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Papel de las nuevas terapias en el cáncer de pulmón no microcítico localizado
Dr. Oscar Juan VidalHospital Universitari i Politècnic La fe
Formigal, 20 de Junio de 2019
Early stage NSCLC• Early stage NSCLC
represents about half of the NSCLC population
• Most of the early stage NSCLC patients are eligible for surgery, with the exception of stage IIIB
Onkos Study, Non-Small-Cell Lung Cancer, Decision Resources, October 2014
Early stage NSCLC
• Despite potentially curative surgery, following complete surgical resection the 5 year survival is approximately:
– Stage I: 73-90%
– Stage II: 46-65%
– Stage IIIA: 41%
• (Neo)adjuvant therapy proven benefit in resectable NSCLC
Goldstraw et al. J Thorac Oncol 2016
Adjuvant therapy in NSCLC
Goldstraw et al. J Thorac Oncol 2016
Trial nameStage
EligibilitySample
sizeTreatment Arm DFS (mos) OS (mos)
IALT I – III 1867CDDP contained regimen +
XRT(optional)40m (HR=0.88) 54m (HR=0.91 ns)
Observation 30m 45m
ANITA IB - IIIA 840CDDP+Vinorelbine 36m (HR=0.76) 66m (HR=0.79)
Observation 21m 44m
ALPI I - IIIA 1209Mitomycin+Vindesine+CDDP NR (HR=0.89 ns) NR (HR=0.96 ns)
Observation NR NR
BLT I-III 381Platinum chemotherapy 27m (HR=0.97, ns) 34m (HR=1.02)
Observation 25m 33m
JBR.10 IB - II 482CDDP+Vinorelbine
Not Reached (HR=0.6)
94m (HR=0.69)
Observation 47m 73m
CALGB IB 344CBDCA + Paclitaxel 89m (HR=0.8, ns) 95m (HR=0.83, ns)
Observation 56m 78m
LACE metanalysis
IB-IIIA 4584Platinum Doublet HR = 0.84 (0.78-
0.91)HR-0.89 (0.82-0.96)
Observation
• LACE metanalysis proved that adjuvant chemotherapy can provide benefit to Stage II and III patients
• No benefit observed for Stage IA patients• Benefit for Stage IB patients not clear
LACE Metanalysis
OS HR
OS benefit at 5 years: 5.4%
Ove
rall
Surv
ival
(%
)
Year
OS by Stage of Disease
JCO 2008; 26: 3552
HR-0.89 (0.82-0.96)
Adjuvant vs neoadjuvant therapy in NSCLC
Lim et al. J Thorac Oncol 2009
NATCH trial: no differences in DFS with the addition of CT pre or postoperatively
Meta-analysis: similar benefits
Adjuvant HR 0.80
Neoadjuvant HR 0.81
Felip et al. J Clinc Oncol 2010
Immunotherapy in early stage
• Advantages (theoretical):
– Patients have a more intact immune system
– Potential for long lasting immune priming against micrometatases
– Opportunity for translational search in neo-adjuvant setting
• Questions:
– Which?
– When? Adjuvant or neo-adjuvant
– To whom?
Immunotherapy in early stages
Chemotherapy Immunotherapy
Chemotherapy
Immunotherapy
Surgery
Surgery
Surgery
ImmunotherapyImmunotherapy
AdjuvantPEARLSBR31ANVIL
IMpower 010
IT in early stage: Adjuvant clinical trialsPlacebo controlled arm
• Stage IB (>4cm), II & III
• PS 0 -1• Post R0 surgery• Adjuvant CT as
indicated
PEARLS (ETOP/EORTC/MSD)
BR31 (NCI-C & other groups)
Ran
do
miz
atio
nR
and
om
izat
ion
Pembrolizumab 200mg q3w (max 18 doses)
Durvalumab 10 mg/kg q2w (max 12 months)
Placebo iv q3w (max 18 doses)
Placebo iv q2w (max 12 months)
Primary endpoint: DFSN= 540 per arm
Primary endpoint: DFS DFS in PDL1+
N = 680 per arm
IT in early stage: Adjuvant clinical trialsObservation arm
• Stage IB (>4cm), II & III
• PS 0 -1• Post R0 surgery• Adjuvant CT as
indicated
ANVIL –ECOG - ACRIN
IMpower 010
Ran
do
miz
atio
nR
and
om
izat
ion
NIvolumab200mg q2w (max 12 months)
Atezolizumab 1200 mg q2w (max 16 doses)
Observation
Observation
Primary endpoint: DFS & OSN= 307 per arm
Primary endpoint: DFS st IB-IIIADFS in st II-IIIA in PDL1+
N = 563 per arm
Immunotherapy in early stages
Immunotherapy
Chemotherapy
Immunotherapy
Surgery
Surgery
Neo-Adjuvant
NivolumabPembrolizumab
AtezolizumabNivo + Ipi
NADIM TRIALATEZO neo-Adj
Su
rviv
al
Pro
ba
bil
ity
Su
rviv
al
Pro
ba
bilit
y
Overall Survival
Pataer A et al., J Thorac Oncol, 2012 Cascone T et al. Ann Thorac Surg, 2017
<=10%
>10%
>10%
<=10%
Histopathologic Response Criteria Predict
Survival of NSCLC Patients Treated with
Neoadjuvant Chemotherapy
Major pathologic response (≤10% viable tumor cells) as a
surrogate for survival after neoadjuvant therapy
Overall Survival
Neoadjuvant Cisplatin Docetaxel
Followed by Surgery and Erlotinib in
NSCLC Patients
Pilot phase 2 Neo-adjuvant nivolumab study
Preoperative Surgical specimen Forde et al.
