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Cesare Gridelli Division of Medical Oncology

Cesare Gridelli Division of Medical Oncology “S.G. Moscati” Hospital – Avellino (Italy) cgridelli@libero.it. POST-IASLC: First-line of advanced NSCLC.

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Cesare Gridelli Division of Medical Oncology

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  1. Cesare Gridelli Division of Medical Oncology “S.G. Moscati” Hospital – Avellino (Italy) cgridelli@libero.it POST-IASLC: First-line of advanced NSCLC

  2. Safety and Resource Use in PRONOUNCE: A randomized, phase 3, open-label study of pemetrexed plus carboplatin with maintenance pemetrexed (PemC) compared to paclitaxel plus carboplatin plus bevacizumab with maintenance bevacizumab (PCB) in patients with advanced non-squamous (NS) non-small-cell lung cancer (NSCLC) Authors: 1Helen J Ross, 2, 3David R Spigel, 4Robert W Weaver, 5Ramaswamy Govindan, 6Viran R Holden, 7Naveed M Chowhan, 8Thaddeus Beck, 9David M Waterhouse, 10Manuel R Modiano, 11Vijay P Rao, 12Katherine B Winfree, 12Symantha A Melemed, 12Jingyi Liu, 12Andrew G Koustenis, 12Susan C Guba, 12Waldo I Ortuzar, 12Coleman K Obasaju, 13Ralph Zinner Affiliations: 1Mayo Clinic, Scottsdale, AZ; 2,3Tennessee Oncology, Nashville, TN; Sarah Cannon Research Institute, Nashville, TN; 4Florida Cancer Specialists, Fort Myers, FL; 5Washington University Medical Center, St. Louis, MO; 6Mercy Clinic Cancer and Hematology, Springfield, MO; 7Floyd Memorial Cancer Center of Indiana, New Albany, IN; 8Highlands Oncology Group, Fayetteville, AR; 9Oncology Hematology Care Inc., Blue Ash, OH; 10ACRC/Arizona Clinical Research Center, Arizona Oncology, Tucson, AZ; 11Mid Dakota Clinic Hematology and Oncology, Bismarck, ND; 12Eli Lilly and Company, Indianapolis, IN; 13University of Texas MD Anderson Cancer Center, Houston, TX

  3. 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 Phaseq21d, 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) 180 patients each R1:1 Bevacizumab Paclitaxel + Carboplatin + Bevacizumab Stratified for: PS (0 vs 1); gender (M vs F); disease stage (M1a vs M1b) Zinner R et al, ASCO 2013

  4. Primary Endpoint: G4PFS Pem+Cb: median G4PFS = 3.9 (mo) -------- Pac+Cb+Bev: median G4PFS = 2.9 (mo) Log-rank p-value = 0.176 HR (90% CI) = 0.85 (0.70, 1.04) Patients at Risk Zinner R et al, ASCO 2013

  5. Secondary Endpoint: OS Pem+Cb: median OS = 10.5 (mo) --------- Pac+Cb+Bev: median OS = 11.7 (mo) Log-rank p-value = 0.615 HR (95% CI) = 1.07 (0.83, 1.36) Patients at Risk Pem+Cb 182 156 125 102 72 48 33 20 11 11 5 5 5 5 5 Pac+Cb+Bev 179 151 121 96 73 59 38 28 10 3 1 1 0 0 0 Zinner R et al, ASCO 2013

  6. Drug related Treatment Emergent Adverse Events (TEAEs) A. Toxicities that differed by treatment P<0.001 P<0.006 P<0.105 P<0.003 P<0.033 P<0.001 P<0.001 P<0.001 P<0.07 Number of Patients P-values result from Fisher’s exact tests in numbers of patients experiencing adverse events by treatment . There was a significantly higher occurrence of anemia and thrombocytopenia in patients treated with PemC. Thrombosis, musculoskeletal pain and joint pain, hemorrhage and hypertension occur significantly more in patients treated with PCB. • The number of patients experiencing adverse events is on the x-axis with the event type on the y-axis. Color indicates grade with grade 1, grade 2, grade 3, and grade 4; See table 5 below for detailed data. Anemia Thrombocytopenia Hypotension Thrombosis Musculoskeletal Pain - Extremity Joint Pain Hemorrhage Pulm, Up Resp/Nose Hypertension Diarrhea

