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PAPEL ACTUAL Y DE FUTURO DE LA INMUNOTERAPIA EN ELABORDAJE TERAPÉUTICO DEL CÁNCER DE VEJIGA Y OTRAS VÍASDE PROGRESO. CÓMO SELECCIONAR PACIENTES PARAINMUNOTERAPIA O PARA QUIMIOTERAPIA.
Sergio Vázquez EstévezSº Oncoloxía MédicaHospital Universitario Lucus Augusti. Lugo
PAPEL ACTUAL Y DE FUTURO DE LA INMUNOTERAPIA EN ELABORDAJE TERAPÉUTICO DEL CÁNCER DE VEJIGA Y OTRAS VÍASDE PROGRESO. CÓMO SELECCIONAR PACIENTES PARAINMUNOTERAPIA O PARA QUIMIOTERAPIA.
Sergio Vázquez EstévezSº Oncoloxía MédicaHospital Universitario Lucus Augusti. Lugo
A MODO DE INTRODUCCIÓN
• El cáncer de vejiga es un tumor agresivo queresponde a la quimioterapia, aunque con pocasRC.
• “Impacto” en población anciana, y en pacientescon bajo PS y aclaramiento de creatinina.
• Es uno de los tumores sólidos con más alta tasa demutaciones somáticas.
• El tratamiento más efectivo para tumores CIS/T1alto grado es la BCG.
• El cáncer de vejiga es un tumor agresivo queresponde a la quimioterapia, aunque con pocasRC.
• “Impacto” en población anciana, y en pacientescon bajo PS y aclaramiento de creatinina.
• Es uno de los tumores sólidos con más alta tasa demutaciones somáticas.
• El tratamiento más efectivo para tumores CIS/T1alto grado es la BCG.
3
IO PRIMERA LÍNEA PACIENTES“UNFIT” PARA CDDPIO PRIMERA LÍNEA PACIENTES“UNFIT” PARA CDDP
4
ATEZOLIZUMAB
Baseline Characteristics<br />Representative of the cisplatin-ineligible population
Presented By Arjun Balar at 2016 ASCO Annual Meeting
Baseline Characteristics<br />Representative of the cisplatin-ineligible population
Presented By Arjun Balar at 2016 ASCO Annual Meeting
Baseline Characteristics<br />Representative of the cisplatin-ineligible population
Presented By Arjun Balar at 2016 ASCO Annual Meeting
Baseline Characteristics<br />Representative of the cisplatin-ineligible population
Presented By Arjun Balar at 2016 ASCO Annual Meeting
Baseline Characteristics<br />Representative of the cisplatin-ineligible population
Presented By Arjun Balar at 2016 ASCO Annual Meeting
Efficacy<br />Response by Baseline Characteristic
Presented By Arjun Balar at 2016 ASCO Annual Meeting
PEMBROLIZUMAB
IO SEGUNDA LÍNEA
ATEZOLIZUMAB
IMvigor210 Cohort 2: Baseline Characteristics<br />Representative of the Greater mUC Population
Presented By Robert Dreicer at 2016 ASCO Annual Meeting
EfficacyResponses to Atezolizumab by PD-L1 IC Subgroup
IC2/3n = 100
IC1/2/3
n = 207
AllaN =310
ORR: confirmed IRF RECISTv1.1(95% CI)
28%(19, 38)
19%(14, 25)
16%(12, 20)
CR rate: confirmed IRFRECIST v1.1(95% CI)
IC1n = 107
IC0n = 103
11%(6, 19)
9%(4, 16)
26
• Responses were seen in all IC subgroups, but ORR was enriched with higher PD-L1 status• Complete responses accounted for nearly half of the observed responses
– CRs were observed in all PD-L1 subgroups, with the highest rate in IC2/3 patients
• ORRs per immune-modified RECIST were concordant
CR rate: confirmed IRFRECIST v1.1(95% CI)
15%(9, 24)
9%(6, 14)
7%(4, 10)
4%(1, 9)
2%(0, 7)
Dreicer R, et al. IMvigor210: atezolizumab in platinum-treated mUC. ASCO 2016
Efficacy <br />Overall Survival by Subgroups
Presented By Robert Dreicer at 2016 ASCO Annual Meeting
DURVALUMAB
Study 1108 – Bladder Cohort: Updated Efficacy and Tolerability of Durvalumab inLocally
Advanced or Metastatic Urothelial Carcinoma• Study 1108 is an ongoing Phase I/II study that has shown a tolerable safety profile with
durvalumab as well as early and durable antitumour activity in several tumour types1-4
• 191 patients with UC were enrolled; 103 patients were eligible for efficacy analysis6
• Tumour assessments were conducted at Weeks 6, 12, 16 then every 8 weeks during the treatmentperiod
• After one year of treatment, patients entered follow-up
• Upon evidence of progressive disease, patients were offered retreatment with durvalumab
ATLAS ID: ESMPDUR009
1. Segal NH et al. Poster presented at: ESMO; September 26-30, 2014; Madrid,Spain;
2. Lutzky J et al. Presented at: ASCO; May 30-June 3, 2014; Chicago, IL;3. Rizvi N et al. J Clin Oncol 2015;33(Suppl). Abstract 8032;
4. Segal NH et al. J Clin Oncol 2015;33(Suppl), Abstract 3011;5. Massard C, et al. Presented at: ASCO; June 4-7, 2016; Chicago, IL Presentation
