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GUIÓN

INTRODUCCIÓN; EL N2

CONSIDERACIONES SOBRE LA

NEOADYUVANCIA

I-O EN NEOADYUVANCIA

CONCLUSIONES

4

Goldstraw et al. J Thorac Oncol 2016

Robinson LA, Wagner H, Ruckdeschel JC. Treatment of Stage IIIA Non-Small Cell Lung Cancer; Chest 2003; 123:202-220

IIIA1Incidental nodal metastases found on final pathologic examination of the resection specimen

IIIA2Nodal (single station) metastases recognized intraoperatively

IIIA3Nodal metastases (single or multiple station) recognized by prethoracotomy staging (mediastinoscopy, other nodal biopsy, or PET scan)

IIIA4Bulky or fixed multistation N2 disease

Pearson, J Thorac CV Surg 1982

N= 702

André et al: J Clin Oncol 18: 2981-89, 2000

Van Meerbeck, J Natl Cancer Inst 2007; 99: 442-50

Ove

rall

surv

ival

Pless et al, Lancet 2015

N=232Fase III

Vansteenkiste ESMO 2018

Goldstraw et al. J Thorac Oncol 2016

Felip et al. JCO 2010

Adyuvancia HR 0.80

Neoadyuvancia HR 0.81

Estudios neoadyuvancia

Lim et al. JTO 2009

Thomas M et al Lancet Onc 2008; 9: 636-48

N=558; estadios IIA-IIIB con afectación mediastínicaAleatorizado

Stefani. J Thorac Cardiovasc Surg Surg 2010;140:356-63

N=175Retrospectivo

Anti–PD-(L)1

Activated T cells enter

tissue and seek out

distant micro-metastases

Activated T cells leave

tumor and enter blood

PD-L1/2

PD-1

T cell

Tumor

Pardoll D et al. Oral presentation at AACR 2018. CT079.

2

1N

o.

CD

8+

T-c

ell

s, c

ell

s/m

L (

x1

02)

P<0.0001

Neoadjuvant

Adjuvant

Tumor-specific CD8+ T cells

in peripheral blood

Survival after neoadjuvant or adjuvant anti–PD-1

100

50

0

0 50 100

Su

rviv

al

(%)

Days After 4T1.2 Tumor Injection

Neoadjuvant control IgGAdjuvant control IgG

Adjuvant α–PD-1Neoadjuvant α–PD-1

Naïve Control

Day: 0

4T1.2 orthotopic injection

17

Neoadjuvant α–PD-1 or control IgG

Surgery

19 21

Adjuvant α–PD-1 or control IgG

23

Surgery

No surgery Adjuvant control IgG

Neoadjuvant α–PD-1/α-CD137

Adjuvant α–PD-1/α-CD137

0

50

100

150

200

P<0.0001

Liu J. Cancer Discov. 2016 Dec 4;6(12):1382–99.

0 1 0 2 0 3 0 4 0 5 0 6 0

0

2 0

4 0

6 0

8 0

1 0 0

3 4 4 S Q O V A+-1 2 9 s v M ic e S u rv iv a l:

N e o a d ju v a n t IO -S u rg e ry A rm # 2

D a y s a fte r tu m o r c e ll in je c tio n

Pe

rc

en

t s

urv

iva

l

N e o a d ju v a n t a n t i-P D -1 +

a n t i-C T L A - 4

A d ju v a n t a n t i-P D -1 +

a n t i-C T L A - 4

Neoadjuvant superior

HR = 0.33; P = .028

Days after Cell Injection

Neoadjuvant combined ICB is superior to

adjuvant therapy in NSCLC-OVA+ murine models

*

Cascone T. et al, AACR 2018, in preparation

Resect

primary

Adjuvant arm (syngeneic Kras LUAC model, OVA+) Survival

analysis,

metastases

Neoadjuvant armSurvival

analysis,

metastases

Dose 1 Dose 2 Dose 3

Adjuvant ICIs

Mono- or combo

Dose 1 Dose

2

Dose

3

Neoadjuvant ICIs

Mono- or combo

Resect

primary

Neoadjuvant combined immune checkpoint blockade prolongs survival and reduces lung mets compared to adjuvant therapy

N=54

Junker, Chest, 2001

Pataer A et al., J Thorac Oncol, 2012

Overall survival

Cascone T et al. Ann Thorac Surg, 2017

N=358 N=47

Qu Y, J Thorac Oncol. 2019 Mar;14(3):482–93.

N=272 pac tratados con neoadyuvancia; retrospectivoMSKCC

Qu Y, J Thorac Oncol. 2019 Mar;14(3):482–93.

