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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