04_Joaquim_Bellmunt.ppsx

Actualización terapéutica del cáncer
urotelial metastásico en 2018
Joaquim Bellmunt, MD PhD
Associate Professor of Medicine
Harvard Medical School
PSMAR-IMIM
September 27th, 2018

Disclosures
• Advisory role:
◦ Genentech, Merck, Pfizer, GSK, BMS, Pierre-Fabre, Sanofi Aventis,
Astellas, OncoGenex, Janssen
• Speaker role:
◦ Pfizer, Merck, GSK, Novartis, Pierre-Fabre, Astellas
• Research funding:
◦ Takeda, Pfizer, Novartis, Sanofi Aventis

Objectives
• Present standard of care in second-line
management of advanced bladder cancer
• Recent results of Phase II and III trials with
PD-1/PD-L1 inhibitors
• Biomarkers
• Future directions with immunotherapy in
urothelial cancer

2017
1989 1993 1997 2001 2005 2009 2013
MVAC (Ph II)1
Paclitaxel (Ph II)2
Docetaxel (Ph II)4
Gemcitabine
+ cisplatin (Ph III)5
HD-MVAC (Ph III)6
Gemcitabine
+ paclitaxel (Ph II)7
Vinflunine (Ph III)9
Gemcitabine
+ carboplatin vs
MCaVi (Ph III)11
Gemcitabine
+ cisplatin
+ paclitaxel (Ph III)12
Gemcitabine
authorisation in UK
(26 Oct 1995)3
Gemcitabine
EMA
harmonisation
(23 Sep 2008)8
Vinflunine
EMA approval
(21 Sep 2009)10
1. Sternberg CN et al. Cancer 1989;64:2448–2458; 2. Roth BJ et al. J Clin Oncol 1994;12:2264–2270; 3. Eli Lilly. SmPC Gemzar® 01 Jul 2014. Available at: http://www.medicines.org.uk; 4.
McCaffrey JA et al. J Clin Oncol 1997;15:1853–1857; 5. Von der Maase H et al. J Clin Oncol 2000;18:3068–3077; 6. Sternberg CN et al. J Clin Oncol 2001;19:2638–2646; 7. Meluch AA et al. J Clin
Oncol 2001;19:3018–3024; 8. EMA. EMEA/CHMP/512295/2008; 24 Sept 2008. Available at: http://www.ema.europa.eu;
9. Bellmunt J et al. J Clin Oncol 2009;2:4454–4461; 10. EMA. EMEA/H/C/000983; 2012. Available at: http://www.ema.europa.eu; 11. De Santis M et al. J Clin Oncol 2009;27:5634–5639; 12.
Bellmunt J et al. J Clin Oncol 2012;30:1107–1113. All links accessed Sept 2017.
Publication
Agency
action
Evolution of systemic therapy for urothelial cancer

Treatment options following
platinum failure

Efficacy and safety in vinflunine + BSC vs BSC:
advanced/metastatic urothelial carcinoma
* The eligible population excludes 13 patients who presented at least one major protocol violation at baseline.
1. Bellmunt J et al. J Clin Oncol. 2009;27:4454–4461.
2L+ mUC
Vinflunine + BSC
(n=248)
BSC (n=117)
Adverse event,
%
All grade
AEs
Grade 3–
4
AEs
All grade
AEs
Grade 3–
4
AEs
Anaemia 93 19 61 8
Neutropenia 77 50 3 <1
Thrombocytopen
ia 51 6 16 <1
Fatigue/asthenia 50 19 61 18
Constipation 48 16 25 <1
Nausea 39 2 21 <1
Stomatitis/muco
sitis 29 2 2 0
Alopecia 29 0 2 0
Vomiting 29 3 15 0
Infusion/injectio
n site 27 <1 0 0
Abdominal pain 16 4 18 6
Myalgia 16 3 7 0
Neuropathy
sensory 12 1 11 0
Febrile
neutropenia 6 6 0 0
Overall Survival in the
Eligible Population*
Time (months)
1.0
0.8
0.6
0.0
0.2
0.4
25
10 35
30
20
0 15
5
VFL + BSC
BSC
Overall
survival
(probability
)
Adapted from Bellmunt et al, 2009.
Vinflunine +
BSC (n=249)
BSC (n=108)
mOS, mos
(95% CI)
6.9
(5.7–8.0)
4.3
(3.8–5.4)
HR: 0.78; 95% CI, 0.61–0.99; P=0.0403