Forde et al. AACR 2018, NEJM 2018

N=21

Primary endpoints:- feasibility- safety

33% estadios III

Eficacia

Respuestas parciales:

10%

86% estabilización

MPR: 45% (95% CI: 23-68)

3 pacientes tuvieron RC patológica

40% (n = 8/20) presentarondown-staging patológico

Forde et al. AACR 2018, NEJM 2018

Reuss et al. ASCO 2019

Median recurrence-free survival (RFS) had not been reached: at 24 months was

70% (95% CI, 53 - 93)

Eficacia

Cascone et al. ASCO 2019

Primary endpoint:

MPR

Secondary endpoints:

• Toxicity, peri-operative morbidity/mortality, ORR, RFS, OS

• R0 and pCR rates

• CD8+ TILs in resected tumors

N = 37 ARM A

Nivo

N=21

ARM B

Nivo/Ipi

N=16

Stage I 11 (52%) 11 (69%)

Stage II 6 (29%) 3 (19%)

Stage III 4 (19%) 2 (13%)

N=44Eligibility- NSCLC stage I-IIIA N2 single station (JCC 7th)- Contralateral 2 and/or 4 node eval to exclude N3Surgical candidate-ECOG PS 0-1Stratification- Stage

Arm A:Nivolumab3 mg/kgD1, 15, 29

Arm B:Nivolumab3 mg/kgD1, 15, 29Ipilimumab1 mg/kg d1

SurgerySOCpostop therapy

CT, PET-TCTumorBlood, stool

CT, PET-TCBlood, stool

TumorUninvolved lung

Cascone T, J Clin Oncol 37, 2019 (suppl; abst 8504)

Response

(RECIST)

Overall

n = 44

N

n = 23

NI

n = 21

n (%) n (%) n (%)

CR 1 (2%) 0 (0%) 1 (5%)

PR 8 (18%) 5 (22%) 3 (14%)

SD28

(64%)15 (65%) 13 (62%)

PD 6 (14%) 3 (13%) 3 (14%)

Not

evaluable1 (2%) 0 (0%) 1 (5%)#

Cascone et al. ASCO 2019

MPR No MPR p-value

RECIST n (%) n (%)

CR/PR7 (78%) 2 (22%) < 0.001

SD/PD 4 (12%) 30 (88%)

NI (n = 21) % change in tumor size from baseline

NI (n = 21) % viable tumor

╬

*

*

no surgery on trial (5 no surgery, 2 surgeries off trial)

N (n = 23) % viable tumor

N (n = 23) % change in tumor size from baseline

*

*

Cascone et al. ASCO 2019

Cascone et al. ASCO 2019

Grade 1-2 TRAE*

N (23) NI (21)

n n/23 (%) n n/21 (%)

Fatigue 8 35% Rash acneiform 11 52%

Rash acneiform 6 26% Fatigue 7 33%

Anemia 3 13% Nausea 7 33%

Hyponatremia 3 13% Cough 6 29%

Diarrhea 2 9% Diarrhea 6 29%

Increased Alanine

Aminotransferase 2 9% Chills 3 14%

Flu like symptoms 2 9% Anemia 2 10%

Headache 2 9% Dyspnea 2 10%

Hypomagnesemia 2 9% Hyperthyroidism 2 10%

Pruritus 2 9% Pruritus 2 10%

Vomiting 2 10%

Grade 3-5 TRAE

N (23) NI (21)

n n/23 (%) n n/21 (%)

Hypermagnesemia

(G3) 1 4% Diarrhea (G3) 1 4%

Hypoxia (G3) 1 4% Hyponatremia (G3) 1 4%

Pneumonia (G3)* 1 4%

Pneumonitis (G5)* 1 4%

Surgical complications

N (23) NI (21)

n n/23 (%) n n/21 (%)

Air Leak 5 22% Air Leak 3 14%

Bronchopleural fistulas* 2 9%

Empyema* 1 4%

Pneumonia* 1 4%

Pneumonitis* 1 4%

* From the same patient

* The maximum grade of TRAE from a patient is considered

Median follow-up time after randomization: 8.4 months

Arm A: 1 pt (IIB) died of steroid-treated pneumonitis 4.1 months after randomization

Arm B: 1 pt (IIIA) had PD 2 months after randomization, and died of disease 17 months after randomizationCascone et al. ESMO 2018

Bas

eli

ne

% P

D-L

1

CR/PR SD/PD

60

80

40

20

0

P = 0.015

Baseline % PD-L1 and RECIST responses

% v

iab

le t

um

or

<1% >1%

60

80

100

40

20

0

Baseline % PD-L1

P = 0.046

Baseline % PD-L1 and % viable tumor

Bas

eli

ne

% P

D-L

1

MPR No MPR

60

80

40

20

0

P = 0.015

Baseline % PD-L1 and MPR

Cascone et al. ASCO 2019

Sepesi, IASLC 2019

Nivolumab Nivolumab Ipilimumab

Kwiatkowski at 2019 ASCO

Estadio III: 43%

Pathological Regression in Intended Surgery Population (n = 90)

Kwiatkowski at 2019 ASCO

Lee, IASLC 2019

Pathological Regression Correlates With Change in Tumor Lesion Size

La regresión patológica se correlaciona con cambios en el tamaño tumoral

La regresión patológica y MPR se observan independientemente de la

expresión de PD-L1

Kwiatkowski at 2019 ASCO

Lee, IASLC 2019

NCT022596211 NEOSTAR2 LCMC33,4†

1. Forde PM et al. N Engl J Med. 2018;378:1976-1986. 2. Cascone T et al. Oral presentation at ASCO 2019. 8504. 3. Kwiatkowski DJ et al. Oral presentation at ASCO 2019. 8503. 4. Clinicaltrials.gov. NCT02927301. Accessed August 22, 2019.

