Filippo de Marinis Department of Thoracic Oncology, IEO, Milan, Italy DEPARTMENT OF THORACIC ONCOLOGY Carboplatino + Gemcitabina 25% Cisplatino + Pemetrexed 23% Docetaxel + Gemcitabina 15% Carboplatino + Pemetrexed 12% Cisplatino + Gemcitabina 8% Carboplatino + Paclitaxel 8% Altro 8% 13% 49% 52% 28% 34.0% 11% 10% 2% Docetaxel Pemetrexed Gemcitabina Vinorelbina Altro C Gridelli, F de Marinis et al, data on file, 2013 ESMO GL WG, Ann Oncol 2012 Final results of CTONG 0806: a phase II trial comparing pemetrexed with gefitinib as secondline treatment of advanced non-squamous NSCLC patients with wild-type EGFR Qing Zhou1, Ying Cheng2, Ming-fang Zhao3, Jin-ji Yang1, Hong-hong Yan1, Li Zhang4, Yong Song5, Jian-hua Chen6, Wei-neng Feng7, Chong-rui Xu1, Yi-long Wu1* Chinese Thoracic Oncology Group (CTONG) 1, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; 2, Jilin Provincial Cancer Hospital, Changchun, China; 3, Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China; 4, Perking Union Medical Hospital, Beijing, China; 5, Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China; 6, Hunan Cancer Hospital, Changsha, China; 7, The First People's Hospital of Foshan, Foshan, China; * Corresponding author Yi-long Wu, E-mail Address: syylwu@live.cn Study Design • A multi-center, randomized, controlled, open-label phase II trial •locally advanced or metastatic, non-squamous NSCLC • previously treated with one platinum-based chemotherapy • no EGFR mutation in exons 1821 tested by direct sequencing Pemetrexed 500mg/m2, iv, d1, with vitamin B12 and folic acid supplement, q3w PD Gefitinib 250mg qd PD Primary endpoint: PFS Secondary endpoints:4- and 6-month PFS rate, OS, ORR, DCR, QoL, Safety Primary endpoint: PFS • The primary endpoint of PFS was met Evaluted by investigators Evaluted by IRC * IRC:independent review committee OS • Median OS showed the trend of superiority in Pemetrexed arm Conclusions • CTONG0806 is the first trial to show significant improvement in PFS, DCR and a trend of improving OS with pemetrexed compared with gefitinib in secondline setting for EGFR wild-type advanced nonsquamous NSCLC. • Pemetrexed should be recommended for EGFR wildtype advanced non-squamous NSCLC in second-line treatment due to its good efficacy and tolerability. STUDY DRUGS PFS ms HR/p V-15-32* GEF vs DOC 2.0 vs 2.0 0.90/ p=.77 INTEREST GEF vs DOC 1.7 vs 2.6 1.24/ p=.14 ISTANA GEF vs DOC 3.3 vs 3.4 0.72/ p=.044 14.1 vs 12.2 0.87/ p=.437 CTONG 0806 GEF vs PEM 1.7 vs 5.6 0.53/p=.001 9.6 vs 12.4 0.72/p=.077 TITAN ERL vs DOC/PEM 1.4 vs 2.0 1.25/ p=.2 6.4 vs 4.5 0.85/p=.37 HORG ERL vs PEM 3.6 vs 2.9 0.92/p=.434 9.7 vs 8.2 1.19/p=528 DELTA ERL vs DOC 1.3 vs 2.9 1.45/p= 9.0 vs 10.1 0.98 TAILOR ERL vs DOC 2.4 vs 2.9 0.71/p=.02 5.4 vs 8.2 0.73/ p=0.05 NCT01565538 ** ERL vs PEM 4.1 vs 3.9 0.92/p=.68 * UNSELECTED PTS ** Phase II trial OS ms HR/p 11.5 vs 14.0 1.12/ p=.330 6.4 vs 6.0 1.02/ p=.91 p=0.970 Erlotinib is dosed adequately to inhibit WT EGFR, whereas gefitinib is not Average plasma concentrations after 28 days (relative to required inhibition levels) Free-drug concentration (ng/mL) 1,000 1,000 100 100 IC50 wild-type