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Department of Thoracic Oncology

Filippo de Marinis Department of Thoracic Oncology, IEO, Milan, Italy. Department of Thoracic Oncology. LIFE STUDY 2nd Line TREATMENT. 13%. 52%. 34.0%. C Gridelli, F de Marinis et al, data on file, 2013. ESMO GL WG, Ann Oncol 2012.

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Department of Thoracic Oncology

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  1. Filippo de Marinis Department of Thoracic Oncology, IEO, Milan, Italy Department of Thoracic Oncology

  2. LIFE STUDY 2nd Line TREATMENT 13% 52% 34.0% C Gridelli, F de Marinis et al, data on file, 2013

  3. ESMO GL WG, Ann Oncol 2012

  4. Final results of CTONG 0806: a phase II trial comparing pemetrexed with gefitinib as second-line 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

  5. Pemetrexed 500mg/m2, iv, d1, with vitamin B12 and folic acid supplement, q3w Study Design Gefitinib 250mg qd • locally advanced or metastatic, non-squamous NSCLC • previously treated with one platinum-based chemotherapy • no EGFR mutation in exons 18-21 tested by direct sequencing PD PD Primary endpoint: PFS Secondary endpoints：4- and 6-month PFS rate, OS, ORR, DCR, QoL, Safety A multi-center, randomized, controlled, open-label phase II trial

  6. Primary endpoint: PFS • The primary endpoint of PFS was met Evaluted by investigators Evaluted by IRC * IRC：independent review committee

  7. OS • Median OS showed the trend of superiority in Pemetrexed arm

  8. 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 second-line setting for EGFR wild-type advanced non-squamous NSCLC. • Pemetrexed should be recommended for EGFR wild-type advanced non-squamous NSCLC in second-line treatment due to its good efficacy and tolerability.

  9. EGFR-TKIs vs CTX IN WT NSCLC 2ND LINE * UNSELECTED PTS ** Phase II trial

  10. Erlotinib is dosed adequately to inhibit WT EGFR, whereas gefitinib is not Average plasma concentrations after 28 days (relative to required inhibition levels) 1,000 100 10 0 1,000 100 10 0 IC50 wild-typeEGFR Free-drugconcentration (ng/mL) IC50 wild-typeEGFR Erlotinib1150mg/day Gefitinib2250mg/day 1F. Hoffmann-La Roche, data on file; 2Li J, et al. J Natl Cancer Inst 2006;98:1714–23

  11. 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

  12. PROSE: Study Design • Cytological or histological diagnosis of NSCLC • Advanced stage IIIB-IV • One previous line platinum-based therapy non EGFR-TKIs • ECOG PS 0-2 VERISTRAT TESTING Patients and investigators blinded to VeriStrat status Pemetrexed 500 mg/m2 or Docetaxel 75 mg/m2 VeriStrat Good 1 : 1 Randomization Stratified: VeriStrat ECOG PS Smoking Center Crossover permitted at progression Erlotinib 150 mg daily VeriStrat Poor • 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

  13. PROSE: Patient Overall Survival by Treatment ArmChemotherapy 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

  14. PROSE OVERALL SURVIVAL Incidence of VS Status V Gregorg et al, P ASCO 2013

  15. PFS in unselected patient and interaction analysis Median PFS, Months 4.8 2.8 2.5 1.7 01.07 PROSE Secondary Endpoint Analysis Vanesa Gregorc, MD, Ph.D

  16. VS GOOD: UNSELECTED VS GOOD: WILD TYPE VS POOR: UNSELECTED VS POOR: WILD TYPE

  17. 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

  18. OS and VeriStrat classification at progression • 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

  19. Grade 4 TFS Median TFS= 7.5 moS HR 0.67 p <.0001 Median TFS= 2.3 mo TFS: Toxicity Free Survival as the time from the date of randomization to the first date of any grade 3/4 toxicity or death due to any cause. JL Pujol et al, J ThoracOncol 2006

