esmo e-learning perioperative treatment of non-small cell ......salazar mc, et al., jama oncol...

PERIOPERATIVE TREATMENT OF NON SMALL CELL LUNG CANCER

Virginie Westeel

Chest Disease Department

University Hospital

Besançon, France

1. To understand the potential of perioperative treatments

2. To identify patients who should receive perioperative treatment for NSCLC

3. To choose the most appropriate perioperative treatment

4. To know the modalities of delivery for perioperative treatments

LEARNING OBJECTIVES

In EGFR wild-type NSCLC

Perioperative chemotherapy

Preoperative chemoradiation

Perioperative targeted treatments

Perioperative immunotherapy

Postoperative mediastinal radiotherapy

In EGFR mutated NSCLC

PERIOPERATIVE TREATMENTS

IN NSCLC

HR 0.86

(95% CI 0.81, 0.92;

p<0.00011)

ADJUVANT CHEMOTHERAPY:

SURVIVAL RESULTS 1

(Individual patient data Meta-analysis)

Simple non-stratified Kaplan-Meier curves for trials of surgery (S) and chemotherapy (CT) vs. surgery

alone and for trials of surgery and chemotherapy and radiotherapy (RT) versus surgery and radiotherapy

1. This article was published in The Lancet 375, NSCLC Meta-analysis Collaborative Group, Adjuvant chemotherapy, with or without postoperative radiotherapy, in

operable non-small-cell lung cancer: two meta-analyses of individual patient data, 1267-77, Copyright Elsevier 2010; 2. Burdett S, et al., Cochrane Database of

Systematic Reviews 2015;2(3):CD011430. Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

THE CISPLATIN-BASED ADJUVANT

CHEMOTHERAPY META-ANALYSIS

+5.4% at 5 yr

Pignon JP, et al., J Clin Oncol 2008;26(21):3552-9. Reprinted with permission. © (2008) American Society of Clinical Oncology. All rights reserved.


WHICH STAGES?

1. Pignon JP, et al., J Clin Oncol 2008; 26(21):3552-9. Reprinted with permission. © (2008), American Society of Clinical Oncology. All rights reserved.

2. Reprinted from J Thorac Oncol 2010; 5, Douillard JY, Adjuvant Cisplatin and Vinorelbine for Completely Resected Non-small Cell Lung Cancer: Subgroup Analysis

of the Lung Adjuvant Cisplatin Evaluation, 220-228, Copyright 2010, with permission from Elsevier.

Overall survival1 Overall survival2

curves by stage for the cisplatin-vinorelbine vs. the

observation (no chemotherapy) groups

Interaction p=0.02

ADJUVANT CHEMOTHERAPY IN

STAGE IB NSCLC

Butts CA, et al., J Clin Oncol 2010; 28: 29-34. Reprinted with permission. © (2010) American Society of Clinical Oncology. All rights reserved.

Strauss GM, et al., J Clin Oncol 2008; 26(31):5043-51. Reprinted with permission. © (2008) American Society of Clinical Oncology. All rights reserved.


WHICH DRUGS? WHICH DOSES?

Pignon JP, J Clin Oncol 2008; 26(21):3552-9. Reprinted with permission. © (2008) American Society of Clinical Oncology. All rights reserved.

12 473 pts

US National cancer database

TIMING OF ADJUVANT

CHEMOTHERAPY

Salazar MC, et al., JAMA Oncol 2017;3(5):610-9.

3 976 propensity-match pairs:

HR=0.664 (95%CI:0.623-0.707)

p<0.001

>56 days vs. no chemotherapy

Covariate No. HR (95% CI) P Value

Adjuvant chemotherapy timing

Reference

interval (39-56 d)

5137 [Reference]

Earlier (<39 d) 3359 1.009 (0.944-1.080) 0.79

Later (>56 d) 3977 1.037 (0.972-1.105) 0.27

Cox proportional hazards model of patients who

underwent adjuvant chemotherapy

Restricted cubic spine modelling of the

relationship between time to initiation of

adjuvant chemotherapy and mortality risk

Days to initiation of adjuvant

chemotherapy

0

0.1

0.2

0.3

1.0

20 40 60 80 100 120

Lo

g h

azar

d r

atio

NEOADJUVANT CHEMOTHERAPY:

SURVIVAL RESULTS 1

Individual patient data Meta-analysis

NSCLC Meta-analysis Collaborative Group. Lancet 2014;383:1561–71. © 2014 NSCLC Meta-analysis Collaborative Group.

