simpÓsio internacional de cÂncer de pulmÃo · 2018-03-22 · carlos henrique teixeira...

CÂNCER DE PULMÃO DE PEQUENAS CÉLULAS: UPDATES 2018Carlos Henrique Teixeira

Coordenador do grupo de tórax do centro de oncologia do HAOC

CONFLITOS DE INTERESSE

• AULAS MÉDICAS – ROCHE, BMS, MSD, BI, AZ

• PESQUISA CLÍNICA – PI estudos AZ, MSD

• APOIO CONGRESSOS – MSD, BMS, AZ, ROCHE, BI

• MEMBRO DO GBOT, SBOC, ASCO

SCLC (CPPC)

Tabagismo, dça bulky

Rápida progressão

Disseminação precoce

15% CP

adeno cec cppc outros

Oronsky B, et al. Neoplasia. 2017;19:842-847. Alvarado-Luna G, et al. Transl Lung

Cancer Res. 2016;5:26-38. Howlander N, et al. SEER Cancer Statistics Review,

1975-2014.

CPPC (SCLC)• DOENÇA LIMITADA ~30% • DOENÇA EXTENSA ~70%

• 74 – 84% recorrência

• 71 - 76 % em 2y

PADRÃO:

• RT + (Cis + Etop) PCI*

• ORR: 70 – 90%;

• OS: 14 – 23 m; 5y 16 – 26%

Definição: EC I-III

INCLUIDO NUM

CAMPO RT.

novas terapias

2L:

•2L Plat-r: No SOC (ORR <5%)

•2L Plat-s (>3 < 6m): topotecan

•ORR: 24%, PFS: 3mo, OS: 6m

•2L Plat-S (> 6 m): Cis + Etop

•ORR: 50-60%, PFS: 4-6m

PADRÃO 1L:

•Cis + Etop PCI*

•ORR: 50-70%

•PFS: 4-6m / OS: 8-10m

Definição: EC IV ou muito

extensa para um campo de

RT

• Lopez-Chavez et al. Curr Probl Cancer. 2012;Turrisi et al. NEJM 1999• SCLC NCCN guidelines 2015, www.nccn.org; Kantar Health CancerMPact SCLC 2014; www.cancer.gov

http://www.nccn.org/

Timeline SCLC

Sabari JK, et al. Nat Rev Clin Oncol. 2017;14:549-561.

1985 1990 1995 2000 2005 2010 2015

First-linesetting

Refractory/recurrentsetting

Radiationtherapy

Cisplatin +etoposide*

1985

Carboplatin +etoposide*

1999

Carboplatin + irinotecan2006

Cisplatin + irinotecan2006

Irinotecan1992

Topotecan*1996

Docetaxel1994

Paclitaxel1998

Gemcitabine2001

Temozolomide2012

Thoracicradiotherapy(LS-SCLC)*

1992

45 Gy BID (LS-SCLC)*

1999PCI (LS-SCLC)*1999

PCI (ES-

SCLC)2007

Thoracicradiotherapy(ES-SCLC)

2015*FDA approved.

INTERGROUP 0096

Nejm 1999

CONVERT TRIAL

• Fase 3 R

• EP: OS

• ESTUDO COM PODER PARA MOSTRAR SUP RT QD SE 2-yr OS 12% MAIOR QUE RT BID

• 2-yr OS rate: 51% for QD vs 56% for BID; absolute difference: 5.3%

• SEM DIF SIGNIFICATIVA RT QD vs BID

• 25 mos for QD vs 30 mosfor BID; HR: 1.18 (95% CI: 0.95-1.45; P = .14)

TOXICIDADE SIMILAR

ADULTOS COM

DOENÇA LOCALIZADA

PS – 0-1

(N = 547)

Fup

5y

BID 1.5 Gy thoracic RT

45 Gy/30F/19D* +

Chemotherapy†

(n = 274)

Once-daily 2 Gy thoracic RT

66 Gy/33F/45D* +

Chemotherapy†

(n = 273)

Faivre-Finn C, et al. Lancet Oncol 2017;18:1116-1125.

