PERIOPERATIVE TREATMENT OF NON SMALL CELL LUNG CANCER. Virginie Westeel Chest Disease Department University Hospital Besançon, France

PERIOPERATIVE TREATMENT OF NON SMALL CELL LUNG CANCER Virginie Westeel Chest Disease Department University Hospital Besançon, France

LEARNING OBJECTIVES 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

PERIOPERATIVE TREATMENTS IN NSCLC In EGFR wild-type NSCLC Perioperative chemotherapy Preoperative chemoradiation Perioperative targeted treatments Perioperative immunotherapy Postoperative mediastinal radiotherapy In EGFR mutated NSCLC

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 HR 0.86 (95% CI 0.81, 0.92; p<0.00011) 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.

ADJUVANT CHEMOTHERAPY: WHICH STAGES? Overall survival 1 Overall survival 2 curves by stage for the cisplatin-vinorelbine vs. the observation (no chemotherapy) groups 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.

ADJUVANT CHEMOTHERAPY IN STAGE IB NSCLC Interaction p=0.02 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.

Log hazard ratio TIMING OF ADJUVANT CHEMOTHERAPY 12 473 pts US National cancer database 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 1.0 Covariate No. HR (95% CI) P Value 0.3 Adjuvant chemotherapy timing Reference interval (39-56 d) 5137 [Reference] 0.2 Earlier (<39 d) 3359 1.009 (0.944-1.080) 0.79 0.1 Later (>56 d) 3977 1.037 (0.972-1.105) 0.27 3 976 propensity-match pairs: HR=0.664 (95%CI:0.623-0.707) p<0.001 >56 days vs. no chemotherapy 0 20 40 60 80 100 120 Days to initiation of adjuvant chemotherapy Salazar MC, et al., JAMA Oncol 2017;3(5):610-9.

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 Kaplan-Meier curves (non-stratified) of the effect of preoperative chemotherapy on time to survival 13% reduction in the relative risk of death + 5% at 5 years 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.

WHO SHOULD RECEIVE NEOADJUVANT CHEMOTHERAPY? 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.

ADJUVANT VS. NEOADJUVANT Neo-adjuvant arm (n=97) Chemotherapy (n=97) Surgery (n=82) Eligible Stage IB-IIIA NSCLC (n=214) Randomly assigned (n=198) Adjuvant arm (n=101) Surgery (n=101) Chemotherapy (n=86) 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 Stop for slow accrual Yang X, et al., J Thoracic Oncol 2017;12(SMA Type 1):S141. Presented at WCLC 2016; 0A09.03.

Disease free survival (%) Overall survival (%) ADJUVANT VS. NEOADJUVANT DFS OS 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) Group N Events Median (95%CI) P Adjuvant 101 45 7.3 0.087 Neoadjuvant 97 59 4.2 (3.2 5.2) 100 Hazard ratio (95% CI) = 0.70 (0.49 1.01) 100 Hazard ratio (95% CI) = 0.71 (0.48 1.05) 80 80 60 60 40 40 20 20 0 0 2 4 6 8 10 12 Time (years) No. at Risk Adjuvant 101 63 54 51 49 49 49 Neoadj. 97 53 33 30 30 30 30 0 0 2 4 6 8 10 12 Time (years) No. at Risk Adjuvant 101 78 66 60 56 56 56 Neoadj. 97 70 51 38 38 38 38 Yang X, et al., J Thoracic Oncol 2017;12(S1):S141. Presented at WCLC 2016; 0A09.03.

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? Phase III Arm 1: N=212 Surgery 624 patients IA (>2 cm) R Arm 2: N=201 Pacli/Carbo 3 cycles Surgery IB, II, T3N1 Arm 3: N=211 Surgery Pacli/Carbo 3 cycles 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.

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 Staging Earlier delivery Compliance Evaluation of tumour response Research purposes Tissue availability x x x x x x

PREOPERATIVE CHEMORADIATION FOR STAGE IIIA N2 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 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.

