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Gene Profiling in Clinical Oncology - Slide 2 - T. Le Chevalier - Treatment of advanced NSCLC: which drugs for which histology? And is histology reliable?
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Gene Profiling in Clinical Oncology - Slide 2 - T. Le Chevalier - Treatment of advanced NSCLC: which drugs for which histology? And is histology reliable?

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  • 451 patients with advanced NSCLC aged between 70 and 89 years and a PS of 0 to 2 ,were randomised 1 to 1 between single agent therapy with either vinorelbine or gemcitabine and the doublet of carboplatin and paclitaxel. At progression or in case of excessive toxicity, both arms were switched to erlotinib 150 mg/d.
  • As you can see on this slide, there is a provocative doubling of median progression free survival from 3 months in the single arm therapy to 6.1 months in the carboplatine + paclitaxel arm.One-year PFS is 15% for the doublet versus 2% for the single agents
  • This improvement in PFS is reflected in the overall survival with a benefit of 4 months in median overall survival time for the doublet arm, with 45% vs 27% of patients surviving 1 year. As you can see, median overall survival time and one year survival time in the single agent arm were near those predicted by previous studies, in elderly patients whereas t he median survival time and one year survival in the doublet arm are as one would expect in a general population of ‘any age’, with advanced NSCLC and a PS 0 to 2.
  • Summary: Based on the results of the phase II study, a placebo controlled phase III trial was designed and conducted in the 1 st line setting for pts with non-squamous cell NSCLC. The trial randomized 842 pts to receive carbo/taxol with or without bevacizumab. Pts that were on the placebo arm were not allowed to cross over. Pts on the bevacizumab arm received carbo/taxol/bev x 6 cycles and then bevacizumab until progression. The primary endpoint of the trial is survival. This trial completed accrual in April 2004 and results of the trial are expected by the end of 2005. KEY POINT Key phase III data in NSCLC are expected this year.
  • KEY POINTS The interim report from this phase III trial indicates that the addition of bevacizumab to carboplatin/paclitaxel in previously untreated patients with advanced NSCLC confers a significant survival advantage. This is the first demonstration of a survival advantage in this patient population when a targeted therapy was added to standard chemotherapy. Notes:
  • A un suivi médian de 7,2 mois (extrêmes : 3-15 mois), 976 décès étaient survenus dans l'étude ISEL et le taux de mortalité totale était de 58 %. Dans la population totale, l'amélioration de la survie avec le géfitinib n'a pas atteint le seuil de significativité statistique versus placebo (rapport de risque [HR] selon le test du log rank : 0,89 ; IC à 95 % : 0,77, 1,02 ; p = 0,087). 1 Une analyse de confirmation utilisant le modèle des risques proportionnels de Cox a toutefois suggéré que le seuil de significativité statistique en faveur du géfitinib était atteint (HR : 0,86 ; IC à 95 % : 0,76, 0,99 ; p = 0,030). La survie médiane dans la population totale a été de 5,6 mois avec le géfitinib versus 5,1 mois avec le placebo. 1 Les taux de survie estimés à 1 an avec le géfitinib et avec le placebo ont été respectivement de 27 % et de 21 % dans la population totale. Références 1. Thatcher N et coll. Lancet 2005 ; 366 : 1527-1537.
  • INTEREST was an international, multicentre, randomised, open-label, parallel-group study of gefitinib vs docetaxel in patients with locally advanced or metastatic recurrent NSCLC who were pretreated with platinum-based chemotherapy. 1 A total of 1466 patients from 149 centres in 24 countries worldwide were randomised to gefitinib (250 mg/day orally) or docetaxel (1-hour 75 mg/m 2 infusion every 3 weeks). The primary objective was to compare OS between the groups with co-primary analyses to assess non-inferiority in the overall per-protocol population and superiority in patients with high EGFR-gene-copy number. Secondary endpoints compared progression-free survival (PFS), ORR, quality of life (QoL), disease-related symptoms and safety and tolerability for gefitinib and docetaxel. Exploratory endpoints included the efficacy outcomes in biomarker subgroups. Reference Kim et al. Lancet 2008; 372: 1809-1818.
  • INTEREST demonstrated non-inferiority of gefitinib relative to docetaxel in terms of OS in the overall study population, according to the pre-specified protocol criteria. The hazard ratio (HR) was 1.020 and the 96% confidence interval (CI) was 0.905, 1.150. This CI fell entirely below the non-inferiority limit of 1.154. 1 Median survival was 7.6 months for gefitinib and 8 months for docetaxel. 1 One-year survival rates for gefitinib and docetaxel were 32% and 34%, respectively. 1 In the co-primary analysis, s uperiority of gefitinib in patients with high EGFR-gene-copy number was not proven (HR 1·09, 95% CI 0·78–1·51; p=0·62; median survival 8·4 vs 7·5 months) (data not presented). Reference Kim et al. Lancet 2008; 372: 1809-1818.
