Câncer de Pulmão Estádio III - rvmais.iweventos.com.br€¦ · • Cerca de 1.800.000 casos de...
Transcript of Câncer de Pulmão Estádio III - rvmais.iweventos.com.br€¦ · • Cerca de 1.800.000 casos de...
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
Auperin A, et al. J Clin Oncol. 2010; 28.
Sequencial x Concomitante
Progressão Locorregional
Auperin A, et al. J Clin Oncol. 2010; 28.
Sequencial x Concomitante
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 primário: SG
Desfecho secundário: SLP
Hipótese: Cirurgia promoveria um aumento de 10% (25% para 35%) na sobrevida
após quimiorrradioterapia concomitante.
Albain K, et al. Lancet 2009; 374: 379.
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
Desfecho primário: SG
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
Albain K, et al. Lancet 2009; 374: 379.
INT 0139
Lobectomia Pneumectomia
Albain K, et al. Lancet 2009; 374: 379.
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.
Resposta patológica à terapia neoadjuvante
prediz melhor evolução clínica em CPCNP
William Jr. NW, et al. J Thorac Oncol. 8(2):222-228,
2013.
Resposta patológica à terapia neoadjuvante
prediz melhor evolução clínica em CPCNP
William Jr. NW, et al. J Thorac Oncol. 8(2):222-228,
2013.
Patients
Presented By Jamie Chaft at 2017 ASCO Annual Meeting
Radiographic responses to 2 doses of nivolumab
Presented By Jamie Chaft at 2017 ASCO Annual Meeting
Pathologic responses to neoadjuvant nivolumab
Presented By Jamie Chaft at 2017 ASCO Annual Meeting
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!