MON 2011 - Slide 24 - R.A. Stahel - NSCLC systemic therapy


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MON 2011 - Slide 24 - R.A. Stahel - NSCLC systemic therapy

  1. 1. Evolution of systemic therapy for non-small cell lung cancer:From empiric to molecular-driven approach<br />Rolf Stahel<br />University Hospital<br />Zürich<br />Switzerland<br />Ermatingen, April 6, 2010<br />
  2. 2. Past developments in advanced NSCLC<br />Cisplatin-based combination prolongs survival Edna Rapp, JCO 1988<br />Reduced nausea and vomiting with ondansetron Ann Intern Med 1990<br />Meta-analysis using data on individual patients from 52 randomized trials definitively confirms survival advantage Non-small cell lung cancer collaborative group, BMJ 1995<br />Similar results with platin combined with any third generation agent: a plateau has been reachedSchiller, NEJM 2001<br />2nd line chemotherapy with docetaxel, pemetrexedShepherd, JCO 2000; Hanna, JCO 2004<br />
  3. 3. Case 1: Presentation<br />58-y/o woman, married, no children, works as executive secretary suffers from back pain since December 2008. After 2 months unsuccessful treatment by a chiropractioner, her family doctor orders an MRI. Here, a tumor leading to destruction of the first lumber vertebra was identified and the patient referred to oncology.<br />The medical history and physical examination is otherwise unrevealing, patients stopped smoking 30 years ago<br />
  4. 4. Case 1: CT at presentation<br />
  5. 5. Case 1: Diagnosis and therapy<br />Howtoproceed?<br />18.2.2009 Surgicaldecompressionand dorsal stabilisation<br />Histology: Adenocarcinoma, TTF-1 positive, ER negative<br />Diagnosis: Adenocarcinomaofthelungwith mediastinal andcervicallymphnodemetastasisandbonemetastasis<br />Howtotreat?<br />
  6. 6. Case 1: Diagnosis and therapy<br />23.2.2009 Initiation of chemotherapy with cisplatin, pemetrexed and bevacizumab, well tolerated<br />16.3. Hospitalization for second cycle. Updated results of pathology:<br /> EGFR genotype (exons 18 bis 21): Deletion in exon 19 (p.746E_750Adel) EGFR-FISH: positive (high-grade polysomy)EGFR-IHC: protein expression score 3 (DAKO Score 0-3)<br />Continuation of cisplatin, pemetrexed, bevacizumab for total of 4 cycles<br />
  7. 7. Evolution of systemic therapy for non-small cell lung cancer:<br />Advanced NSCLC:Histological classification is necessary for decision making<br />Advanced NSCLC: Reconsideration of extended therapy<br />Molecular classification: Present necessities and future directions<br />Consequences for second line therapy<br />Consequences for adjuvant therapy<br />
  8. 8. 1. Histological classification is necessary for today‘s decision making<br />A diagnosis of “non-small cell lung cancer” is no longer acceptable as sufficient basis for treatment decisions:<br />Cisplatin superior to carboplatin in adenocarcinoma Ardizzoni, JNCI 2007<br />Benefit of bevacizumab added to first line chemotherapy in non-squamous cell carcinoma Sandler, JCO 2006; Reck JCO 2009<br />Differential effect of pemetrexed in non-squamous vs squamous cell carcinoma Scagliotti, JCO 2008<br />Histology will help guide decision about which molecular analysis is performed<br />
  9. 9. Immunohistochemistry of NSCLC<br />TTF-1<br />Surfactant apoproteins (A+B)<br />Napsin A<br />CK7<br />p63<br />HMWCK (CK5-6, 34βE12)<br />Desmocollin 3<br />Adenocarcinoma<br />Squamous cell carcinoma<br />
