Câncer de Pulmão Estádio III - rvmais.iweventos.com.br€¦ · • Cerca de 1.800.000 casos de câncer de pulmão no mundo - 85% são CPCNP - Aproximadamente 35% dos casos são

Câncer de Pulmão Estádio III:

o novo papel da imunoterapia.

Vladmir Cláudio Cordeiro de Lima, MD, PhD

Oncologista Clínico – Coordenador do Grupo de Tumores Torácicos - A. C. Camargo Cancer Center

Pesquisador associado – Laboratório de Imuno-Oncologia-Translacional - CIPE

Membro do GBOT, LACOG, ASCO, ESMO, AACR e IALSC

Declaração de Conflito de Interesse

• Recebi honorários da BMS, Roche, Boehringer-Ingelheimer eMSD para apresentações acadêmico-científicas.

• Participação em Advisory Board da Roche, Pfizer, Astra-Zenecae BMS.

• Auxílio financeiro da BMS, Astra-Zeneca e MSD paraparticipação em Congressos e Cursos.

• Participação em estudos clínicos da Celgene, Millenium, Abbvie,BMS, Astra-Zeneca, Janssen e MSD.

CPCNP estádio III cenário atual• Cerca de 1.800.000 casos de câncer de pulmão no mundo

- 85% são CPCNP

- Aproximadamente 35% dos casos são estádio III

• ~535.000 casos com estádio III

- Sobrevida em 5 anos varia de 36% a 13%

- Padrão de falha predominantemente sistêmico

- Terapias sistêmicas mais efetivas poderiam salvar milhões de vidas

GLOBOCAN 2012 Goldstraw P, et al. J Thorac Oncol. 2016; 11(1):39-51

CPCNP estádio III – cenário mutante

Goldstraw P, et al. J Thorac Oncol. 2016;

11(1):39-51

Sétima Edição Oitava Edição

Tópicos abordados

• Tratamento padrão da doença localmente

avançada

• Terapia de indução para CPCNP localmente

avançado N2+

• Imunoterapia em CPCNP localmente avançado

• Possíveis futuros cenários para IO no

tratamento CPCNP estádio III

Tratamento padrão da doença

localmente avançada

Ramnath N, et al. Chest. 2013; 143(5S):e314S-40S

CPCNP estádio III – doença

heterogênea

20%

Ressecáv

el

20%

Cenário

não

radical

60%

Irresecáve

l

Auperin A, et al. J Clin Oncol. 2010; 28.

Sequencial x Concomitante



Progressão Locorregional



Progressão à distância

Tratamento de CPCNP no Brasil

PARSIMONY

Tratamento de CPCNP no Brasil

PARSIMONY

Terapia de indução para CPCNP

localmente avançado N2+

N=341 (target=406)Paclitaxel+

Carboplatina

3 ciclos

Sorensen JB, et al. ASCO 2013; Abst. 7504.

CPCNP

T1-3N2 – EC IIIA

Tumores ressecáveis

Confirmação

histológica do N2 Paclitaxel+

Carboplatina

3 ciclos

Cirurgia

RDT

60Gy Con.

61,2Gy HF.

NTOG trial

N=170

N=171

Desfecho primário: SG

Hipótese: A adição de cirurgia promoveria um aumento

de 10% (15% para 25%) comparada com radioterapia.

RDT

60Gy Con.

61,2Gy HF.

Sorensen JB, et al. ASCO 2013; Abst. 7504.

NTOG trial

N=429

RDT 45 GY

Cisplatina +

Etoposide x 2 Ciclos

Cirurgia

Albain K, et al. Lancet 2009; 374: 379.

CPCNP

T1-3 pN2 – EC IIIA

Tumores

considerados

ressecáveis

Confirmação

histológica do N2RDT 61 Gy

EP x 2

EP x 2

INT 0139

N=202

N=194


Desfecho secundário: SLP

Hipótese: Cirurgia promoveria um aumento de 10% (25% para 35%) na sobrevida

após quimiorrradioterapia concomitante.