EGFR IC50 wild-type EGFR 10 0 Erlotinib1 150mg/day 1F. 10 0 Gefitinib2 250mg/day Hoffmann-La Roche, data on file; 2Li J, et al. J Natl Cancer Inst 2006;98:1714–23 01.07 | Randomized Proteomic Stratified Phase III Study of Second Line Erlotinib (E) versus Chemotherapy (CT) in Patients with Inoperable Non-Small Cell Lung Cancer (PROSE): Secondary Endpoint Analysis Presenting Author: Vanesa Gregorc1 Co-Authors: Chiara Lazzari1, Silvia Novello2, Sandro Barni3, Michele Aieta4, Francesco Grossi5, Tomasso De Pas6, Filippo de Marinis7, Manlio Mencoboni8, Alessandra Bearz9, Irene Floriani10, Valter Torri10, Fred Hirsch11, Heinrich Roder12, Julia Grigorieva12, Joanna Roder12, Alessandra Bulotta1, Silvia Foti1, Mariagrazia Viganò1, Matteo Giaj Levra2, Angela Bachi1 PROSE: Study Design Crossover permitted at progression •Cytological or histological diagnosis of NSCLC •Advanced stage IIIB-IV •One previous line platinumbased therapy non EGFR-TKIs VERISTRAT TESTING Patients and investigators blinded to VeriStrat status VeriStrat Good 1:1 Randomization VeriStrat Poor Stratified: VeriStrat ECOG PS Smoking Center Pemetrexed 500 mg/m2 or Docetaxel 75 mg/m2 Erlotinib 150 mg daily •ECOG PS 0-2 • Objective: To prospectively evaluate the predictive utility of VeriStrat classification on the survival outcome of erlotinib vs chemotherapy in the 2nd line NSCLC setting. • Primary Endpoint: Overall Survival ; Secondary Endpoints: PFS (CT scans 8 week interval), DCR and ORR (RECIST investigators based, no central review) . • EGFR and K-RAS exploratory analysis performed in 190/263 (72%) and 166/263 (63%) patients, respectively. 01.07 PROSE Secondary Endpoint Analysis Vanesa Gregorc, MD, Ph.D PROSE: Patient Overall Survival by Treatment Arm Chemotherapy vs. erlotinib (for primary analysis) Third-line treatment at progression: • CT arm: 41% overall (48% VS-G and 27% VS-P) • ERL arm: 52% overall (56% VS-G and 39% VS-P) Presented by: Vanesa Gregorc, MD PROSE OVERALL SURVIVAL Incidence of VS Status V Gregorg et al, P ASCO 2013 PFS in unselected patient and interaction analysis Median PFS, Months (95% CI) Median PFS, Months 4.2 (2.6 – 5.0) 2.2 (2.0 – 2.4) HR=1.27(95%CI:.99 – 1.62) p =0.060 4.8 2.8 2.5 1.7 01.07 PROSE Secondary Endpoint Analysis Vanesa Gregorc, MD, Ph.D VS GOOD: UNSELECTED VS POOR: UNSELECTED VS GOOD: WILD TYPE VS POOR: WILD TYPE Randomized Proteomic Stratified Phase III Study of Second Line Erlotinib (E) Versus Chemotherapy (CT) in Patients with Inoperable Non-Small Cell Lung Cancer (PROSE): VeriStrat Analysis of Longitudinal Samples Authors: Alessandra Bulotta1, Chiara Lazzari1, Silvia Foti1, Mariagrazia Viganò1, Domenico Ghio2, Silvia Novello3, Sandro Barni4, Michele Aieta5, Francesco Grossi6, Tomaso De Pas7, Filippo de Marinis8, Manlio Mencoboni9, Alessandra Bearz10, Joanna Roder11, Heinrich Roder11, Julia Grigorieva11, Irene Floriani12, Valter Torri12, Vanesa Gregorc1 OS and VeriStrat classification at progression Group Median Group Median A : VS-G to VS-G E 14.6 months A : VS-G to VS-G CT 16.2 months B : VS-G to VS-P E 10.0 months B : VS-G to VS-P CT 6.3 months C : VS-P to VS-P E 5.0 months C : VS-P