  7. Drug related Treatment Emergent Adverse Events (TEAEs) B. Toxicities considered most important to patients P<0.064 P<0.011 P<0.587 P<0.058 P<0.001 P<0.001 P<0.001 Number of patients P-values result from Fisher’s exact tests in numbers of patients experiencing adverse events by treatment. Significantly more patients treated with PemC experience fatigue and nausea. Febrile neutropenia, alopecia, sensory neuropathy and neutropenia occur significantly more often in patients treated with PCB. **Febrile neutropenia and neutropenia not usually reported because lab tests are required. Fatigue Nausea Vomiting **Febrile Neutropenia Alopecia Sensory Neuropathy Neutropenia

  8. Concomitant medications by treatment p=0.355 Number of patients PemC PCB p=0.574 p=0.323 p=0.005 p<0.001 *On therapy or within 30 days of discontinuation; No statistical comparison of the total number of patients on ≥1 medication between treatments. PemC, pemetrexed plus carboplatin followed by maintenance pemetrexed; PCB, paclitaxel plus carboplatin plus bevacizumab followed by maintenance bevacizumab; ESA, erythropoietic stimulating agent; G-CSF, Granulocyte colony stimulating factor

  9. Resource Utilization

  10. Conclusions • ■ Toxicity of PemC and PCB were consistent with previous reports. • ■ Mild to moderate nausea was more common for patients treated with PemC. • ■ Alopecia, infection and neuropathy were more common for patients treated with PCB. • ■ Hospitalizations did not differ between treatment arms. • ■ ESA and RBC transfusions were more common for patients treated with PemC. • ■ G-CSF use was more common for patients treated with PCB.

  11. ToPPS : phase II randomized trial on advanced NSCLC patients with PS 2 RANDOMI SED PEMETREXED Previously untreated, stage IIIb, IV non-squamous NSCLC CARBOPLATIN + PEMETREXED CBDCA + PEMETREXED + BEVACIZUMAB 15mg/kg Bevacizumab PD Primary endpoint: PFS Mount Sinai, and Sarah Cannon Cancer Center Primary endpoint: PFS Lilenbaum R et al, WLCC 2013

  12. Efficacy (N=163)

  13. Progression Free Survival

  14. Overall Survival

  15. Adverse Events * All Adverse Events per CTCAE version 4 occuring in >5% of the total treated patient population

  16. Conclusions • This is the largest prospective trial of bevacizumab in poor performance status patients with advanced NSCLC. • All three regimens were safe and well-tolerated. • ORRs with Pem/Bev +/- Cb were encouraging and comparable to historical outcomes in patients with better performance status.

  17. Efficacy and Safety of Paclitaxel and Carboplatin With Bevacizumab for theFirst-Line Treatment of Patients With Nonsquamous Non–Small Cell Lung Cancer: Analyses Based on Age in the Phase 3 E4599 and PointBreak Trials CJ Langer,1 MA Socinski,2 JD Patel,3 AB Sandler,4JH Schiller,5 L Leon,4 SJ Hazard,4 SS Ramalingam6 1Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; 2University of Pittsburgh Medical Center, UPMC Cancer Pavilion, Pittsburgh, PA; 3Feinberg School of Medicine, Northwestern University, Chicago, IL; 4Genentech, Inc., South San Francisco, CA; 5Harold C. Simmons Cancer Center, University of Texas Southwestern, Dallas, TX; 6Winship Cancer Institute of Emory University, Atlanta, GA

  18. Outcomes for Elderly A-NSCLC Pts (28%)treated with bevacizumab + carboplatin and paclitaxel Retrospective Analysis of ECOG 4599 Trial S Ramalingam et al, JCO 2008

  19. The PointBreak Study Randomized Phase III Trial PEM + BEV Until TOX or PD Non squam NSCLC St IIIB wet/IVECOG PS 0-1 N. Pts: 900 Pr Obj: = OS CBDCA+ PEM+ BEV x 4 R CBDCA+TAX+BEV X 4 BEV until TOX or PD