  10. 10. Meta-analysis: Cisplatinvs carboplatin-based chemotherapy<br /><ul><li>Ardizzoni, JNCI 2007</li></li></ul><li>Cisplatin-Pemetrexed vs Cisplatin-Gemcitabine in Advanced NSCLC<br />No difference in overall <br />PFS or survival between<br />study arms<br />Cis/pem improves survival over cis/gem<br /> in non-squamous cell carcinoma (HR 0.81, p=0.005)<br />Cis/gem improves survival over cis/pem<br /> in squamous cell carcinoma (HR 1.23, p=0.05)<br />Scagliotti, JCO 2008<br />
  11. 11. Bevacizumab added to chemotherapy:Design of 2 phase III trials<br />E45991<br />CP x 6 (n=444)<br />Previously untreated, stage IIIB, IV or recurrent non-squamous NSCLC<br />(n=878)<br />PD<br />Bevacizumab (15mg/kg) every 3 weeks + CP x 6 (n=434)<br />Bev<br />PD<br />Primary endpoint: OS<br />Bevacizumab (15mg/kg) every 3 weeks + CG x 6 (n=351)<br />Bev<br />2<br />RANDOMISE<br />PD<br />AVAiL2<br />1<br />Placebo (15mg/kg) +CG x 6<br />Previously untreated, stage IIIB, IV or recurrent non-squamous NSCLC (n=1,043)<br />Placebo<br />PD<br />(n=347)<br />1<br />Placebo (7.5mg/kg) +CG x 6<br />Primary endpoint: PFS<br />Bevacizumab (7.5mg/kg) every 3 weeks + CG x 6 (n=345)<br />Bev<br />2<br />PD<br />CP = carboplatin/paclitaxel<br />CG = cisplatin/gemcitabine<br />Sandler, 2006; Reck, JCO 2009<br />
  12. 12. Bevacizumab added to chemotherapy:Significant increase of response<br />Sandler, 2006; Reck, JCO 2009<br />
  13. 13. Bevacizumab added to chemotherapy: Significant Increase of PFS<br />PFS in E45991<br />PFS in AVAiL2<br />1.0<br />0.9<br />0.8<br />0.7<br />0.6<br />0.5<br />0.4<br />0.3<br />0.2<br />0.1<br />0<br />1.0<br />0.9<br />0.8<br />0.7<br />0.6<br />0.5<br />0.4<br />0.3<br />0.2<br />0.1<br />0<br />Bev 7.5mg/kg + CG<br />Bev 15mg/kg + CP<br />CP<br />Bev 15mg/kg + CG<br />Placebo + CG<br />Probability of PFS<br /> 0 6 12 18 24 30<br /> 0 6 12 18 24 30<br />Duration of PFS (months)<br />Duration of PFS (months)<br />Median PFSBev 15mg/kg<br />Median PFSBev 7.5mg/kg<br />Median PFSBev 15mg/kg<br />6.2 months<br />HR=0.66<br />p<0.001<br />6.7 months<br />HR=0.75<br />p=0.003<br />6.5 months<br />HR=0.82<br />p=0.03<br />Sandler, 2006; Reck, JCO 2009<br />
  14. 14. OS benefit in adenocarcinoma histology: Pre-planned subgroup analysis (E4599)<br />Bevacizumab-based therapy (n=602)<br />extends OS to 14.2 months<br />31% reduction in the risk of death (HR=0.69)<br />1.0<br />0.75<br />0.50<br />0.25<br />0<br />Avastin + CP (n=300)<br />CP (n=302)<br />Probability of OS<br />10.3<br />14.2<br /> 0 6 12 18 24 30 36 42 48<br />Duration of OS (months)<br />Pre-planned subgroup analysis (E4599)<br />Sandler, JTO 2008<br />
  15. 15. Case 1: Response assessment after 4 cycles of therapy<br />February 09<br />June 09<br />
  16. 16. Case 1: How to proceed<br />Systemic therapy:<br />Discontinue therapy?<br />Maintain pemetrexed?<br />Maintain bevacizumab?<br />Change to erlotinib?<br />Other:<br />Radiotherapy to lumber spine?<br />Bisphosponates or denosumab?<br /> Maintenance bevacizumab monthly<br />
  17. 17. 2. Advanced NSCLC: Reconsideration of extended therapy<br />Significant prolongation of PFS by extended chemotherapy Soon, JCO 2009<br />Significant improvement OAS with pemetrexed maintenance after standard cisplatin-based combination chemotherapy (without pemetrexed) in patients with non-squamous cell lung cancerCiuleanu, Lancet 2009<br />Significant prolongation of OAS with erlotinib maintenance after standard chemotherapy, independent of histology Cappuzzo, Lancet Oncology 2010<br />In booth studies benefit in particular for patients with stable disease<br />
