imunoterapia para neoplasias torácicas - iweventos · pa th o lo g ic a l as s e s s m e n t of re...

Imunoterapia para Neoplasias Torácicas

William N. William Jr., MD

Director, Oncology and HematologyHospital BP, a Beneficência Portuguesa de São Paulo

Adjunct Associate ProfessorThe University of Texas MD Anderson Cancer Center

Outline

• Non-small cell lung cancer• Neoadjuvant treatment

• Consolidation treatment for stage III

• First-line therapy

• Treatment after platinum failure

• Small cell lung cancer• First-line combination therapy


• Mesothelioma• Treatment after platinum failure

• Thymic malignancies• Second-line therapy and beyond

Neoadjuvant Nivolumab

Forde et al., ESMO 2016

PatientsCharacteristics N=21

Age – yrs, median (range) 67 (55-84)

Male/Female 10/11

Adenocarcinoma

Pleomorphic carcinoma

Squamous

13

2

6

Clinical Stage (AJCC 7th ed)

IA/IB

IIA

IIB

IIIA

4

5

5

7

Smoking status

Never

Former/Current

3

18

22 enrolled

21 treated with

preoperative intent

20 resected

1 unresectable

1 withdrawn

(diagnosis change to

SCLC)

Forde et al., NEJM 2018

Radiographic responses to 2 doses of

nivolumab

RECIST* N(%)

PR 2 (10%)

Stable

Disease

18 (85%)

PD 1 (5%)

*Measurements per RECIST v1.1

but not confirmed as surgery

followed 1st assessment

Pre-

nivo

Post-

nivo

Pleomorphic,

Pathologic CR

Squamous,

Pathologic CR

4 w

ee

ks


14 of 19

NEJMoa1716078_Forde(Pardoll) Content2(author) Fri Apr 06 2018 10:25:55

Figure 2. Pathological Assessment of Response to Neoadjuvant Blockade of Programmed Death 1 (PD-1).

Panel A shows pathological regression in the resected primary lung tumor after neoadjuvant administration of nivolumab, according to the

percentage of remaining viable tumor cells, for each of the 20 patients who underwent surgical resection. The gray horizontal line indicates

the threshold for a major pathological response (90% regression). Clinical and pathological features{q37} that include the presence or

absence of lymph-node (LN) metastases in the surgical specimen and preoperative radiologic response (according to Response Evaluation

Criteria in Solid Tumors [RECIST]) are annotated for each patient. AC denotes adenocarcinoma, SCC squamous-cell carcinoma, PR {q38}

pathological response, SD stable disease, and PD-L1 programmed death ligand 1. Also shown are biopsy specimens obtained before (Panel

B) and after (Panel C) neoadjuvant administration of nivolumab in a patient who had a {q39}XXX response (multiplex immunofluorescence

staining). With this staining technique, visible structures include cytokeratin-positive tumor cells (orange), CD68+ macrophages (magenta),

FoxP3+ regulatory T cells (yellow), CD8+ T cells (green), PD-1+ cells (red), and PD-L1+ cells (white). In the pretreatment specimen, only a

few intratumoral macrophages are seen expressing PD-L1. However, there are multiple foci where PD-L1 and PD-1 are expressed in close

proximity to each other (inset with white circle) in the pretreatment specimen. Focal, geographic tumor-cell PD-L1 expression was observed

in an adaptive pattern (not shown in this image). After two doses of nivolumab, the tumor is infiltrated by liquid containing CD8+ and PD-

1+ immune cells. Some of the infiltrating immune cells express PD-L1, which is consistent with an adaptive immune resistance

mechanism.19,20

A Percentage of Pathological Regression, According to Subgroup B Biopsy Sample before Nivolumab

C Biopsy Sample after Nivolumab

Regr

essi

on (%

)

0

–40

–60

–100

–20

–80

PD-L1+

PD-L1–

Unknown

Smoking StatusHistologic SubtypeRECIST Response

LN Metastases

Never smoked

Current/ex-smoker Never smoked AC SCC

Other PR SD LN+ LN–

(MD043-008)

major

pathologic

Percent Pathologic Response According to Subtype

Never

smoker


MAJOR PATHOLOGIC RESPONSE RATE: 45%

Key

PD-L1

PD-1

CD8

FOXP3

CD68

Tumor

DAPI

Pre-treatment Post-treatment

Multiplexed immunofluorescence shows post-

treatment influx of CD8+ T-cells

Tricia Cottrell and Janis Taube – LB-154//21

Neoadjuvant Atezolizumab

Rush et al., ASCO 2018

Neoadjuvant Atezolizumab

Rush et al., ASCO 2018

MPR: 19%

ORR: 6%

PI: Cascone and William

Neostar – Neoadjuvant Nivolumab+/- Ipilimumab in Resectable NSCLC

Primary endpoint: major pathologic response

Outline









Phase III - PACIFICDurvalumab vs. Placebo Consolidation

Paz Ares et al. ESMO 2017; NEJM 2017



POSITIVE RESULTS FOR OVERALL SURVIVAL TO BE PRESENTED SOON

Time to Distant Metastasis or Death 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

tyofdea

thor

dis

tantm

eta

sta

sis

Time from randomization (months)