  • However, a mong patients with EGFR mutation, PFS was longer for gefitinib compared with docetaxel. There was no significant difference in PFS between treatments among EGFR mutation-negative patients. 1 Reference Douillard et al. J Clin Oncol 2008; 26 (20 May Suppl): Abstr 8001.
  • Prevoir HR de BR 21 of 0,61

Gene Profiling in Clinical Oncology - Slide 2 - T. Le Chevalier - Treatment of advanced NSCLC: which drugs for which histology? And is histology reliable? Gene Profiling in Clinical Oncology - Slide 2 - T. Le Chevalier - Treatment of advanced NSCLC: which drugs for which histology? And is histology reliable? Presentation Transcript

  • Treatment of advanced NSCLC Which drugs for which patients? Is histology reliable? Thierry Le Chevalier Gene Profiling in Clinical Oncology Viareggio, April 8, 2011
  • From: R. Peto et al. Brit. Med. J. 321: 323-329 (2000). And many physicians continue to smoke !!!
  • Lung cancer: histological types Patients (%) Male Female Adapted from Rosenow EC, and Carr DT. CA Cancer J Clin 1979;29:233–45
  • NSCLC: stage at diagnosis, treatment, and 5-year survival rates Stage I–II Surgery ± RT ± CT 5yr S : 24–61% Stage IIIA/IIIB RT ± CT ± surgery 5yr S : 5–13% Stage IV CT + supportive care 5yr S : 1% RT = radiotherapy CT = chemotherapy Mountain C. Chest 1997;111:1710–17
  • Factors influencing treatment strategy in NSCLC
    • Disease stage
    • Patient characteristics
      • age
      • general health
      • performance status
      • quality of life (disease-related symptoms)
    • Knowledge of treatment’s impact on survival
    • Tumor histopathology & gene profile
    • Patient preference
    Elderly patients and those with poor PS are often not considered suitable for intensive cytotoxic chemotherapy
  • IDB Meta-analysis of advanced NSCLC Chemo. vs BSC Absolute 1 year benefit 20 to 29% NSCLC Meta-Analyses Collaborative Group JCO 2008 1240 1315 1293 1399 Events Totals Patients at risk SC alone SC + CT 1315 884 552 363 231 161 107 77 55 1399 1052 779 519 349 233 165 115 91 SC alone SC + CT Probability 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Time 0 3 6 9 12 15 18 21 24 HR = 0.77 (0.71-0.83) p<0.000001
  • Survival by Patient Subgroup: [no. events/no. entered] SC+chemo SC alone Hazard Ratio (Fixed) Age <60 429/456 368/382 60-64 275/299 267/289 65-69 243/268 253/267 ≥ 70 336/365 344/367 SC + CT better SC alone better 0 1 2 0.5 1.5 Sex Male 997/1076 933/984 Female 287/313 301/322 Trend p=0.642 Interaction p=0.766
  • Survival by Patient Subgroup: Stage I & II 37/40 27/28 IIIa 86/92 101/106 IIIb 313/337 289/300 IV 477/508 451/466 [no. events/no. entered] Hazard Ratio (Fixed) SC + CT better SC alone better 0 1 2 0.5 1.5 Histology AdenoCa 302/320 295/300 SqCCa 567/605 532/554 Other 214/224 194/204 Trend p=0.348 Interaction p=0.745 SC + CT SC alone
  • META-ANALYSIS Single agents vs doublets vs triplets * Trial excluded because the number of patients/arm is not available ** Patients excluded of published analysis although randomized (trials not analyzed in ITT) C Delbaldo et al., JAMA
  • META-ANALYSIS Doublets versus triplets C Delbaldo et al., JAMA
    • Chemotherapy in advanced NSCLC has reached a plateau
    • No clear benefit among various combinations of agents
    • Chemotherapy prolongs survival (median survival is <1 year), but more effective therapeutic strategies are needed
    First-line chemotherapy for NSCLC Schiller JH, et al. N Engl J Med 2002;346:92 – 8 Survival distribution function 1.0 0.8 0.6 0.4 0.2 0 0 5 10 15 20 25 30 Months Cisplatin/paclitaxel Cisplatin/gemcitabine Cisplatin/docetaxel Carboplatin/paclitaxel
  • Cisplatin or carboplatin ?