INT 0139Sobrevida livre de

progressão

Sobrevida Global

SG mediana: 23,6 x 22,0 meses SLP mediana: 12,8 x 10,5 meses

N=579

Quimioterapia

baseada em Platina

x 3 Ciclos

Cirurgia

Van Meerbeeck JP, et al. J Natl Cancer Inst 2007; 99: 442.

T1-3N2 – EC IIIA

CPCNP

Irressecável

RT

60-62 Gy

EORTC 8941

Fora de

estudo

DE ou PD

RC, RP ou

resposta menor

N=167

N=165

N=175


Desfechos secundários: SLP e segurança

Hipótese: Cirurgia resultaria em aumento da SG de

15% para 25% em 5 anos

Van Meerbeeck JP et al. J Natl Cancer Inst 2007; 99: 442.

Curvas de sobrevidaSobrevida livre de progressão Sobrevida Global


INT 0139

Lobectomia Pneumectomia


INT 0139

• Mais pacientes morreram sem

progressão no braço da

cirurgia.

• Menos casos com progressão

no braço da cirurgia.

EORTC 8941

Fatores associados

maior sobrevida no

braço de cirurgia:

• ypN0-N1

• R0

• Lobectomia

• PORT

Van Meerbeeck JP, et al. J Natl Cancer Inst 2007; 99: 442.

Imunoterapia em CPCNP

localmente avançado

Imunoterapia no tratamento de CPCNP localmente

avançado – Tecemotide – START trial

• Tecemotide (L-BLP25) – lipopeptídeo – MUC1

Butts C, et al. Lancet Oncol. 15:59-68, 2014.

CPCNP é imunogênico mas apresenta

um microambiente imunossupressor

Schumacher TN & Schreiber RD. Science. 2015 Syn NL, et al. Lancet Oncol. 18:e731-741,

2017

Quimioterapia como moduladora da resposta

imuneMorte Celular Imunogênica

DAMPs – damage

associated

molecular patterns

Morte Celular

Imunogênica

Pitt JM, et al. Ann Oncol. 2016; 27:1482-

1492

Depleção

de Tregs e

MSDCs

Radioterapia também modula o

microambiente tumoral e à resposta imune

local

Kordbacheh T, et al. Ann Oncol. 29:301-301,

2018.

PACIFIC: A DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE III STUDY OF DURVALUMAB AFTER CHEMORADIATION THERAPY IN PATIENTS

WITH STAGE III, LOCALLY ADVANCED, UNRESECTABLE NSCLC

Luis Paz-Ares1, Augusto Villegas2, Davey Daniel3, David Vicente4, Shuji Murakami5, Rina Hui6,

Takashi Yokoi7, Alberto Chiappori8, Ki Hyeong Lee9, Maike de Wit10, Byoung Chul Cho11, Maryam Bourhaba12,

Xavier Quantin13, Takaaki Tokito14, Tarek Mekhail15, David Planchard16, Haiyi Jiang17, Yifan Huang17,

Phillip A. Dennis17, MustafaÖzgüroğlu18

1Hospital Universitario 12 de Octubre, CiberOnc, Universidad Complutense and CNIO, Madrid, Spain; 2Cancer Specialists of North

Florida, Jacksonville, FL, USA; 3Tennessee Oncology, Chattanooga, TN, and Sarah Cannon Research Institute, Nashville, TN, USA; 4Hospital Universitario Virgen Macarena, Seville, Spain; 5Kanagawa Cancer Center, Yokohama, Japan; 6Westmead Hospital and the

University of Sydney, Sydney, NSW, Australia; 7Kansai Medical University Hospital, Hirakata, Japan; 8H. Lee Moffitt Cancer Center and

Research Institute, Tampa, FL, USA; 9Chungbuk National University Hospital, Chungbuk National University College of Medicine,

Cheongju, Korea; 10Vivantes Klinikum Neukoelln, Berlin, Germany; 11Yonsei Cancer Center, Yonsei University College of Medicine,

Seoul, Korea; 12Centre Hospitalier Universitaire de Liège, Liège, Belgium; 13CHU Montpellier and ICM Val d'Aurelle, Montpellier, France; 14Kurume University Hospital, Kurume, Japan; 15Florida Hospital Cancer Institute, Orlando, FL, USA; 16Gustave Roussy, Villejuif,