4502.6. Powles T et al. Presented at: ASCO-GU; February 16-18, 2017. Orlando, FL.
DCR = disease control rate; DoR = duration of response; ORR =objective response rate; OS =overall survival; PD-L1 = programmedcell death ligand-1; PFS = progression-free survival; RECIST =Response Evaluation Criteria in SolidTumors; UC = urothelial cancer.
CARACTERÍSTICAS BASALES DE LOS PACIENTES
Powles T et al. Presented at: ASCO-GU;February 16-18, 2017. Orlando, FL.
Confirmed ORR and DCR by PD-L1 Expression
A. Includes 3 patients with unknown PD-L1 status due to biopsy samples with insufficient tumour who are not included inthe PD-L1 high or low groups.B. PD-L1 high defined as >25% of tumour/immune cell staining; PD-L1 low/negative defined as <25% of tumour/immunecell staining.C. Objective response rate (ORR) defined as confirmed complete (CR) or partial response (PR) per RECIST v1.1 in response-evaluable patients.2D. Disease Control Rate (DCR) defined as confirmed CR or PR or stable disease (SD) for ≥6 weeks.Data cut off July 24, 2016. 1. Adapted from Powles T et al. Presented at: ASCO-GU; February
16-18, 2017. Orlando, FL.2. Massard C et al. J Clin Oncol. 2016;34:3119-3125.
Kaplan-Meier Survival Estimates in Primary Efficacy Population of UC Cohort
Data cut-off July 24, 2016; NE = not evaluable; No. = number; OS= overall survival;PFS = progression free survival.
1. Powles T et al. Presented at: ASCO-GU; February 16-18, 2017. Orlando, FL.
AVELUMAB
Figure 1. JAVELIN Solid Tumor pooled mUC analysis study design
36Apolo AB et al. ASCO 2017
Table 2. Clinical activity in patients with ≥6 months of follow-up
37
* Persistence of ≥1 nontarget lesion(s) and/or maintenance of tumor markers abovenormal levels
† Missing and/or not assessable information: 24 patients had no post-baseline tumorassessment (21 died within 8 weeks, and 3 withdrew from the trial); 1 patient had post-baseline assessments with an overall response of not evaluable;3 patients started new anticancer therapy prior to the first post-baseline assessment;and 1 patient had stable disease of insufficient duration
‡ Proportion of patients with a best overall response of complete response, partialresponse, or stable disease
Apolo AB et al. ASCO 2017
Figure 5: ORR by subgroup in patients with ≥6 months of follow-up (1 of 2)
38
Apolo AB et al. ASCO 2017
Figure 5: ORR by subgroup in patients with ≥6 months of follow-up (2 of 2)
39
Apolo AB et al. ASCO 2017
Figure 4: PFS and OS in all post-platinum patients (2 of 2)
40Apolo AB et al. ASCO 2017
PEMBROLIZUMAB
NIVOLUMAB
CheckMate 275: Study design
Open-label, single-arm, phase II study Blinded independent review committee(BIRC) assessment of response using
RECIST v1.1
• Metastatic or locallyadvanced mUC
• Disease progressionon a prior platinum-based therapy
• Evaluable PD-L1tumor tissue samplea
TreatmentPatients
aPatients were required to have an evaluable tumor tissue sample for PD-L1 expression testing at screening, but were not excludedbased on PD-L1 statusbPatients could have been treated beyond progression under protocol-defined circumstances
Treat until progressionb
orunacceptable toxicity
Nivolumab3 mg/kg IV Q2W
N=270
• Metastatic or locallyadvanced mUC
• Disease progressionon a prior platinum-based therapy
• Evaluable PD-L1tumor tissue samplea
Sharma P et al. Lancet Oncol 2017
Checkmate 275: Patient Demographics andBaseline Characteristics
Characteristic and Demographics Nivolumab (N=270)
Median age, years (range) 66 (38–90)Male, % 78.1Race, %
WhiteAsianBlackOther/not reported
85.611.1<1.02.6
No. of prior regimens in metastatic setting, %01≥2
28.542.229.3
No. of prior regimens in metastatic setting, %01≥2
28.542.229.3
ECOG PS, %0≥1*
53.746.3
Baseline metastases,%Visceral (overall)LiverLymph node only
84.127.815.9
PD-L1 expression, %≥1%≥5%
46.030.6
• One patient had ECOG performance status of 3. Galsky M et al. Oral presentation at ESMO 2016. LBA31_PR.