*RT started on Day 22 after starting chemotherapy. †Cisplatin 25 mg/m2 on Days 1-3 or cisplatin 75 mg/m2 on Day 1 and etoposide 100 mg/m2 on Days 1-3 for 4 or 6 cycles Q3W.

JAMA OncologyPublished online January 4, 2018

ALL POP:

23% No QT

41% - No RT

Treatment Patterns in Extensive Disease Small Cell Lung Cancer Across the United States, Europe, and Japan

Karen Higginbottom,1 Marco DiBonaventura,1 John R. Penrod,2 Yong Yuan2

1Ipsos Healthcare, Mahwah, NJ, USA; 2Bristol-Myers Squibb, Princeton, NJ, USA

8479: Treatment Patterns in Extensive Disease Small Cell Lung Cancer Across the United States, Europe, and Japan – Yong Yuan

13

n = 5849 2605 2203 1041

Total United States EU5 Japan

Real-world 1L Treatment Patterns for ED-SCLC

1L = first-line; ED = extensive disease; EU5 = European Union 5 (France, Germany, Italy, Spain, and the United Kingdom); SCLC = small cell lung cancer

8387

82

73

52 <1

23

6 7 6 164

11 3

0

10

20

30

40

50

60

70

80

901

L t

rea

tme

nt,

%Platinum + etoposide Platinum + irinotecan

Other platinum therapy Non-platinum therapy

• 94% of treated patients with ED-SCLC received 1L platinum-based chemotherapy

• Platinum + irinotecan was more common in Japan (23%) than in the United States (2%) or the EU5 (<1%)

14

Real-world 2L Treatment Patterns for ED-SCLC

aTotals may not equal 100% due to rounding

2L = second-line; ED = extensive disease; EU5 = European Union 5 (France, Germany, Italy, Spain, and the United Kingdom); SCLC = small cell lung cancer

30

1930

20

59 60

42

48

60

56

5

2

8

6

6

4

5 1

11

10

1

2 15

8

817

4

18 16

30

0

10

20

30

40

50

60

70

80

90

100

2L

tre

atm

en

t, %

aPlatinum + etoposide

Platinum + irinotecan

Other platinum therapy

Topotecan

Other non-platinum therapy

n = 227 273 148 214 143 112

Platinum group Resistant Sensitive Resistant Sensitive Resistant Sensitive

United States EU5 Japan

• 19% of patients received 2L treatment (19% in the United States, 16% in the EU5, and 24% in Japan)

• Among platinum-resistant patients receiving a 2L treatment, 27% in the United States, 11% in the EU5, and

36% in Japan were administered platinum-based therapy

• Despite platinum sensitivity, the most common 2L treatment in the United States and EU5 was topotecan

EORTC Japanese

Results

Survival better not better

Progression free survival

better comparable

Time to brain metastases

Better better

Study design

MRI at enrollment no yes

Induction chemotherapy

including non platinum

platinum doublets

PCI dose and fraction

various 2.5Gy x 10fr

Follow up symptom imageMajor difference between EORTC and Japanese trials is exclusion of the pts with asymptomatic BM by MRI. And earlier detection of disease progression before symptomatic by images such as CT and MRI.

TRT PRO

Alta incidência ED dx

Controle local melhora meta

dist

Aumento SV 2y 5.4%

local controle with 25.3%

TRT CON

CREST negativo para EP

p=0.066

Sec end positivo aos 2y

Highlights of the Day: Paul Baas, MD, PhD

Warde & Payne, J Clin Oncol 1992;10:890-895


13 X

3%


• TRT mais indicada em pacientes com massa

residual

• Pacientes > 2 sítios metástases – pior

Take home messages

Karve et al. BMC Health Services Research 2014, 14:555

Rovalpituzumab Tesirine: Mecanismo de ação

Tumor

Cell

DLL3

PBD

Nucleu

s

1. Rova-T binds DLL3

2. Rova-T–DLL3

complex

internalized by

endocytosis

4. PBD released

to cytoplasm,

enters nucleus,

cross-links DNA

5. Apoptosis

(cell death)

Sau S, et al. Drug Discovery Today. 2017;[Epub ahead of print].