Progression-free Survival
Median follow-up duration in the full ITT population was 5.0 months (interquartile range [IQR], 2.3–8.9)
0 2 4 6 8 10 12 14 16 18
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Progression-free
Survival
Probability
Ramucirumab + docetaxel (n=216); median, 4.07 months
Placebo + docetaxel (n=221); median, 2.76 months
HR, 0.757 (95% CI, 0.607 to 0.943)
Log-rank P=0.0118
Ramucirumab + docetaxel (n=216); median, 4.04 months
Placebo + docetaxel (n=221); median, 2.46 months
HR, 0.672 (95% CI, 0.536 to 0.842)
Log-rank P=0.0005
Progression-free Survival (Month) Progression-free Survival (Month)
216
221
132
124
96
77
40
34
28
19
19
7
12
3
4
2
1
2
0
0
216
221
117
102
87
67
34
28
21
14
10
4
7
3
2
2
0
1
0
0
Investigator assessment Independent blinded assessment
28.5 %
18.9 %
11.9 %
4.5 %
28.6 %
16.7 %
8.3%
5.1 %

Emerging Treatment Options in
mUC:
Immunotherapy with Check-point
Inhibitors

Checkpoint Inhibitors Approved for Use in
Urothelial Carcinoma
7 US FDA Approvals May 2016-May 2017
Setting Antibody Approval Status
1st line
(cisplatin-
ineligible)
Atezolizumab  Accelerated approval granted in April 2017
Pembrolizumab  Accelerated approval granted in May 2017
Platinum-
pretreated
Atezolizumab  Accelerated approval granted in May 2016.
 In May 2017, the subsequent phase 3
IMvigor211 trial did not meet primary endpoint
of overall survival
Nivolumab  Accelerated approval granted in February
2017
Durvalumab  Accelerated approval granted in May 2017
Avelumab  Accelerated approval granted in May 2017
Pembrolizumab  Full approval granted in May 2017

Checkpoint Inhibitors Approved for Use in
Urothelial Carcinoma
7 US FDA Approvals May 2016-May 2017
5 EAU approvals
Setting Antibody Approval Status
1st line
(cisplatin-
ineligible)
Atezolizumab  Accelerated approval granted in April 2017
Pembrolizumab  Accelerated approval granted in May 2017
Platinum-
pretreated
Atezolizumab  Accelerated approval granted in May 2016.
 In May 2017, the subsequent phase 3
IMvigor211 trial did not meet primary endpoint
of overall survival
Nivolumab  Accelerated approval granted in February
2017
Durvalumab  Accelerated approval granted in May 2017
Avelumab  Accelerated approval granted in May 2017
Pembrolizumab  Full approval granted in May 2017

OVERVIEW OF LATEST DATA FOR CHECKPOINT INHIBITORS IN
BLADDER CANCER

Atezolizumab1,6 Nivolumab2 Pembrolizumab3 Avelumab4 Durvalumab5
Phase
Phase II single
arm
Phase III
randomized
Phase II single arm
Phase III
randomized
Phase Ib Phase I/II
Number of
patients
3101
4676 265 270
249 (242 pts ≥12
months follow-up)
191
Dosing 1200 mg q3w 3 mg/kg q3w 200 mg q3w 10 mg/kg q2w 10 mg/kg q2w
ORR 15%; IC2/3 23% 19.6% 21.1% 16.1% 17.8%
Duration of
response
84% ongoing at
median follow-up
of 11.7
months/15.9month
s6
77% ongoing at
median follow-up of
7.0 months
72% ongoing at
median follow-up of
14.1 months
64% ongoing at
data cut
Not reached at data
cut
Median OS 7.9/11.1 months 8.7 months 10.3 months 7.7 months 18.2 months
Median PFS 2.1 months 2.0 months 2.1 months 1.5 months 1.5 months
Grade 3/4
TRAEs
16%1/20%6 18%
13.5%
(15% G3–5)
10.8% G3‒5 6.8%
Immune checkpoint inhibitors in platinum-refractory setting
1. Rosenberg JE et al. Lancet 2016;387:1909–1920; 2. Sharma P et al. Lancet Oncol 2017;18:312–322; 3. Bellmunt J et al. N Engl J Med 2017 2017;376:1015–1026; 4. Apolo AB et al. ESMO 2017.
Abst 856P; 5. Powles T et al. JAMA Oncol. doi:10.1001/jamaoncol.2017.2411. 6. Powles T et al The Lancet 2018 Table adapted from Grivas P. ASCO 2017.