  20. PointBreak: OS from Randomization (ITT) Censoring rate for Pem+Cb+Bev was 27.8%; for Pac+Cb+Bev was 27.2%

  21. Elderly Results: OS in the Pooled Population Unadjusted Kaplan–Meier estimates for OS among pts (A) <75 yrs and (B) ≥75 yrs receiving PC + Bev in the pooled population of E4599 and PointBreak relative to pts receiving PC alone in E4599 A. <75 years Median OS in pts <75 yrs was 13.4 months with PC + Bev vs 10.2 months with PC (HR, 0.78; 95% CI, 0.68–0.89 ) PC + Bev PC alone 1.0 0.9 0.8 HR (95% CI)=0.76 (0.66–0.87) Log-rank P <.001 0.7 0.6 Proportion Surviving 0.5 0.4 0.3 0.2 0.1 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Time (months) Pts at risk n= 787 708 611 512 404 331 239 162 104 67 39 19 7 6 2 0 0 n= 401 352 288 218 169 125 94 61 32 15 9 7 5 4 1 1 1 B. ≥75 years Median OS in pts ≥75 yrs was 9.6 months with PC + Bev vs 13.0 months with PC (HR, 1.05; 95% CI, 0.70–1.57) PC + Bev PC alone 1.0 0.9 0.8 HR (95% CI)=1.1 (0.74–1.6) Log-rank P =.652 0.7 0.6 Proportion Surviving 0.5 0.4 0.3 0.2 0.1 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Time (months) Pts at risk n= 114 99 79 56 43 31 21 13 9 6 3 2 1 1 1 1 1 n= 43 37 30 24 21 15 10 5 4 2 0 0 0 0 0 0 0 Bev, bevacizumab; CI, confidence interval; E4599, Eastern Cooperative Oncology Group 4599; HR, hazard ratio; OS, overall survival; PC, paclitaxel + carboplatin.

  22. Conclusions • This exploratory, pooled analysis of pt data from the E4599and PointBreak studies demonstrated a statistically significant and clinically meaningful OS and PFS benefit with the addition of Bev to PC for all pts <75 yrs of age • No significant PFS or OS benefit was observed for pts ≥75 yrs of age receiving PC + Bev compared with PC alone • Incidence of grade 5 events was 8% vs 2% for PC + Bev vs PC • However, the small number of pts in this subgroup (n=157) may notallow firm conclusions to be made • Outside of a clinical trial, clinicians must use careful judgmentwhen administering Bev to pts ≥75 yrs with advanced NSCLC

  23. The Spanish Lung Cancer Group (SLCG) BRCA1-RAP80 Expression Customization (BREC) randomized phase III trial of customized chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients with wild-type epidermal growth factor receptor (EGFR) (NCT00617656/GECP-BREC) Rafael Rosell1, Teresa Moran1, manuel A. Cobo Dols2, Manuel Domine3, Maria Sanchez-Ronco4, Isabel Bover5, Mariano Provencio6, Bartomeu Massuti7, Alain Vergnenegre8, Guillermo Lopez-Vivanco9, Gilles Robinet10, Amelia Insa11, Margarita Majem12, Ramon De Las Peñas13, Maria Angeles Sala14, Dolores Isla15, Nathalie Baize16, Javier Garde17, Imane Chaib1, Carlos Camps18 1Catalan Institute Of Oncology, Badalona/SPAIN, 2HRU Carlos Haya, Malaga/SPAIN, 3Fundacion Jiménez-Díaz, Madrid/SPAIN, 4University of Alcala de Henares, Madrid/SPAIN, 5Hospital Son Llatzer, Palma De Mallorca/SPAIN, 6Hospital Puerta de Hierro, Madrid/SPAIN, 7Hospital General de Alicante, Alicante/SPAIN, 8Centre Hospitalier Universitaire de LIMOGES, Limoges/FRANCE, 9Hospital de Cruces de Barakaldo, Vizcaya/SPAIN, 10Hôpital Morvan, Brest/FRANCE, 11Hospital Clínico Universitario, Valencia/SPAIN, 12Hospital de Sant Pau, Barcelona/SPAIN, 13Hospital de Castellon, Castellon/SPAIN, 14Hospital de Basurto, Bilbao/SPAIN, 15Hospital Lozano Blesa, Zaragoza/SPAIN, 16Hôpital de l'Archet, Nize/FRANCE, 17Hospital Arnau de Vilanova, Valencia/SPAIN, 18Hospital Clínico Universitario de Valencia, Valencia/SPAIN

