ENFERMEDAD LOCALMENTE AVANZADA: Estado del Arte y Eventual Papel de las Nuevas Terapias. Dolores Isla H. Clínico Universitario Lozano Blesa ZARAGOZA

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1 ENFERMEDAD LOCALMENTE AVANZADA: Estado del Arte y Eventual Papel de las Nuevas Terapias Dolores Isla H. Clínico Universitario Lozano Blesa ZARAGOZA Formigal, 28 de Junio de 2018

2 CÓMO DEFINÍAMOS EL ESTADIO III DE CPNM? DIFÍCIL ABURRIDO

3 INTRODUCTION OUTLINE STANDARD TREATMENT: SURGERY RT CT TARGETED THERAPY IMMUNOTHERAPY CONCLUSIONS

4 INTRODUCTION

5 INTRODUCTION HETEROGENEITY: Tumor histopathology Tumor location / extension Patient risk profile: comorbidities, age, PS, weight loss Inter-institution diversity: EXPERTISE!! STAGING: stage migration / multiple subgroups / different treatment options OPTIMAL DIAGNOSTIC WORK-UP: PET-CT Mediastinal staging Brain image DIFFERENT STRATEGIES: Few head-to-head studies Optimal drug and duration undefined

6 MULTIDISCIPLINARY MANAGEMENT

7 8 th Edition of TNM Staging System

8 RESECTABLE UNRESECTABLE Ann Oncol 2017

9 STANDARD TREATMENT

10 1) POTENTIALLY RESECTABLE STAGE III DISEASE INTRAOPERATIVE / PREOPERATIVE DIAGNOSIS OF N2: Surgery followed by Adjuvant CT +/- RT Induction CT/CT-RT to Surgery: One mediastinal node / No bulky / Downstaging / No pneumonectomy CT-RT with better local control but similar PFS / OS Definitive Concurrent CT-RT: N2 multistation-bulky Postmus P, Ann Oncol 2017 Santana-Davila R, JOP 2016 Guo SX, Sci Rep 2016

11 OS was not significantly different between Surgical and definitive RT arms Further research on predictive factors supporting individual therapy selection

12 1) POTENTIALLY RESECTABLE STAGE III DISEASE SUPERIOR SULCUS TUMOUR / SELECTED T3-T4 CENTRAL TUMOURS: Induction CT-RT to Surgery INDUCTION CT: Platinum-based, preferably Cisplatin Multidisciplinary Team: VERY IMPORTANT Postmus P, Ann Oncol 2017 Santana-Davila R, JOP 2016

13 2) UNRESECTABLE STAGE III DISEASE CONCURRENT DEFINITIVE CT-RT: Fit Patients SEQUENTIAL CT-RT: UnFit / Elderly Patients Postmus P, Ann Oncol 2017 Santana-Davila R, JOP 2016

14 Increased acute esophageal toxicity G3-4 from 4% to 18% Auperin A, JCO 2010

15 OPTIMAL CHEMOTHERAPY for Concurrent CT-RT Based on Cisplatin Regimen: cisplatin + etoposide / vinorelbine / pemetrexed, carbo + paclitaxel.. : similar results Factors to select: Histology Toxicity Length of treatment Cost Number of cycles: 2-4 cycles, No evidence of Induction or Consolidation CT Postmus P, Ann Oncol 2017 Santana-Davila R, JOP 2016

16 PROCLAIM Study PE vs Carbo/PAC NEGATIVE, Less neutropenia G3 Senan S, JCO 2016 Santana-Davila R, JCO 2015

17 BETTER SAFETY PROFILE FOR OVNR ARM Phase II NORA Study (GECP): Oral VNR with Metronomic approach

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19 OPTIMAL RADIOTHERAPY Dose: Gy / fractions (74 Gy vs 60 Gy in RTOG 0617 Study was detrimental 1 ) Gy as Induction CT-RT Investigational Areas : Accelerated RT: sequential or RT alone, promising? (No Phase III studies) Proton / Carbon-ion RT-CT 2 : less toxicity?, RTOG 1308 Study (60 vs 74 Gy) IMRT: to protect normal tissues, RTOG (less pneumonitis, better QoL) Adaptive RT: PET to personalize treatment, RTOG 0116 Study (60 vs 80 Gy) SBRT 4 : a tool to increase RT dose NEGATIVE Postmus P, Ann Oncol 2017 Santana-Davila R, JOP Bradley J, Lancet Oncol Chang J, JAMA Oncol Movsas B, JAMA Oncol Tekati H, JTO 2016

