Il Paziente senza target Grande Lung Slam Roma, 9 Ottobre 2015 Il Paziente senza target Francesco Grossi U.O.S. Tumori Polmonari IRCCS Azienda Ospedaliera Universitaria San Martino IST Istituto Nazionale per la Ricerca sul Cancro Genova

Interlinking factors to guide personalized therapy in caucasian NSCLC patients 80% of patients Clinical Factors Histologic Factors Molecular Factors 20% of patients

ASCO practice guideline update (1/2) Masters GA, JCO 2015

ASCO practice guideline update (2/2) Masters GA, JCO 2015

Old algorithm for the therapy of advanced NSCLC Proposed treatment algorithm EGFR mutation positive or ALK fusion positive Molecular Good PS Clinical (PS) Poor PS EGFR TKIs or Crizotinib Nonsquamous Histologic Squamous Single-agent chemotherapy Bevacizumab eligible First line Clinical Bevacizumab ineligible Platinum/pemetrexed (or other*) ± bevacizumab Platinum/pemetrexed (or other*) Platinum/gemcitabine (or other*) End of first-line chemotherapy Maintenance Bevacizumab or erlotinib or pemetrexed Pemetrexed or erlotinib Erlotinib Based on prior therapy Progression Second line Chemotherapy by algorithm Based on prior therapy Based on prior therapy Based on prior therapy *Docetaxel, paclitaxel, or vinorelbine. Adapted from Gandara DR, Clin Lung Cancer 2009

Biomarker-unselected non-squamous NSCLC in the real life Present/Future algorithms: Cisplatin + Pemetrexed  Pemetrexed (maintenance)  Docetaxel + Nintedanib/Erlotinib/Nivolumab (IInd line)  Erlotinib/Nivolumab (IIIrd line)  Erlotinib/ Nivolumab (IVth line) Carboplatin + Paclitaxel + Bevacizumab  Bevacizumab (maintenance)  Pemetrexed/ Erlotinib/Docetaxel+Nintedanib/Nivolumab (IInd line)  Erlotinib/Nivolumab (IIIrd line)  Erlotinib/ Nivolumab (IVth line)

Biomarker-unselected squamous NSCLC in the real life Present/Future algorithm: Cisplatin + Gem/VNR/Taxanes  Nivolumab/ Docetaxel/Erlotinib (IInd line) Erlotinib/Nivolumab (IIIrd line)  Erlotinib/Nivolumab (IVth line)

Biomarker-unselected non-squamous NSCLC in the real life Present/Future algorithms: Cisplatin + Pemetrexed  Pemetrexed (maintenance)  Docetaxel + Nintedanib/Erlotinib/Nivolumab (IInd line)  Erlotinib/Nivolumab (IIIrd line)  Erlotinib/ Nivolumab (IVth line) Carboplatin + Paclitaxel + Bevacizumab  Bevacizumab (maintenance)  Pemetrexed/ Erlotinib/Docetaxel+Nintedanib/Nivolumab (IInd line)  Erlotinib/Nivolumab (IIIrd line)  Erlotinib/ Nivolumab (IVth line)

JMDB: OS in non-squamous & squamous patients Scagliotti G, JCO 2008

Continuation maintenance: Continuation (PARAMOUNT) or switch (JMEN) maintenance with pemetrexed: OS Continuation maintenance: PARAMOUNT Switch maintenance: JMEN 13.9 mos vs 11.0 mos (+2.9mos) 16.9 mos vs 14 mos (+2.9mos) 13.4 mos vs 10.6 mos (+2.8mos) 16.5 mos vs 13.9 mos (+2.6mos)

Association between TS and efficacy of pemetrexed: PFS & OS Wang T, PLOS ONE 2013

A better clinical outcome with pemetrexed/cisplatin in low TS only Sun JM, J Clin Oncol 2015

E4599: Bevacizumab-based therapy until progression increases OS Sandler A, JTO 2010 & NEJM 2006

Efficacy of first-line regimens: pre-planned OS & PFS analyses in adenocarcinoma patients 1. Scagliotti G, Oncologist 2009 2. Sandler A, JTO 2010

PRONOUNCE: Study Design Randomized, open-label, phase III superiority study conducted in US Pemetrexed 500 mg/m2, Carboplatin AUC 6 (Pem+Cb) Paclitaxel 200 mg/m2, Carboplatin AUC 6, Bevacizumab 15 mg/kg (Pac+Cb+Bev) Induction Phase q21d, 4 cycles Maintenance Phase q21d until PD Bev-Eligible Population Inclusion: - Chemo-naïve patients - PS 0/1 - Stage IV, nonsquam - Stable treated CNS mets Exclusion: - Uncontrolled effusions Pemetrexed (folic acid & vitamin B12) + Carboplatin Pemetrexed (folic acid & vitamin B12) R 1:1 180 patients each Paclitaxel + Carboplatin + Bevacizumab Bevacizumab Stratified for: PS (0 vs 1); gender (M vs F); disease stage (M1a vs M1b) Zinner RG, JTO 2015 15