    • Response CIS 30 % CARBO 24% OR = 1.37 IC 95% = 1.16-1.61 P <.001
    • Survival HR = 1.07 IC 95% = 0.99 to 1.15 P = .100
    Ardizzoni JNCI 2007 Survival benefit for 3rd generation combo Carbo Cis
  • Pemetrexed or gemcitabine (+CDDP)
    • Pemetrexed 500 mg/m² D 1
    • Cisplatin 75 mg/m² D 1
    • Adenocarcinoma + LCC  pemetrexed better
    • SCC  Gemcitabine better
    Scagliotti JCO 2008 Adenocarcinoma
  • ELDERLY NSCLC TREATMENT ELVIS Activity and Efficacy Data JNCI, 1999 20 - 0R% 76 78 No. Pts 32 6.5 VNB 14 4.9 BSC 1-YS % MST mos
  • Miles Study: Results
  • Weekly paclitaxel combined with monthly carboplatin versus single agent therapy in patients aged 70 to 89 : IFCT-0501 randomized phase III study in advanced non-small cell lung cancer *Choice of the center at the beginning of the study ** In case of PD or excessive toxicity R A N D O M Stratification by centre, PS 0-1 vs. 2, age ≤ 80 vs. >80 and stage III vs. IV Quoix, ASCO 2010 NSCLC Stage III-IV Age 70-89 years PS 0-2 n = 451 Vinorelbine or Gemcitabine * Carboplatin + paclitaxel Erlotinib** 150 mg/d
  • Doublet Single Doublet Single PFS probabi l I t y Median : 6.1 months (95% CI 5.5-6.9) 1-year PFS : 15.4% (95% CI 10.8-20.8) Median : 3.0 months (95% CI 2.6-3.9) 1-year PFS : 2.3% (95% CI 0.8-5.3) p <10 -6 PFS (ITT) Quoix, ASCO 2010 Months 0 6 12 18 24 30 36 42 Single 226 50 4 1 1 1 0 Doublet 225 107 27 12 7 4 3
  • Doublet Single agent Doublet Single s u r v i v a l p r o b a b i l i t y MST = 10.3 months (95% CI 8.3-13.3 1-year survival 45.1% (95% CI 38.2-51.8) MST = 6.2 months (95% CI 5.3-7.4) 1-year survival 26.9% (95% CI 21-33.1) p= 0.00004 Overall survival (ITT) Quoix, ASCO 2010 Months 0 6 12 18 24 30 36 42 Single 226 112 45 24 11 4 1 Doublet 225 150 78 46 30 14 7
  • Platinum again in second line?
    • Pemetrexed vs. pemetrexed-carboplatin
    • N=240
    • ORR : 7 vs 17%
    • PFS med : 2,8 vs 4,6 m
    • ADK : 2,9 vs 4,3 m
    • SCC : 2,6 vs 3,5 m
    • OS med 7,6 vs 8 m HR=0,85 [0,63- 1,2]
    HR = 0,67 [0,51- 0,89] p=0,005
  • Docetaxel versus Pemetrexed in Second-Line NSCLC: Overall Survival Pemetrexed (n=283) Docetaxel (n=288) Survival distribution function Months 1.00 0.75 0.50 0.25 0 0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 HR=0.99 95% CI of HR (0.82, 1.20) Hanna N, et al. J Clin Oncol 2004;22:1589 –97
  • Tailored Chemotherapy
    • TS mRNA expression and TS promoter polymorphism correlate with response and survival with TS inhibitors
    • ERCC1 mRNA levels predict cisplatin response
    • Beta-tubulin III mRNA levels correlate with paclitaxel and vinorelbine response
    • Ribonucleotide reductase influences response to gemcitabine
    • But it is highly speculative….