Open Access article distributed under the terms of CC BY 3.0. Published by Elsevier Ltd.

NEOADJUVANT CHEMOTHERAPY:

SURVIVAL RESULTS 2

13% reduction in the

relative risk of death

+ 5% at 5 years

Kaplan-Meier curves (non-stratified) of the effect of preoperative chemotherapy on time to survival



WHO SHOULD RECEIVE

NEOADJUVANT CHEMOTHERAPY?



Multi-centre phase 3 trial

Mar. 2006 ~ May 2011

Stratification:

Gender, centre, stage (IB vs.

II vs. IIIA), pathology (adeno

vs. non-adeno)

Objectives:

Primary endpoint: 3-yr DFS

Secondary endpoints: safety,

5-yr OS

Eligible Stage IB-IIIA

NSCLC

(n=214)

Randomly assigned

(n=198)

Neo-adjuvant arm (n=97) Adjuvant arm (n=101)

Chemotherapy (n=97) Surgery (n=101)

Surgery (n=82) Chemotherapy (n=86)

Stop for slow accrual

ADJUVANT VS. NEOADJUVANT

Yang X, et al., J Thoracic Oncol 2017;12(SMA Type 1):S141. Presented at WCLC 2016; 0A09.03.

Group N Events Median (95%CI) P

Adjuvant 101 52 5.2 (1.3–9.0)0.057

Neoadjuvant 97 67 2.3 (1.6–3.0)

ADJUVANT VS. NEOADJUVANT

No. at Risk

Adjuvant 101 63 54 51 49 49 49

Neoadj. 97 53 33 30 30 30 30

No. at Risk

Adjuvant 101 78 66 60 56 56 56

Neoadj. 97 70 51 38 38 38 38

DFS OS

Yang X, et al., J Thoracic Oncol 2017;12(S1):S141. Presented at WCLC 2016; 0A09.03.

Group N Events Median (95%CI) P

Adjuvant 101 45 7.30.087

Neoadjuvant 97 59 4.2 (3.2–5.2)

Time (years)

20

40

60

80

100

0

20 4 6 8 10 12

Ove

rall

surv

ival

(%

)

Hazard ratio (95% CI) = 0.71 (0.48–1.05)

Time (years)

20

40

60

80

100

0

20 4 6 8 10 12

Dis

ease

fre

e su

rviv

al (

%)

Hazard ratio (95% CI) = 0.70 (0.49–1.01)

ADJUVANT OR NEOADJUVANT

CHEMOTHERAPY VS. SURGERY

A meta-analysis

Reprinted from J Thorac Oncol 2009;4, Lim E, et al., Preoperative versus Postoperative Chemotherapy in Patients with Resectable Non-small Cell Lung Cancer: Systematic

Review and Indirect Comparison Meta-Analysis of Randomized Trials :1380-8. Copyright 2009, with permission from Elsevier.

ADJUVANT OR NEOADJUVANT?

Paclitaxel 200 mg/m² + carboplatin AUC 6 q3wk

Main objective: PFS at 5 yr chemotherapy vs. surgery

Felip E, et al., J Clin Oncol 2010; 28:3138-3145.

Phase III

624 patients

IA (>2 cm)

IB, II, T3N1

SurgeryArm 1:

N=212

Arm 2:

N=201

Arm 3:

N=211

R

Surgery

Pacli/Carbo

3 cyclesSurgery

Pacli/Carbo

3 cycles

ADJUVANT OR NEOADJUVANT?

COMPLIANCE

Trials At least 1 cycle 2 cycles 3 cycles 4 cycles

ALPI

IALT

ANITA

JBR10

NATCH adj

90%

92%

90%

95.5%

66%

ND

ND

72%

64%

ND

69%

ND

61%

55%

61%

NA

ND

50%

45%

NA

Depierre

NATCH neoadj

Gilligan

SWOG 9900

98%

97%

96%

ND

90%

ND

89%

ND

NA

90%

96%

79%

NA

NA

NA

NA

RESPECTIVE ADVANTAGES OF

(NEO)ADJUVANT CHEMOTHERAPY

Neoadjuvant Adjuvant

Level of evidence x

Staging x

Earlier delivery x

Compliance x

Evaluation of tumour response x

Research purposes

Tissue availability x









IN NSCLC

PREOPERATIVE CHEMORADIATION

FOR STAGE IIIA N2

HR=1.1 (95% CI=0.8-1.4); p=0.67

Reprinted from The Lancet, 386, Pless M, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial, 1049-56.