3. Cathepsin

B cleaves

linker in

lysosome

Nucleus

Lancet Oncol 2017; 18: 42–51c

Nat Rev Clin Oncol. 2017 Sep;14(9):549-561

Owonikoko TK, et al. WCLC 2016. Abstract OA05.05

Presented By Taofeek Owonikoko at 2017 ASCO Annual Meeting

MA 01 - SCLC: Research Perspectives. Abstract #8480

Lanreotide Maintenance in SCLC Expressing Somatostatine Receptors: Efficacy Results of Multicenter Randomized G04.2011 Trial – Sara Pilotto

Phase III ITT: No survival benefit

Standard upfront

CT o CT-RT

• Stratified for LD and ED

• SST receptors expressed (Octreoscan positive)

Responders

(CR/PR)

Lanreotide 120 mg sc

q28d max 1 year (n = 39)

Observation (n = 32)

Arm A

Arm B

Random

1:1PD 2nd line

80

60

40

20

pro

gre

ss

ion

-fre

e s

urv

iva

l

(%)

0

0 24months since randomization

PFS, months

median

95% CI

HR (95% CI)

1 year PFS

Lanreotide

(n=39)

Placebo

(n=32)

3.6

(3.2-3.9)

2.3

(1.7-2.9)1.51 (0.90-2.50)

10.3% 7.3%

p = 0.11

80

60

40

20

0

0

ove

rall

su

rviv

al (%

)

30months since randomization

OS, months

median

95% CI

HR (95% CI)

Lanreotide

(n=39)

Placebo

(n=32)

9.5

(4.8-14.3)

4.7

(0-16.6)1.30 (0.64-2.65)

p = 0.47

66 12 18 12 18 24

100 100

months since randomization

pro

gre

ss

ion

-fre

e s

urv

iva

l (%

)

PFS, months

median

95% CI

Lanreotide

(n=14)

Placebo

(n=14)

7.0

(0.56-13.5)

3.8

(0-8.6)

p = 0.21

LD

PFS Analysis Univariate Multivariate

AGE

(>65 vs < 65)

1.52 (0.92-2.51)

P=0.10

1.75 (1.05-2.92)

P=0.03

STAGE

(ED vs LD)

2.76 (1.58-4.80)

P<0.0001

3.14 (1.77-5.57)

P<0.0001

Limited Disease may have a signal for PFS

benefit

Patient DemographicsLanreotide

(N=39)

Placebo

(N=32)

ECOG performance status

0 21 (53.8) 19 (59.4)

1 16 (41.0) 13 (40.6)

2 2 (5.2) 0

Stage

Limited disease 14 (35.9) 14 (43.8)

Extensive disease 25 (64.1) 18 (56.2)

Best tumor response to upfront therapy

CR 1 (2.6) 2 (6.2)

PR 38 (97.4) 30 (93.8)

Time from diagnosis to study inclusion (months) 5.6 (3-12) 5.8 (3-160)

Time from end of 1st line to study inclusion (days) 29 (0-119) 30 (0-108)

MA 01 - SCLC: Research Perspectives. Abstract #8480

Lanreotide Maintenance in SCLC Expressing Somatostatine Receptors: Efficacy Results of Multicenter Randomized G04.2011 Trial – Sara Pilotto

Tratada com Cisp e Etop x 4 + RT bid C#2 com excelente

RP

Recidiva em LN para esofágico e frênico em menos de 3

meses.....