PRONOUNCE Zinner RG, JTO 2015

PointBreak: study design Randomized, open-label, phase III superiority study conducted in US Pemetrexed 500 mg/m2; Carboplatin AUC 6; Bevacizumab 15 mg/kg Paclitaxel 200 mg/m2; Carboplatin AUC 6; Bevacizumab 15 mg/kg Induction Phase q21d, 4 cycles Maintenance Phase q21d until PD Inclusion: - No prior systemic therapy for lung cancer - PS 0/1 - Stage IIIB-IV NS-NSCLC - Stable tx’t brain mets Exclusion: Peripheral neuropathy > Gr 1 - Uncontrolled pleural effusions Pemetrexed (folic acid & vitamin B12 ) + Carboplatin + Bevacizumab Pemetrexed (folic acid & vitamin B12 ) + Bevacizumab R 1:1 450 patients each Paclitaxel + Carboplatin + Bevacizumab Bevacizumab Stratified for: PS (0 vs 1); sex (M vs F); disease stage (IIIB vs IV); measurable vs nonmeasurable disease Patel JD, JCO 2013 17

PointBreak: PFS and OS from randomization (ITT) Patel JD, JCO 2013

Primary endpoint Overall Survival ECOG 5508: Schema Bevacizumab IIIB/IV NSCLC PS0/1 No Prior Tx N=1495 R A N D M I Z E Carboplatin Paclitaxel Bevacizumab X 4 cycles CR PR SD N=897 Pemetrexed Bevacizumab Pemetrexed Stratification Factors: Smoking status, Gender Histology, Best response, Stage Primary endpoint Overall Survival Status: Accrual completed April 2015 http://www.clinicaltrial.gov/ct2/show/NCT01107626.

AvaALL: bevacizumab continued beyond progression in NSCLC Primary endpoint: OS Stage IIIB/IV non-squamous NSCLC treated with platinum- doublet (4–6 cycles) + bevacizumab PLUS > 2 cycles of bevacizumab maintenance SOC2* + bevacizumab SOC3‡ + bevacizumab SOC4 ± bevacizumab Randomise 1:1 PD1 PD2 PD3 SOC2* SOC3‡ SOC4 Enroll n=600 Graphical elaboration from text data Primary endpoint: OS Secondary endpoints include PFS, safety, QoL and biomarker analysis *SOC2: labelled agents for second-line treatment of NSCLC ‡SOC3 and beyond: choice of labelled agents is the investigator’s choice Gridelli C, Clin Lung Cancer 2011

Trials with PD-1 Inhibitors Added to E4599 Backbone Arm 1 - Control Carbo/Paclitaxel + Bevacizumab Untreated Non-squamous Stage IV NSCLC Arm 2 Carbo/Paclitaxel + Bevacizumab + PD-1 Inhibitor Atezolizumab: carbo/paclitaxel +/- bevacizumab +/- atezolizumab N=1200, PFS primary endpoint Identifier: NCT02366143 Pembrolizumab: Keynote-021- phase I-II, PFS, N=308, One arm is Pembro/carbo/paclitaxel/ bevacizumab Identifier: NCT02039674 Additional trial looks at bevacizumab maintenance with nivolumab (Identifier:NCT01454102)

Second-line strategies in EGFR w/t or ALK- patients Old second-line Docetaxel Pemetrexed Erlotinib New second-line Nivolumab Docetaxel+nintedanib

Biomarker-unselected non-squamous NSCLC in the real life Present/Future algorithms: Cisplatin + Pemetrexed  Pemetrexed (maintenance)  Docetaxel + Nintedanib/Erlotinib/Nivolumab (IInd line)  Erlotinib/Nivolumab (IIIrd line)  Erlotinib/ Nivolumab (IVth line) Carboplatin + Paclitaxel + Bevacizumab  Bevacizumab (maintenance)  Pemetrexed/ Erlotinib/Docetaxel+Nintedanib/Nivolumab (IInd line)  Erlotinib/Nivolumab (IIIrd line)  Erlotinib/ Nivolumab (IVth line)

Docetaxel vs Docetaxel+Nintedanib (LUME Lung 1): PFS and OS Adenocarcinoma & time since start of first-line therapy of less than 9 months Total population Adenocarcinoma Adenocarcinoma Total population Squamous-cell Reck M, Lancet Oncol 2014

Docetaxel vs Docetaxel+Nintedanib (LUME Lung 1): toxicities Reck M, Lancet Oncol 2014

BeTa: Erlotinib ± Bevacizumab in the second-line setting Erlotinib 150mg/day + Bevacizumab 15mg/kg every 3 weeks PD Previously treated advanced non-squamous NSCLC Erlotinib 150mg/day orally + placebo PD Arm N RR (%) Median PFS (mos) Median OS (mos) Erlotinib 6.2 1.7 9.2 Beva+Erlot 12.6 3.4 9.3 HR 0.62 0.97 P-value 0.006 <0.0001 0.75 Herbst RS, Lancet 2011