France; 17AstraZeneca, Gaithersburg, MD, USA; 18Istanbul University Cerrahpasa School of Medicine, Istanbul, Turkey

esmo.org

Acknowledgement: Dr. Scott J. Antonia of H. Lee Moffitt Cancer Center and Research Institute is the lead author for this study;

Dr. Paz-Ares is presenting on his behalf

Durvalumab Blocks PD-L1 Binding

to PD-1 and CD80

Immune

cell

T cell

TumorantigenTumor cellMHC I TCR

MHC IITCR

PD-1

PD-L1

InhibitionXCD80

PD-L1

CD80

InhibitionX

Activation CD28

CD80

PD-1

PD-L1

Tumorantigen

Durvalumab1

Human IgG1 mAb,

engineered to prevent

antibody-dependent

cell-mediated cytotoxicity

Blocks PD-1-mediated

inhibitory signalling

Enhances effectorT-cell

function and tumor cell

killing

mAb, monoclonal antibody; MHC, major histocompatibility complex; PD-1, programmed cell dealth-1; PD-L1, programmed cell death ligand-1; TCR, T-cell receptor

Durvalumab

1. Stewart R, et al. Cancer Immunol Res 2015;3:1052-62

*Defined as the time from randomization (which occurred up to 6 weeks post-cCRT) to the first documented event of tumor progression or death in the absence of progression.

ClinicalTrials.gov number: NCT02125461 BICR, blinded independent central review; cCRT, concurrent chemoradiation therapy; DoR, duration of response;

NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PROs, patient-reported outcomes;

• Patients with stage III, locally

advanced, unresectable NSCLC

who have not progressed following

definitive platinum-based cCRT

(≥2 cycles)

• 18 years or older

• WHO PS score 0 or 1

• Estimated life expectancyof

≥12 weeks

• Archived tissue was collected

All-comers population

Durvalumab

10 mg/kg q2w for

up to 12 months

N=476

Placebo

10 mg/kg q2w for

up to 12 months

N=237

2:1 randomization,

stratified by age, sex,

and smoking history

N=713Key secondary endpoints

• ORR (per BICR)

• DoR (per BICR)

• Safety and tolerability

• PROs

Co-primary endpoints

• PFS by BICR using RECIST v1.1*

• OS

R

PS, performance status; q2w, every 2 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; WHO, World Health Organization

1–42 days

post-cCRT

PACIFIC: study design

Durvalumab

(N=476)

Placebo

(N=237)

Age Median (range), years

≥65 years, %

64 (31–84)

45.2

64 (23–90)

45.1

Male, % 70.2 70.0

WHO performance status score, %* 0 / 1 49.2 / 50.4 48.1 / 51.5

Smoking status, % Current / Former / Never 16.6 / 74.4 / 9.0 16.0 / 75.1 / 8.9

Disease stage, %† IIIA / IIIB 52.9 / 44.5 52.7 / 45.1

Histology, % Squamous / Non-squamous 47.1 / 52.9 43.0 / 57.0

PD-L1 status, % Known: TC <25% / TC≥25%

Unknown‡

39.3 / 24.2

36.6

44.3 / 18.6

37.1

Prior chemotherapy, % Induction / Definitive cCRT 25.8 / 99.8 28.7 / 99.6

Prior radiotherapy, %* <54 Gy

54 to ≤66 Gy

>66 to ≤74 Gy

0.6

92.9

6.3

0

91.6

8.0

Best response to prior cCRT, %¶ CR / PR / SD / PD 1.9 / 48.7 / 46.6 / 0.4 3.0 / 46.8 / 48.1 / 0

Baseline Characteristics (ITT)

PF

Spro

babili

ty

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 3 6 21 24 279 12 15 18

Time from randomization (months)

Placebo

Durvalumab

No. at riskDurvalumab 476 377 301 264 159 86 44 21 4 1

Placebo 237 163 106 87 52 28 15 4 3 0

Durvalumab

(N=476)

Placebo

(N=237)