to VS-P E CT 10.2 months HR (A vs B): 0.68 (95% CI: 0.34-1.28); log-rank p = 0.222 HR (A vs B): 0.51 (95% CI: 0.18-1.08); log-rank p = 0.079 HR (B vs C): 0.29 (95% CI: 0.04-0.37); log-rank p = 0.001 HR (B vs C): 0.70 (95% CI: 0.27-1.58); log-rank p = 0.377 • Patients whose VeriStrat classification changed from VS-G to VS-P at progression had numerically worse OS • compared with those whose classification remained VS-G regardless of therapy. These patients had significantly better survival outcomes than those whose classification remained VS-P when treated with E. MO21.01 PROSE: VeriStrat analysis of longitudinal samples Silvia Novello, MD Grade 4 TFS Median TFS= 7.5 moS Median TFS= 2.3 mo F de Marinis et al, The Oncologist 2008 O01.05: EGFR wild-type NSCLC patients with high miR-200c expression can benefit from EGFR-TKIs Presenting Author: Jiayu Li, Ph.D Shanghai Pulmonary Hospital, Tongji University, Shanghai, China miR-200c miRNA ? EMT miR-200c was identified as a suppressor of EMT TKI resistance EMT= epithelial-to-mesenchymal transition O01.05: EGFR wild-type NSCLC patients with high Presentation miR-200c expression Number: can Presentation benefit from Title EGFR-TKIs – Presenting – Jiayu Author Li O01.05: EGFR wild-type NSCLC patients with high Presentation miR-200c expression Number: can Presentation benefit from Title EGFR-TKIs – Presenting – Jiayu Author Li Conclusions-Part2 Conclusions-Part1 • Our study showed for the first time that miR-200c expression • MiR-200c regulated EMTbiomarker by targeting ZEB1 in patients might be a potent predictive in EGFR–WT NSCLC cell lines treatment. receiving EGFR-TKIs • EGFR TKIs may be a non-inferior option to second line chemotherapy if EGFR-WT patients resulted with highinmiR-200c • Ectopic expression of miR-200c partial expression were willingsensitivity to chooseinorNSCLC unablecell to tolerant restoration ofnot gefitinib lines chemo drugs. • miRNAs are stable in serum or plasma, circulating miR-200c • miR-200c be responsible could become low-expression a non-invasive, may blood-based NSCLCfor gefitinib resistance through PI3K/AKT and MEK/ERK biomarker. pathwayclinical trials are wanted to confirm the miR-200c • Prospective as a predicting biomarker in EGFR-WT NSCLC patients. O01.05: EGFR wild-type NSCLC patients with high miR-200c expression can benefit from EGFR-TKIs – Jiayu Li Abstract: 3284 Presentation: O16.01 Impact of tumour burden on the overall survival analysis of the LUME-Lung 1 study: a randomized, double-blind phase 3 trial of nintedanib (BIBF 1120) + docetaxel in NSCLC patients progressing after first-line chemotherapy Presenting Author: M Reck Authors: M Reck, S Novello, A Mellemgaard, S Orlov, R Kaiser, J Barrueco, B Gaschler-Markefski, J-Y Douillard, for the LUME-Lung 1 Study Group LUME-Lung 1 Study Design • Stage IIIB/IV* or recurrent NSCLC • Failed 1st-line chemotherapy • Any histology • ECOG PS 0 or 1 • No prior docetaxel or VEGF/VEGFR inhibitors** • No active brain metastases R A N D O M I S E Nintedanib 200 mg BID PO, D2–21, + Docetaxel 75 mg/m2 IV, D1, 21-day cycles (n=655) PD Placebo BID PO, D2–21, + Docetaxel 75 mg/m2 