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.

ADJUVANT GEFITINIB IN ALL-COMERS (BR19) Stage IB, II, IIIA completely resected Trial prematurely closed Gefitinib x 2 yr Goss G, et al. J Clin Oncol 2013; 31:3320-26. Reprinted with permission (2013) American Society of Clinical Oncology. All rights reserved.

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

ADJUVANT BEVACIZUMAB *Investigator Choice of 4 chemotherapy regimens 21-day cycles all with Cisplatin given at 75 mg/m 2 on day 1 Cisplatin / Vinorelbine: 30 mg/m 2 day 1, 8 Cisplatin / Docetaxel: 75 mg/m 2 day 1 Cisplatin / Gemcitabine: 1200 mg/m 2 day 1,8 Cisplatin / Pemetrexed: 500 mg/m 2 day 1 (2009 amendment) Bevacizumab 15 mg/kg IV q 3 weeks for up to 1 year Primary endpoint: Overall survival Arm A: Chemotherapy x 4 cycles* ELIGIBLE: STRATIFIED: Resected 1. Cisplatin Doublet* Stage IB (>/= 4cm)-IIIA 2. Stage R 6-12 weeks post-op 3. Histology (AJCC 6 th edition) Arm B: 4. Gender 1:1 Chemotherapy x 4 cycles* + Bevacizumab x 1 year Wakelee H, WCLC 2015: Plen 04-03.

OS probability DFS probability ADJUVANT BEVACIZUMAB OS DFS 1.0 OS hazard ratio (B:A): 0.99 95% CI: 0.81 1.21 p=0.93 1.0 DFS hazard ratio (B:A): 0.98 95% CI: 0.84 1.14 p=0.75 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.0 Chemo (208 events/749 cases) Chemo + bevacizumab (204 events/752 cases) 0.2 0.0 Chemo (338 events/749 cases) Chemo + bevacizumab (334 events/752 cases) 0 12 24 36 48 60 72 84 Months from registration 0 12 24 36 48 60 72 84 Months from registration Wakelee H, et al., Presented at WCLC 2015: Plen 04-03. With permission from Professor Heather Wakelee.

MAGE A-3 VACCINE IN MAGE A-3+ NSCLC: DFS Resected stage I, II, IIIA NSCLC - 13 intramuscular injections in 27 months - Primary endpoint: 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.

NEOADJUVANT NIVOLUMAB 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 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) Atezolizumab (Impower 010) MEDI 4736 (international) Pembrolizumab (Keynote 091 EORTC/ETOP) observation placebo placebo placebo IB (4 cm) IIIA, after adjuvant chemo and/or radiotherapy IB (4 cm) IIIA, after adjuvant chemo IB (4 cm) IIIA, after adjuvant chemo IB (4 cm) IIIA, after adjuvant chemo all all all all OS/DFS DFS DFS DFS

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 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% Burdett S, et al., Cochrane Database Syst Rev. 2016;10:CD002142. Copyright 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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 Complete resection Pathological N2 Eligible: Pre and/or postoperative chemotherapy accepted Primary endpoint: Disease-free survival 433/500 pts included R 1:1 Arm A: Control Arm B: Conformational radiotherapy (54 Gy)

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 IMPACT WJOG 6401L Japan gefitinib Cisplatin vinorelbine x4 C-TONG 1104 China gefitinib Cisplatin vinorelbine x4 NCT02125240 without adjuvant chemo NCT01996098 (after 4 cycles of adjuvant platinum-based chemo) 2 yr 2 yr 2 yr China Icotinib Placebo 6-12 months China Icotinib observation 6-12 months

CONCLUSIONS: PERIOPERATIVE CHEMOTHERAPY 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/m 2

CONCLUSIONS: PERIOPERATIVE RADIOTHERAPY Preoperative radiotherapy does not add to preoperative chemotherapy in stage IIIA N2 Postoperative radiotherapy can be delivered in pn2 disease

CONCLUSIONS: NEW TREATMENTS 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

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