abordagem atual de 1ª linha do cpnpc no brasil · socinski et al, esmo 2016; reck et al, esmo...

ABORDAGEM ATUAL DE 1ª LINHA DO CPNPC NO BRASIL

Clarissa BaldottoOncologista Clínica

Diretora Médica Americas Oncologia

Membro da Diretoria SBOC e GBOT

DECLARAÇÃO DE CONFLITOS DE INTERESSE

• Participação em advisory boards:

• Pfizer, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, MSD, Eli Lilly

• Atividades educacionais e patrocínios para congressos:

• Roche, AstraZeneca, Eli Lilly, MSD, Novartis, BMS, MSD, Boehringer-Ingelheim

• Financiamento Pesquisa

• PRONON - MS

• Ações

• Clínicas Oncológicas Integradas - COI

ALK Gene Fusion

Crizotinib or ALK Inhibitor

0-49% PD-L1 Expression

Chemo

Alectinib or Ceritinib or

ALK Inhibitor then Chemo

Bevacizumabif eligible

Pemetrexedif eligible

First linetreatment

Maintenance(responders only)

Non-Squamous Cell

Second/Third linetreatment

Nivolumab orPembrolizumab or

Atezolizumabthen Chemo

T70M + Osimertinibthen Chemo

Nivolumab orPembrolizumab or

Atezolizumab

ROS1+Gene Fusion

Crizotinib

Chemo Chemo

≥50% PD-L1 Expression

Pembrolizumab1st or 2nd

generation EGFR-TKI

EGFR Mutation +

Chemo ±Bevacizumab

0-49% PD-L1 Expression

≥50% PD-L1 Expression

Pembrolizumab

Chemo

Squamous Cell

T790M-Chemo

Tudo começou com um milagre...

Inibição de um Checkpoint

Imunológico...

DE ONDE VIEMOS?

Nivolumab – CheckMate 017 (PIII)1

2nd Line, squamous, PD-L1 All-ComerNivolumab – CheckMate 057 (PIII)2

2nd Line, non-squamous, PD-L1 All-Comer

Pembrolizumab - Keynote 010 (PII/III)3

2nd+ Line, PD-L1 TPS ≥1%Atezolizumab – OAK (PIII)4

2nd+ Line, PD-L1 All-Comer

1. Borghaei H et al. Poster presentation at ASCO 2016. 9025. 2. Brahmer JR et al. Oral presentation at AACR 2017. CT077. 3. Herbst RS et al. Poster presentation at ASCO 2017. 9090. 4. Rittmeyer A et al. Lancet. 2017;389(10066):255-265.

Borghaei et al., 2016, ASCO.1Time (Months)

100

80

60

40

20

00 6 30

OS

(%

)

1812 24 36

Nivolumab

Docetaxel

Checkmate 017 (SQ)1

Time (Months)

2-yr OS = 23%

2-yr OS = 8%

Nivolumab

Docetaxel

100

80

60

40

20

00 6 30

OS

(%

)

1812 24 36

Checkmate 057 (NSQ)1

2-yr OS = 29%

2-yr OS = 16%

Herbst et al., 2017, ASCO.3

OS

(%

)

Rittmeyer et al., 2017, Lancet.4Time (Months)

100

80

60

40

20

00 3 6 9 12 15 18 21 24 27

Atezolizumab

Docetaxel

OAK4

18-mo OS = 40%

18-mo OS = 27%

Time (Months)

100

80

60

40

20

00 5 10 15 20 25 30 35

OS

(%

)

Pembro 2 mg/kg

Pembro 10 mg/kg

Docetaxel

KEYNOTE-010 (≥1% PD-L1)3

30-mo OS = 29.5%

30-mo OS = 22.1%

30-mo OS = 12.3%

1. Borghaei H et al. Poster presentation at ASCO 2016. 9025. 2. Brahmer JR et al. Oral presentation at AACR 2017. CT077. 3. Herbst RS et al. Poster presentationat ASCO 2017. 9090. 4. Rittmeyer A et al. Lancet. 2017;389(10066):255-265.

SOBREVIDA GLOBAL – 2a LINHA DE TRATAMENTO

KEYNOTE 001– IMPACTO DO BIOMARCADOR (PD-L1)

Prevalência PD-L1> 50% = 23,2%

1. NEJM 2015; 372: 2018

QUEM SOMOS?

