auristatin E (MMAE) Protease cleavable linker
Tisotumab Vedotin3 Tissue factor (thromboplastin) MMAE Protease cleavable linker
ASG-15ME4 SLITRK6 MMAE Protease cleavable linker
Sacituzumab Govitecan5 Trop-2 SN-38 Hydrolysable cleavable linker
RC-486 Her-2 MMAE Cathepsin cleavable linker
ADCs with data on mUC
Image: Nejadmoghaddam MR, et al. Avicenna J Med Biotechnol 2019;11(1):3–23. Reproduced under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/. Accessed Sept 2019).
1. Rosenberg JE, et al. J Clin Oncol 2018;36(15_suppl): Abstract TPS4590. Presented at ASCO 2018; 2. Petrylak D, et al. J Clin Oncol 2019;37(18_suppl); Abstract LBA4505. Presented at ASCO 2019;
3. de Bono JS, et al. Lancet Oncol 2019;20(3):383–93; 4. Petrylak D, et al. Ann Oncol 2016;27(6):266–95. Abstract 780PD. Presented at ESMO 2016; 5. Tagawa S, et al. J Clin Oncol 2019;37(7_suppl): Abstract 354. Presented at ASCO
GU 2019; 6. Sheng X, et al. J Clin Oncol 2019;37(15_suppl): Abstract 4509. Presented at ASCO 2019.
Grade 5 TRAEs: diabetic ketoacidosis, multiple organ dysfunction syndrome, respiratory failure, urinary tract obstruction
EV-101 PHASE 1 STUDY: DESIGN, POPULATION
AND SAFETY
Rosenberg JE, et al. J Clin Oncol 2018;36(15_suppl): Abstract TPS4590. Presented at ASCO 2018. Reproduced with permission from Dr JE Rosenberg.
Part A (closed to accrual)
Dose-escalation/-expansion adaptive trial design
utilising a Continual Reassessment Method to
determine RP2D
◆ Cohort 1: 0.5 mg/kg
◆ Cohort 2: 0.75 mg/kg
◆ Cohort 3: 1 mg/kg
◆ Cohort 4: 1.25 mg/kg
Nectin-4 expressing tumours, including mUC
Part B (enrolling)*
Dose expansion: 3 cohorts
◆ Cohort 1: mUC with severe renal insufficiency
(0.75 mg/kg escalating to 1.25 mg/kg)
◆ Cohort 2: NSCLC (1.25 mg/kg)
◆ Cohort 3: Ovarian cancer (1.25 mg/kg)
RP2D
1.25 mg/kg
Part C (closed to accrual)
Dose expansion: 1 cohort
◆ CPI-treated mUC patients (1.25 mg/kg)
*Only Cohort 1 is a actively recruiting
Petrylak DP, et al. J Clin Oncol 2017;35:106.
Progression-free Survival
Overall Survival
ORR: 41%
ENFORTUMAB-VEDOTIN PHASE 1 STUDY: ACTIVITY
Rosenberg JE, et al. J Clin Oncol 2018;36(15_suppl): Abstract TPS4590. Presented at ASCO 2018. Reproduced with permission from Dr JE Rosenberg.
ENFORTUMAB-VEDOTIN PHASE 2 TRIAL
Patient profile: post-platinum and post-ICI treated
Treatment: E-V 1.25 mg/kg D1, 8 and 15, q28 days
Objectives: ORR (primary), DOR, PFS, OS, safety
Radiological response
◆ ORR: 44%
◆ Liver M1: 38%
◆ ICI-non responders: 41%
◆ PD-L1 negative (CPS <10): 47%
Median DOR: 7.6 months
AEs of special interest
◆ Peripheral neuropathy: any grade 50%; ≥G3 3%
◆ Rash: any grade 48%; ≥G3 12%
◆ Hyperglycemia: any grade 11%; ≥G3 6%
Toxicity leading to discontinuation: 12%
Survival
◆ Median PFS: 5.8 mo
◆ Median OS: 11.7 mo
Petrylak D, et al. J Clin Oncol 2019;37(18_suppl); Abstract LBA4505. Presented at ASCO 2019. Reproduced with permission from Dr D Petrylak.
SACITUZUMAB GOVITECAN (IMMU-132): PHASE 1/2 TRIAL
Phase 1/2 open-label, single-arm, multicenter, basket trial
Sacituzumab govitecan 10 mg/kg on Days 1 and 8, every 21 days
Endpoints: ORR, DoR, PFS, OS
◆ 11% of patients discontinued due to drug-related AEs
◆ No treatment-related deaths
Tagawa S, et al. J Clin Oncol 2019;37(7_suppl): Abstract 354. Presented at ASCO GU 2019. Reproduced with permission from Dr S.Tagawa.
SACITUZUMAB GOVITECAN (IMMU-132): PHASE 1/2 TRIAL
• Median PFS: 7.3 months
(95% CI: 5.0, 10.7)
• Median OS: 16.3 months
(95% CI: 9.0, 31)
Tagawa S, et al. J Clin Oncol 2019;37(7_suppl): Abstract 354. Presented at ASCO GU 2019. Reproduced with permission from Dr S.Tagawa..