Antitumor activity to nivolumab
Outcome, % AllN=265b
Confirmed ORR byBIRCa 19.6
95% CI 15.0–24.9
Best overall response
PD-L1 <1%n=143
PD-L1 ≥1%n=122
PD-L1 ≥5%n=81
16.1 23.8 28.4
10.5–23.1 16.5–32.3 18.9–39.5
• Median follow-up was 7 months (minimum of 6 months)
Best overall response
Complete response 2.3
Partial response 17.4
Stable disease 22.6
Progressive disease 39.2
Unable to determine 18.5aBy RECIST v1.1b265 of 270 patients were evaluated for efficacy, as 5 patients had insufficient follow-up
• Confirmed ORR in patients with PD-L1 <5% was 15.8% (95% CI, 10.8–21.8)
<1 4.1 4.9
15.4 19.7 23.5
17.5 28.7 28.4
46.9 30.3 25.9
19.6 17.2 17.3
Sharma P et al. Lancet Oncol 2017
Overall survival
PD-L1 ≥1%
Median OS, Months (95% CI)a
All treated 8.74 (6.05–NR)PD-L1 <1% 5.95 (4.30–8.08)PD-L1 ≥1% 11.30 (8.74–NR)
0.5
0.6
0.7
0.8
0.9
1.0O
vera
ll Su
rviv
al (P
roba
bilit
y)
All treated patients
No. at RiskAll treated patients
PD-L1 <1%PD-L1 ≥1%
0.0
0.1
0.2
0.3
0.4
0 3 6 9 12 15
Ove
rall
Surv
ival
(Pro
babi
lity)
Months
PD-L1 <1%
aSimilar results were seen using the 5% PD-L1 tumor expression cutoff; NR, not reached
265 198 148 63 5 0143 101 69 26 2 0122 97 79 37 3 0
Sharma P et al. Lancet Oncol 2017
Presented by Elizabeth Plimack at 2016 ASCO Annual Meeting
BellmuntNEJM, 2016
III Pembrolizumab Postplatinum
542 ≥1% tumor o stroma ≥10% 28.5% 21.6% 21.1%
BalarASCO-GU,2017
II Pembrolizumab First line cisineligible
370 ≥1% tumor o stroma ≥10%, 22% 39% 24%
CARACTERÍSTICAS MOLECULARES
PD-L1
PD-L1 as a biomarker: lights and shadowsPD-L1 expression is generally associated with
higher response rate, although responses can stilloccur in PD-L1–negative tumors1-25
PD-L1 expression is generally associated withhigher response rate, although responses can still
occur in PD-L1–negative tumors1-25
Pitfalls of using PD-L1 IHCas a biomarker test26
Pitfalls of using PD-L1 IHCas a biomarker test26
Smallbiopsy
specimens
Changesover time
andanatomical
part
1. Weber, et al. Lancet 2015; 2. Robert, et al. N Engl J Med 2015; 3. Wolchok, et al. ASCO 2016; 4. Sharma, et al. ASCO 2016; 5. Borghaei, et al. N Engl J Med 2015; 6. Brahmer, et al. N Engl J Med 2015; 7. Motzer, et al. J Clin Oncol 2015; 8.Janjigan, et al. ASCO 2016; 9. Kefford, et al. ASCO 2014; 10. Plimack, et al. ASCO 2015; 11. Hui, et al. ASCO 201612. Hodi, et al. SMR 2014; 13. Dreicer, et al. ASCO 2016; 14. Balar, et al. ASCO 2016; 15. Smith, et al. ASCO 2016; 16. McDermott,et al. J Clin Oncol 2015; 17. Massard, et al. ASCO 2016; 18. Antonia, et al. ASCO 2016; 19. Segal, et al. ASCO 2015; 20. Kaufman, et al. ASCO 2016; 21. Apolo, et al. ASCO 2016; 22. Verschraegen, et al. ASCO 2016; 23. Dirix, et al. SABCS 2015; 24.Chung, et al. ASCO 2016; 25. Disis, et al. ASCO 2016; 26. Topalian. Nat Rev Cancer 2016; 26. Topalian S. Nature Reviews Cancer 2016
PD-L1 expression is generally associated withhigher response rate, although responses can still