  • ERCC1 negative ERCC1 positive Benefit of Cisplatin-based CT in ERCC1 NEGATIVE patients Olaussen et al, New England J Med 2006 NSCLC Adjuvant setting
  • Therapeutic needs in NSCLC
    • Improved survival
    • Improved disease-related symptoms/ quality of life
    • Better-tolerated regimens/regimens for patients not suitable for chemotherapy
    • Lengthened time to disease progression
  • Targeted Agents in NSCLC *
    • Angiogenesis (VEGF) inhibitors
      • Bevacizumab (Avastin ™)
      • BAY43-9006 (sorafenib)
      • GW786034 (pazopanib)
      • AG3340 (prinomastat)
      • BMS-275291
    • EGFR inhibitors
      • Gefitinib (Iressa ®)
      • Erlotinib (Tarceva ™)
      • Cetuximab (Erbitux ™)
    • EGFR + VEGF inhibitor
      • ZD6474
    • Antisense
      • LY90003 (Affinitak ™)
    • Her2 inhibitors
      • Lapatinib
    • Rexinoid
      • Bexarotene (Targretin ™)
    • Proteasome inhibitors
      • Bortexomib (Velcade ™)
    • mTOR inhibitors
      • Rad001, CC1779
  • Phase III Trial of Paclitaxel/Carboplatin Plus Bevacizumab (E4599) First-line Stage IIIB/IV NSCLC (N = 842) Nonsquamous cell CP  6* CP  6 + Bevacizumab (15 mg/kg q3wk), then Bevacizumab until PD PD PD
    • Primary end point: Survival
    • Exclusion criteria: Squamous cell histology, CNS metastases, and active cardiovascular disease
    C: carboplatin; P: paclitaxel. *No crossover allowed in this trial. Sandler et al. PASCO 2005
  • E4599: Efficacy
    • Median survival increase by 2.3 months
    • All efficacy parameters positive
      • Grade 4-5 neutropenia (16.4% vs. 24%)
      • Grade 3-4 thrombosis/embolism (3% vs. 3.8%)
      • Grade 3-4 hemorrhage (1.0% vs 4.1%)
      • 5 due to hemoptysis,
    • First time “3 beats 2” in lung cancer
    • Maintenance therapy
    Sandler et al. PASCO 2005 < 0.05 12.5 10.2 Median survival, mos P Value C-P + Avastin C-P
  • E4599 -70.7 170.2 0.66 [0.57;0.77] Trial O-E Variance Hazard Ratio HR [95% CI] Bevacizumab better | Control better AVAiL 7.5 mg -47.1 163.6 0.75 [0.64;0.87] AVAiL 15 mg -25.3 155.7 0.85 [0.73;0.99] Total -143.1 489.4 Test for heterogeneity: 2 2 = 5.21 p = 0.07 0.75 [0.68;0.82] ; p < 0.001 Bevacizumab : pooled analysis – PFS Soria & Pignon, ESMO 2008 Non SCC, 10-20% of patients ? 0.0 0.5 1.0 1.5 2.0 2.5 3.0
  • 3-5% caucasian 5000 cases/year Molecular classification of lung adenocarcinoma
  • BR.21: Overall Survival *HR and p-value adjusted for stratification factors at randomisation plus HER1/EGFR status 42.5% improvement of Median Survival Fonction distribution de survie Temps de survie (mois) Tarceva TM Placebo *HR=0.73, p<0.001 1.00 0.75 0.50 0.25 0 0 5 10 15 20 25 30
  • ISEL : Overall Survival Thatcher N, et al. Lancet 2005;366:1527-37 0 2 4 6 8 10 12 14 16 Time (months) At risk : 1692 1347 877 485 252 104 31 Median, months 1 yr Survival, % HR : 0,89 ; 95 %CI : 0,77, 1,02 ; p = 0,087 Cox, p = 0,030 IRESSA 5,6 27 Placebo 5,1 21 0,0 0,2 0,4 0,6 0,8 1,0 IRESSA Placebo
  • Positions of Mutations Detected in HER1/EGFR Tyrosine Kinase Domain in NSCLC 747-750 Activation loop L858 G719 Autophosphorylation Tyrosine kinase EGF ligand binding K R H DFG GXGXXG L L Y 718 745 776 835 858 861 869 964 18 19 20 21 22 23 24 757-750 Exon: Paez: Lynch: Pao: Tumor with point mutation (amino acid substitution) Tumor with in-frame deletion TM = transmembrane Adapted from: Pao et al. Proc Natl Acad Sci U S A. 2004;101:13306; Lynch et al. N Engl J Med . 2004;350:2129; Paez et al. Science . 2004;304:1497. 719 858 TM K DFG Y Y Y Y
  • INTEREST: NSCLC 2 nd line
    • Patients
    • Age ≥18 yo
    • Life expectancy
    • ≥ 8 weeks
    • Disease progression after 1 st /2nd line
    • Previous Docetaxel acceptable
    • PS 0-2
    Kim et al 2008 Gefitinib 250 mg/day n=733 Docetaxel 75 mg/m 2 q 3 weeksn=733 1:1 randomization