• 50% of responses were ≥12 months
• 3 patients still on treatment with
response ongoing at data cut-off (17+,
19+ and 29+ months
TISOTUMAB VEDOTIN IN PATIENTS WITH ADVANCED
OR METASTATIC SOLID TUMOURS: PHASE 1/2 TRIAL
N=174 (bladder cancer: 17)
Reprinted from Lancet Oncol, 20(3), De Bono JS, et al. Tisotumab vedotin in patients with advanced or metastatic solid tumours (InnovaTV 201): a first-in-human, multicentre, phase 1-2 trial, 383-393. Copyright 2019, with
permission from Elsevier.
All patients
(N=147)
Bladder cancer
(n=15)
Cervical cancer
(n=34)
Endometrial
cancer (n=14)
Oesophageal
cancer (n=15)
NSCLC
(n=15)
Ovarian cancer
(n=36)
Prostate cancer
(n=18)*
Objective response
n (%) 23 (15.6%) 4 (26.7%) 9 (26.5%) 1 (7.1%) 2 (13.3%) 2 (13.3%) 5 (13.9%) 0
95% CI 10.2, 22.5 7.8, 55.1 12.9, 44.4 0.2, 33.9 1.7, 40.5 1.7, 40.5 4.7, 29.5 0, 0.2
Duration of response
INTERIM ANALYSIS OF A PHASE 1 DOSE ESCALATION
TRIAL OF AGS15E IN PATIENTS WITH MUC
**Evaluable subjects are defined as subjects who received ≥1 dose of drug and ≥1 post-baseline assessment.Petrylak D, et al. Ann Oncol 2016;27(6):266–95. Abstract 780PD. Presented at ESMO 2016. Reproduced with permission from Dr D Petrylak.
Best overall response for evaluable patients
Max
imum
cha
nge
from
bas
elin
e (%
)
RC-48: ADC TARGETING HER-2 IN BIOMARKER-
SELECTED PATIENTS
Most common toxicities:
◆ All grades: Hypoesthesia (55.8%), alopecia (55.8%), leukopenia (55.8%), neutropenia (41.9%)
◆ Grade 3/4: hypoesthesia (16.3%), neutropenia (14.0%)
◆ SAEs: intestinal obstruction (4.7%) and incomplete intestinal obstruction (4.7%)
Sheng X, et al. J Clin Oncol 2019;37(15_suppl): Abstract 4509. Presented at ASCO 2019.. Reproduced with permission from Prof X. Sheng.
SURVIVAL:
◆Median PFS: 6.9 months
◆12 m OS rate: 59.6%
ANTIBODY DRUG CONJUGATES – CONCLUSIONS
ADCs show promising activity in heavily pretreated patients, with a favourable comparison to historical controls
Unlike ICIs, ADCs may maintain a high efficacy level in poor prognostic groups, such as patients with hepatic
metastases
ADCs have the potential to become an additional treatment option in the armamentarium of available therapies for UC
Development of surrogate markers of response is critical
Larger trials testing these agents are ongoing, both as single agent or in combinational strategies.* A Phase 3 trial is
comparing enfortumab-vedotin with vinflunine/taxanes in the third-line setting (post-platinum, post-ICI)
*NCT03474107, NCT03219333, NCT03547973, NCT03288545
A STEP-AHEAD INTO THE PRECISE FUTURE?
THE BISCAY TRIAL
Diagnostic sample
analysed
Module A: Durvalumab + AZD4547 OR
AZD4547
Module C: Durvalumab + AZD1775
Module B: Durvalumab + Olaparib
Module D: Durvalumab alone
FGFR
inhibitor
WEE1
inhibitor
PARP
inhibitor
PD-L1
Treatment option MOA
FGFR3 mutations/
fusions
CDKN2A /RB1 del
CCNE1 ampl
MYC ampl
ATM trunc mut/del
BRCA2 trunc
mut/del
ERCC2 mut
Biomarkers
considered
Module B2: Durvalumab + Tremelimumab + Olaparib
Module C2: Durvalumab + Tremelimumab + AZD1775
Module E*: Durvalumab+ Vistusertib mTOR inhRICTOR amplif,
TSC1 / TSC2 mut
Module F: Durvalumab+ AZD9150 STAT3 inh
None
Second-/third-line
metastatic
urothelial cancer
*:cohort unselected, but RICTOR, TSC1 and TSC2 directed to this cohort
SECOND-LINE THERAPY FOR METASTATIC
UROTHELIAL CARCINOMA
The race against bladder cancer
Taxanes / gemcitabine Vinflunine
IO agents? Immuno combos
? Targeted therapy
? ADCs
Taxanes / gemcitabine Taxanes / gemcitabine
CONCLUSIONS
The therapeutic scenario in post-platinum mUC patients has evolved rapidly within the last 5 years with multiple
additions
Checkpoint inhibitors have superseded chemotherapy, with impressive results in a subset of patients (15–20),
although the lack of predictive biomarkers might limit the success of this treatment option
FGFR inhibitors have shown remarkable activity in a biomarker-selected population and erdafitinib has been recently
added to the treatment armamentarium in this setting (FDA approval)
The Antibody Drug Conjugates represent an attractive alternative to all patients (they do not require biomarker
selection) and their preliminary activity appears very promising
Biomarker driven studies are ongoing and hopefully will soon refine mUC treatment
THANK YOU!