Copyright 2015, with permission from Elsevier.

Multicentre phase III

Pathologically proven

stage IIIAN2

1:1 randomisation

Cisplatin docetaxel

+/- sequential RT

(44 Gy / 22 F / 3 wk)

Primary endpoint:

event-free survival

PREOPERATIVE CHEMORADIATION

FOR STAGE IIIA N2:

OVERALL SURVIVAL

HR=1 (95% CI= 0.7-1.4)

Reprinted from The Lancet, 386, Pless M, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial, 1049-56.

Copyright 2015, with permission from Elsevier.









IN NSCLC

ADJUVANT GEFITINIB IN

ALL-COMERS (BR19)

Goss G, et al. J Clin Oncol 2013; 31:3320-26. Reprinted with permission © (2013) American Society of Clinical Oncology. All rights reserved.

Stage IB, II, IIIA completely resected

Trial prematurely closed

Gefitinib x 2 yr

ADJUVANT ERLOTINIB

IN ALL-COMERS

Kelly K, et al., J Clin Oncol 2015; 33:4007-14. Reprinted with permission © (2015) American Society of Clinical Oncology. All rights reserved.

Primary endpoint: DFS

Phase III trial

Adjuvant erlotinib

(2 yr) vs. placebo

pStage IB-IIIA

OS: HR=1.09

(95%CI=0.545-2.161)

p=.815

*Investigator Choice of 4 chemotherapy regimens

21-day cycles all with Cisplatin given at 75 mg/m2 on day 1

Cisplatin / Vinorelbine: 30 mg/m2 day 1, 8

Cisplatin / Docetaxel: 75 mg/m2 day 1

Cisplatin / Gemcitabine: 1200 mg/m2 day 1,8

Cisplatin / Pemetrexed: 500 mg/m2 day 1 (2009 amendment)

Bevacizumab 15 mg/kg IV q 3 weeks for up to 1 year

Primary endpoint: Overall survival

STRATIFIED:

1. Cisplatin Doublet*

2. Stage

3. Histology

4. Gender

Arm A:

Chemotherapy

x 4 cycles*ELIGIBLE:

Resected

Stage IB (>/= 4cm)-IIIA

6-12 weeks post-op

(AJCC 6th edition) Arm B:

Chemotherapy

x 4 cycles* +

Bevacizumab

x 1 year

ADJUVANT BEVACIZUMAB

Wakelee H, WCLC 2015: Plen 04-03.

R

1:1

ADJUVANT BEVACIZUMAB

OS hazard ratio (B:A): 0.99

95% CI: 0.81–1.21

p=0.93

DFS hazard ratio (B:A): 0.98

95% CI: 0.84–1.14

p=0.75

Wakelee H, et al., Presented at WCLC 2015: Plen 04-03. With permission from Professor Heather Wakelee.

Months from registration

0.2

0.4

0.6

0.8

1.0

0.0

120 24 36 48 60 72 84

Chemo (208 events/749 cases)

Chemo + bevacizumab (204 events/752 cases)

OS

pro

bab

ility

Months from registration

0.2

0.4

0.6

0.8

1.0

0.0

120 24 36 48 60 72 84

Chemo (338 events/749 cases)

Chemo + bevacizumab (334 events/752 cases)

DF

S p

rob

abili

ty

OS DFS









IN NSCLC

Resected stage I, II, IIIA NSCLC - 13 intramuscular injections in 27 months -

Primary endpoint: DFS

MAGE A-3 VACCINE

IN MAGE A-3+ NSCLC: DFS

Reprinted from The Lancet Oncology, 17, Vansteenkiste JF, et al., Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in

patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled,

phase 3 trial; 822-35. Copyright 2016, with permission from Elsevier.

MAGE A-3 VACCINE IN MAGE A-3+

NSCLC: OVERALL SURVIVAL

Reprinted from The Lancet Oncology, 17, Vansteenkiste JF, et al., Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in

patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled,

phase 3 trial; 822-35. Copyright 2016, with permission from Elsevier.