Placebo

Durvalumab

No. at risk

Durvalumab

476

407 336 288 173 91 46 22 4 1 0

Placebo

23

7

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

Efficacy of Consolidation Pembrolizumab

Durm EL AL. ASCO 2018

Outline









Algoritmo Primeira Linha – 2018 Não Escamosa

*Outros importante drives genes incluem ROS1, BRAF, RET, MET, HER-2, NTRK

Biópsia

Inicial

CPCNP

Não

Ecamosa

EGFR, ALK,

ROSConsiderar NGS*

Terapia Alvo

• Platina, pemetrexede,

pembrolizumabe

• Carboplatina,paclitaxel,

bevacizumab,

atezolizumabe

+

-Neg

≥ 1%

PDL-1

(22C3)• Platina, pemetrexede,

pembrolizumabe


bevacizumab,

atezolizumabe

• Pembrolizumabe

Algoritmo Primeira Linha – 2018 Não Escamosa

*Outros importante drives genes incluem ROS1, BRAF, RET, MET, HER-2, NTRK

Biópsia

Inicial

CPCNP

Não

Ecamosa

EGFR, ALK,

ROSConsiderar NGS*

Terapia Alvo

• Platina, pemetrexede,

pembrolizumabe


bevacizumab,

atezolizumabe

+

-Neg

≥ 1%

PDL-1

(22C3)

a opção de pembrolizumabe isolado talvez seja menos favorecida, especialmente em PD-L1 1-49%

Algoritmo Primeira Linha – 2018 Escamosa

*checar driver genes se nunca fumante

Biópsia

Inicial

CPCNP

Escamosa*

Carboplatina,

paclitaxel (ou nab-

paclitaxel),

pembrolizumabe

PDL-1

(22C3)

• Carboplatina, paclitaxel (ou nab-

paclitaxel), pembrolizumabe

• Pembrolizumabe

Negativo

≥1%

Algoritmo Primeira Linha – 2018 Escamosa

*checar driver genes se nunca fumante

Biópsia

Inicial

CPCNP

Escamosa*

Carboplatina,

paclitaxel (ou nab-

paclitaxel),

pembrolizumabe

PDL-1

(22C3)

Negativo

≥1%

a opção de pembrolizumabeisolado é menos favorecidaem PD-L1 1-49%

Outline









Nivolumab in NSCLCCA209-003 Phase I Study

Brahmer et al. AACR 2017

Phase II/III - Keynote 010Pembrolizumab vs. Docetaxel in NSCLC

Herbst et al. Lancet 2015

Median overall survival:

Docetaxel: 8.5 monthsPembrolizumab 2 mg/kg: 10.4 months (HR=0.71, 95% CI 0.58-0.88; p=0.0008)Pembrolizumab 10 mg/kg: 12.7 months (HR=0.61, 95% CI 0.49-0.75; p<0.0001)

Phase III - CheckMate 057 2-year Overall Survival – Non-Squamous NSCLC

Borghaei H et al. ASCO 2016.

Phase III - OAKAtezolizumab versus Docetaxel in NSCLC

Barlesi et al. ESMO 2016

Efficacy According to PD-L1Phase III - CheckMate 017

2nd Line Nivolumab vs. Docetaxel in SCC

Reckamp K et al, IASLC 2015

CheckMate 078 Study Design

27

Co-primary endpoints• OS of nivolumab vs docetaxel• Consistency of OS benefit with CheckMate 017 & 057

Secondary endpoints: • ORR,c PFS,c TTF, efficacy (histology, PD-L1 expression, Chinese ethnicity),

safety and tolerability

Key eligibility criteria

• Stage IIIB/IV NSCLCa

• No EGFR mutation or ALK translocation

• Prior platinum-based doublet chemotherapy

• Prior maintenance therapy allowed

• Available tumor tissue for PD-L1 analysisb

• ECOG PS 0–1

Stratified by ECOG PS, histology, and

PD-L1 (≥1% vs <1%/not evaluable)

Docetaxel75 mg/m² Q3W

(n = 166)

