papel actual y de futuro de la inmunoterapia en el ... · presented by arjun balar at 2016 asco...
TRANSCRIPT
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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
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A MODO DE INTRODUCCIÓN
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• 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.
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IO PRIMERA LÍNEA PACIENTES“UNFIT” PARA CDDPIO PRIMERA LÍNEA PACIENTES“UNFIT” PARA CDDP
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ATEZOLIZUMAB
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Baseline Characteristics<br />Representative of the cisplatin-ineligible population
Presented By Arjun Balar at 2016 ASCO Annual Meeting
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Baseline Characteristics<br />Representative of the cisplatin-ineligible population
Presented By Arjun Balar at 2016 ASCO Annual Meeting
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Baseline Characteristics<br />Representative of the cisplatin-ineligible population
Presented By Arjun Balar at 2016 ASCO Annual Meeting
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Baseline Characteristics<br />Representative of the cisplatin-ineligible population
Presented By Arjun Balar at 2016 ASCO Annual Meeting
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Baseline Characteristics<br />Representative of the cisplatin-ineligible population
Presented By Arjun Balar at 2016 ASCO Annual Meeting
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Efficacy<br />Response by Baseline Characteristic
Presented By Arjun Balar at 2016 ASCO Annual Meeting
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PEMBROLIZUMAB
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IO SEGUNDA LÍNEA
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ATEZOLIZUMAB
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IMvigor210 Cohort 2: Baseline Characteristics<br />Representative of the Greater mUC Population
Presented By Robert Dreicer at 2016 ASCO Annual Meeting
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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
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Efficacy <br />Overall Survival by Subgroups
Presented By Robert Dreicer at 2016 ASCO Annual Meeting
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DURVALUMAB
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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.
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CARACTERÍSTICAS BASALES DE LOS PACIENTES
Powles T et al. Presented at: ASCO-GU;February 16-18, 2017. Orlando, FL.
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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.
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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.
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AVELUMAB
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Figure 1. JAVELIN Solid Tumor pooled mUC analysis study design
36Apolo AB et al. ASCO 2017
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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
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Figure 5: ORR by subgroup in patients with ≥6 months of follow-up (1 of 2)
38
Apolo AB et al. ASCO 2017
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Figure 5: ORR by subgroup in patients with ≥6 months of follow-up (2 of 2)
39
Apolo AB et al. ASCO 2017
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Figure 4: PFS and OS in all post-platinum patients (2 of 2)
40Apolo AB et al. ASCO 2017
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PEMBROLIZUMAB
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NIVOLUMAB
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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
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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.
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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
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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
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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%
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CARACTERÍSTICAS MOLECULARES
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PD-L1
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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
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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
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CARGA MUTACIONAL
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Presented by Min Yuen Teo at ASCO 17
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Presented by Min Yuen Teo at ASCO 17
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MUTACIONES SOMÁTICAS EN LOSGENES REPARADORES DEL DNA
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Presented by Min Yuen Teo at ASCO 17
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Presented by Min Yuen Teo at ASCO 17
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SUBTIPO TCGA
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TCGA 2017
Lerner SP et al. J Clin Oncol 35, 2017 (suppl; abstr 4500)
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TCGA 2017
Lerner SP et al. J Clin Oncol 35, 2017 (suppl; abstr 4500)
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TCGA 2017
Lerner SP et al. J Clin Oncol 35, 2017 (suppl; abstr 4500)
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TCGA 2017
Lerner SP et al. J Clin Oncol 35, 2017 (suppl; abstr 4500)
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TCGA 2017
Lerner SP et al. J Clin Oncol 35, 2017 (suppl; abstr 4500)
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Lerner SP et al. J Clin Oncol 35, 2017 (suppl; abstr 4500)
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CONCLUSIONES
76
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• 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?
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Author: Robert Dreicer MD
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GRACIAS
79