Immune checkpoint inhibitors as first-line in
cisplatin-ineligible patients
Atezolizumab1 Pembrolizumab2
Phase
Phase II (IMvigor
Cohort 1)
Phase II (Keynote-
052)
Number of patients 119 370
Dosing
1200 mg every 3
weeks
200 mg every 3 weeks
ORR 23% (9% CR) 29% (7% CR)
Duration of response
70% of responses
ongoing at 17.2
months
82% of responses
ongoing at
≥ 6 months
Median OS 15.9 months 11.5 months
Median PFS 2.7 months 2.0 months
Rate of Grade 3/4 treatment-
related AEs
16% 19%
1. Balar AV et al. Lancet 2017; 389:67–76; 2. O’Donnell, ASCO 2017. Abstract No. 4502. Table reproduced from Grivas P. ASCO 2017.

Use PD-L1 Expression To Select Therapy For
Cisplatin-ineligible Patients? (US)
5/18/2018 - FDA Alert
•In 2 ongoing clinical trials (KEYNOTE-361
and IMVIGOR-130), the Data Monitoring
Committees’ (DMC) found patients in the
monotherapy
(pembrolizumab/atezolizumab) arms of both
trials with PD-L1 low status had decreased
survival compared to patients who received
cisplatin- or carboplatin-based
chemotherapy
•Both trials have stopped enrolling patients
whose tumors have PD-L1 low status to the
pembrolizumab or atezolizumab monotherapy
arms
•The monotherapy arms remain open only to
patients whose tumors have PD-L1 high status
FDA. https://www.fda.gov/Drugs/DrugSafety/ucm608075.htm. May 18, 2018.
Pembrolizumab/
Atezolizumab?
Carboplatin-based
chemotherapy
Pembrolizumab/
atezolizumab
PD-L1 (IHC)
Low High
Cisplatin Ineligible
Ineligible for any
Platinum
J. Bellmunt 2018

KEYNOTE-045 Study Design (NCT02256436)1
SECOND LINE Phase III
IMvigor211 Study Design (NCT02302807)2
Estimated timelines
Estimated completion:
Sept 2016 (Early
termination)
Pembrolizuma
b
SOC:
Paclitaxel,
Docetaxel or
Vinflunine
Secondary end points
•ORR
•Safety
Primary end points
OS & PFS
• Urothelial cancer
• Progression or recurrence of
urothelial cancer following a first-
line platinum-containing
regimen.
• No more than 2 prior lines of
systemic chemotherapy.
Randomization
N = 542 patients
1Bellmunt J, et al. N Engl J Med. 2017; 2Clinicaltrials.gov.
Estimated timelines
Estimated completion:
Nov 2017
Atezolizumab
SOC:
Docetaxel,
Paclitaxel or
Vinflunine
•ORR
•PFS
•DOR
•Safety
Primary end points
OS
• Urothelial cancer
• Progression or recurrence of
urothelial cancer following a
first-line platinum-containing
regimen.
Randomization
N = 932 patients

KEYNOTE-045: OVERALL SURVIVAL
Bellmunt, J.; De Wit, R.; Vaughn, D.J.; Fradet, Y.; Lee, J.L.; Fong, L.; Vogelzang, N.J.; Climent, M.A.; Petrylak, D.P.; Choueiri, T.K.; et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med
2017;376:1015-26.