occur in PD-L1–negative tumors1-25
Pitfalls of using PD-L1 IHCas a biomarker test26
Changesover time
andanatomical
part
Effect ofprevious
treatments
Epitopesinstability
Differentantibodie,differentaffinities
Multiplecells
expressingPD-L1,
differentalgorithms
Potential biomarkers under investigation
Effector cells
CD3 count
ActivationsignatureTreg/CD3 ratio
Antibodyresponse
Mutation burden
Immunologicallyunresponsive tumour
Immunologicallyresponsive tumour
Low
CD3 cells
Clonality
↓↑↓
PoorLow
Low
↓
High↑
↓
↑
Robust
High
High
↑
T TT
T
T
T
T
T
TT
TT
Yuan, et al. J Immunother Cancer 2016; Rizvi, et al. Science 2015;Fehrenbacher, et al. Lancet 2016
In-depth understanding of the immune biology of tumors will helpguide the
development of personalised cancer immunotherapies
T
BloodVessel
LymphNode
Livetumour
Dyingtumour
MemoryT-cell
ImmatureDC
MatureDC
NaïveT-cell
Effector cells
Suppressorcells
Teff/Treg ratio
PD-L1 ontumour/TIL
↓
↓
↑
Low
↑
↑
↓High
T TT
CARGA MUTACIONAL
Presented by Min Yuen Teo at ASCO 17
Presented by Min Yuen Teo at ASCO 17
MUTACIONES SOMÁTICAS EN LOSGENES REPARADORES DEL DNA
Presented by Min Yuen Teo at ASCO 17
Presented by Min Yuen Teo at ASCO 17
SUBTIPO TCGA
TCGA 2017
Lerner SP et al. J Clin Oncol 35, 2017 (suppl; abstr 4500)
TCGA 2017
Lerner SP et al. J Clin Oncol 35, 2017 (suppl; abstr 4500)
TCGA 2017
Lerner SP et al. J Clin Oncol 35, 2017 (suppl; abstr 4500)
TCGA 2017
Lerner SP et al. J Clin Oncol 35, 2017 (suppl; abstr 4500)
TCGA 2017
Lerner SP et al. J Clin Oncol 35, 2017 (suppl; abstr 4500)
Lerner SP et al. J Clin Oncol 35, 2017 (suppl; abstr 4500)
CONCLUSIONES
76
• La elevada carga mutacional del cáncer de vejiga y el tipode población que lo padece ha abierto una “ventana deoportunidades” para la IO
• En 1ª línea “unfit”: SM de Atezolizumab >datos históricosde GEM + CBCDA. No datos maduros para Pembrolizumab
• Si no hay contraindicación a IO, Pembrolizumab es ya unSOC en 2ª línea
• Datos no extrapolables, por ahora, a 1ª línea “fit”, dondeCDDP produce respuestas duraderas
• Hay un 40% de progresiones: perfil molecular de pacienteidóneo para IO, a confirmar en estudios prospectivos. Noperfil clínico, al menos en 1ª línea “unfit” y 2ª línea
• Papel para la QT en 3ª línea?
• La elevada carga mutacional del cáncer de vejiga y el tipode población que lo padece ha abierto una “ventana deoportunidades” para la IO
• En 1ª línea “unfit”: SM de Atezolizumab >datos históricosde GEM + CBCDA. No datos maduros para Pembrolizumab
• Si no hay contraindicación a IO, Pembrolizumab es ya unSOC en 2ª línea
• Datos no extrapolables, por ahora, a 1ª línea “fit”, dondeCDDP produce respuestas duraderas
• Hay un 40% de progresiones: perfil molecular de pacienteidóneo para IO, a confirmar en estudios prospectivos. Noperfil clínico, al menos en 1ª línea “unfit” y 2ª línea
• Papel para la QT en 3ª línea?
Author: Robert Dreicer MD
GRACIAS
79
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