IV, D1, 21-day cycles (n=659) PD 1:1 N=1314 Number of docetaxel cycles not restricted Monotherapy allowed after ≥4 cycles of combination therapy LUME-Lung 1 met its primary endpoint: PFS (HR: 0.79 p=0.0019) *AJCC 6th/7th edition; **Other than bevacizumab LUME-Lung 1 Overall Survival Probability of survival (%) Patients with Squamous Cell Carcinoma and Sum of Longest Diameters (SLD) of Target Lesions ≥7.5cm Nintedanib + docetaxel Placebo + docetaxel Median, mo 7.7 6.1 HR (95% CI) 0.82 (0.65 to 1.04) 100 80 p-value 60 0.0995 Feb 2013, 328 events 40 20 0 0 No. at risk Nintedanib Placebo 2 4 6 166 148 124 102 159 133 102 74 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) 77 59 59 42 43 34 29 24 25 13 22 10 18 7 17 4 13 3 9 3 7 2 5 2 3 1 2 1 1 1 HR interaction analysis revealed values <1 at SLD values around 7.5 cm; consequently, an SLD ≥7.5 cm was chosen as the cut-point for further in-depth analyses in patients with squamous cell carcinoma. LUME Lung 1 Overall Survival: Patients with Adenocarcinoma Histology and Time Since Start of 1st Line Therapy < 9months Nintedanib + docetaxel Placebo + docetaxel Median, mo 10.9 7.9 HR (95% CI) 0.75 (0.60 to 0.92) Probability of survival (%) 100 80 p-value 60 0.0073 Feb 2013, 345 events 46.8% 40 20.7% 20 34.3% 10.4% 0 No. at risk Nintedanib Placebo 0 4 8 12 206 154 167 91 119 62 92 42 16 20 24 Time (months) 73 25 51 17 35 12 28 32 36 16 5 9 1 3 199 Summary • LUME-Lung 1 met its primary endpoint: PFS (HR: 0.79 p=0.0019) • A significant improvement in OS was demonstrated in patients with adenocarcinoma (OS; HR: 0.83 p=0.0359 median 12.6 vs 10.3 months) • Patients with a poor prognosis had the highest OS benefit: – adenocarcinoma histology and time since start of 1st line therapy <9 months (HR: 0.75 p=0.0073 median OS 10.9 vs 7.9 months) – adenocarcinoma histology with PD as best response to 1st line treatment (HR: 0.62 p=0.0246 median OS 9.8 vs 6.3 months) – squamous cell histology with a high tumour burden showed a trend towards improved OS (SLD ≥7.5 cm; HR=0.82 p=0.0995 median OS 7.7 vs 6.1 months) • Nintedanib plus docetaxel had a manageable safety profile with no unexpected safety findings • Further investigations are warranted to identify molecular and clinical markers for nintedanib benefit in NSCLC including the effects of high tumour burden (squamous) and tumour dynamics (adenocarcinoma) Abstract ID 2812 Analysis of Patient-Reported Outcomes from the LUME-Lung 1 Trial: A Randomized, Double-Blind, Placebo-Controlled Phase III Study in Second-Line Advanced Non-Small Cell Lung Cancer (NSCLC) Patients Silvia Novello,1 Rolf Kaiser,2 Anders Mellemgaard,3 Jean-Yves Douillard,4 Sergei Orlov,5 Maciej Krzakowski,6 Joachim von Pawel,7 Maya Gottfried,8 Igor Bondarenko,9 Meilin Liao,10 José Barrueco,11 Birgit Gaschler-Markefski,2 Ingolf Griebsch,2 Martin Reck,12 for the LUME-Lung 1 Study Group Longitudinal model estimate of differences in cough, dyspnea and pain (adenocarcinoma patients) Longitudinal model analysis of differences in mean global health status and functional scales (adenocarcinoma patients) Conclusions • In second-line NSCLC patients, no