  24. BREC (BRCA1 RAP80 Expression Customization) Docetaxel/Cis CONTROL Advanced NSCLC 1:1 T1 RAP80 (T1-T3 BRCA1) Gem/Cis T2-T3 RAP80 (T1-T2 BRCA1) Docetaxel/Cis EXPERIMENTAL T2-T3 RAP80 (T3 BRCA1) Docetaxel Presented by: Rafael Rosell

  25. PFS in control arm and in the experimental groups Control Arm (n=142): 5.5 months ( 95% CI 5.08-5.91) Experimental Group 1 (n=45): 5.4 months ( 95% CI 5.08-5.77) Experimental Group 2 (n=49): 5.5 months ( 95% CI 3.83-7.16) Experimental Group 3 (n=43): 2.5 months ( 95% CI 1.16-3.84) Control 5·5 Exp. Group 2 2·5 5·4 5·5 Exp. Group 3 Exp. Group 1 Patients at risk

  26. OS in control arm and in the experimental groups Control Arm (n=142): 12.66 months ( 95% CI 10.07-15.26) Experimental Group 1 (n=45): 7.7 months ( 95% CI 3.85-11.55) Experimental Group 2 (n=49): 11.3 months ( 95% CI 7.66-14.84) Experimental Group 3 (n=43): 7.3 months ( 95% CI 5.36-9.11) Exp. Group 2 Control 7·2 7·7 12·7 Exp. Group 3 Exp. Group 1 11·3 Patients at risk

  27. Response by treatment arm Experimental Arm Control Arm Response Rate: 42% • Response Rate: 31% ( p: 0.35) • Group 1: 34% • Group 2: 40% • Group 3: 18%

  28. Conclusions • Prespecified interim analysis of the BREC trial showed a detrimental effect in the experimental arm. • BREC trial was prematurely closed • Interaction between PS and treatment arm. • Favorable non- significant effect for the experimental arm among patients with ECOG PS 0 • Significant increased risk of death in the experiental ar in atients with ECOG PS1 • We are currently examining alternative biomarkers that could elucidate DNA repair mechanisms.

  29. First-line erlotinib versus cisplatin/gemcitabine (GP) in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC): phase 3, open-label, ENSURE study Yi-long Wu,1 Chong-Kin Liam,2 Caicun Zhou,3 Gang Wu,4 Xiaoqing Liu,5 Zhaoyang Zhong,6 Shun Lu,7 Ying Cheng,8 Baohui Han,7 Lei Chen,9 Yunzhong Zhu,10 Shukui Qin,11 Cheng Huang,12 Hongming Pan,13 Houjie Liang,14 Enxiao Li,15 Soon Hin How,16 Guoliang Jiang,17 Marie Cherry Lynn Fernando,18 Meng Chen,19 Yunxia Zuo,19 Guia Ladrera20 1Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangdong, China; 2Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 3Department of Oncology, Affiliated Shanghai Pulmonary Hospital of Tongji University, Shanghai, China; 4Cancer Centre of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 5Internal Medicine Tumor Department, 307 Hospital of the Academy of Military Medical Sciences, Beijing, China; 6Cancer Centre, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China; 7Department of Lung Cancer, Shanghai Chest Hospital, Shanghai, China; 8Jilin Cancer Hospital, Changchun, China; 9Medical Oncology Department, Cancer Hospital of Shantou University Medical College, Shantou, China; 10Lung Cancer Department, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China; 11Nanjing Bayi Hospital, Nanjing, China; 12Fujian Provincial Tumor Hospital, Fujian, China; 13Department of Oncology, Sir Run Run Shaw Hospital, Hangzhou, China; 14Affiliated Xinan Hospital of Third Military Medical University, Chongqing, China; 15First Affiliated Hospital, Medical School Xi’an Jiaotong University, Xi’an, China; 16Hospital Tengku Ampuan Afzan, Kuantan, Malaysia; 17Cancer Hospital, Fudan University, Shanghai, China; 18Manila Doctors Hospital, Manila, the Philippines; 19Roche (China) Holding Ltd; 20Lung Center of the Philippines, Quezon City, Philippines