KEYNOTE 024- Desenho do Estudo

N Engl J Med 2016; 375:1823

KEYNOTE 024- Sobrevida Livre de Progressão

N Engl J Med 2016; 375:1823

KEYNOTE 024- Sobrevida Global

N Engl J Med 2016; 375:1823

KEYNOTE 024- Taxa de Resposta

N Engl J Med 2016; 375:1823

KEYNOTE

024-Subgrupos

KEYNOTE 024- Eventos adversos

N Engl J Med 2016; 375:1823

KEYNOTE 024- Eventos adversos Imunomediados

N Engl J Med 2016; 375:1823

CHECKMATE 026- Desenho do Estudo

Nivolumab3 mg/kg IV Q2W

n = 271

Randomize 1:1

Key eligibility criteria:

• Stage IV or recurrent NSCLC

• No prior systemic therapy for

advanced disease

• No EGFR/ALK mutations

sensitive to available targeted

inhibitor therapy

• ≥1% PD-L1 expressiona

• CNS metastases permitted if

adequately treated at least 2

weeks prior to randomization

Chemotherapy (histology dependent)b

Maximum of 6 cycles

n = 270

Disease progression or

unacceptable toxicity

Disease

progression

Crossover

nivolumab

(optional)

Tumor scans Q6W until

wk 48 then Q12W

Carbone D et al, NEJM 2017; 376 (25): 2415-2426

CHECKMATE 026- SLP


• SLP: 4.2 vs 5.9 m (QT) (HR 1.15, p=0.25)

• TR: 26% vs 33% (QT)

• Sem diferenças de acordo comexpressão de PDL-expression =/> 50%

• TRAE 3/4: 18% vs 51% (QT)

CHECKMATE 026- SG


• SG: 13.2 vs 14.4 m (QT) (HR1.02)

CHECKMATE 026 x KEYNOTE 024

Keynote 024 CheckMate 026

Tumor biopsy After metastatic

diagnosis

Within 6 months

PD-L1 cut off 50% (22C3 clone) 5% (28-8 clone)

Prevalence 30% 50%

Imaging interval Q 9 weeks Q 6 weeks for first 48 weeks

Primary endpoint PFS (RECIST) PFS (IRRC)

Never smokers (PD-1) 3% 11%

Squamous histology 19% 24%

Time from diagnosis to treatment ? 2 months

Prior radiation ? 1 37.6 %

Socinski et al, ESMO 2016; Reck et al, ESMO 2016, NEJM 2016

1 Prior radiation therapy of > 30 Gy disallowed within

6 months of first dose of trial treatment

CHECKMATE 026- Tumor Mutational Burden

Peters S et al AACR 2017

ESTUDOS DE 1a LINHA E 2a LINHA EM PERSPECTIVA

Estudos com imunoterapia 1a versus 2a linha: Eficácia

Study K024 K021G ()$ C026 C017 C057 K010 OAK

ORR (%) 44.8 55 (57) $ 26 20 19 18 (30)* 14

DoR (m) NR NR (NR) $ 12.1 25.2$ 18.3$ NA 16.3

mPFS 10.3 13 (19) $ 4.2 3.5 2.3 4,0 (5.2)* 2.8

mOS NR NR (NR) $ 14.4 9.2 12.2 12.7 (17.3)* 13.8

* PD-L1>50% subgroup$ update

2017

Borghaei H et al, NEJM 2015; Brahmer et al, NEJM 2015; Herbst et al, Lancet 2016; Reck M et al, NEJM 2016; Langer C et al, Lancet Oncol

2016; Borghaei H et al. Ann Oncol 2017; Rittmeyer A et al, Lancet 2016; Felip E et al. Ann Oncol 2017

$ update

2017

ESTUDOS DE 1a LINHA E 2a LINHA EM PERSPECTIVA

Borghaei H et al, NEJM 2015; Brahmer et al, NEJM 2015; Herbst et al, Lancet 2016; Reck M et al, NEJM 2016; Langer C et al, Lancet Oncol

2016; Borghaei H et al. Ann Oncol 2017; Rittmeyer A et al, Lancet 2016; Felip E et al. Ann Oncol 2017

Estudos com imunoterapia 1a versus 2a linha: Segurança

Drug-

rel. Aes

(%)

K024 K021G ()$ C026 C017 C057 K010 OAK

All

Grades73.4 93 (93)$ 71 58 69 63 64

Grades

3-426.6 39 (41)$ 18 7 10 13 15

Dose

del./mod

.

NA NA NA 37 NA NA 25

Drug

withdr.7.1 9 (15)$ 10 3 5 4 8

$ update

2017

Nsq PDL1 >50 NSq PDL1 <50

Sq PDL1 >50 Sq PDL1 <50

100%ECOG

PS0/1

…

60-70%ECOG

PS0/1

…

Nsq PDL1 >1 NSq PDL1 <1Sq PDL1 >1 Sq PDL1 <1

PARA ONDE VAMOS?

