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