  18. 18. Increased time to PD<br />Maintenance approach<br />Maintenance therapy<br />PD<br />PD<br />Diagnosis<br />CR/PR/SD<br />Maintenance in advanced NSCLC: treating before disease progression<br />First-line treatmentPlatinum doublet chemotherapy<br />(4–6 cycles)<br />Traditional approach<br />2nd/3rd line treatment<br />Break from treatment<br />Diagnosis<br />PD<br />PD<br />CR/PR/SD<br />
  19. 19. Cisplatin based chemotherapy in NSCLC: 2 + 2 vs 2 + 4 cycles<br />TTP<br />OAS<br />Park, JCO 2007<br />
  20. 20. Duration of therapy in advanced NSCLC: Progression-free survival<br />Gem<br />Doc<br />Soon, JCO 2009<br />
  21. 21. Pemetrexed 15.5 mos<br />Pemetrexed 9.9 mos<br />Placebo <br />10.3 mos<br />Placebo <br />10.8 mos<br />Maintenance pemetrexed vs placebo:Overall survival by histology<br />Non-squamous (n=481)<br />Squamous (n=182)<br />HR=0.70 (95% CI: 0.56-0.88)<br /> P =0.002<br />HR=1.07 (95% CI: 0.49–0.73)<br /> P =0.678<br />Survival Probability<br />Time (months) <br />Time (months) <br />Belani, ASCO 2009; Ciuleanu, Lancet 2009<br />
  22. 22. SATUTRN: OAS with erlotinib maintanance in EGFR WT tumors<br />Erlotinib<br />150mg/day<br />PD<br />Chemonaïve advanced NSCLC<br />n=1,949<br />4 cycles of 1st-line platinum-based doublet<br />Non-PD<br />n=889<br />1:1<br />Placebo<br />PD<br />Mandatory tumour sampling<br />Maintenance treatment with erlotinib (SATURN)<br />Cappuzzo,. Lancet Oncol 2010<br />
  23. 23. SATURN: OS in EGFR WT group with SD on first-line chemotherapy<br />1.0<br />0.8<br />0.6<br />0.4<br />0.2<br />0<br />Erlotinib (n=114) <br />Placebo (n=103)<br />HR=0.65 (0.48–0.87)<br />Log-rank p=0.0041<br />OS probability<br />8.7<br />12.4<br /> 0 3 6 9 12 15 18 21 24 27 30 33 36<br />Time (months)<br />Measured from time of randomisation into the maintenance phase<br />Coudert, ECLC 2010<br />
  24. 24. 0.4<br />0.6<br />0.8<br />1.0<br />1.4<br />1.2<br />Both pivotal maintenance studies suggestgreater benefit in patients with SD vs PR/CR<br />JMEN OS Pemetrexed<br />SATURN OS Erlotinib<br />ITT population (n=663)<br />CR/PR (n=322)<br />SD (n=337)<br /> ITT population(n=889)<br />CR/PR (n=394)<br />SD (n=487)<br />0.4<br />0.8<br />0.6<br />1.0<br />1.4<br />1.2<br />HR<br />HR<br />Favours erlotinib<br />Favours placebo<br />Favours placebo<br />Favours pemetrexed<br />
  25. 25. Case 1: Follow-up on bevacizumab<br />March 10<br />June 09<br />October 09<br />
  26. 26. 3. Molecular classification: Present necessities and future directions<br />Adenocarcinoma of the lung is not a uniform disease and needs to be classified by additional molecular analysis<br />Present needs include EGFR mutation status and determination of EML4-ALK fusion gene<br />Knowledge about resistance mechanisms to available agents and the opportunity of agents against new molecular targets mandate change in the trial design<br />Potential driver mutations are also being identified in squamous cell lung cancer<br />
  27. 27. Mutations identified in EGFR gene<br />Confer sensitivity/resistance to EGFR TKIs<br />Unclear effect on sensitivity to EGFR TKIs<br />EGFR transcript<br />L688P<br />V689M<br />I715S<br />L718P<br />S720X<br />18<br />P694X<br />V700D<br />E709X<br />18<br />Exons 1–16<br />G719A/S<br />G735S<br />V738F V742A<br />T751IS752Y<br />D761N<br />Deletions<br />L730F P733L<br />E746K<br />19<br />Exon 17<br />D761Y<br />A763V<br />N765A<br />S768I<br />T783A<br />L792P<br />L798F<br />G810S<br />D770_N771 insNPG<br />20<br />Exons 18–24<br />T790M<br />N826S<br />L838VT847I<br />I853TA859T<br />E866K<br />L833VH835L<br />H850NV851X<br />G863DA864T <br />21<br />L858R<br />Exons 25–28<br />L861X<br />Riely, Clin Cancer Res 2006<br />