  20. F de Marinis et al, The Oncologist 2008

  21. 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

  22. ? miR-200c miR-200c was identified as a suppressor of EMT TKI resistance miRNA EMT EMT= epithelial-to-mesenchymal transition Presentation Number: Presentation Title – Presenting Author O01.05: EGFR wild-type NSCLC patients with high miR-200c expression can benefit from EGFR-TKIs – Jiayu Li

  23. Presentation Number: Presentation Title – Presenting Author O01.05: EGFR wild-type NSCLC patients with high miR-200c expression can benefit from EGFR-TKIs – Jiayu Li

  24. Conclusions-Part1 • MiR-200c regulated EMT by targeting ZEB1 in NSCLC cell lines • Ectopic expression of miR-200c resulted in partial restoration of gefitinib sensitivity in NSCLC cell lines • miR-200c low-expression may be responsible for gefitinib resistance through PI3K/AKT and MEK/ERK pathway Conclusions-Part2 • Our study showed for the first time that miR-200c expression might be a potent predictive biomarker in EGFR–WT patients receiving EGFR-TKIs treatment. • EGFR TKIs may be a non-inferior option to second line chemotherapy if EGFR-WT patients with high miR-200c expression were not willing to choose or unable to tolerant chemo drugs. • miRNAs are stable in serum or plasma, circulating miR-200c could become a non-invasive, blood-based NSCLC biomarker. • Prospective clinical trials are wanted to confirm the miR-200c 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

  25. 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

  26. 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 RANDOMISE Nintedanib 200 mg BID PO, D2–21,+ Docetaxel 75 mg/m2 IV, D1,21-day cycles (n=655) PD 1:1 Placebo BID PO, D2–21,+ Docetaxel 75 mg/m2 IV, D1,21-day cycles (n=659) PD 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

  27. LUME-Lung 1 Overall SurvivalPatients with Squamous Cell Carcinoma and Sum of Longest Diameters (SLD) of Target Lesions ≥7.5cm 100 80 60 Probability of survival (%) Feb 2013, 328 events 40 20 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) No. at risk Nintedanib Placebo 166 148 124 102 77 59 43 29 25 22 18 17 13 9 7 5 3 2 1 159 133 102 74 59 42 34 24 13 10 7 4 3 3 2 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.

  28. LUME Lung 1 Overall Survival: Patients with Adenocarcinoma Histology and Time Since Start of 1st Line Therapy < 9months 100 80 60 Feb 2013, 345 events 46.8% Probability of survival (%) 40 20.7% 20 34.3% 10.4% 0 0 4 8 12 16 20 24 28 32 36 Time (months) No. at risk Nintedanib Placebo 206 167 119 92 73 51 35 16 9 3 199 154 91 62 42 25 17 12 5 1

  29. 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)

  30. 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,1Rolf 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

  31. Longitudinal model estimate of differences in cough, dyspnea and pain (adenocarcinoma patients)

  32. Longitudinal model analysis of differences in mean global health status and functional scales (adenocarcinoma patients)

  33. 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

  34. 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

  35. THE RE-BIOPSY IS MANDATORY!

  36. Description of rebiopsies Rebiopsy done 82 (82%) no 18 (18%) Reasons for no rebiopsy inaccessible lesion 4 (22.2%) medical limit 13 (72.2%) patient refusal 1 (5.6%) Site of rebiopsy nodes 3 (3.0%) lung 60 (73.2%) liver 2 (2.4%) bone 6 (7.3%) skin 2 (2.4%) other 9 (11.0%) Methods for rebiopsy bronchial endoscopy 41 (50.0%) per cutaneous trans thoracic pon 18 (22.0%) thoracic surgery 2 (2.4%) other 21 (25.6%) MO-07: Rebiopsy– A Vergnenegre

  37. In this prospective multicentricstudy, in case of progression, rebiopsyhad 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

  38. ALGHORITM for TREATMENT of EGFR MUT+ve TKI Resistance NSCLC EGFR Mut+ve responder to TKI Oligo-Progression Systemic Progression SystemicPD Local therapy + continuation of TKI Systemic therapy Targeting the resistant gene Chemotherapy Chemotherapy + TKI TKI at 2nd PD

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