KEYNOTE-045: PFS , ORR
Bellmunt, J.; De Wit, R.; Vaughn, D.J.; Fradet, Y.; Lee, J.L.; Fong, L.; Vogelzang, N.J.; Climent, M.A.; Petrylak, D.P.; Choueiri, T.K.; et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med
2017;376:1015-26.

Atezolizumab
IMvigor 211: fase III.
OS in PD-L1 IC2/3.
OS in patirents PD-L1 IC 1/2/3. OS in ITT
Powles T, et al. Lancet 2017 Dec 18 [epub ahead of print].
Second Line
Media F/U: 17.3 mo

• Positive PD-L1 expression (score of 2–4) in TIMCs was significantly associated with longer OS
(12 versus 23 months) in both univariate (P = 0.04) and multivariable analysis (P = 0.0007)
(adjusting for ECOG status and visceral disease)
• PD-L1 expression in tumor cell membrane was not associated with survival (P = 0.45)
Bellmunt J, et al Ann Oncol. 2015 Apr;26(4):812-7.
Why no differences in survival
Chemo outperforming ?

Atezolizumab beyond the evidence

Long term follow-up data
• Phase I & II Atezolizumab
• Phase II Nivolumab
• Phase III Pembrolizumab

JAMA Oncol.
doi:10.1001/jamaoncol.2017.5440
Published online February 8, 2018.

1. Sternberg CN et al. Cancer 1989;64:2448–2458; 2. Roth BJ et al. J Clin Oncol 1994;12:2264–2270; 3. Eli Lilly. SmPC Gemzar® 01 Jul 2014. Available at: http://www.medicines.org.uk;
4. McCaffrey JA et al. J Clin Oncol 1997;15:1853–1857; 5. Von der Maase H et al. J Clin Oncol 2000;18:3068–3077; 6. Sternberg CN et al. J Clin Oncol 2001;19:2638–2646; 7. Meluch AA et al.
J Clin Oncol 2001;19:3018–3024; 8. EMA. EMEA/CHMP/512295/2008; 24 Sep 2008. Available at: http://www.ema.europa.eu; 9. Bellmunt J et al. J Clin Oncol 2009;27:4454–4461; 10. EMA.
EMEA/H/C/000983; 2012. Available at: http://www.ema.europa.eu; 11. De Santis M et al. J Clin Oncol 2009;27:5634–5639; 12. Bellmunt J et al. J Clin Oncol 2012;30:1107–1113; 13. Rosenberg JE
et al. Lancet 2016;387:1909–1920; 14. Massard C et al. ASCO 2016. Abstract #4502 and oral presentation; 15. AstraZeneca. Press release 17 Feb 2016. Available at: http://www.astrazeneca.com;
16. FDA. Press release 18 May 2016. Available at: http://www.fda.gov); 17. Apolo AB et al. ASCO 2016. Abstract #4514 and poster; 18. Galsky MD et al. ESMO 2016. Abstract #LBA31_PR; 19.
Balar A et al. ESMO 2016. Abstract #LBA32_PR; 20. FDA. Press release 2 Feb 2017. Available at http://www.fda.gov; 21. FDA. Press release 9 May 2017. Available at http://www.fda.gov. All links
accessed Sept 2017.
1989 1993 1997 2001 2005 2009 2013
MVAC (Ph II)1
Paclitaxel (Ph II)2
Docetaxel (Ph II)4
Gemcitabine
+ cisplatin (Ph III)5
HD-MVAC (Ph III)6
Gemcitabine
+ paclitaxel (Ph II)7
Vinflunine (Ph III)9
Gemcitabine
+ carboplatin vs
MCaVi (Ph III)11
Gemcitabine
+ cisplatin
+ paclitaxel (Ph III)12
Nivolumab (Ph II)18
Pembrolizumab (Ph I/II)19
Gemcitabine
authorisation in UK
(26 Oct 1995)3
Gemcitabine
EMA harmonisation
(23 Sep 2008)8
Vinflunine
EMA approval
(21 Sep 2009)10
Durvalumab
FDA breakthrough
designation
(17 Feb 2016)15
Atezolizumab
FDA approval
(18 May 2016)16
Atezolizumab (Ph II)13
Durvalumab (Ph I/II)14
Avelumab (Ph I)17
Evolution of systemic therapy for urothelial cancer to 2018
Publication
AgencyaActi
on
Nivolumab
FDA/EMA approval
(2 Feb 2017)20
2016 2017
Avelumab
FDA approval
(9 May 2017)21
Pembrolizumab
FDA/EMA approval
(18 May 2017)
Atezolizumab
EMA approval
(18 May 2016)16