Median PFS (95% CI), months 16.8 (13.0–18.1) 5.6 (4.6–7.8)

12-month PFS rate (95% CI) 55.9% (51.0–60.4) 35.3% (29.0–41.7)

18-month PFS rate (95% CI) 44.2% (37.7–50.5) 27.0%(19.9–34.5)

BICR, blinded independent central review; CI, confidence interval; ITT, intention-to-treat; PFS, progression-freesurvival

Stratified hazard ratio, 0.52 (95% CI,0.42–0.65)Two-sided P<0.0001

PFS by BICR (Primary

Endpoint; ITT)

*Hazard ratio and 95% CI not calculated if the subgroup has less than 20 events.

BICR, blinded independent central review; CI, confidence interval; CR, complete response; HR, hazard ratio; ITT, intention-to-treat; EGFR, epidermal growth factor receptor

PFS Subgroup Analysis by BICR

(ITT)

*Patients with measurable disease at baseline, as determined by either of the two independent reviewers; †One patient could not be grouped into any of the best overall response categories

due to inconsistency in the baseline assessment for measurable disease between the two independent central reviewers. ‡Percentages calculated by Kaplan-Meier method; ¶Placebo was

the reference group when RR and HR were calculated; therefore, an RR value greater than 1 is in favor of durvalumab and an HR value less than 1 is in favor of durvalumab

Durvalumab

(N=443)*

Placebo

(N=213)*

Treatment effect

(HR [95% CI])¶

Best overall response, n (%)†

Complete response 6 (1.4) 1 (0.5)

Partial response 120 (27.1) 33 (15.5)

Stable disease 233 (52.6) 119 (55.9)

Progressive disease 73 (16.5) 59 (27.7)

Non-evaluable 10 (2.3) 1 (0.5)

Duration of response, months

Median (95% Cl) NR 13.8 (6.0–NR) 0.43 (0.22–0.84)

Ongoing response at data cutoff,%‡

At 12 months

At 18 months72.8

72.8

56.1

46.8

0

BICR, blinded independent central review; CI, confidence interval; HR, hazard ratio; ITT, intention-to-treat; NR, not reached; RR, relative risk

10

5

20

15

30

25

35

Durvalumab(N=443)*

Placebo(N=213)*

% p

atie

nts

(95

%C

I)

Objective Response

P<0.001

(24.28–32.89)

28.4

(11.31–21.59)

16.0

Treatment effect (RR [95% CI])¶:

1.78 (1.27–2.51)

Antitumor Activity by BICR (ITT)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

1 3 6 9 12 15 18 21 24 27 30

Pro

babili

tyofde

ath

or

dis

tantm

eta

sta

sis

Time from randomization (months)

Placebo

Durvalumab

No. at riskDurvalumab 476 407 336 288 173 91 46 22 4 1 0

Placebo 237 184 129 106 63 32 16 5 4 0 0

Durvalumab Placebo

23.2 (23.2–NR) 14.6 (10.6–18.6)Median time (95% CI),

months

Stratified hazard ratio, 0.52 (95% CI,0.39–0.69)Two-sided P<0.0001

BICR, blinded independent central review; ITT, intention-to-treat

Time to Distant Metastasis or Death by BICR

(ITT)

Safety analysis set. AE, adverse event; SAE, serious adverseevent

*Two patients randomized to placebo received at least one dose of durvalumab and were considered part of the durvalumab arm for safety reporting.

Durvalumab

(N=475)

Placebo

(N=234)

Any-grade all-causality AEs, n (%) 460 (96.8) 222 (94.9)

Grade 3/4 142 (29.9) 61 (26.1)

Grade 5 21 (4.4) 13 (5.6)

Leading to discontinuation 73 (15.4) 23 (9.8)

Any-grade treatment-related AEs, n (%) 322 (67.8) 125 (53.4)

SAEs, n (%) 136 (28.6) 53 (22.6)

Any-grade immune-mediated AEs, n (%) 115 (24.2) 19 (8.1)

Grade 3/4 16 (3.4) 6 (2.6)

Safety Summary*

Durvalumab (N=475) Placebo (N=234)