Adenocarcinoma: second-line treatment options

CheckMate 057 (NCT01673867) Study Design Randomize 1:1 Stage IIIB/IV non-SQ NSCLC Pre-treatment (archival or recent) tumor samples required for PD-L1 ECOG PS 0–1 Failed 1 prior platinum doublet Prior maintenance therapy alloweda Prior TKI therapy allowed for known ALK translocation or EGFR mutation N = 582 Nivolumab 3 mg/kg IV Q2W until PD or unacceptable toxicity n = 292 Docetaxel 75 mg/m2 IV Q3W until PD or unacceptable toxicity n = 290 Primary Endpoint OS Additional Endpoints ORRb PFSb Safety Efficacy by tumor PD-L1 expression Quality of life (LCSS) Patients stratified by prior maintenance therapy and line of therapy (second- vs third-line) PD-L1 expression measured using the Dako/BMS automated IHC assay14,15 Fully validated with analytical performance having met all pre-determined acceptance criteria for sensitivity, specificity, precision, and robustness a Maintenance therapy included pemetrexed, bevacizumab, or erlotinib (not considered a separate line of therapy); b Per RECIST v1.1 criteria as determined by the investigator. Paz-Ares L , ASCO 2015

CheckMate 057: OS update Horn L , ECCO/ESMO 2015

Biomarker-unselected squamous NSCLC in the real life Present/Future algorithm: Cisplatin + Gem/VNR/Taxanes  Nivolumab/ Docetaxel/Erlotinib (IInd line) Erlotinib/Nivolumab (IIIrd line)  Erlotinib/Nivolumab (IVth line)

Squire: study design Thatcher N, ASCO 2014

Squire: primary outcome OS Thatcher N, Lancet Oncol2015

Nab-Paclitaxel vs paclitaxel: study design and objectives Stage IIIb/IV NSCLC No prior therapy for metastatic disease ECOG PS 0-1 N = 1052 sb-Paclitaxel 200 mg/m2 d1 (3-h infusion) Carboplatin AUC 6 d1 21-day cycles with premedication of dexamethasone + antihistamines nab®-Paclitaxel 100 mg/m2 d1, 8, 15 (30-min infusion) No premedication Stratification factors: Stage (IIIb vs IV); age; (< 70 vs ≥ 70); sex; histology (adenocarcinoma vs squamous cell vs other); geographic region Objective: To compare the efficacy and safety of nab-paclitaxel plus carboplatin vs sb-paclitaxel plus carboplatin in advanced NSCLC Primary endpoint: ORR by independent radiological review (CR + PR) Secondary endpoints: PFS, OS, DCR (CR + PR + SD), and safety Socinski MA, JCO 2012

Nab-Paclitaxel vs paclitaxel: PFS and OS Socinski MA, JCO 2012 Socinski MA et al. J Clin Oncol. 2012 April 30. [Epub ahead of print].

Biomarker-unselected squamous NSCLC in the real life Present/Future algorithm: Cisplatin + Gem/VNR/Taxanes  Nivolumab/ Docetaxel/Erlotinib (IInd line) Erlotinib/Nivolumab (IIIrd line)  Erlotinib/Nivolumab (IVth line)

CheckMate 017 (NCT01642004) - Study Design Nivolumab 3 mg/kg IV Q2W until PD or unacceptable toxicity n = 135 Docetaxel 75 mg/m2 IV Q3W until PD or unacceptable toxicity n = 137 Randomize 1:1 Primary Endpoint: OS Additional Endpoints: Investigator-assessed ORR Investigator-assessed PFS Correlation between PD-L1 expression and efficacy Safety Quality of life (LCSS) Stage IIIb/IV SQ NSCLC 1 prior platinum doublet- based chemotherapy ECOG PS 0–1 Pre-treatment (archival or fresh) tumor samples required for PD-L1 analysis N = 272 Patients stratified by region and prior paclitaxel use One pre-planned interim analysis for OS At time of DBL (December 15, 2014), 199 deaths were reported (86% of deaths required for final analysis) The boundary for declaring superiority for OS at the pre-planned interim analysis was P <0.03 Spigel DR , ASCO 2015

CheckMate 017: OS update Reck M , ECCO/ESMO 2015

Docetaxel vs Docetaxel + Ramucirumab (Revel trial): OS and PFS Garon EB, Lancet Oncology 2014

Docetaxel vs Docetaxel + Ramucirumab (Revel trial): toxicities Garon E, Lancet 2014

NSCLC: “old” schedules and OS Pemetrexed/Bevacizumab/Histology 8 Reck M, Lancet 2013

Grazie per l’attenzione! francesco.grossi@hsanmartino.it