Thoracic Oncology Division, IEO, Milan, Italy Filippo de Marinis Thoracic Oncology Division, IEO, Milan, Italy

Driver, TT= 3.5 ys Driver, NO TT= 2.4 ys NO driver= 2.1 ys M Kris et al, JAMA 2014

H Beltran et al, JAMA Oncol 2015

SL Wood et al, Cancer Treat Reviews 2015

ONCOGENIC DRIVERS IN LUNG ADENOCARCINOMA Incidence Difference between China And Usa

M Juchum et al, Drug Resistance Updates 2015

A Russo et al , Oncotarget 2015

Benefit of 1st-line EGFR TKIs: 9 randomized phase III studies Study Ref. TKI CTx N # PFS mos HR 95% CI OS mos IPASS Mok NEJM 2009 gefitinib Cb/Pac 261 9.5 vs. 6.3 0.48 0.36 – 0.64 21.6 vs. 21.9 First-signal Han JCO 2012 Cis/Gem 42 8.0 vs. 6.3 0.54 0.26-1.10 27.2 vs. 25.6 NEJ002 Maemondo NEJM 2010 194 10.8 vs. 5.4 0.35 0.22-0.41 30.5 vs. 23.6 WJTOG 3405 Mitsudomi Lancet 2010 Cis/Doc 172 9.2 vs. 6.3 0.49 0.33-0.71 30.9 vs NR OPTIMAL Zhou Lancet Oncol 2011 erlotinib 164 13.1 vs. 4.6 0.16 0.10-0.26 Not mature EURTAC Rosell Lancet Oncol 2012 P/Doc or Gem 174 10.4 vs 5.1 0.34 0.23-0.29 19.3 vs 19.5 ENSURE Wu P WCLC 2013 P/ Gem 217 11.0 vs. 5.6 0.42 0.27-0.66 LUX-LUNG 3 Sequist JCO 2014 afatinib Cis/Pem 308 13.6 vs. 6.9 0.47 0.34-0.65 31.5 vs 28.3 LUX-LUNG 6 Lancet Oncol 2014 364 0.28 0.20-0.39 23.6 vs. 23.5

9.5 mos 6.3 mos T Mok et al, NEJM 2009

First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study PFS OS J-Y Douillard et al. BJC, 2014

GEFITINIB IN EGFR MUT+ FIRST IT HAS CHANGED THE «PARADIGM» OF TREATMENT CHEMO-BASED, BEING LINKED THEREFORE TO THE INNOVATIVE DISCOVERY OF EGFR MUTATION

PFS NOT assessed by IRC C Zhou et al, Lancet Oncology 2011

PFS assessed by IRC Y Wu et al, P WCLC 2013

R Rosell..F de Marinis et al, Lancet Oncology 2012

F de Marinis…R Rosell et al, Future Oncology 2015

ERLOTINIB IN EGFR MUT+ THIS WAS THE FIRST TKI REGISTERED IN EU AND US WITH A PHASE III EUROPEAN (ITALY INCLUDED) TRIAL ON CAUCASIAN RACE

AFATINIB RESULTS IN LUX-LUNG 3 & 6 TRIALS Sequist L et al, J Clin Oncol 2013, Wu Y et al, Lancet Oncol 2014

L Sequist et al, JCO 2013

Yang JC et al, Lancet Oncol 2015

Yang JC et al, Lancet Oncol 2015

AFATINIB in EGFR MUT+ THIS HAS BEEN THE FIRST TKI TO OBTAIN A PFS > 13 MS IN TWO RANDOMIZED TRIALS AND THE ONLY ONE SHOWING MORE EFFICACY vs CHEMO FOR EXON 19 IN A SUBGROUP ANALYSIS

CK Lee et al, JCO 2015

EGFR TKIs IN COMPARISON DOES THE GOLD STANDARD EXIST ?

ER Haspinger et al, CROH 2015

B Haaland et al, JTO 2014

THE IMPACT OF FIRST-LINE TYROSINE KINASE INHIBITORS ON OVERALL SURVIVAL IN PATIENTS WITH A-NSCLC AND ACTIVATING EGFR MUTATIONS: META-ANALYSIS OF PHASE III TRIALS BY MUTATION TYPE (DEL19 OR L858R) T Kato …F de Marinis et al, The Oncologist 2015 (in press)

EFFICACY vs TOLERABILITY Toxicity

STATISTICALLY SIGNIFICANT = CLINICALLY SIGNIFICANT ? IPASS EURTAC LUX-L3 GEFINITIB ERLOTINIB AFATINIB VS VS NO

JJ Yang et al, Lung Cancer 2013

A Matikas et al, Lung Cancer 2015

LOCAL THERAPY IN AR at MSKCC 18/184 pts/7+ yrs underwent local therapy for extracranial PD CNS PD excluded From time of local therapy: Median TTP: 10 months Median time to new systemic Rx: 22 months Median OS: 41 months Yu et al, ASCO 2012, Abst#7527

ALGHORITM for TREATMENT of EGFR MUT+ve TKI Resistance NSCLC EGFR Mut+ve responder to TKI Oligo-Progression Systemic 1st Progression Systemic PD Systemic 2nd-line therapy Local therapy + continuation of TKI 3rd gen. TKI Targeting the resistant gene Irreversible/pan HER TKI Chemo

ASPIRATION TRIAL RESULTS K Park et al, P ESMO 2014

Q Chen et al, Oncotarget 2015

Chairmen F. de Marinis C. Gridelli Panelists F. Cappuzzo F. Ciardiello F. Hirsch T. Mok R. Rosell D. Spigel J. Yang

