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Neoplasie uroteliali 2017 Highlights
Andrea Necchi Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
Disclosures
Available from the ASCO COI website
Consulting or Advisory Role:
• Company: Roche, Bayer, Merck & Co. Inc., Astra Zeneca
Travel, Accommodations, Expenses:
• Company: Roche, Merck & Co. Inc., Pierre Fabre
Research Funding (Institution):
• Company: Merck & Co. Inc., Astra Zeneca, Amgen
Presentation topics & objectives
• Bladder and urinary tract tumors
• Review current translational data from clinical trials/retrospective studies
• Gain insights on the impact of the latest data and future developments of immunotherapy in UBC
From 2016 White Paper of Bladder Cancer
Little progress in UBC therapeutic paradigm with the use of “old” pathological and clinical aids in the last 20 years
Hall et al, Lancet, 1999; updated: J Clin Oncol 2011 Grossman et al, N Engl J Med, 2003
Burger M et al, Eur Urol 2012 Meeks JJ et al, Eur Urol 2012
Grey zone of High Risk NMIBC ± BCG-failure
Perioperative (neoadjuvant) systemic therapy is underutilized worldwide
Little progress in UBC therapeutic paradigm with the use of “old” pathological and clinical aids in the last 20 years
0.0
0.2
0.4
0.6
0.8
1.0
0 6 12 18 24 30 36
Months
Surv
ival P
roba
bility
Carboplatin
Cisplatin
381 260 132 74 47 33 23
639 515 349 225 152 118 79
No. pts at risk
Carboplatin
Cisplatin
P < 0.0001
A
Necchi A et al, Eur Urol 2016
+2.3 months
VFL+BSC (N=253)
BSC (N=117)
No. of events 237 115
No. censored (%) 16 (6.3) 2 (1.7)
Median in months (95% CI) 6.9 (5.7 - 8.0) 4.6 (4.1 - 6.6)
Hazard ratio (95% CI) 0.88 (0.70 -1.10)
p-valuea 0.2613 aStratified log-rank test
The salvage chemotherapy landscape
Mean c-index across bootstrap samples of 0.646
Bellmunt J et al, Ann Oncol 2013 Sonpavde G et al, J Urol 2015
Presented By Elizabeth Plimack at 2017 Genitourinary Cancers Symposium
Presented By David McConkey and Roland Seiler at 2017 Genitourinary Cancers Symposium
Presented By Roland Seiler at 2017 Genitourinary Cancers Symposium
N=343 Discovery: 250 Validation: 93
Time Tumor site
“Waves” of CT-induced clonal
tumor evolution
Even mutations in previously reported driver genes, including PIK3CA, KMT2D (MLL2), ATM and TP53, were not consistently shared by matched pre-CT and post-CT tumors
Faltas BM et al, Nat Genet 2016
Liu D et al, ASCO 2016 Jones S et al, Sci Transl Med 2015
Genomic evolution in MIBC after neoadjuvant chemotherapy
New neoantigens are detected in post-CT samples 32% of pts had gain or loss in targetable mutations
Targeted drug class-1 in the neoadjuvant setting
Targeted drug class-2 in the adjuvant setting
Any driver of chemoresistance?
• High-grade UTUC tumors display a spectrum of genetic alterations similar to high-grade UCB
• However, there were significant differences in the prevalence of several recurrently mutated genes including FGFR3, HRAS, TP53, and RB1
Genomic Characterization of Upper Tract Urothelial Carcinoma
Sfakianos JP et al, Eur Urol 2016
PURE01: an open label, single-arm, phase 2 study of the anti-programmed death (PD)-1 monoclonal antibody (moAb) Pembrolizumab for neoadjuvant therapy of muscle-invasive urothelial bladder carcinoma (miUBC)
ClinicalTrials.gov NCT02736266
Future development of PD-L1/PD-1 inhibitors in UC 1
st li
ne
Low grade High grade
In development
BCG-unresponsive
Pembrolizumab Atezolizumab
Neoadjuvant Adjuvant
Trimodality
Cisplatin-eligible
Maintenance
Cisplatin-ineligible
Platinum-refractory
Pembrolizumab±CarboG
Atezolizumab±CarboG
Immuno-Oncology Combinations
Personalized medicine
Atezolizumab Ph III
Nivolumab Ph III
Avelumab (Ph III)