Pilot phase 2 Neo-adjuvant nivolumab studySurgical Feasibility
Feasibility:• Nivolumab did not delay or interfere
with surgery in any patients
Safety:• One death in the post-operative safety
period was unrelated to study drug (sequelae or traumatic fall)
Forde et al. AACR 2018, NEJM 2018
Pilot phase 2 Neo-adjuvant nivolumab study
Forde et al. NEJM 2018
RECIST vs Pathological responses
9/21 MPR
LCMC3: Phase II of neo-adjuvant atezolizumab
Kwiatkowski et al. ASCO 2019
Stage IB, II, IIIA or selcted IIIB resectable
LCMC3: Phase II of neo-adjuvant atezolizumab
Major Pathological Response (MPR; ≤10% Viable Tumour Cells)Kwiatkowski et al. ASCO 2019
Pathological regression in intended Surgery population (N=90). 11 pts no surgery (5 PD)
NEOSTAR: phase II study of induction checkpoint blockade for resectable stage I-IIIA NSCLC
Cascone et al. ESMO 2018
NEOSTAR: Primary endpoint MPR rateMajor pathologic response (≤10% viable tumor cells)
Cascone et al. ASCO 2019
NEOSTAR: Radiographic responses and association with MPR
Cascone et al. ASCO 2019
ORR 22% ORR 19%
Biomarkers in neoadjuvant setting: PD-L1 expression
LCMC3 NEOSTAR Forde et al
MPR were observed irrespective of PD-L1 expression
Biomarkers in the neoadjuvant setting: TMB
LCMC3 Forde et al
Tumor burden is associated with pathologic response to neoadjuvant nivolumab, but there is not a clear association with neoajuvant atezolizumab
ctDNA as biomarker of residual disease
ctDNA identifies patients with molecular residual disease after surgery o radiotherapy
Neo-adjuvant CT-IO for resectable stage IIIA
Adjuvant treatment initiated between
3 and 8 weeks after surgical resection
• Phase II• Single-arm• Open-label• Multicenter• Resectable IIIA NSCLC• 46 patients
NADIM: Study design & Flow-chart
Neoadjuvant treatment Radiological response (n =46)
NADIM: Response
Provencio et al. ASCO 2019
Pathological response ( n= 41)
Neo-adjuvant CT-IO: Atezo+carbo+nab-apclitaxel
Shu et al. ASCO 2018
Neo-adjuvant CT-IO: Atezo+carbo+nab-paclitaxel
Shu et al. ASCO 2018
Neo-adjuvant IO studies
Study N resected
Stage Drug Cycles MPR RECIST ORR
Imm
un
oth
era
py LCMC3 84 IB-IIIB Atezo 2 18% (10-28) 7%
NEOSTARArm AArm B
2321
IA-IIIAIA-IIIA
NivoNivo/Ipi
33
17% (5-39)33% (15-57)
22%19%
Forde et al 20 IB-IIIA Nivo 2 45% (23-68) 10%
CT-
IO
NADIM 30 IIIA Nivo/Carbo/pacli
3 80% (61-92) 70%
Shu et al 11 IB-IIIA Atezo/Carbo/Nab-pacl
2 64% (32-88) 73%
Selected ongoing neoadjuvant clinical trials
All include immunotherapy + chemotherapy arm
Stage III NSCLC is heterogeneous
Goldstraw et al. J Thorac Oncol 2016
PACIFIC trial
Paz-Arez L et al. ESMO 2017, Antonia et al NEJM 2017
Phase III, randomized, double-blind, placebo-controlled, multicenter, international study
PACIFIC trial
Antonia et al NEJM 2017; Antonia et al NEJM 2018
Durvalumab after definitive CT/RT increases PFS and OS
Progression-free survival Overall survival
Immunotherapy in unresectable stage III
CT/RT Immunotherapy
CT/RT
Immunotherapy
CT/RT
Immunotherapy
Immunotherapy
CT/RT
Immunotherapy Immunotherapy
Consolidation CT
1
2
4
3
PACIFIC
Phase I Pembrolizumab: best timing of Pembro
Jabbour et al. ASCO 2019
Phase I Pembrolizumab: best timing of Pembro
Jabbour et al. ASCO 2019
Lin SH et al.
Primary endpoint: Safety of combining atezo with CRT
Lin SH. ASCO 2019
Early preliminary efficacy resultsMedian PFS 1 yr PFS Median OS 1 yr OS
Part 1 20.1 mos 60% 20.1 mos 60%
Part 2 NR 66% NR 77%
Lin SH. WCLC 2018; ASCO 2019
Pacific 2
Conclusions
• IO is being translated to early stages with exciting results
• Neo-adjuvant IT seems to have many advantages. What is the best approach? IT or CT+IT?
• Important phase III trials in both scenarios, adjuvant and neo-adjuvant
• Possible positive interaction between radiotherapy and PD-1/PD-L1 immunotherapy
• PACIFIC schema is the new standard in unresectable NSCLC
• Future trial will define the best approach