  28. 28. First line EFGR TKI or chemotherapy for non-squamous cell lung cancer harboring activating EGFR mutation<br />
  29. 29. IPASS: Objective RR in EGFR mutation positive and negative patients<br />Overallresponserate (%)<br />Gefitinib <br />Carboplatin / paclitaxel<br />EGFR M+ odds ratio (95% CI) = 2.75(1.65, 4.60), p=0.0001 <br />EGFR M- odds ratio (95% CI) = 0.04(0.01, 0.27), p=0.0013 <br />71.2%<br />47.3%<br />23.5%<br />1.1%<br />(n=132)<br />(n=129)<br />(n=91)<br />(n=85)<br />Odds ratio >1 implies greater chance of response on gefitinib<br />Mok, ESMO 2008; NEJM 2009<br />
  30. 30. Improvement of lung cancer symptoms<br />Adapted from Mok, NEJM 2009; supplementary appendix<br />
  31. 31. Mean change from baseline in LCS by EGFR mutation status (EFQ)<br />10<br />8<br />EGFR M+<br />Gefitinib (n=131)Carboplatin / paclitaxel (n=128)<br />6<br />4<br />Change from baseline<br />2<br />0<br />-2<br />-4<br />-6<br />57<br />0<br />3<br />6<br />9<br />12<br />15<br />18<br />24<br />30<br />36<br />42<br />48<br />54<br />10<br />8<br />6<br />EGFR M-<br />Gefitinib (n=89)Carboplatin / paclitaxel (n=80)<br />4<br />2<br />0<br />Change from baseline<br />-2<br />-4<br />-6<br />-8<br />-10<br />3<br />6<br />9<br />12<br />15<br />18<br />24<br />30<br />0<br />21<br />27<br />33<br />Week<br />White dotted line indicates baseline; Purple dotted lines indicate a clinically meaningful change from baseline in LCS; Mean change from baseline by EGFR mutation status was calculated post hoc; Error bars are the 95% CI of the mean; N = number of evaluable patients at baseline; Data after Week 54 (EGFR M+) and Week 30 (EGFR M-) not presented as n<20; <br />
  32. 32. IPASS: Overall survivalin EGFR mutation positive and negative patients<br />EGFR mutation +<br />EGFR mutation -<br />Gefitinib (n=91)Carboplatin /paclitaxel(n=85)<br />HR (95% CI) 1.18 (0.86, 1.63); p=0.309No. events G 82 (90%)C / P 74 (87%)Median OS G 11.2 monthsC / P 12.7 months<br />Gefitinib (n=132)Carboplatin /paclitaxel(n=129)<br />HR (95% CI) 1.00 (0.76, 1.33); p=0.990No. events G 104 (79%)C / P 95 (74%)Median OS G 21.6 monthsC / P 21.9 months<br />1.0<br />1.0<br />0.8<br />0.8<br />0.6<br />0.6<br />0.4<br />0.4<br />Probability of survival<br />Probability of survival<br />0.2<br />0.2<br />0.0<br />0.0<br />52<br />52<br />0<br />4<br />8<br />12<br />16<br />20<br />44<br />24<br />28<br />32<br />36<br />40<br />48<br />0<br />4<br />8<br />12<br />16<br />20<br />44<br />24<br />28<br />32<br />36<br />40<br />48<br />Patients at risk:<br />Gefitinib<br />C / P<br />Time from randomisation (months)<br />Time from randomisation (months)<br />132<br />129<br />126<br />123<br />103<br />95<br />70<br />68<br />24<br />26<br />11<br />15<br />121<br />112<br />88<br />80<br />58<br />55<br />46<br />48<br />38<br />40<br />6<br />7<br />3<br />0<br />0<br />0<br />5<br />1<br />69<br />76<br />52<br />57<br />40<br />44<br />29<br />33<br />26<br />25<br />1<br />1<br />19<br />19<br />16<br />16<br />11<br />11<br />8<br />3<br />0<br />1<br />91<br />85<br />0<br />0<br />Cox analysis with covariates; a hazard ratio <1 implies a lower risk of death on gefitinib No formal adjustment for multiple testing was made, therefore statistical significance at the traditional 5% level cannot be claimed<br />Yang, ESMO 2010<br />