22/11/17

22/11/17 21/02/18

22/11/17

21/02/18

1000

100

10

1.0

0.1

0.001So

mati

c m

uta

tio

n p

revale

nce

(# m

uta

tio

ns/m

eg

ab

ase

)

0.01

1. Adapted by permission from Macmillan Publishers Ltd: Alexandrov LB, et al. Nature 2013;500:415-421, copyright 2013. 2. Morabito A, et al. Crit Rev Oncol Hematol 2014;91:257–

270. 3. Carbone DP et al. N Engl J Med. 2017;376:2415–2426. 4. Snyder A, et al. N Engl J Med 2014;371:2189–2199. 5 Galsky MD, et al. Poster Discussion at ESMO 2017. 848PD.

CheckMate 032

46

DOR = duration of response; EQ-5D = EuroQoL-5 Dimensions; ORR = objective response rate; OS = overall survival; PD-L1 = programmed death ligand 1; PFS = progression-free survivalaMedian follow-up 23.3 months; bMedian follow-up 28.6 months; cMedian follow-up 10.8 months; dMedian follow-up 11.2 months; eBased on data from the previous database lock, only patients in the 1 mg/kg nivolumab + 3 mg/kg ipilimumab and 3 mg/kg nivolumab monotherapy cohorts were selected for further development in SCLC

Randomized cohort

Primary objective: ORR per RECIST v1.1Secondary objectives: safety, OS, PFS, DOR

Prespecified exploratory objectives: biomarker analysis; heath status using the EQ-5D instrument

Randomize 3:2

Database lock: March 30, 2017

Nivolumab 3 mg/kg IV Q2W

(n = 98)a

Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg IV

Q3W for 4 cycles

(n = 61)b

Nivolumab 3 mg/kg IV Q2W

(n = 147)c

Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg IV

Q3W for 4 cycles

(n = 95)d

Until disease progression or

unacceptable toxicity

Nivolumab 3 mg/kg IV Q2W until disease progression or


Until disease progression or


Nivolumab 3 mg/kg IV Q2W until disease progression or


Patients with SCLC

≥1 prior platinum-containing regimen (1 or 2 prior therapies for randomized cohort)

PD-L1 unselected

Non-randomized cohort

Patients (ITT, N = 401)e received either nivolumab monotherapy (n = 245) or nivolumab + ipilimumab (n = 156)

Matthew D , et al. ASCO 2017 Abstract 8503

aFor germline sequencing; bDNA was sequenced on the Illumina HiSeq 2500 using 2 × 100-bp paired-end reads

ITT population

(N = 401)

Patients with paired tumor and whole blood samplesa

(n = 246; 61%)

TMB-evaluable patients

(n = 211; 53%) [86% of patients with paired samples]

Nivolumab

(n = 133; 54.3%)

Nivolumab + ipilimumab

(n = 78; 50.0%)

Nivolumab

(n = 245)

Nivolumab + ipilimumab

(n = 156)

• TMB was determined by whole exome sequencingb and calculated as the total number of

missense mutations in the tumor

• For exploratory analyses, patients were divided into 3 subgroups based on TMB tertile

TMB

ORR by TMBCheckMate 032 Exploratory TMB Analysis

11,3

4,86,8

21,3

28,2

22,2

16,0

46,2

0

10

20

30

40

50

TMB-evaluable Low TMB Medium TMB High TMB

OR

R, %

Nivolumab Nivolumab + ipilimumab

42 27 44 25 47 26n 133 78

PFS - TMB

52

44 5 1 1 1 0 0 0 5 2 2 2 2 1 1 0 0 0

47 15 12 8 5 5 5 2 15 10 5 4 4 3 2 1 0 0

42 3 2 1 0 0 0 0 6 2 1 0 0 0 0 0 0 0No. at risk

1-y PFS = 21.2%1-y PFS =

30.0%

1-y PFS = NC

1-y PFS =

3.1%

1-y PFS = 8.0%1-y PFS = 6.2%

Median (95% CI) PFS, overall TMB-evaluable population: 1.4 (1.3, 1.4) months for nivolumab and 1.7 (1.4, 2.7) months for nivolumab + ipilimumab