Pembrolizumab
Durvalumab +
Tremelimumab (Ph III)
Pembro+GC
Atezo+GC
Pembrolizumab + RT (Atezolizumab+RT)
Atezolizumab Pembro + Chemo Pembrolizumab
Non-muscle-invasive bladder
cancer
Muscle-invasive bladder cancer
Metastatic urothelial
cancer
2n
d li
ne
an
d b
eyo
nd
Pembrolizumab + BCG
Modified from Bellmunt J et al, ESMO 2016
• Key cohort 1 inclusion criteria:
– No prior treatment for mUC (> 12 months since perioperative chemotherapy) – ECOG PS 0-2 – Cisplatin ineligibility based on ≥ 1 of the following:1 GFR < 60 and > 30 mL/min (Cockcroft-
Gault), Grade ≥ 2 hearing loss (25 dB at 2 contiguous frequencies) or peripheral neuropathy, ECOG PS 2
• Cohort 1–specific endpoints:
– Primary: confirmed ORR per RECIST v1.1 (central IRF) – Key secondary: DOR, OS, safety
Phase II IMvigor210 Study Design and Objectives
Balar AV et al, Lancet 2017
• Inoperable locally advanced or metastatic UC
• Predominantly UC histology
• Tumor tissue evaluable for PD-L1 testinga
Cohort 1 (N = 119): 1L cisplatin ineligible
Cohort 2: Platinum-treated mUC
Atezolizumab 1200 mg IV q3w until RECIST v1.1 progression
Atezolizumab 1200 mg IV q3w until loss of clinical benefit
IMvigor210 Study (Cohort 1): OS by PD-L1 Status in Cisplatin-Ineligible Patients
• NE, not estimable. Patients at risk of an event are displayed at indicated time points below plot. Censored values are indicated with a plus (+) symbol. Data cut-off: 4 July 2016.
Noteworthy survival was observed in octogenarians, those with SD as best RECIST v1.1 response and patients with poor prognostic factors
Balar AV et al, Lancet 2017
Pembrolizumab 200 mg Q3W
Primary Endpoints
•ORR in all patients
•ORR in patients with
PD-L1–positive tumors
Patients (N = 350)
•Advanced urothelial cancer
•No prior chemotherapy for
metastatic disease
•ECOG PS 0-2
•Ineligible for cisplatin based
on ≥ 1 of the following: – CrCl <60 mL/min
– ECOG PS 2
– ≥ grade 2 neuropathy or
hearing loss
– NYHA class III CHF
Phase 2 KEYNOTE-052 Study Design: Pembrolizumab as First-Line Therapy for Cisplatin-Ineligible Advanced/Metastatic Urothelial Cancer
Results from an interim analysis of the first 100 patients were presented at the 2016 ESMO. Results from the total study population (N = 370) are presented herein (from GU-ASCO 2017 poster)
• The primary end point was confirmed ORR per RECIST v1.1 by central imaging vendor review
• Secondary efficacy end points included duration of response, OS, and progression-free survival (PFS) per RECIST v1.1
• Safety and tolerability and determination of a cut point for PD-L1 expression were secondary objectives
• Efficacy and safety were assessed in all patients who received ≥1 dose of pembrolizumab
Presented By Arjun V Balar at 2017 Genitourinary Cancers Symposium
KEYNOTE-052: ORR by PD-L1 Status
Presented By Arjun V Balar at 2017 Genitourinary Cancers Symposium
MK3465-361 (Pembro vs Pembro+CT* vs CT)
IMvigor130 (Atezo vs Atezo+CT* vs CT)
DANUBE (Durva vs Durva+Treme vs CT*)
Ongoing trials in the first-line metastatic setting
*Consisting of Cis or Carboplatin and Gemcitabine
1. Loriot Y et al. ESMO 2016; Abstr 783P. 2. Petrylak DP et al. ASCO 2015. 3. Patel MR et al. ESMO 2016; Abstr. 777PD. 4. Massard C et al. J Clin Oncol 2016;34:3119-25. 5. Sharma P et al. Lancet Oncol 2016;217:1590-1598. 6. Galsky MD et al. Lancet Oncol 2017;doi: http://dx.doi.org/10.1016/S1470-2045(17)30065-7.
7. Plimack ER et al. Lancet Oncol 2017;doi: 10.1016/S1470-2045(17)30007-4. 8. Bellmunt J et al. J Clin Oncol 2009;27:4454-4461. 9. Sonpavde G et al. Lancet Oncol 2010;11:861-870. 10. Choueiri TK et al. J Clin Oncol 2012;30:507-512. 11. Agarwal N et al. Clin Genitourin Cancer 2014;12:130-137.