18 pts with resectable stage I–IIIA NSCLC

Nivolumab 3 mg/kg D-28&14, prior to surgery

Responses:

7 major pathologic response (<10% residual tumour)

1 complete pathologic response

13 stable disease

1 Grade 3–4 adverse event

No delay in surgery in any patient

Increased T cell infiltrate in responders

NEOADJUVANT NIVOLUMAB

Forde P, ESMO 2016: Abstract LBA41_PR

ONGOING PHASE III TRIALS OF

ADJUVANT CHECKPOINT

INHIBITORS

Drug (trial) Control Stages PD-L1 Primary

endpoint

Nivolumab

(ALCHEMIST/ANVL

– US NCI)

observation IB (4 cm) – IIIA,

after adjuvant chemo and/or

radiotherapy

all OS/DFS

Atezolizumab

(Impower 010)

placebo IB (4 cm) – IIIA, after adjuvant

chemo

all DFS

MEDI 4736

(international)


chemo

all DFS

Pembrolizumab

(Keynote 091 –

EORTC/ETOP)


chemo

all DFS









IN NSCLC

POSTOPERATIVE RADIOTHERAPY

Reprinted from Int. J. Radiation Oncology Biol. Phys., 2008; 72, Douillard JY, et al., Impact of Postoperative Radiation Therapy on Survival in Patients with Complete

Resection and Stage I, II, or IIIA Non-Small-Cell Lung Cancer treated with Adjuvant Chemotherapy: The Adjuvant Navelbine International Trialist Association (ANITA)

Randomized Trial, 695–701. Copyright 2008, with permission from Elsevier.

POSTOPERATIVE RADIOTHERAPY:

THE UPDATED META-ANALYSIS

Burdett S, et al., Cochrane Database Syst Rev. 2016;10:CD002142. Copyright © 2016 The Cochrane Collaboration.

Published by John Wiley & Sons, Ltd.

IPD meta-analysis

11 trials / 2343 pts

HR=1.18

18% relative increase in

risk of death

Absolute detriment: 5%

at 2 yr (95% CI=2-9%)

Reducing survival from

58 to 53%

POSTOPERATIVE RADIOTHERAPY

FOR STAGE III? FOR N2?

Postoperative radiotherapy may be detrimental in earlier stages

Burdett S, et al., Cochrane Database Syst Rev. 2016;10:CD002142. Copyright © 2016 The Cochrane Collaboration.

Published by John Wiley & Sons, Ltd.

LUNG ART IFCT05-03

Eligible:

Pre and/or postoperative

chemotherapy accepted

Primary endpoint:

Disease-free survival

433/500 pts included

Complete resection

Pathological N2

Arm A:

Control

Arm B:

Conformational

radiotherapy (54 Gy)

R

1:1









IN NSCLC

ERLOTINIB IN EGFR-MUT

IN RADIANT

NS due to hierarchical testing

OS immature

Kelly K, et al., J Clin Oncol 2015; 33:4007-14. Reprinted with permission © 2015 American Society of Clinicl Oncology. All rights reserved.

ONGOING EGFR TKI ADJUVANT

TRIALS IN EGFR-MUT PATIENTS

Trial Country EGFR TKI Control EGFR TKI

duration

ALCHEMIST USA Erlotinib

Crizotinib

(for ALK+)

Placebo 2 yr

IMPACT WJOG 6401L Japan gefitinib Cisplatin

vinorelbine x4

2 yr

C-TONG 1104 China gefitinib Cisplatin

vinorelbine x4

2 yr

NCT02125240 without adjuvant

chemo

China Icotinib Placebo 6-12 months

NCT01996098

(after 4 cycles of adjuvant

platinum-based chemo)

China Icotinib observation 6-12 months

Neoadjuvant and adjuvant chemotherapy increase survival in resectable NSCLC:

Comparable effectiveness of +5% at 5 years

Adjuvant chemotherapy:

Stage II-III, IB ≥4 cm

Best evidence for cisplatin-vinorelbine

Cisplatin ≥300 mg/m2

CONCLUSIONS:

PERIOPERATIVE CHEMOTHERAPY

Preoperative radiotherapy does not add to preoperative chemotherapy

in stage IIIA N2

Postoperative radiotherapy can be delivered in pN2 disease

CONCLUSIONS:

PERIOPERATIVE RADIOTHERAPY

No indication for targeted therapies in wild-type EGFR

Activity of EGFR and ALK TKIs to be demonstrated in EGFRmut/ALK+ NSCLC

Activity of immune checkpoint inhibitors to be demonstrated

CONCLUSIONS:

NEW TREATMENTS

THANK YOU!

esmo e-learning perioperative treatment of non-small cell ......salazar mc, et al., jama oncol...

Documents