20 PCI There is currently NO role Postmus P, Ann Oncol 2017 Santana-Davila R, JOP 2016

21 Proportion brain-metastases free Survival probability PCI vs Observation in Radically Treated Stage III NSCLC: A R Phase III NVALT11 Study Time to symptomatic BMs OS Median, NEGATIVE Observation HR 0.25 (95%CI ), p=0.001 PCI Follow-up time, months PCI increased time to symptomatic brain mets but had no effect on OS Worse Toxicity and QoL months 95%CI PCI , 38.7 Observation , 33.7 p=0.52 PCI Observation Follow-up time, months De Ruysscher D, JCO 2018

22 TARGETED THERAPY

23 INVESTIGATIONAL DRUGS Veliparib Olaparib

24 TARGETED THERAPY Unselected Patients: Negative results: Gefitinib (SWOG 0023 Study) Cetuximab (RTOG 0617 Study) Veliparib Selumetinib Selected Patients: Ongoing Trials Erlotinib / Crizotinib (RTOG 1306 Study) Afatinib (ASCENT Trial)

25 IMMUNOTHERAPY

26 Newly diagnosed resectable stage I (>2cm)/II/IIIA NSCLC Nivolumab 3mg/kg IV (Day -14 & Day -28) Surgical resection (Day 0) Standard of care postoperative treatment RECIST* N(%) PR 2 (10%) Stable Disease 18 (85%) PD 1 (5%) 45% of resected tumors demonstrated a Major Pathologic Response TMB was predictive of pcr Treatment induced expansion of mutationassociated, neoantigenspecific T-cell clones in peripheral blood 2018

27 N=46 p. NADIM Study

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29 ASCO 2018

30 ARGUMENTS TO COMBINE RT + IMMUNOTHERAPY Release of neoantigens Up-regulation of PD-L1 on tumor cells Recruitment of T-cells to the tumor bed Neutralization of the immunosuppresive effects of tumor microenvironment Efficacy should be weighed against toxicities, especially radiation pneumonitis Vatner RE, Front Oncol 2014 Kordbacheh T, Ann Oncol 2018 Tang C, Cancer Immunol Res 2014

31 Melero I, Nat Rev Cancer 2015

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33 Antonia S, NEJM 2017

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37 Baseline Scores for Key Symptoms, Physical Function and Global Health Status/QoL High compliance (>80%) in completion of the questionnaires up to Week 48 No differences between arms at baseline for key symptoms, physical function or global health status/qol Higher scores indicate greater symptom severity Higher scores indicate better health status Hui R, WCLC 2017

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41 NICOLAS Study

42 NICOLAS Study ASCO 2018

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44 Durn G, ASCO 2018

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47 R A N D O M I Z E 2:1 ALLIANCE FOUNDATION TRIAL (AFT-16) Phase II/III trial of induction immunotherapy with atezolizumab for patients with unresectable stage IIIA and IIIB NSCLC eligible for chemoradiotherapy with curative intent and whose tumors express PD-L1 Phase III Objectives and Endpoints: 1. Primary endpoint: OS 2. Secondary endpoint: PFS, safety, QoL Chemo/RT + Consolidation Adjuvant Immunotherapy NSCLC Stage IIIA & IIIB PDL1+ Induction Immunotherapy Atezolizumab 1200 mg IV q3w X 4 cycles CT/RT + Consolidation CT Alliance Standard Chemo/RT* regimen Alliance Standard Chemo Consolidation Atezolizumab 1200 mg q3w for 1 year *Chemo/RT= carboplatin (AUC2) + paclitaxel 50 mg/m2 IV weekly x6 cycles +60 Gy qd x 30fxn Consolidation chemotherapy = carboplatin AUC6 + paclitaxel 200 mg/m2 IV q21 days x 2 cycels ORR=objective response rate; PD=progressive disease; RT=radiotherapy; QoL=quality of life

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49 CONCLUSIONS

50 Stage III NSCLC remains a Heterogeneus Disease Concurrent CT-RT is Standard treatment but not always in clinical practice: FIT PATIENTS Therapeutic plateau reached regarding CT with RT: 5-ys OS 30-35% No role for available Targeted Agents yet IMMUNOTHERAPY offers now a POSITIVE Phase III study (PACIFIC): First step after many years... PFS & OS + Toxicity no relevant Other studies ongoing: neodjuvant setting Need of more INDIVIDUALIZED THERAPIES: clinical factors / biomarkers.. MULTIDISCIPLINARY and EXPERT TEAM?

51 Gracias