Cancer immunity cycle

Chen and Mellman. Immunity 2013; Hegde, et al. Clin Cancer Res 2016; Kim and Chen. Ann Oncol

2016; Chen and Mellman. Nature 2017

INFLAMED

KILLtumour

IMMUNE EXCLUDED

INFILTRATEtumour

Essential T-cell activity required

IMMUNE DESERT

GENERATEactive, tumour-directed T cells

Chen and Mellman. Immunity 2013; Hegde, et al. Clin Cancer Res 2016; Kim and Chen. Ann Oncol

2016; Chen and Mellman. Nature 2017

IMMUNE DESERTIMMUNE EXCLUDEDINFLAMED

High PD-L1 expression &

high TMB

No identified target

Low/no PD-L1 expression

No identified target

T cells at periphery

No effectors MHC loss

EVALUATE TUMOUR IMMUNOLOGY

aPD(L)1aPD(L)1 +

chemo/targeted therapy/XRT

aPD(L)1 + other CIT (IDOi, aTIGIT,

aCSF1R, TCBs, IL2v)

aPD(L)1+ chemo/targeted

therapy/XRT

aPD(L)1+ antiangiogenic

+ anti-stromal agents

aPD(L)1+ vaccines,

+aOX40,+IL2v, +aCD40, aCTLA4

aPD(L)1+MEKi, +TCBs+IFN, +CART

HYPOTHETICAL TREATMENT ALGORITHM

KEYNOTE 021- Coorte G


Borghaei H. WCLC 2017

0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

T i m e , m o n t h s

Pr

og

re

ss

ion

-F

re

e S

ur

viv

al,

%

60 51 43 32 24 22 17 9 1 0 63 42 35 25 18 13 8 5 1 0

N o . a t r i s k

Progression-Free Survival (RECIST v1.1 by Blinded, Independent Central Review)

aP value is descriptive (one-sided P < 0.025).

Data cut-off: May 31, 2017.

Events,

n/N

HR (95%

CI)

Pembro + PC 26/60 0.54

(0.33–0.88)

P = 0.0067aPC alone 40/63

Median (95% CI)

19.0 (8.5–NR)

8.9 (6.2–11.8)

57%

37%

52%

29%


0 3 6 9 12 15 18 21 24 270

10

20

30

40

50

60

70

80

90

100

Time, months

Ove

rall S

urv

ival, %

60 57 55 51 46 44 36 22 7 1 63 58 57 51 43 39 29 18 9 0

No. at risk

a24 additional deaths since primary analysis (pembro + PC, n = 7; PC alone, n = 17). bP value is descriptive (one-sided P < 0.025).

Median Follow-Up: 18.7 mo

Events,

n/N

HR (95%

CI)

Pembro + PC 20/60a 0.59

(0.34–1.05)

P = 0.03bPC alone 31/63a

77%

69%

Median (95% CI)

NR (22.8–NR)

20.9 (14.9–NR)

70%

56%

Overall SurvivalData Cut-Off: May 31, 2017

Borghaei H. WCLC 2017


Langer C, et al. Lancet Oncology 17: 1497, 2016

TAXA DE RESPOSTA POR BIOMARCADORES


Langer C, et al. Lancet Oncology 17: 1497, 2016Borghaei H, et al. ESMO2017

36

*KEYNOTE-0108.2%*

4.7%*4.5%*

Herbst R, et al. Lancet 387: 1540, 2016

IMPOWER 150

RECK M ET AL. ESMO IO 2018

KEYNOTE 189

Estudos de Fase III de anti-PD-1/PD-L1 com QT em 1a linha para CPNPC

POSEIDON

PhIII (N=801)

1L NSCLC

Durvalumab ±

Tremelimumab

+ chemotherapy

NCT03164616

KEYNOTE-189

PhIII (N=570)

1L non-squamous

NSCLC

Pembrolizumab +

chemotherapy

NCT02578680

KEYNOTE-407

PhIII (N=560)

1L squamous NSCLC

Pembrolizumab +

chemotherapy

NCT02775435

CheckMate 227

PhIII (N=2220)

1L NSCLC

Nivolumab

monotherapy

Nivolumab +

ipilimumab

Nivolumab +

chemotherapy

NCT02477826

Nivolumab Pembrolizumab Durvalumab AvelumabAtezolizumab

IMpower130

PhIII (N=650)

1L non-squamous

NSCLC

Atezolizumab +

chemotherapy

NCT02367781IMpower131

PhIII (N=1025)

1L squamous NSCLC

Atezolizumab +

chemotherapy

NCT02367794

IMpower132

PhIII (N=568)