T Mok et al, P ASCO 2013

DIRECT COMPARISON: LUX Lung 7 Randomized explorative phase IIb Study Mutations de l’EGFR Sample size Increased to 319 Complete accrual on Aug 16 2013

M Takeda et al, Lung Cancer 2015

W Liang et al, PLOS One 2014

IS TOXICITY A REAL DRIVER FOR PATIENTS SELECTION? Efficacy Toxicity NO

N-H TOXICITY ACROSS THE TKIs REGISTRATION TRIALS Symptom LUX-LUNG 6 1 LUX-LUNG 3 2 EURTAC 3 IPASS 4 Afatinib 40 n = 239 (%) Afatinib 40 n = 229 (%) Erlotinib 150 n= 84 (%) Gefitinib 250 n= 132* (%) All Gr Gr ≥3 Gr≥ 3 Diarrhoea 88.3 5.4 95.2 14.4 57.0 5.0 46.6 3.8 Rash/acne 80.8 14.6 89.1 16.2 80.0 13.0 66.2 3.1 Stomatitis/ mucositis 51.9 72.1 8.3 NR 17.0 0.2 Paronychia 32.6 - 56.8 11.4 13.5 0.3 1Y Wu et al, P ASCO 2013; 2Yang et al, P ASCO 2012; 3Rosell et al, Lancet Oncol 2012; 4Mok et al, NEJM 2009; * Toxicity is referred to total 607 pts

M Takeda et al, Lung Cancer 2015

JC Yang et al, JCO 2013

incidences and trends of toxicities with different TKIs A Passaro…F de Marinis et al. CLC, 2014

F de Marinis …R Rosell et al, Future Oncology 2015

ALGORITHM: DOSE MODIFICATION DUE TO TREATMENT-RELATED DERMATOLOGIC AEs Proactive management Grade 1 or tolerable grade 2 skin reaction Grade ≥3 or intolerable grade 2 Refer to dermatologist or continue dermatologic treatment Use alcohol-free skin products Minimise exposure to the sun Use protective clothing/hat Use sunscreen with a high protection factor and UVA/UVB protection Avoid any perfume or perfume- based skin products Initiate dermatologic treatment CONTINUE TKI AT CURRENT DOSE INTERRUPT UNTIL GRADE 0/1 1. Resume treatment with dose reduction by 10-mg decrements 2. If patient cannot tolerate 20 mg/day, permanent discontinuation should be considered According to CTCAE Version 3.0 Lacouture et al. Expert Rev Anticancer Ther. 2013

F de Marinis …R Rosell et al, Future Oncology 2015

J Yang… F de Marinis et al, ASCO 2015

J Yang… F de Marinis et al, ASCO 2015

! TOXICITY BECOME A DRIVER WHEN… Efficacy … efficacy don’t confirm the Oncologist expectations

Takezawa et al, Cancer Discovery 2012

A Matikas et al, Clin Lung Cancer 2015

EGFR mut associated with EGFR TKI sensitivity Stage IIIB/IV NSCLC EGFR mut associated with EGFR TKI sensitivity Not PD ≥6 months after EGFR TKI PD while on EGFR TKI or within 30 days of ceasing EGFR TKI¶ ECOG PS 0–2 Expand MTD: afatinib + cetuximab (n=100 ± T790M+) Afatinib 40 + cetuximab 250-500 (escalating dose cohorts) YY Janjigian et al, P ESMO 2012

DIFFERENT SEQUENCE HYPOTHESIS… First-line Second-line Gefitinib AZD9291 Erlotinib AZD9291 Afatinib AZD9291 ? ? T790M

COMBO ?

T Seto et al, Lancet, 2014

PFS by EGFR mutation type T Seto et al, Lancet, 2014

ETOP 2-11 BELIEF: An open-label multicenter phase II trial Screening and Registration Phase Treatment and Evaluation Phase Procedures at Progression Eligible and EGFR ex 19 del or L858R mutations Translational research study subprojects 150 mg erlotinib daily and 15 mg/kg bevacizumab every 3 weeks until progression or unacceptable toxicity Substudy 1: T790M present (n=35) Substudy 2: T790M absent (n=67) Tumor gene expression array Plasma EGFR mutation monitoring Recommendation for rebiopsy Tumor rebiopsy, gene expression array and mutation analysis EVERYWHERE, we use a color code for easy reading: ALL pts is black, T790M positive is RED, T790M negative is BLUE (in the plots too) ETOP 2-11 BELIEF | 18th ECCO – 40th ESMO European Cancer Congress, September 2015

ETOP 2-11 BELIEF: Erlotinib and bevacizumab in EGFR mutated non-small cell lung cancer ETOP 2-11 BELIEF | 18th ECCO – 40th ESMO European Cancer Congress, September 2015

BEVERLY Study design R Control arm Erlotinib 150 mg orally once daily Experimental arm Bevacizumab 15 mg/kg iv every 21 days NSCLC Non-squamous Activating EGFR mutation Stadio IIIB o IV PS 0-2 R 1:1 Treatment in both arms will be given until disease progression or unacceptable toxicity or patient’s or physician’s motivated decision to stop Strata: PS (0-1 vs 2) Type of mutation (exon19 del vs 21 L858R mut vs others) Primary endpoints: investigator-assessed and blinded, indipendent centrally-reviewed PFS Sample size: 200 pts Centres involved: about 60 Principal Investigator: C Gridelli