Event Any Grade Grade 3 or 4 Any Grade Grade 3 or 4

Any event, n (%) 460 (96.8) 142 (29.9) 222 (94.9) 61 (26.1)

Cough 168 (35.4) 2 (0.4) 59 (25.2) 1 (0.4)

Pneumonitis/radiation pneumonitis† 161 (33.9) 16 (3.4) 58 (24.8) 6 (2.6)

Fatigue 113 (23.8) 1 (0.2) 48 (20.5) 3 (1.3)

Dyspnea 106 (22.3) 7 (1.5) 56 (23.9) 6 (2.6)

Diarrhea 87 (18.3) 3 (0.6) 44 (18.8) 3 (1.3)

Pyrexia 70 (14.7) 1 (0.2) 21 (9.0) 0

Decreased appetite 68 (14.3) 1 (0.2) 30 (12.8) 2 (0.9)

Nausea 66 (13.9) 0 31 (13.2) 0

Pneumonia 62 (13.1) 21 (4.4) 18 (7.7) 9 (3.8)

Arthralgia 59 (12.4) 0 26 (11.1) 0

Pruritus 58 (12.2) 0 11 (4.7) 0

Rash 58 (12.2) 1 (0.2) 17 (7.3) 0

Upper respiratory tract infection 58 (12.2) 1 (0.2) 23 (9.8) 0

Constipation 56 (11.8) 1 (0.2) 20 (8.5) 0

Hypothyroidism 55 (11.6) 1 (0.2) 4 (1.7) 0

Asthenia 51 (10.7) 3 (0.6) 31 (13.2) 1 (0.4)

Back pain 50 (10.5) 1 (0.2) 27 (11.5) 1 (0.4)

Most Frequent AEs*

Two patients randomized to placebo received at least one dose of durvalumab and were considered part of the durvalumab arm for sa fetyreporting.

Safety analysis set (all-causality). *Pneumonitis/radiation pneumonitis was assessed by investigators with subsequent review and adjudication by the study sponsor.

In addition, pneumonitis, as reported in the table, is a grouped term, which includes acute interstitial pneumonitis, interstitial lung disease, pneumonitis, and pulmonaryfibrosis.

Pneumonitis (grouped terms) or radiation

pneumonitis, n (%)*

Durvalumab

(N=475)

Placebo

(N=234)

Any grade 161 (33.9) 58 (24.8)

Grade 3/4 16 (3.4) 6 (2.6)

Grade 5 5 (1.1) 4 (1.7)

Leading to discontinuation 30 (6.3) 10 (4.3)

Pneumonitis or Radiation

Pneumonitis

Patient-Reported Outcomes With Durvalumab

After Chemoradiation in Locally Advanced,

Unresectable NSCLC: Data From PACIFIC

Rina Hui1, Mustafa Özgüroğlu2, Davey Daniel3, David Vicente4, Shuji Murakami5, Takashi Yokoi6, Alberto Chiappori7, Ki Hyeong

Lee8, Maike de Wit9, Byoung Chul Cho10, Jhanelle E. Gray7, Anna Rydén11, Louis Viviers12, Lynne Poole13, Phillip A. Dennis14,

Scott J. Antonia7

1Westmead Hospital and the University of Sydney, Sydney, NSW, Australia; 2Istanbul University Cerrahpasa School of Medicine, Istanbul,

Turkey; 3Sarah Cannon Research Institute, Nashville and Tennessee Oncology, Chattanooga, TN, USA; 4Hospital Universitario Virgen

Macarena, Seville, Spain; 5Kanagawa Cancer Center, Yokohama, Japan; 6Kansai Medical University Hospital, Hirakata, Japan; 7H. Lee Moffitt

Cancer Center and Research Institute, Tampa, FL, USA; 8Chungbuk National University Hospital, Cheongju-si, Korea; 9Vivantes Klinikum

Neukoelln, Berlin, Germany; 10Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea; 11AstraZeneca, Gothenburg,

Sweden; 12QuintilesIMS, Saint Ouen Cedex, France; 13Astrazeneca, Cambridge, UK; 14AstraZeneca, Gaithersburg, MD, USA