Where Do We Go from Here?
Select Ongoing Trials in Bladder Cancer
Non-Muscle Invasive
KEYNOTE-057 (Ph 2):
• Pembrolizumab in BCG
unresponsive NMIBC
NCT02792192 (Ph 1/2):
• Atezolizumab ± BCG in high
risk NMIBC
Muscle Invasive
CheckMate 274 (Ph 3):
• Nivolumab vs placebo
postsurgery MIBC
IMvigor 010 (Ph 3):
• Atezolizumab vs observation
postsurgery PD-L1+ MIBC
DANUBE (Ph 3):
• Durvalumab ± Tremelimumab
vs chemo Tx-naïve,
unresectable, urothelial
carcinoma
KEYNOTE-052 (Ph 2):
• Pembrolizumab Tx-naïve,
cisplatin ineligible, locally
advanced mUC
KEYNOTE-361 (Ph 3):
• Pembrolizumab ± chemo vs
chemo in Tx-naïve advanced
or mUC
IMvigor 130 (Ph 3):
• Atezolizumab gem-cis vs gem-
cis in untreated advanced or
mUC
Pretreated Metastatic
CheckMate 275 (Ph 2):
• Nivolumab for locally
advanced or mUC after Pt
failure
IMvigor 211 (Ph 3):
• Atezolizumab vs chemo in
locally adv or mUC, after Pt
failure
KEYNOTE-045 (Ph 3):
• Pembrolizumab vs chemo in
locally adv or mUC, after Pt
failure
JAVELIN Bladder 100 (Ph 3):
• Avelumab as maintenance vs BSC for locally advanced mUC
Bellmunt J, et al. Cancer Treat Rev. 2017
Treatment naïve
Metastatic

First line trials
exploring IO/IO or
chemo
Immunotherapy
given concurrently
Study of Nivolumab in Combination With
Ipilimumab Compared to the Standard of Care
Chemotherapy in Treatment of Patients With
Untreated Inoperable or Metastatic Urothelial
Cancer (CheckMate901)

MAINTENANCE PHASE III
JAVELIN Bladder 100 Study Design (NCT02603432)
Maintenance treatment in patients with metastatic urothelial cancer after first-line
platinum-based chemotherapy
Estimated timelines
Estimated completion: July 2019
Avelumab
BSC
•PFS
•ORR
•Duration of response
•Pk
•QOL
Primary end point
OS
• Advanced or metastatic
transitional cell
carcinoma of the
urothelium
• Prior first-line
chemotherapy (4
cycles- 6 cycles of
gemcitabine + cisplatin
and/or gemcitabine +
carboplatin)
• No evidence of
progressive disease
following completion of
first-line chemotherapy
Randomization
N = 668 patients
71

1st
• Potential synergistic combos
– IO/IO
– IO/+ other immune approaches
• ADC, BSA, Vaccines
– IO/targeted therapies 1.- Exhausted Tumor infiltrating
lymphocytes express
multiple immunoinhibitory
receptors:
2.- These are druggable targets
for tumor immunotherapy

Chemotherapy Can Modulate Distinct Features of Tumor Immunobiology
in a Drug-, Dose-, and Schedule Dependent Manner1
1.-Chen G, Emens LA. Chemoimmunotherapy: reengineering tumor immunity.
Cancer Immunol Immunother 2013;62:203–16.