Single-Arm Trials of Salvage Immunotherapy Targeting the PD-1/PD-L1 pathway – Pre ASCO-GU17 landscape
Phase N Population
Atezolizumab IMvigor 2101 2 310 All comers
PCD4989g2 1a 48 PD-L1+
Avelumab JAVELIN3 1b 109 All comers
Durvalumab Study 11084 1 40 PD-L1+
Nivolumab
CheckMate 0325 1/2 78 All comers
CheckMate 2756 2 265 All comers
Pembrolizumab KEYNOTE-0127 1b 33 PD-L1+
Not reported
Not reported
Not reported
*Historical ORR for chemotherapy.8-10 †Historical 1-y OS for chemotherapy.11
ORR 1-year OS
0 20 40 60 80
% (95% CI)
10* 0
% (95% CI)
20† 40 60 80
Updated Durvalumab results from MEDI1108 trial
Presented By Thomas Powles at 2017 Genitourinary Cancers Symposium
Overall Survival
Data cutoff date: Sep 7, 2016.
Events, n HR (95% CI) P
Pembro 155 0.73 (0.59-0.91)
0.0022
Chemo 179
43.9% 30.7%
Median (95% CI) 10.3 mo (8.0-11.8) 7.4 mo (6.1-8.3)
0 2 4 6 8 10 12 14 16 18 20 22 24
10
20
30
40
50
60
70
80
90
100
Time, months
OS,
%
270 226 194 169 147 131 87 54 27 13 4 0 0
272 232 171 138 109 89 55 27 14 3 0 0 0
No. at risk
Events, n HR (95% CI) P
Pembro 44 0.57 (0.37-0.88)
0.0048
Chemo 60
Total Population
0
0 2 4 6 8 10 12 14 16 18 20 22 24
0
10
20
30
40
50
60
70
80
90
100
Time, months
OS,
%
74 60 51 42 35 31 18 12 7 3 0 0 0
90 76 51 36 28 24 16 8 4 1 0 0 0
No. at risk
Median (95% CI) 8.0 mo (5.0-12.3) 5.2 mo (4.0-7.4)
CPS ≥10% Population
39.8% 26.9%
0
Confirmed Objective Response Rate
0
5
10
15
20
25
30
35
40
OR
R, %
(9
5%
CI)
0
5
10
15
20
25
30
35
40
OR
R, %
(9
5%
CI)
No alpha allocated to the comparison of ORR in the CPS ≥10% population. Assessed per RECIST v1.1 by blinded, independent central review.
Data cutoff date: Sep 7, 2016.
21.1%
11.4%
Δ9.6% P = 0.0011 PR
CR
Total Population
21.6%
6.7%
CPS ≥10% Population
7.0%
14.1%
3.3%
8.1%
6.8%
14.9%
2.2%
4.4%
Pembrolizumab (N = 270)
Chemotherapy (N = 272)
Pembrolizumab (N = 74)
Chemotherapy (N = 90)
1. Galsky MD et al. Lancet Oncol 2017;doi: http://dx.doi.org/10.1016/S1470-2045(17)30065-7.
2. Rosenberg JE et al. Lancet 2016;387:1909-1920. 3. Sharma P et al. Lancet Oncol 2016;17:1590-1598.
RE Model
Median OS, months
Pembrolizumab Phase 3, ECCO 2017
Nivolumab Phase 1-2, Sharma, 2016 [3]
Atezolizumab Phase 2, Rosenberg, 2016 [2]
Nivolumab Phase 2, Galsky, 2016 [1]
10.30 [8.44, 12.16]
9.70 [5.34, 14.06]
7.90 [6.58, 9.22]
8.74 [6.05, not reached]
8.96 [7.54 , 10.37]
Meta-Analysis of OS in Studies of Second-Line Immunotherapy For Advanced Urothelial Carcinomaa
aPembrolizumab phase 1 study by Plimack et al (Lancet Oncol 2017;doi: 10.1016/S1470-2045(17)30007-4) not included because only patients with PD-L1+ tumors were enrolled.