  • INTEREST: Overall Survival Overall PP population PP, per-protocol; HR, hazard ratio; CI, confidence interval Pre-specified non inferiority limit in HR terms = 1.154 723 593 (82.0%) 710 576 (81.1%) N Events Primary Cox analysis without covariates HR (96% CI) = 1.020 (0. 905 , 1.150 ) Median Survival (m) 1yr Survival 7.6 32% 8.0 34% Gefitinib Docetaxel non-inferiorité dans la population entière 0 4 8 12 16 20 24 28 32 36 40 0.0 0.2 0.4 0.6 0.8 1.0 Mois Kim et al 2008
  • INTEREST PFS according to EGFr mutation Douillard et al 2008 0 4 8 12 16 20 24 28 32 1.0 0.8 0.6 0.4 0.2 0.0 Months 0 4 8 12 16 20 24 28 32 No EGFr mutation EGFr mutation Months 1.0 0.8 0.6 0.4 0.2 0.0 N Events Mediae (m) Gefitinib 19 18 7.0 Docetaxel 19 17 4.1 HR (95% CI) = 0.16 (0.05, 0.49) p =0.0012 N Events Median (m) Gefitinib 106 96 1.7 Docetaxel 123 107 2.6 HR (95% CI) = 1.24 (0.94, 1.64) p =0.1353
  • IPASS (Iressa PAn Asia Study) Gefitinib (250 mg / day) Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m 2 ) 3 weekly # 1:1 randomisation
    • Patients
    • Chemonaïve
    • Age ≥18 years
    • Adenocarcinoma histology
    • Never or light ex-smokers*
    • Life expectancy ≥12 weeks
    • PS 0-2
    • Measurable stage IIIB / IV disease
    Mok et al NEJM 2009 Primary objective : PFS HR = 0.74; p<0.001
  • IPASS OS Yang ESMO 2010
  • Conclusions for EGFR TKI Inhibitors
    • Things we know
      • Response seems better in patients:
        • EGFR Mutation
        • Females
        • Adenocarcinomas with BAC features
        • Limited-smoking population
        • Asians
    • Things we are trying to find out
      • Does this correlate to survival?
      • Are some EGFR mutations more predictive of others?
      • Role of KRAS mutation
      • Role of EGFR protein expression assessed by IHC
      • How to overcome resistance
  •  
  • PARP-1 Inhibitors in Development AZD2281 (Olaparib) AstraZeneca BS-201 BiPar Sciences (Sanofi-Aventis) CEP-9722 Cephalon GPI 21016 MGI Pharma INO-1001 Inotek/Genentec AG014699 Pfizer Product Company
  • Crizotinib in EML4-ALK tumors
  • Molecular targeted therapies in NSCLC Phase I Phase II Phase III Aproved Iressa Tarceva Vatalanib Bexarotene Vandetanib AMG-706 Sorafenib Avastin Matuzumab Cetuximab Bortezomib BSI 251 AZD6244 AMG 655 Talabostat Figitumumab Celecoxib Sunitinib AS1404 VEGF TRAP Lapatanib RAD001 ARQ917 ABT-751 AZD2171 Panitumumab Angiogenesis inhibitors HER inhibitors Others BIB2992
  • Chemotherapy + Targeted Agents Biological Agent Class Trial Phase Target Population Outcome Gefitinib (Iressa) EGFR-TKI III All NSCLC Negative for survival Gefitinib (Iressa) EGFR-TKI III All NSCLC Negative for survival Erlotinib (Tarceva) EGFR-TKI III All NSCLC Negative for survival Erlotinib (Tarceva) EGFR-TKI III All NSCLC Negative for survival Bexarotene (Targretin) Rexinoid III All NSCLC Negative for survival Bexarotene (Targretin) Rexinoid III All NSCLC Negative for survival Lonafarnib (Sarasar) Farnesyl Transferase III All NSCLC Negative for survival Bevacizumab (Avastin) VEGF III Non-squam, no brain mets Positive for survival
  • 0 2 4 6 8 10 12 14 16 18 20 Overall survival (median) 70’s 80s 90s BSC 2–4 m. Cisplatin ‘ old fashion’ 6–8 m. Platinum + 3 rd gen. 8–10 m. 2000 Platinum + 3 rd gen. 8–10 m. Docetax. 2 m. Pemetrex 2 m. Pemetrex 2 m. Erlotinib 2 m. 2005 Platinum + 3 rd gen. 8–10 m. Erlotinib 2 m. 2007-8 2013 Pemetrex. > 2 m. Erlotinib >2 m. Bev./Cet 2 m. Gefitinib EGFRm+ Platinum + 3 rd gen. 8–10 m. Platinum + 3 rd gen. >10 m. COST-EFFECTIVEMESS BIOLOGY-DRIVEN THERAPY TO REDUCE COST Cost in metastatic NSCLC
  • Conclusions
    • More and more non-smokers and females
    • More and more 2 nd / 3rd/4th lines
    • Modest overall improvement in the general population
    • Targeted treatments are presently the most attractive, particularly for adenocarcinoma
    • More and more small niches ( <5-10% of the population )