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