Presented by: Dr Rina Hui

0

10

20

30

40

50

60

70

80

90

Cough (LC13) Dyspnea(LC13)

Chest pain(LC13)

Fatigue (C30) Appetite loss(C30)

Physicalfunction (C30)

Global healthstatus/QoL

(C30)

Me

an

sco

re a

t b

ase

line

Durvalumab Placebo

Higher scores indicate

better health status

Higher scores indicate

greater symptom severity

Baseline Scores for Key Symptoms, Physical

Function and Global Health Status/QoL• High compliance (>80%) in completion of the questionnaires up to Week 48

• No differences between arms at baseline for key symptoms, physical function or global health status/QoL

QoL, quality of life

No Changes from Baseline:

Functioning and Global Health Status• Functioning and global health status scores remained stable throughout the study

• No significant differences between arms in changes from baseline

Durvalumab Placebo

Global health status/QoL

(C30)

15

0

-5

-10

-15

Change

from

baselin

e

4(n=649)

Week

8(n=591)

16(n=506)

24(n=443)

32(n=393)

40(n=356)

48(n=311)

10

5

15

10

-5

-10

-15

Change

from

baselin

e

4(n=647)

Week

8(n=593)

16(n=507)

24(n=444)

32(n=393)

40(n=355)

48(n=310)

5

0

Physical functioning

(C30)

Gaps of knowledge

Radioterapia com imunomodulador em

CPCNP

Kordbacheh T, et al. Ann Oncol. 29:301-301,

2018.

Possíveis futuros cenários para

IO no tratamento CPCNP estádio

III

Resposta patológica à terapia neoadjuvante

prediz melhor evolução clínica em CPCNP• N=160 CPCNP tratamento neoadjuvante

• RECIST versus avaliação patológica (10% de células viáveis) SG

William Jr. NW, et al. J Thorac Oncol. 8(2):222-228,

2013.


prediz melhor evolução clínica em CPCNP


2013.


prediz melhor evolução clínica em CPCNP


2013.

Patients

Presented By Jamie Chaft at 2017 ASCO Annual Meeting

Radiographic responses to 2 doses of nivolumab


Pathologic responses to neoadjuvant nivolumab


CHECKMATE 816: STUDY DESIGN

Footnote and bbreviations can be found in speaker notes.

1. Clinicaltrials.gov. NCT02998528. Accessed December 6, 2017. 2. Forde et al. Poster presentation at ASCO

2017. TPS8577.

Phase 3, randomized, open label trial of nivolumab and ipilimumab or platinum doublet chemotherapy ±nivolumab in early-stage NSCLC.

Start Date: January 2017

Estimated Completion Date: November 2028

Estimated Primary Completion Date: May 2023

Status: Recruiting

Sponsor: Bristol-Myers Squibb

Primary Outcome Measures:

• EFS, cPR

Secondary Outcome Measure:

• OS, MPR

Key Eligibility Criteria

• Operable, stage IB–IIIA

NSCLC

• ECOG PS ≤1

• Core tissue biopsy

available at screening

Surgery

Within 6 weeks

Nivolumab

3 mg/kg Q2W up to 3 doses

+

Ipilimumab

1 mg/kg single dose at cycle 1

N=642

Platinum doublet†

Q3W up to 3 doses

Nivolumab + Platinum doublet*R

Mensagens Finais• CPCNP estádio III é uma doença estremamente heterogênea e

necessita sempre de uma discussão multidisciplinar.

• O tratamento padrão para maior parte dos casos (tumoresirressecáveis ou N2+) é quimiorradioterapia concomitante.

• A adição de durvalumabe como terapia de consolidação estáassociada a aumento de sobrevida livre de progressão e do tempo para metástase ou morte após quimiorradioterapia para CPCNP localmente avançado.

• Novas estratégias, como imunoterapia neoadjuvante, parecembastante promissoras.

Obrigado!

Documents

Câncer de Pulmão Estádio III - rvmais.iweventos.com.br€¦ · • Cerca de 1.800.000 casos de câncer de pulmão no mundo - 85% são CPCNP - Aproximadamente 35% dos casos são