significant differences in cough, dyspnea or pain were observed in patients receiving nintedanib + docetaxel compared with placebo + docetaxel – there were trends towards improvements in TTD for global health status/QoL in patients with adenocarcinoma, and for pain in adenocarcinoma patients with a time since start of first-line therapy <9 months – QoL scores for nausea and vomiting, appetite loss and diarrhea were worsened in patients who received nintedanib + docetaxel compared with those who received placebo + docetaxel • Overall, PFS was improved in all patients with nintedanib + docetaxel compared with placebo + docetaxel and OS was significantly improved in patients with adenocarcinoma;1 this analysis demonstrates that these improvements were achieved without substantial alterations in self-reported QoL ABSTRACT ID NUMBER: 1045 FEASIBILITY AND CLINICAL IMPACT OF RE-BIOPSY IN ADVANCED NON SMALL CELL LUNG CANCER: A PROSPECTIVE MULTICENTRIC STUDY IN REAL WORLD SETTING (GFPC study 12-01) PRESENTER: Professor Alain VERGNENEGRE C Dujon (Le Chesnay, France), C Chouaid (Saint Antoine, France), P Do (Caen, France), I Monnet (Creteil, France), A Madroszyk (Marseille Calmette, France), H Le Caer (Draguignan, France), JB Auliac (Mantes la Jolie, France), H Berard (Toulon HIA, France), P Thomas (Gap, France), H Lena (Rennes, France), G Robinet (Brest, France), N Baize (Angers, France), A Bizieux-Thaminy (La Roche sur Yon, France), G Fraboulet (Cercy Pontoise, France), C Locher (Meaux, France), J Le Treut (Aix-en-Provence, France), S Hominal (Pringy, France), A Vergnenegre (Limoges, France) MO-07: Rebiopsy– A Vergnenegre THE RE-BIOPSY IS MANDATORY! Description of rebiopsies Rebiopsy Reasons for no rebiopsy Site of rebiopsy Methods for rebiopsy done no inaccessible lesion medical limit patient refusal nodes lung liver bone skin other bronchial endoscopy per cutaneous trans thoracic pon thoracic surgery other 82 (82%) 18 (18%) 4 (22.2%) 13 (72.2%) 1 (5.6%) 3 (3.0%) 60 (73.2%) 2 (2.4%) 6 (7.3%) 2 (2.4%) 9 (11.0%) 41 (50.0%) 18 (22.0%) 2 (2.4%) 21 (25.6%) MO-07: Rebiopsy– A Vergnenegre Initial molecular profil (n=100) EGFR mutated n=50 Post biopsy molecular profil (n=82) EGFR mutated: KRAS mutated: Re biopsy done: n = 40 T790M mutation: 16 1 2 EGFR wild type: 2 small cell LC: 1 No profil available: 18 KRAS mutated n=7 KRAS mutated: 1 Re biopsy done: n = 5 No profil available: 3 KRAS wild type: 1 EGFR- KRAS wild type n=25 9 EML4ALK : Ros1 : 1 1 KRAS mutated: 5 EGFR-KRAS wild type EGFR mutated: 1 Her2: 1 Re biopsy done: n = 22 No profil available: 9 No biological profil n=18 EGFR mutated: 1 No profil available: 9 Re biopsy done: n = 15 In this prospective multicentric study, in case of progression, rebiopsy had a good acceptability rate (99%), a fisability of 82% and a clinical impact (new oncologic driver, histologic change or biological change) in 19,5%. Abstract 1045: Rebiopsy– A Vergnenegre NSCLC EGFR Mut+ve responder to TKI Oligo-Progression Local therapy + continuation of TKI Systemic Progression Systemic PD Targeting the resistant gene Systemic therapy Chemotherapy Chemotherapy + TKI TKI at 2nd PD