Response Rate to Chemotherapy After Immune
Checkpoint Inhibition in Metastatic Urothelial Cancer
Bernadett Szabados et al EUROPEAN UROLOGY 73 ( 2 018 ) 14 9 – 15 2

Randomization
Metastatic UC
• 1st line platinum-unfit
• ECOG PS 0-2
Avelumab
2 cycles
Carboplatin/gemcitabine
(standard chemotherapy)
Avelumab
maintenance
Avelumab +
carbo/gem
6 cycles
Phase II: 40 patients (35
evaluable) per arm
probability 0.9 of
selecting the treatment
that has a true response
rate of 30%+15%=45%
(D=0.15)
-Primary end point: ORR
-2nd: PFS, OS, DoR
Phase III : The study will
randomize 412 patients
-Primary end point: OS
Improving IO/Chemo with Sequential Administration vs Chemo
INDUCTION
https://clinicaltrials.gov/ct2/show/NCT03390595

CONFIDENTIAL
3
2
Ph II randomized trial of avelumab plus
gemcitabine/carboplatin in mUC
1. Gemcitabine (1000 mg/m2, IV
perfusion over 30 minutes)
2. Carboplatin (5AUC, IV perfusion
over 15 to 60 minutes)
Avelumab (10 mg/kg, IV
infusion over 60 minutes
1. Gemcitabine (1000 mg/m2, IV perf, 30 min)
2. Carboplatin (5AUC, IV perf, 15-60 min)
2w cycle
Avelumab (10 mg/kg, IV
infusion over 60 minutes
Gemcitabine (1000 mg/m2, IV
3w cycles (x6)
D1
D1 D8 D15
MONOTHERAPY
(Induction & Maintenance)
COMBINED TMT
(Consolidation)
3w cycle (x6)
Gemcitabine (1000 mg/m2, IV
D1 D8
EXPERIMENTAL ARM (ARM A)
CONTROL ARM (ARM B)

Novel Biomarkers: Beyond PD1
Early data suggests the following may enrich for response to PD1
pathway inhibition:
• Higher mutational load
• TCGA Subtype (Luminal II)
• CD8 infiltration
• Immune related gene expression signatures (Nanostring)
• Peripheral expansion of certain TCR clones

Biomarkers beyond PD-L1:
Mutation load is associated with OS and
RR with CI

Alterations in DNA
Damage Response
and Repair Genes as
Potential Marker of
Clinical Benefit From
PD-1/PD-L1
Blockade in Advanced
Urothelial Cancers
Min Yuen Teo, & J Rosenberg
J Clin Oncol February 28, 2018.

NIVOLUMAB PATIENT SELECTION
Putative biomarker: TCGA groups?
16.6
25.4
21.7
15.1
22.7
30.9
39.1
24.2
59.1
41.8
30.4
60.6
0%
25%
50%
75%
100%
Cluster 1 (Luminal
1) n=66
Cluster 2 (Luminal
2) n=55
Cluster 3 (Basal 1)
n=23
Cluster 4 (Basal 2)
n=33
Complete
Responsea
Partial
Response
Stable
Disease
Progressive
Disease
50
25
0
75
100
Percentage
Luminal 2
(Cluster 2)
n=55
Basal 1
(Cluster 3)
n=23
Basal 2
(Cluster 4)
n=33
Luminal 1
(Cluster 1)
n=66
8.7
Courtesy of L Albiges Galsky et al. LBA 31. ESMO 2016
Discordant
results with
Atezolizumab
study where:
- Luminal II have
high T eff and low
stromal genes.
- Basal subtypes
in TCGA have
more immune
suppressed
phenotypes (high
T eff and High
stromal),
Interferon-γ genes are enriched in responders vs those
with progressive disease (P<0.01)

Framework for prospective hypothesis testing in clinical trials, as well as for validation in ongoing or completed clinical trials
that test, or have tested, treatment strategies
Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, et al
Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer.
Cell. 2017 Oct 19;171(3):540-556
Future treatment paradigm??
CLASSIFICATION
INTO
DIFFERENT
MOLECULAR
SUBTYPES

Gene expression publicly available were
combined and reanalyzed. The dataset
contained 2411 unique tumors encompassing
non-muscleinvasive (NMIBC) and muscle-
invasive BLCA (MIBC). Subtypes were
reproduced on The Cancer Genome Atlas,
UROMOL, and IMvigor210.
https://doi.org/10.1016/j.eururo.2018.08.027

