vale a pena solicitar o status do pd -l1 no muc ? …...vale a pena solicitar o status do pd -l1 no...

Vale a pena solicitar o status do PD-L1 no mUC ? Quando? Qual método?

Ricardo CarvalhoOncologista Clínico Titular

Departamento de Tumores GenitourináriosBeneficência Portuguesa de São Paulo

São Paulo-SP, 05 de Abril de 2019

@rcarvalhoonco

De acordo com a Resolução 1595 / 2000 do Conselho Federal de Medicina e com a RDC 96 / 2008 da ANVISA, declaro:

Speaker: Astrazeneca, Astellas; Janssen, MSD, Pfizer, Bayer, Ferring, Merck e Roche.

Não possuo ações em quaisquer destas companhias farmacêuticas

Declaração de conflitos de interesses

Landscape

1. Bellmunt et al. Ann Oncol 2014; 2. von der Maase et al. J Clin Oncol 2005; 3. De Santis et al. J Clin Oncol 20124. Bellmunt et al. J Clin Oncol 2009; 5. von der Maase et al. J Clin Oncol 2000

Antes de 2017: necessidade médica não atendida no tratamento do câncer urotelial metastático

Inelegível à cisplatina

Tolerabilidade desfavorável3–5

Quimioterapia como padrão de tratamento1

1L

Elegível à cisplatina

SG mediana14–15 meses2

SG mediana<10 meses3

SG mediana<7 meses4

2L

Respostas pouco duráveis

PD-L1 is frequently overexpressed in solid tumors, including NSCLC, HNSCC and UC1

PD-L1 expression on either TCs or tumor-infiltrating ICs may be a biomarker of patients most likely to respond to PD-L1/PD-1 immunotherapies2-4

HNSCC = head and neck squamous cell carcinoma; IC = immune cell; NSCLC = non-small cell lung cancer; PD-1 = programmed cell death-1; PD-L1 = programmed cell death-ligand 1; TC = tumor cell; UC = urothelial carcinoma.

•Percentage of tumor cells exhibiting positive membrane staining at any intensity5TC Staining

•Presence of discernible PD-L1 staining of any intensity in tumor-infiltrating immune cells6

IC Staining

TC area with PD-L1 expression

TC area

tumor area

IC area with PD-L1 expression

Diagnostic Testing

1. Chen DS et al. Clin Cancer Res. 2012;18:6580-6587. 2. Massard C et al. J Clin Oncol. 2016;34:3119-3125. 3. Powles T et al. Nature. 2014;515:558-562. 4. Rebelatto MC et al. Diagn Pathol. 2016;11:95. 5. PD-L1 IHC 28-8 pharmDx [package insert]. Agilent Pathology Solutions website. Accessed April 19, 2017. 6. Ventana PD-L1 (SP142) assay. Ventana Medical Systems website. Accessed April 19, 2017.

Apresentador

Notas de apresentação

References Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy--inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580-6587. Massard C, Gordon MS, Sharma S, et al. Safety and efficacy of durvalumab (MEDI4736), an anti-PD-L1 antibody, in urothelial bladder cancer. J Clin Oncol. 2016;34:3119-3125. Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014;515:558-562. Rebelatto MC, Midha A, Mistry A, et al. Development of a programmed cell death-ligand 1 immunohistochemical assay validated for analysis of non-small cell lung cancer and head and neck squamous cell carcinoma. Diagn Pathol. 2016;11:95. Dako Agilent Pathology Solutions. PD-L1 IHC 28-8 pharmDx [package insert]. Agilent Pathology Solutions website. http://www.agilent.com/cs/library/packageinsert/public/128912002.PDF. Accessed April 19, 2017. Ventana Medical Systems. Ventana PD-L1 (SP142) assay. Ventana Medical Systems website. http://www.ventana.com/product/1827?type=2357. Accessed April 19, 2017.

Powles T et al. ASCO GU 2018

Durvalumab Atezolizumab Nivolumab Pembrolizumab

PD-L1 assay Ventana SP263 VentanaSP142

Dako28.8

Dako22C3

Cell-typesscored for UC IC and TC IC TC TC and IC

Study (Phase)

Study 1108 –UC cohort

(phase 1/2)1

IMvigor 210(phase 2)2

IMvigor 210(phase 2)3

CM-032 –UC cohort

(phase 1/2)4

CM-275(phase 2)5

KN-045(phase 3)6

KN-052a

(phase 2)7

Line of therapy ≥1L ≥2L 1L (cis-inel.) ≥2L ≥2L 2L 1L (cis-ineligible)