NC = not calculable

Medium

High

Low

Months

100

75

50

25

0

0 3 6 9 12 15 18 21 24 27 30 33 36

PF

S, %

100

75

50

25

0

0 3 6 9 12 15 18 21 24 27 30 33 36

Months

Low TMB Med TMB High TMB

Median PFS

(95% CI), mo

1.3

(1.2, 1.4)

1.3

(1.2, 1.4)

1.4

(1.3, 2.7)


Median PFS

(95% CI), mo

1.5

(1.3, 2.7)

1.3

(1.2, 2.1)

7.8

(1.8, 10.7)


25 0

26 0

27 0

0 0 0 0 0

2 2 2 2 1

0 0 0 0 0

3

12

5

100

75

50

25

0

0 3 6 9 12 15 18 21 24 27 30 33 36

1-y OS = 62.4%

1-y OS = 19.6%1-y OS = 23.4%

Months

OS - TMB

53

44 23 17 12 6 2 2 1 0 0 0 0 0 25 15 9 4 3 2 2 2 2 1 1 0 0

47 29 20 14 8 5 5 5 2 2 2 2 2 26 20 17 14 10 9 8 8 6 2 0 0 0

42 19 13 9 4 3 1 0 0 0 0 0 0 27 15 9 7 5 2 2 1 1 1 1 1 1

Months

100

75

50

25

0

0 3 6 9 12 15 18 21 24 27 30 33 36

OS

, %

1-y OS = 35.2%

1-y OS = 22.1%

1-y OS = 26.0%


Median OS

(95% CI), mo

3.1

(2.4, 6.8)

3.9

(2.4, 9.9)

5.4

(2.8, 8.0)


Median OS

(95% CI), mo

3.4

(2.8, 7.3)

3.6

(1.8, 7.7)

22.0

(8.2, NR)


Median (95% CI) OS, overall TMB-evaluable population: 3.9 (2.8, 6.1) months for nivolumab and 7.0 (3.2, 8.8) months for nivolumab + ipilimumab

NR = not reached

No. at risk

Medium

High

Low

KEYNOTE-028: SCLC Cohort

ASCO 2015 Abstract 7502; ESMO 2017, Abstract 427O; 2016WCLC, OA05.01

-1 0 0

-8 0

-6 0

-4 0

-2 0

0

2 0

4 0

6 0

8 0

1 0 0

Ch

an

ge

Fro

m B

as

eli

ne

in

Su

m o

f

Lo

ng

es

t D

iam

ete

r o

f T

arg

et

Le

sio

n,

%

S D

P R

P D

C R

Change From Baseline in Tumor Size (RECIST v1.1,

investigator review)

Primary endpoint

Updated ORR: 33.3%

(95% CI, 15.6%-55.3%)

Fig 3. Survival of patients with small-cell lung cancer in KEYNOTE-028: (A) progression-free survival; (B) overall survival. Percentages are the proportion of patients with survival at that

time point.

Published in: Patrick A. Ott; Elena Elez;

Sandrine Hiret; Dong-Wan Kim; Anne

Morosky; Sanatan Saraf; Bilal Piperdi;

Janice M. Mehnert; JCO 2017, 35,

3823-3829.