  33. 33. Gefitiniborcarboplatin/paclitaxelfor NSCLC withmutated EGFR<br />2-year survival rate<br />Gefitinib 61.4%<br />Carbo/Pacli 46.7%<br />Gefitinib Carbo/Pacli<br />(n=114) (n=114)<br />Median survival 30.5 m23.6 m<br />P value =0.31<br />Maemondo, NEJM 2010<br />
  34. 34. First line erlotinib in patients with (activating) EGFR mutations<br />2105 pt screened for mutations (non-squamous cell)<br />350 (16.6%) had mutations<br />Current smoker 5.8%<br />Former smoker 9.5%<br />Non-smoker 37.7%<br />217 ptstreated<br />RR 71%<br />Median PFS 14 months<br />Median survival 27 months<br />Rosell, NEJM 2009<br />
  35. 35. Case 1: Second line treatment with EGFR TKI<br />July 10<br />March 10<br />July 10<br />
  36. 36. Case 1: Re-treatment with EGFR TKI atreduced dose andshort-term prednison<br />February 11<br />August 10<br />
  37. 37. Presence of EGFR mutations an imperfect predictor of outcometo EGFR TKIs<br />PFS 27 months in patients with low BRCA1 mRNA levels, 18 months in those with intermediate levels, 10 months in those with high levels: <br />Randomized phase I/II study with gefitinib and olaparibstratified for BCCA1 mRNA (SLCG)<br />Rosell, CCR 2011<br />
  38. 38. Presence of EGFR mutations an imperfect predictor of outcometo EGFR TKIs<br />EGFR T790Mmutation before therapy in 35%. Shorter PFS (8 vs 18 ms): <br />Stratified phase II study with erl/bev (SLCG/ETOP)<br />?Irreversible TKIs (PF299, afatinib)<br />Rosell, CCR 2011<br />Naumov, CCR 2009<br />
  39. 39. Findings associated with resistance to EGFR TKI<br />T790M mutation: 50% of tissue samples from patients with acquired gefitinib resistance and a proportion of patients at diagnosisKosaka, Clin Cancer Res 2006<br />?Irreversible TKIs (PF299, afatinib)<br />MET amplification of : 22% of patients with acquiredTKI resistance: Engelman, Science 2007<br />? Combination of TKI and met inhibitor<br />
  40. 40. LUX-lung 1: afatinib (irreversible HER2 and EGFR inhibition) vs placebo<br /><ul><li> Adenocarcinoma of the lung, stage IIIB/IV, ECOG 0–2
  41. 41. Progression after one or two lines of chemotherapy (incl. one platinum- based regimen) and ≥12 weeks of treatment with erlotinib or gefitinib</li></ul>Miller, ESMO 2010<br />
  42. 42. MET and ALK in lung cancer<br />Pao & Girard, Lancet Oncol, 2011<br />
  43. 43. 43|<br />Clinical trials and translational research in lung cancer: The advances over the last years<br />Advanced adenocarcinoma: Molecular determinants<br /><ul><li> BRAF mutation
  44. 44. HER2 mutation</li></ul>ETOP | EMCTO | Lugano, February 24, 2011<br />
  45. 45. 44|<br />Clinical trials and translational research in lung cancer: The advances over the last years<br />Advanced squamous cell carcinoma: Molecular determinants<br />ETOP | EMCTO | Lugano, February 24, 2011<br />
  46. 46. 45|<br />Clinical trials and translational research in lung cancer: The advances over the last years<br />All histologies:<br />EGFR antibody in EGFR high expressing tumors<br />ETOP | EMCTO | Lugano, February 24, 2011<br />
  47. 47. 46|<br />Molecular based clinical trials in lung cancer: Issues<br />Molecular pathology both at diagnosis and at relapse for definition or stratification of study population mandatory<br />Centralized analysis or standardization of methodologies between sites<br />Availability of integrated services at sites<br />Rarity of molecular subgroups<br />Large networks of sites necessary to detect eligible patients<br />Optimal number or sites for a given trial <br />Emphasis on early decision in molecularly-driven trials<br />New models of collaboration with diagnostic and pharmaceutical companies<br />ETOP | Milano, February 2, 2011<br />