  30. Kaplan–Meier curves for PFS assessed by IRC

  31. ORR and DCR results • OS data were still immature at the latest data cut-off • ORR and DCR for the interim and updated analyses are shown

  32. EGFR mutation subgroup analysis • Meaningful treatment benefit was observed in both EGFR mutation type subgroups (exon 19 deletions and exon 21 L858R mutations), and was more marked in the exon 19 deletion subgroup

  33. AEs of special interest

  34. Conclusions • These analyses demonstrate that erlotinib provides statistically significant and clinically meaningful improvement in investigator-assessed PFS, which was corroborated by IRC assessment, compared with GP in Asian patients with EGFR mutation-positive NSCLC • Primary efficacy results were also supported by secondary endpoints including ORR and DCR, with no new safety concerns compared with previous studies of erlotinib • These results support the data from other first-line studies in Asian populations, showing that erlotinib provides a PFS benefit over chemotherapy in this patient subgroup with EGFR mutation-positive NSCLC1,2 1. Zhou C, et al. Lancet Oncol 2011 2. Goto K, et al. Lung Cancer 2013

  35. Activity of afatinib in uncommon epidermal growth factor receptor (EGFR) mutations: Findings from three prospective trials of afatinib in EGFR mutation-positive lung cancer J. C.-H. Yang1, L.V. Sequist2, S. L. Geater3, C.-M. Tsai4, T. Mok5, M. H. Schuler6,N. Yamamoto7, D. Massey8, V. Zazulina8, Yi-Long Wu9 1National Taiwan University Hospital, Taipei, Taiwan; 2Massachusetts General Hospital, Boston, MA, USA; 3Division of Respiratory and Respiratory Critical Care Medicine, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand; 4Taipei Veterans General Hospital, Taipei, Taiwan; 5The Chinese University of Hong Kong, Hong Kong; 6West German Cancer Center, University Duisburg-Essen, Essen, Germany; 7Shizuoka Cancer Center, Shizuoka, Japan; 8Boehringer Ingelheim Limited, Bracknell, UK; 9Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China

  36. EGFR mutation-positive patients in LUX-Lung trials Uncommonn=75 n=26 n=26 n=23 Patients with uncommon mutations treated with afatinib

  37. Objective response and disease control rates Independent review

  38. Progression-free survival and overall survival in patients Independent review

  39. Conclusions • Largest prospective dataset in patients with uncommon EGFR mutations (n=75) • High heterogeneity within the subgroup with uncommon EGFR mutations • Low response rate in patients with exon 20 insertions and T790M tumours • Durable tumour control observed in some cases (PFS up to 13.8 months) • Activity was observed in other exon 18 (G719X), 20 (S768I) and 21 (L861Q) mutations that are known to be less responsive to reversible EGFR TKIs • Activity was in the range of efficacy observed with afatinib in common EGFR mutations

  40. INDIRECT COMPARISONS OF EFFICACY AND SAFETY PROFILE OF EGFR TYROSINE KINASE INHIBITORS AS FIRST-LINE TREATMENT IN EGFR MUTATED NSCLC PATIENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS Eva Regina Haspinger*, Francesco Agustoni*, Francesco Gelsomino*, Marina Chiara Garassino*, Valter Torri** and Michela Cinquini** * Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy **Laboratorio di Metodologia per la Ricerca Biomedica Dipartimento di Oncologia "IRCCS - Istituto di Ricerche Farmacologiche Mario Negri"

  41. RESULTS: Relative Risks for PFS

  42. RESULTS: Relative Risks for overall response rate

  43. RESULTS according to AEs (any grade): skin toxicity (panel A), diarrhea (panel B) and hypertransaminasemia (panel C)

  44. Indirect comparisons among EGFR-TKIs: Panel A (gefitinib vs erlotinib), panel B (gefitinib vs afatinib), panel C (erlotinib vs afatinib) Panel A Panel B Panel C

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