4.00 8.00 12.00 16.00
Necchi A, et al. Poster Board #: G5 Abstract ID: 341
Presented By Vaughn DJ at 2017 Genitourinary Cancers Symposium
Presented By Andrea Apolo at 2017 Genitourinary Cancers Symposium
Patient Characteristics N = 48
Age
Median 58
Range (35-77)
Sex
Male 41 Female 7
Tumor type
Urothelial carcinoma 19 Castration-resistant prostate cancer 9 Urachal adenocarcinoma 4 Germ cell tumor 4 Penile 4 Squamous cell carcinoma of the bladder or urethra
2
Renal cell carcinoma—clear cell 2
Renal cell carcinoma—sarcomatoid 2
Trophoblastic 1
Sertoli Cell carcinoma 1
Presented By Andrea Apolo at 2017 Genitourinary Cancers Symposium
Adverse Event CaboNivo N=30 CaboNivoIpi N=18
Any Grade*
N (%)
Grade 3
N (%)
Grade 4
N (%)
Any Grade
N (%)
Grade 3
N (%)
Grade 4
N (%)
Alanine Aminotransferase Increased 20 (67) 0 0 8 (44) 1 (6) 0
Fatigue 19 (63) 2 (7) 0 13 (72) 2 (13) 0
Diarrhea 18 (60) 2 (7) 0 11 (61) 0 0
Hypothyroidism 17 (57) 0 0 5 (28) 0 0
Aspartate aminotransferase increased 15 (50) 0 0 4 (22) 0 0
Anorexia 14 (47) 0 0 11 (61) 1 (6) 0
Hoarseness 12 (40) 0 0 4 (22) 0 0
Mucositis 12 (40) 0 0 6 (33) 0 0
Hypocalcemia 12 (40) 0 0 4 (22) 0 0
Hyponatremia 11 (37) 1 (3) 0 5 (28) 2 (13) 0
Hypophosphatemia 11 (37) 4 (13) 0 8 (44) 3 (17) 0
Palmar plantar erythrodysesthesia 11 (37) 0 0 5 (28) 0 0
Thrombocytopenia 11 (37) 1 (3) 1 (3) 6 (33) 0 0
Dysgeusia 9 (30) 0 0 8 (44) 0 0
Hypoalbuminemia 9 (30) 0 0 3 (17) 0 0
Myalgia 9 (30) 0 0 3 (17) 0 0
Nausea 9 (30) 0 0 7 (39) 2 (13) 0
Rash€ 8 (27) 0 0 6 (33) 1 (6) 0
Neutropenia 8 (27) 5 (17) 0 4 (22) 0 0
Dry mouth 7 (23) 0 0 6 (33) 0 0
Dry skin 7 (23) 0 0 4 (22) 0 0
Vomiting 7 (23) 1 (3) 0 4 (22) 0 0
Hypertension 7 (23) 3 (10) 0 3 (17) 3 (17) 0
Hypomagnesemia 7 (23) 0 0 2 (11) 0 0
Proteinuria 7 (23) 1 (3) 0 2 (11) 0 0
Headache 7 (23) 0 0 0 0 0
Anemia 6 (20) 1 (3) 0 4 (22) 0 0
Weight loss 6 (20) 0 0 5 (28) 0 0
Abdominal Pain 5 (17) 0 0 3 (17) 0 0
Hypokalemia 5 (17) 0 0 4 (22) 0 0
Lipase increase 5 (17) 2 (7) 2 (7) 8 (44) 2 (13) 1 (6)
Cough 3 (10) 0 0 5 (28) 0 0
Dehydration 3 (10) 2 (7) 0 3 (17) 0 0
Hyperthyroidism 3 (10) 1 (3) 0 2 (11) 0 0
Amylase increase 4 (13) 1 (3) 0 1 (6) 0 0
Thromboembolic event 1 (3) 1 (3) 0 0 0 0
Colitis 0 0 0 1 (6) 1 (6) 0
Aseptic meningitis 1 (3) 1 (3) 0 0 0 0 *Reported in at least 10% of patients or > grade 2; €Rash includes abdomen/chest rash, acneiform, and maculo-papular Apolo AB, et al. GU ASCO 2017 abstract 293
Sharma P et al, SITC 2016
Sharma P et al, SITC 2016
Sharma P et al, SITC 2016
Ipilimumab/Nivolumab in mUC: Overall Survival
0 3 6 9 12 15 18 21 24 27 0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Ove
rall
Surv
ival
(P
rob
abili
ty)
Months No. at risk
NIVO 1 + IPI 3 26 21 17 7 3 3 3 2 1 0
NIVO 3 + IPI 1 104 84 59 45 38 27 8 0 0 0
Median OS, months (95% CI)
NIVO 1 + IPI 3 10.2 (4.5–NR)
NIVO 3 + IPI 1 7.3 (5.6–11.4)
NIVO 1 + IPI 3
NIVO 3 + IPI 1
Sharma P et al, SITC 2016
What is needed by the bladder cancer patient community The case of second-line therapy
Vinflunine ….
Atezolizumab in 1L and 2L, Nivolumab 2L (Durvalumab and Avelumab granted breakthrough therapy designation) …Pembrolizumab
[email protected] @AndreaNecchi