DOI: 10.1200/JCO.2017.72.5069

Copyright © 2017 American Society of

Clinical Oncology

Agents Phase NCT Target Population Planned NPrimary

endpoint

REACTION: Cis-etop +/- pembrolizumab

EORTCII 02580994 PD-1 + chemo

Frontline ES-

SCLC118 PFS

KEYNOTE 011 SCLC cohort

Pembrolizumab +/- platinum-etoposideI 01840579 PD-1 +/- chemo

Frontline ES-

SCLC75 Safety (DLT)

Pembrolizumab after chemo II 02359019Chemo then maintenance

PD-1 inhibitor

Maintenance ES-

SCLC54 PFS

Pembrolizumab+chemo +/- XRT II 02934503 PD-1 + chemo +/- XRT ES-SCLC 60Change n PD-L1

IHC status

KEYNOTE 158 SCLC cohort

pembrolizumabII 02628067 PD-1 ES-SCLC 1100 ORR

Pembrolizumab vs topotecan

AllianceII 02963090 PD-L1 vs chemo Salvage ES-SCC 98 PFS

Pembrolizumab + chemoXRT I 02402920 PD-1+ chemoXRTES-SCLC and

LS-SCLC80 Safety (MTD)

Carbo-etoposide +/- atezolizumab I/II 02748889 Chemo +/- PD-L1Frontline ES-

SCLC178 Toxicity

Carbo-etoposide +/- atezolizumab

IMpower133I/III 02763579 Chemo +/- PD-L1

Frontline ES-

SCLC400

Duration OS,

PFS

Atezolizumab vs topotecan II 03059667 PD-L1 vs chemoSalvage ES-

SCLC 70 ORR

Selected SCLC Immunotherapy trials

Clinical trials.gov

Agents Phase NCT Target Population Planned NPrimary

endpoint

CASPIAN: chemo vs chemo+durvalumab

vs chemo + Durvalumab + tremelimumabIII 03043872

Chemo vs Chemo +PD-L1

vs Chemo + PD-L1 +

CTLA4

Frontline ES-

SCLC795 OS, PFS

Durv + treme +/- XRT II 02701400 PD-L1 vs chemo Salvage ES-SCC 20 PFS, ORR

Durvalumab + tremelimumab vs AZD1775 +

carboII 02937818 PD-L1 + CTLA4 vs

Refractory ES-

SCLC80 ORR

Olaparib + durva I/II 02734004 PD-L1 SCLC cohort 133 Safety

CHECKMATE 451 chemo followed by nivo,

ipi-nivo, or placebo maintenanceIII 02538666

PD-1 vs PD-1+CTLA4 vs

placebo maintenance

Maintenance

ES-SCLC 810 OS, PFS

CHECKMATE 331

Nivo vs topotecan vs amrubicinIII 02481830 PD-1 vs chemo

Salvage ES-

SCLC558 OS

Chemo followed by ipi-nivo + XRT I/II 03043599 PD-1 + CTLA4 ES-SCLC 52 OS

STIMULI: Ipi-nivo after chemoXRT

ETOPII 02046733

PD-1+CTLA4 after

chemoXRT

Consolidation

LS-SCLC260 OS, PFS

Selected SCLC Immunotherapy trials (con’t)

Clinical trials.gov

Selected Other AgentsAntibody-Drug Conjugates

Rovalpituzumab Tesirine (Rova-T)

Sacituzumab Govitecan (IMMU-132)

PARP inhibitors

Veliparib

Talazoparib

Wee-1 inhibitors

AZD1775

Apoptotic Agents

ABT-263 +/- mTOR AZD8055

Epi-immune agents

RRx-001

Aurora kinase inhibitors

Alisertib

AZD1152

Notch inhibitors

MEDI0639 (DLL4)

OMP-59R5

Demcizumab

FGFR inhibitors

Ponatinib

Lucitanib

PIK3CA inhibitors

VS5584

Transcription Targeting

Ruzolitinib

Tofactinib

AZD1480

Cytotoxic Agents

amrubicin

palifosfamide

aldoxorubicin

CARLOS HENRIQUE TEIXEIRA

HAOC – CPO/ONCOCLÍNICAS

OBRIGADO!!

simpÓsio internacional de cÂncer de pulmÃo · 2018-03-22 · carlos henrique teixeira...

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