  48. 48. The European Thoracic Oncology Platform<br />Ermatingn, April 6, 2011<br />
  49. 49. 48|<br />Specific aims of ETOP according to bylaws<br />To serve as a meeting platform for European study groups and institutions dealing with thoracic malignancies<br />To foster intergroup studies among, but not exclusively, European study groups and institutions<br />To sponsor and/or perform own studies<br />To foster scientific exchange on laboratory and clinical issues among interested parties and beyond<br />To provide knowledge to partners in the field<br />ETOP | Ermatingen, April 6,, 2011<br />
  50. 50. Participating groups <br />and institutions<br />Austria<br /><ul><li>CECOG – Central European Cooperative Oncology Group</li></ul>Belgium<br /><ul><li>ELCWP – European Lung Cancer Working Party
  51. 51. EORTC Lung Cancer
  52. 52. Leuven Lung Cancer Group
  53. 53. TOGA – Thoracale Oncologie Groep Antwerpen</li></ul>Czech Republic<br /><ul><li>Czech Lung Cancer Cooperative Group</li></ul>Denmark<br /><ul><li>DLCG – Danish Lung Cancer Group
  54. 54. DOLG – Danish Oncological Lungcancer Group</li></ul>France<br /><ul><li>GFPC – Groupe Français de Pneumo-Cancérologie
  55. 55. IFCT – Intergroupe francophone de Cancérologie thoracique
  56. 56. IGR – Institut Gustave Roussy</li></ul>Germany<br /><ul><li>AOT – Arbeitsgemeinschaft Onkologische Thoraxchirurgie
  57. 57. Arbeitsgruppe Thorakale Onkologie der Arbeitsgemeinschaft Internistische Onkologie der Deutschen Krebsgesellschaft
  58. 58. Lung Cancer Group Cologne</li></ul>Greece<br /><ul><li>HeCOG – Hellenic Co-operative Oncology Group
  59. 59. HORG – Hellenic Oncology Research Group</li></ul>Hungary<br /><ul><li>Thoracic Oncology Program</li></ul>Italy<br /><ul><li>AIOT – Associazione Italiana di Oncologia Toracica</li></ul>Poland<br /><ul><li>Polish Lung Cancer Group
  60. 60. Medical University of Gdansk TOP Group</li></ul>Portugal<br /><ul><li>GECP – Grupo de estudos do cancro do pulmão</li></ul>Spain<br /><ul><li>SLCG – Spanish Lung Cancer Group</li></ul>Sweden<br /><ul><li>Swedish Lung Cancer Study Group</li></ul>Switzerland<br /><ul><li>SAKK – Schweizerische Arbeitsgemeinschaft fuer Klinische Krebsforschung</li></ul>The Netherlands<br /><ul><li>NVALT – Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose
  61. 61. ROTS – Rotterdam Thoracic Oncology Study Group</li></ul>United Kingdom/Ireland<br /><ul><li>Birmingham Group
  62. 62. BTOG – British Thoracic Oncology Group
  63. 63. London Lung Cancer Group
  64. 64. Manchester Lung Cancer Group
  65. 65. National Cancer Research Institute – Lung Cancer Clinical Study Group</li></li></ul><li>About LUNGSCAPE<br />The LUNGSCAPE addresses the challenges of studying the molecular epidemiology of lung cancer <br />by coordinating and harmonizing the procedures of of lung cancer specialists working in translational research across Europe<br />by facilitating analysis of larger series of cases. <br />This will:<br />Expedite knowledge of the prevalence and context of current and emerging molecular biomarkers<br />Facilitate more rapid translation of biomarker knowledge to the clinic<br />Provide a platform for marker-driven trials of novel therapeutics.<br />50|<br />ETOP | LUNGSCAPE | Milano, February 2, 2011<br />