Number of patients 191 310 119 78 265 270 370

PD-L1 cut-offs:High/positiveLow/negative

≥25% TC or IC<25% TC and IC

≥5% IC<1% IC

≥5% IC<1% IC

≥1% TC<1% TC

≥1%, ≥5% TC<1% TC

≥10% CPS NA

≥10% CPS <10% CPS

ORR in unselected patients ORR in PD-L1 high/positive patients ORR in PD-L1 low/negative patients

0

10

20

30

40

OR

R (%

)

17.8

27.6

5.1

15

26

8

24.4 24 26.2

19.6

23.8–28.4

16.1

21.1 21.6

NA

24

39

2023

2821

Imunoterapia e expressão de PDL-1 em carcinomas uroteliais

1L = first line; 2L = second line; cis = cisplatin; CPS = combined proportion score; IC = immune cell; NA = not applicable; ORR = objective response rate; PD─L1 = programmed cell death-ligand 1; TC = tumor cell; UC = urothelial carcinoma.aKN-052; 307 patients (>4 month follow-up). ORR unselected 27%, CPS≥10 48%; CPS<10 22%7

Pesquisamos o PD-L1 usando kits e anticorpos diferentes

Pesquisamos o PD-L1 em células diferentes

Classificamos como PD-L1 “positivo” e “negativo” de forma diferente

Indefinição

Apresentador


Annotations From 69400 Bladder diagnostics ad board showfile, slide 11. References Hahn NM, Powles T, Massard C, et al. Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma [poster]. Presented at: American Society of Clinical Oncology (ASCO); June 2-6, 2017; Chicago, IL. Abs 4525. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387:1909-1920. Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 2017; 389: 67-76. Rosenberg JE, Bono P, Kim J, et al. Nivolumab monotherapy in metastatic urothelial cancer (mUC): updated efficacy by subgroups and safety results from the CheckMate 032 study [poster]. Presented at European Society for Medical Oncology (ESMO) 2016; October 7-11, 2016; Copenhagen, Denmark. Abs 784. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18:312-322. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017; 376:1015-1026. Balar AV, Castellano DE, O’Donnell PH, et al. Pembrolizumab as first-line therapy in cisplatin-ineligible advanced urothelial cancer: results from the total KEYNOTE-052 study population [poster]. Presented at: American Society of Clinical Oncology (ASCO) – Genitourinary Cancers Symposium; February 16-18, 2017; Orlando, FL. Abs 284. Patel M, Ellerton JA, Infante JR, et al. Avelumab in patients with metastatic urothelial carcinoma: pooled results from 2 cohorts of the phase 1b JAVELIN Solid tumor trial [poster]. Presented at: American Society of Clinical Oncology (ASCO) – Genitourinary Cancers Symposium; February 16-18, 2017; Orlando, FL. Abs 330.

Apresentador


Annotations From 69400 Bladder diagnostics ad board showfile, slide 11. References Hahn NM, Powles T, Massard C, et al. Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma [poster]. Presented at: American Society of Clinical Oncology (ASCO); June 2-6, 2017; Chicago, IL. Abs 4525. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387:1909-1920. Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 2017; 389: 67-76. Rosenberg JE, Bono P, Kim J, et al. Nivolumab monotherapy in metastatic urothelial cancer (mUC): updated efficacy by subgroups and safety results from the CheckMate 032 study [poster]. Presented at European Society for Medical Oncology (ESMO) 2016; October 7-11, 2016; Copenhagen, Denmark. Abs 784. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18:312-322. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017; 376:1015-1026. Balar AV, Castellano DE, O’Donnell PH, et al. Pembrolizumab as first-line therapy in cisplatin-ineligible advanced urothelial cancer: results from the total KEYNOTE-052 study population [poster]. Presented at: American Society of Clinical Oncology (ASCO) – Genitourinary Cancers Symposium; February 16-18, 2017; Orlando, FL. Abs 284. Patel M, Ellerton JA, Infante JR, et al. Avelumab in patients with metastatic urothelial carcinoma: pooled results from 2 cohorts of the phase 1b JAVELIN Solid tumor trial [poster]. Presented at: American Society of Clinical Oncology (ASCO) – Genitourinary Cancers Symposium; February 16-18, 2017; Orlando, FL. Abs 330.