Tumor mutational burden correlates with response to immune checkpoint
blockade in multiple solid tumors, although in microsatellite-stable tumors this
association is of uncertain clinical utility. Limited utility of TMB as a clinical
biomarker for individual patients.
WES of 249 tumors and matched normal w outcomes to immune checkpoint Therapy
multiple cancer types. 7 published studies (n = 171) + 78 newly sequenced pre- Tto.
Identified genomic correlates of response beyond TMB:
• Somatic events in individual driver genes,
• Certain global mutational signatures,
• Specific HLA-restricted neoantigens.
• Often interrelated
Miao, D et al. Nat Genet. 2018 Sep;50(9):1271-1281

1.- Mutational burden and
response to immune
checkpoint therapy
CR or PR had significantly higher TMB
compared with PD.
- Persisted within types
TMB had poor predictive power to
differentiate CR or PR from PD in this
cohort
Higher mutational loads in patients with
stable disease with long
compared to short duration of OS
Clonal nonsynonymous MB strongly
predicted CR or PR versus PD across
cancer types and responses
Subclonal mutations (> 50%), (=high
intratumoral heterogeneity), were
substantially more likely to have
progressive disease than complete or
partial response

2.- Mutations in specific genes
associated with response or
resistance o IO checkpoint
therapy
Analysis limited to known hotspot
Clonal driver alterations in PIK3CA,
KRAS, and PBRM1 were enriched
in patients with CR or PR, while
clonal driver mutations in EGFR
were enriched in patients with PD
After correcting for TMB, KRAS
and PIK3CA remained associated
with complete or partial response
(did not pass FDR)
Clonal hotspot mutations in
PIK3CA, those with CR or PR had
melanoma, HNSCC, anal cancer, or
bladder cancer, whereas the
majority of those with SD or PD
had lung cancer

3.- Integrated analysis of
mutational burden, intratumoral
heterogeneity, and mutational
signatures in melanoma,
HNSCC, and bladder cancer
In bladder cancer and HNSCC,
analyses demonstrated association of
APOBEC-associated signatures (S2
and S13) with higher mutational
burdens and greater likelihood of
complete or partial response.
APOBEC mRNA expression has also
previously been associated with
increased PD-L1
immunohistochemical staining and
high tumor mutational burden in
urothelial carcinoma

871 predicted
neoantigens were
generated by driver
mutations.
8 of these ‘driver’
neoantigens occurred
recurrently in
patients with CR or
PR but not in patients
with PD in a human
leukocyte antigen
(HLA)-dependent
manner
Response-associated in silico–predicted neoantigens

Any new resistance mechanism ?
TGFbeta papers

Infiltrating T-cell abundance and EMTrelated gene expression are positively correlated, these
signatures convey disparate prognostic information
In patients Nivolumab treated pts with T-cell infiltrated tumors, higher EMT/stroma-related
gene expression is associated with lower RR and shorter PFS and OS
Nat Commun. 2018 Aug 29;9(1):3503.

The luminal-infiltrated and
basal-squamous TCGA UC
subtypes have been proposed
for prioritization for immune
checkpoint blockade based on
the relatively high infiltration of
immune cells but these
subtypes are also enriched in
EMT-related genes providing
potential insight for responses
observed in only a subset of
patients.
They show that EMT-related
gene expression and T-cell
infiltration are positively
correlated in UC yet confer
disparate treatment response
and prognostic information.
Regimens combining therapies
targeting stromal elements plus
PD-1/PD-L1 blockade in UC
NATURE COMMUNICATIONS | (2018) 9:3503 | DOI: 10.1038/s41467-018-05992-x |

Take Home Messages
• Immunotherapy in Urothelial Cancer is here to stay
• New FDA approvals:
• Pembrolizumab and atezolizumab in 1st line cisplatin-
unfit (requires PD-L1+)
• First FDA approval in mUC in the last 30 years
• Does PD-L1 expression guide treatment selection?
• Several ongoing phase III trials with chemo-IO or IO-IO
combinations for platinum-fit or unfit patients
• Promising biomarker results…but still very preliminary

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