  66. 66. 51|<br />Stepwise evolution<br />Step 1: Retrospective analysis of 1500 completely resected NSCLC from a limited number of 7-10 sites: Mutation testing, immunohistochemistry, selected FISH on formalin-fixed, paraffin-embedded tumor tissue <br />Step 2: Expansion to biopsies from advanced disease and a phased approach increasing to the number of participating sites with the aim to have participation from at least one site from all countries represented in ETOP<br />Further steps and issues under considerations:Enlargement of biobank, exon sequencing (selected frozen tissue), circulating biomarkers, technology platforms, resource utilization and health economics research<br />ETOP | LUNGSCAPE | Milano, February 2, 2011<br />
  67. 67. 5. Considerations for second line<br /><ul><li>Patients with activating EGFR mutation:
  68. 68. If EGFR TKI in first line, second line platin-based combination (first line chemotherapy)
  69. 69. If not in first line, now EGFR TKI
  70. 70. Patients with EML4-Alk fusion gene
  71. 71. Crizotinib
  72. 72. EGFR WT or n/a
  73. 73. Choice is between second line chemotherapy with docetaxel, for non-squamous disease pemetrexed, if not used first line, or erlotinib</li></li></ul><li>6. Adjuvant systemic therapy in NSCLC<br />Postoperative chemotherapy with cisplatin-based combination has become standard for resected stage II and III NSCLC<br />Suggestion of benefit in stage IB >4 cm<br />Many open questions remain<br />Is there a preferable chemotherapy regimen?<br />Targeted therapy?<br />How to improve efficiency?<br />Integration of radiotherapy? <br />Adjuvant or neoadjuvant?<br />How to integrate tumor characteristics? (histology, molecular features, metabolic imaging)<br />
  74. 74. Lung Adjuvant Cisplatin Evaluation Chemotherapy vs control<br />No. <br />Deaths<br />Hazard ratio<br />No. <br />Deaths<br />Hazard ratio<br />Category<br />HR<br />[95% CI]<br />Category<br />HR<br />[95% CI]<br />(Chemotherapy / Control)<br />(Chemotherapy / Control)<br />/ No.<br />Entered<br />/ No.<br />Entered<br />Stage IA<br />102 / 347<br />1.41<br />[0.96;2.09]<br />Stage IA<br />102 / 347<br />1.41<br />[0.96;2.09]<br />Stage IB<br />509 / 1371<br />0.92<br />[0.78;1.10]<br />Stage IB<br />509 / 1371<br />0.92<br />[0.78;1.10]<br />Stage II<br />880 / 1616<br />Stage II<br />880 / 1616<br />0.83<br />[0.73;0.95]<br />0.83<br />[0.73;0.95]<br />Stage III<br />865 / 1247<br />0.83<br />[0.73;0.95]<br />Stage III<br />865 / 1247<br />0.83<br />[0.73;0.95]<br />0.5<br />1.0<br />1.5<br />2.0<br />2.5<br />0.5<br />1.0<br />1.5<br />2.0<br />2.5<br />|<br />|<br />Chemotherapy<br />better<br />Control<br />better<br />Chemotherapy<br />better<br />Control<br />better<br />Test for trend: p = 0.051<br />Test for trend: p = 0.051<br />CT may be detrimental for stage IA, but stage IA patients were generally not given the potentially best combination cisplatin+vinorelbine (13% of stage IA patients versus ~43% for other stages)<br />Pignon, ASCO 2006, JCO 2008<br />
  75. 75. Adjuvant gefitinib in unselected NSCLC<br />After “curative chemoradiotherapyfor stage III:<br />After curative resection:<br />Kelly, JCO 2008<br />Goss, ASCO 2010<br />
  76. 76. Stage IB with tumor size over 4 cm<br />CALGB 9633: adjuvant carboplatin/paclitaxel in stage IB<br />Adjuvant cisplatin and vinorelbinein stage I and II NSCLC: JBR.10 update <br />Strauss, JCO 2008<br />Butts, JCO 2010<br />
  77. 77. Adjuvant chemotherapy long term update<br />Arriagada, JCO 2010<br />Butts, JCO 2010<br />
  78. 78. ETOP | European Thoracic Oncology Platform | c/o IBCSG | Effingerstrasse 40 | 3008 Bern |<br />Visit us at<br />