1L non-squamous

NSCLC

Atezolizumab +

chemotherapy

NCT02657434

IMpower150

PhIII (N=1200)

1L non-squamous

NSCLC

Atezolizumab +

chemotherapy

± bevacizumab

NCT02366143

ONO-4538-52

PhIII (N=530)

1L NSCLC

Carboplatin + paclitaxel

+bevacizumab ±

Nivolumab

NCT03117049

Nivolumab Pembrolizumab Atezolizumab Durvalumab

- Chemotherapy

- Radiation/ Ablation

- EGFR/ ALK TKI

- Anti-VEGF/ VEGFR inhibitor

- Vasc Disrupt Agent

- Hypomethylating Agent

- HDAC inhibitor

- SPK Inhibitor

- C-Met inhibitor

- Glutaminase inhibitor

- Dasatinib

- Vaccine

- Gene therapy

- IL15 agonist

- PEG IL10

- TGFᵦR1 inhibitor

- Anti-CD27

- Ant-CXCR4

- Anti-CSF-1R

- IDO-1 inhibitor

- Anti-CTLA4

- Anti-LAG

- Anti-TIM-3

- Anti-KIR

- Chemotherapy

- Radiation

- EGFR/ ALK TKI

- Anti-VEGF/VEGFR inhibitor

- Hyomethylating Agent

- HDAC inhibitor

- CDK Inhibitor

- BTK inhibitor

- PI3K Inhibitor

- KIT/CSF1R/FLT3 Inh

- FGFR inhibitor

- JAK1 Inhibitor

- CRM1 Inhibitor

- FAK Inhibitor

- Anti-EGFR

- Anti-CEACAM1

- PEG hyaluronidase

- Vaccine

- Oncolytic

- PEG IL10

- Anti-CSF-1

- IDO1 Inhibitor

- Anti-CTLA4

- Anti-B7-H3

- Chemotherapy

- Radiation

- EGFR/ ALK TKI

- Anti-VEGF/Ang-2

- MEK Inhibitor

- Vaccine

- Adoptive Cell Therapy

- Anti-CEA/CD3

- Anti-CEA/ IL-2

- Anti-OX40

- Anti-CD40

- Anti-CD27

- Anti-CSF-1

- Adenosine A2A

Inhibitor

- IDO-1 Inhibitor

- Anti-CTLA4

- Anti-TIGIT

- Chemotherapy

- Radiation

- EGFR/ALK TKI

- VEGFR Inhibitor

- BTK Inhibitor

- MEK Inhibitor

- HAD Inhibitor

- PARP Inhibitor

- WEE1 Inhibitor

- ATR Inhibitor

- Anti-OX40

- CXCR4 Inhibitor

- CSF

- Anti-CD73

- Anti-CCR4

- Anti-CSF1R

- Anti-NKG2A

- Adenosine A2a Inhibitor

- IDO1 Inhibitor

- Anti-CTLA4

- Anti-PD1

Avelumab: ALK inhibitor (crizotinib and lorlatinib),

Anti-41BB, Anti-OX40

Outras Combinações Propostas

Estudos de fase II/III IO em CPNPC que levaram a registro no FDA

Study Drug PDL1

selectio

n

Line of

therapy

Control

arm

Primary

end-point

HR for 1ry

endpoint

Approva

l*

K024 Pembro >50% 1st Plat. Cx PFS 0.50 Yes

K021G Pembro/Cx None 1st Plat. Cx ORR

(PFS$)

NR (0.53) Yes

CM026 Nivo >5% 1st Plat. Cx PFS 1.15 No

CM017 Nivo None 2nd Docetaxe

l

OS 0.62 Yes

CM057 Nivo None 2nd & 3rd Docetaxe

l

OS 0.75 Yes

K010 Pembro >1% 2nd & 3rd Docetaxe

l

OS & PFS 0.61 Yes

OAK Atezo None 2nd & 3rd Docetaxe

l

OS 0.73 Yes

PACIFI

C

Durva None Loc Adv Placebo PFS 0.52 Yes

1. Mutational status – EGFR, ALK,

ROS-1…

ASK FOR…

TKI

2. PD-L1

> 50%PEMBROLIZUM

ABEou < 49%

CHEMOTHERA

PY

THINK

ABOUT…3. Non-squamous

patients

PEMBROLIZUM

ABE

CHEMOTHERA

PY

DON’T

FORGET

4. Second line

PEMBROLIZUM

ABE

ATEZOLIZUMA

BE NIVOLUMABE

ONLY FOR PD-L1>

1%

[email protected]

abordagem atual de 1ª linha do cpnpc no brasil · socinski et al, esmo 2016; reck et al, esmo...

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