Nivolumab 3 mg/kg Q2W

(n = 338)Until disease

progression or unacceptable

toxicity

R2:1

aAccording to version 7 of the International Association for the Study of Lung Cancer staging manual; bUsing Dako PD-L1 IHC 28-8 pharmDx assay; cInvestigator assessed per RECIST v1.1Database lock: October 27, 2017; minimum follow-up: 8.8 months

(N = 504)

CheckMate 078 - Overall Survival

28

No. at risk Months

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0 3 6 9 15 18 2412 21

Pro

ba

bilit

y o

f s

urv

iva

l

240 132 72 21 1

051845102130

295338

166Docetaxel

Nivolumab

82

189 0

Nivolumab

Docetaxel

0

6-mo OS = 65%

6-mo OS = 72%

Nivolumab(n = 338)

Docetaxel(n = 166)

Median OS(95% CI), mo

12.0

(10.4, 14.0)

9.6

(7.6, 11.2)

HR (97.7% CI)a

P value0.68 (0.52, 0.90)

0.0006

aStatistical model for HR and P value: Cox proportional hazard model and weighted log-rank test, stratified by histology (squamous vs non-squamous), PD-L1 expression (≥1% vs <1%/not evaluable) and ECOG PS (0 vs 1); bMinimum follow-up was 8.8 months

12-mo OSb = 50%

12-mo OSb = 39%

Outline









First-Line Combination Therapy SCLCIMPOWER 133

Horn et al., ASCO 2017

First-Line Combination Therapy SCLCIMPOWER 133

Outline









CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC Phase I/II CheckMate 032 Study Design

Hellman et al. ASCO 2017

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC Summary of Response per BICR – Non-Randomized Cohort

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC OS – Non-Randomized Cohort

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC Summary of Response per BICR

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC Summary of Safety – Pooled Cohorts

Baseline Biomarker Status

Presented By Hyun Chung at 2018 ASCO Annual Meeting

Keynote 158 – Pembrolizumab for SCLC

Antitumor Activity by PD-L1 Status (RECIST v1.1, Independent Central Reviewa)

Overall Survival by Tumor PD-L1 Status (RECIST v1.1, Independent Central Review)

Outline









Nivolumabe ± Ipilimumabe em 2L/3L

Scherpereel A, et al. J Clin Oncol 35, 2017 (suppl; abstr LBA8506).

• Mesotelioma pleural• Irressecável• ≥1 QT prévia(incluindoplatina/pemetrexede)• ECOG PS 0-1• Perda de peso <10%

R

Nivolumabe3 mg/kg a cada 2 semanas

(24 meses)

Nivolumabe3 mg/kg a cada 2 semanas

Ipilimumabe1 mg/kg a cada 6 semanas

(24 meses)

*Tomografias a cada 12 semanas

Objetivo primário: Taxa de controle da doença em 12 semanaspor comitê independente

Objetivos secundários: Segurança, SLP, SG, qualidade de vida, biomarcadores

MAPS2



NIVO(n=54)

NIVO+IPI(n=54)

Resposta Objetiva 18,5% 25,9%

Doença Estável 25,9% 24,1%

Taxa de Controleda Doença

44,4% 50,0%

Progressão de Doença

51,9% 42,6%

Não Avaliável 3,7% 7,4%

NIVO(n=63)

NIVO+IPI(n=62)

17,5% 24,2%

22,2% 27,4%

39,7% 51,6%

57,1% 37,1%

3,2% 11,3%

Avaliação Tumoral em 12 semanas

Primeiros 108 pacientes elegíveis População ITT (n=125)



Overall Survival

Outline









Cho et al. ASCO 2017

Pembrolizumab for Thymoma / Thymic Carcinoma

Giaccone et al. ASCO 2017

Pembrolizumab for Thymic Carcinoma

Conclusions

• Neoadjuvant immunotherapy promising for NSCLC but not a standard of care yet

• Consolidation durvalumab after chemoXRT for stage III is the new standard of care

• Most patients with stage IV NSCLC should be treated with first-line immunotherapy +/-chemotherapy

• Impressive 5-year survival (16%) with immunotherapy after platinum failure in NSCLC

• Platinum/etoposide/atezolizumab may become a new standard of care for extensive SCLC

• Nivolumab +/- ipilimumab or pembrolizumab (specially PD-L1 CPS+) are reasonable optionsfor SCLC after platinum failure and may lead to long-term survival

• Nivolumab +/- ipilimumab are reasonable options for mesothelioma after platinum failure

• Pembrolizumab associated with a high rate of toxicities in thymomas, despite efficacy – not a reasonable option

• Toxicity of pembrolizumab in thymic carcinoma is still higher than usual, but the benefit / riskratio may be more favorable if used with caution

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