Stages I-IIIA

Nivolumab 2 doses q2w

Stages I-IIIA

Nivolumab 3 doses q2w

Stages IB-IIIA‡

Atezolizumab 2 doses q3w

*

0

-20

-40

-60

-80

-100

Re

gre

ss

ion

(%

)

NCT022596211

No. patients n=20

MPR, n (%) 9 (45%)

pCR, n (%) 2 (10%)

NEOSTAR2

n=23

4 (17%)

2 (9%)

LCMC33

n=77§

15 (19%)

4 (5%)

0

-20

-40

-60

-80

-100No surgery on trial (1 no surgery, 1 surgery off trial)

0

-20

-40

-60

-80

-100

++

+ +

+

+ ++

+ EGFR+. + ALK+.

Nivo monotherapy Nivo + ipi

No. patients n=23 n=21

MPR, n (%) 4 (17%) 7 (33%)

pCR, n (%) 2 (9%) 6 (29%)

45

Cascone T et al. Oral presentation at ASCO 2019. 8504.

CT scans are unable to identify many pathological responses: of 7 MPRs demonstrated with nivo + ipi, only 4 were an ORR radiologically

– CR: 1, PR: 3, SD: 13, PD: 3, not evaluable: 1

0

-20

-40

-60

-80

-100No surgery on trial (4 no surgery, 1 surgery off trial)

Reg

res

sio

n (

%)

45

Study design: Stages I-IIIA; nivolumab 3 doses q2w + ipilimumab on D1

(Within 3 to 8 weeks after

surgical resection)

Provencio, M. IASLC 2019

Primary Endpoint: PFS at 24 months; OS at 3 yearsStudy start: April 2017Enrollment completion: August 2018Data analysis cut-off: 27th June 2019

89%: N2 N=46

Secondary Endpoints: Down-staging rate, complete resection rate, ORR, safety, TTP, OS at 3 y

A ll d a ta (% T V ) - a ll g r o u p s P D X4

Tim e (days)

%T

um

or

Vo

lum

e

2 00

0

4 00

6 00

8 00

1000

Vehicle

Nivolumab

Cisplatin

C isplatin+N ivolumab

Nivolumab + Cisplatin (sec)

Cisplatin + Nivolumab (sec)

Ruiz-Valdepeñas, ProvencioPendiente publicación

Rizvi NA. J Clin Oncol. 2016 Sep;34(25):2969–79.

N %

Complete response

(CR)2 4.3

Partial Response (PR) 32 69.6

Stable disease (SD) 12 26.1

Tasa de respuestas

(RECIST v1.1)

Eventos adversos relacionados con el tratamiento (100 d post), N=46)

Grade 1-2 TRAE N %

Fatigue 21 45.6

Alopecia 16 34.8

Nausea 15 32.6

Diarrhea 11 23.9

Arthralgia 10 21.7

Vomiting 8 17.4

Myalgia 8 17.4

Constipation 8 17.4

Pruritus 7 15.2

Anemia 7 15.2

Peripheral sensory

neuropathy6 13

Anorexia 6 13

Thrombocytopenia 3 6.5

Increased blood

creatinine1 2.2

Grade 3-5

TRAE

N %

Neutropenia 3 6.6

Febrile

Neutropenia

2 4.4

Peripheral s

ensory

neuropathy

2 4.4

Alopecia 1 2.2

Anorexia 1 2.2

Fatigue 1 2.2

Nephritis 1 2.2

Todos los pacientes recibieron 3 ciclos excepto

uno, que recibió 2

Provencio, M. IASLC 2019

Pathologic response N=41 % (CI 95%)

Major Pathological Response (MPR)

Complete Response (CR)

34/41

24/41

83 (68-93)

59 (42-74)

> 10% residual viable tumor 7/41 17 (7-32)

Provencio, M. IASLC 2019

PFS at 12 months: 96% (95% CI: 84; 99)

PFS at 18 moths: 81% (95% CI: 61; 91)

PROGRESSION FREE SURVIVAL (ITT)0

25

50

75

10

0

46 46 44 43 18 5Number at risk

0 3 6 12 18 24Time from inclusion (months)

Overall Survival at 12 months: 98% (95% CI: 85; 100)

Overall Survival at 18 months: 91% (95% CI: 73; 97)

OVERALL SURVIVAL (ITT)

02

55

07

51

00

46 46 46 44 20 5Number at risk

0 3 6 12 18 24

Time from inclusion (months)

Provencio, M. IASLC 2019

Stage I-III Resectable