Powles T et al. ASCO GU 2018

Drake C et al. ASCO 2018

RTU’s: Múltiplos fragmentos, presença de necrose e artefatos de cauterização…

Vida real…

Dicas práticas para otimizar qualidade da amostra tecidual

Evitar o uso do eletro cautério em altas temperaturas

Retirar a superfície do tecido com bisturi frio que será enviado ao patologista

Após se necessário usar o eletro cautério que não prejudicará mais a amostra que o patologista analisará

Bellmunt J, et al. N Engl J Med 2017;376:1015; Bellmunt J, et al. ASCO GU 2018

KEYNOTE-45 (Pembrolizumabe na 2ª linha): OS

CPS ≥ 10 = PD-L1 +ITT

10,3 vs 7,4 mo 8,0 vs 5,2 mo

Bellmunt J, et al. N Engl J Med 2017;376:1015; Bellmunt J, et al. ASCO GU 2018

CPS < 10 = PD-L1 -

10,8 vs 7,7 mo

PD-L1 não é biomarcador para OS com o Pembrolizumabe na 2ª linha

KEYNOTE-45 (Pembrolizumabe na 2ª linha): ORR

Bellmunt J, et al. ASCO GU 2018; R de Wit et al. ESMO 2017: abstract LBA37.

PD-L1 não é biomarcador para ORR com o Pembrolizumabe na 2ª linha

CPS ≥ 10 = PD-L1 +ITT CPS < 10 = PD-L1 -

Powles T et al. Lancet 2018;391:748-75

IMvigor 211 (Atezolizumabe na 2ª linha): OS

IC 2/3 (≥ 5%) = PD-L1 +ITT


IC 0/1 (< 5%) = PD-L1 -

PD-L1 não é biomarcador para OS com o Atezolizumabe na 2ª linha

IMvigor 211 (Atezolizumabe na 2ª linha): ORR


20

Pembrolizumab 200 mg q3w

N=370

Primary EndpointsORR in all patients

ORR in PD-L1-positive

Secondary EndpointsDoR, PFS, OS, and ORR

in all patients, PD-L1 positive and

PD-L1 high expressing patients;

Safety and tolerability; establish an assay cut point for high PD-L1

expression

Treatment until disease

progression, unacceptable

toxicity, or for up to 24 months in patients without

disease progressiona

• Advanced urothelial cancer

• No prior chemotherapy or metastatic disease

• ECOG PS 0-2• Ineligible for cisplatin-

based therapy

KEYNOTE-052: Fase 2 de Pembrolizumabe em 1ª linha em pacientes inelegíveis à Cisplatina

O’Donnel PH, et al. ASCO 2017 (abstr 4502)

KEYNOTE-52 (Pembrolizumabe na 1ª linha): OS

“PD-L1 +” = CPS ≥10%

Vuky J et al. ASCO 2018 (#4524)

ITT

KEYNOTE-52 (Pembrolizumabe na 1ª linha): ORR

“PD-L1 +” = CPS ≥10%ITT

Balar AV et al. Lancet Oncol 2017;18(11):1483-1492

• Phase II trial, single-arm, multicenter

Locally advanced (T4b and any N; or any T and N2-3) or metastatic urothelial carcinoma

Predominantly TCC histology

Tumor tissue for PD-L1 testing

Cohort 11: cisplatin-ineligible patients

n=119

Cohort 22: prior treatment on

platinum-containing regimenn=310

Tecentriq 1200 mg IV

q3w

Cohort 1: treated until unacceptable toxicity or disease

progression

Cohort 2: treated until unacceptable toxicity or either radiographic or

clinical progression

Primary EndpointsORR assessed by IRF using RECIST v1.1 and investigator-assessed

ORR by immune-modified RECIST

Secondary EndpointsDoRa

PFSa

OS (12 mo)Safety

Balar AV et al. ASCO 2016 (LBA4500)

IMvigor210 (coorte 1): Atezolizumabe em 1ª linha em pacientes inelegíveis à cisplatina

IMvigor 210 coorte 1 (Atezolizumabe na 1ª linha): OS

Balar AV et al. Lancet 2017;389:67

IMvigor 210 coorte 1 (Atezolizumabe na 1ª linha): ORR


PD-L1 não é um biomarcador para ORR na 1ª linha com Atezolizumabe...

7 Aprovações pelo PDA para IO em mUC (de maio/2016 a maio/2017)


O PD-L1 é um biomarcador consistentemente inconsistente

Seria o PD-L1 um bimarcador em mUC?

21% 23%

10%

23%19.9% 20.3%18%

39%

Apresentador


Importante sabermos que as interpretações dos laudos para PDL1 em pulmão e bexiga são diferentes. Foi comentado durante a discussão com oncologistas que os oncologistas costumam não ter essa visão.

Estudos de fase 3 na 1ª linha: em andamento

https://clinicaltrials.gov/ct2/show/NCT02807636; https://clinicaltrials.gov/ct2/show/NCT02516241 https://clinicaltrials.gov/ct2/show/NCT02853305; https://clinicaltrials.gov/ct2/show/NCT03036098

Alerta FDA: Atezo (IMvigor130) e Pembro (KEYNOTE-361) contra-indicados na 1ª linha em PD-L1 negativo

Alerta EMEA: Atezo (IMvigor130) e Pembro (KEYNOTE-361) contra-indicados na 1ª linha em PD-L1 negativo

AML = acute myeloid leukemia; CLL = chronic lymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma; ESO AD = esophageal adenocarcinoma; GBM = glioblastoma multiforme; RCC = renal cell carcinoma.

Som

atic

Mut

atio

n Fr

eque

ncy

(/Mb)

More mutations

Fewer mutations

High prevalence of mutations may lead to a

higher neoantigen load and increased

immunogenicity1,2

Third highest mutational burden after lung cancer

and melanoma1,3

102

101

100

10-1

10-2

102

101

100

10-1

10-2

| | | | | | | | | | | | | | | | | | | | | | | | | | | |

High Mutational Load of Bladder Cancer May Correlate with Immunogenicity1,2

1. Choudhury NJ, et al. Eur Urol Focus. 2016;2:445-452. 2. Kandoth C, et al. Nature. 2013;502(7471):333-339. 2. 3. Rajasagi M, et al. Blood. 2014;124(3):453-462

Apresentador


Talking Points - Bladder cancer is among the tumor types with the highest mutational burden, third after lung cancer and melanoma1,2 - The high prevalence of mutations may lead to a higher neoantigen load, resulting in higher immunogenicity2,3 - Presence of neoantigens also may provide valuable prognostic information in MIBC2 References Rajasagi M, Shukla SA, Fritsch EF, et al. Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. Blood. 2014;124(3):453-462. Choudhury NJ, Kiyotani K, Yap KL, et al. Low T cell receptor diversity, high somatic mutation burden, and high neoantigen load as predictors of clinical outcome in muscle-invasive bladder cancer. Eur Urol Focus. 2016;2:445-452. Kandoth C, McLellan MD, Vandin F, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502(7471):333-339.

CheckMate 275 - Nivolumabe (Fase II): Carga mutacional

ESMO 2017: abstract 848PD.

IMvigor 211: Atezolizumabe vs QT na 2a linha

Apresentador


Speaker notes: Atezo Estudo de Fase III (Imvigor 211) Avaliação de subgrupo: alta expressão PD-L1 mais alta TMB o HR 0,50. High TMB was associated with OS favoring atezolizumab but not chemotherapy, suggesting that it may be an independent predictor of clinical benefit

DDR alterations are associated with PD1/PD-L1 blockade* RR and OS

ORR ORR

Yuen TM et al. ASCO 2017

*1/3 Atezolizumabe2/3 Nivolumabe

Response by Genomic Subtypes

Rosemberg JE et al. Lancet 2016;387: 1909–20

IMvigor 210 (coorte 2): atezolizumabe na 2ª linha ORR de acordo com TMB e TCGA

Respondedores: maiorTumor Mutation Burden

(TMB)

Esta associação também foi consistente de acordo com o subtipo molecular (TCGA) e status de PD-L1.

IC I IC II IC III IC IV

ORR 10% 34% 16% 20%

Take home message

O PD-L1 é um biomarcador consistentemente inconsistente

Como lidar com a heterogeneidade intratumoral e intertumoral ? Alguns pacientes PD-L1 negativo alcançam CR olhar além do PD-L1: - TMB, MSI e TCGA

Questões ainda não bem compreendidas:- Timming ideal para a pesquisa do PD-L1- Como identificar um agente de escolha na ausência de estudos head-to-head ?- Existe uma sequência ótima de tratamento ?- Existe papel para a combinação IO + IO ou IO + QT ?- Existe papel para o uso em linhas mais precoces ?- Pseudo-PD ? Hiper-PD? - Tratamento pós-PD?

Gem-CIS orddMMVAC or

PCG

PD-L1 status

CIS-eligible

CIS-ineligible &Chemo-eligible

CPI

Chemo-ineligible

+ -

Atezolizumab orPembrolizumab

Gem-Carbo

My take in mUC 1st line

Pembro or Nivo or Atezo or Durva or

Avelumab

PD

QT

PDPD

Pembro or Nivo or Atezo or Durva or

Avelumab

QT / BSC

PD

Slide from @rcarvalhoonco

1st line

2nd line

[email protected]

Obrigado!!

@rcarvalhoonco

mailto:[email protected]

vale a pena solicitar o status do pd -l1 no muc ? …...vale a pena solicitar o status do pd -l1 no...

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