13.00 14.00, Friday 6 March satellite symposium held in conjunction with the 10th European Congress: Perspectives in Lun

13.00 14.00, Friday 6 March satellite symposium held in conjunction with the 10th European Congress: Perspectives in Lun PowerPoint PPT Presentation


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Chair's welcome and introduction. Johan VansteenkisteUniversity Hospital Gasthuisberg Leuven, Belgium. Information about future treatment approaches and clinical trials will be presented, including unlicensed indications and/or novel agents . . Housekeeping. . Please turn off mobile phone, BlackBe

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13.00 14.00, Friday 6 March satellite symposium held in conjunction with the 10th European Congress: Perspectives in Lun

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2. Chair’s welcome and introduction Johan Vansteenkiste University Hospital Gasthuisberg Leuven, Belgium

3. Housekeeping

6. Revolutions in care: how are new therapies changing treatment paradigms in NSCLC?

7. Historical perspective: shifting goalposts for clinical trials in oncology Approval based on OS Tarceva (NSCLC) FDA 2004 Docetaxel (NSCLC) FDA 2002 Pemetrexed (NSCLC) FDA 2004 Gemcitabine (pancreatic) FDA 1997 Tarceva (pancreatic) FDA 2005 Avastin (CRC) FDA 2004 Irinotecan (CRC) FDA 2000 Oxaliplatin (CRC) FDA 2004 Approval based on PFS Sorafenib (RCC) FDA 2005; EMEA 2006 Sunitinib (RCC) FDA 2007; EMEA 2007 Avastin (RCC) EMEA 2007 Gemcitabine (Ovarian) FDA 2006 Herceptin (Breast) FDA 2006 Lapatinib (Breast) FDA 2007 Avastin (Breast) FDA 2008; EMEA 2007 Ixabepilone (Breast) FDA 2007 Panitumumab (CRC) FDA 2006 Approval based on OS Tarceva (NSCLC) FDA 2004 Docetaxel (NSCLC) FDA 2002 Pemetrexed (NSCLC) FDA 2004 Gemcitabine (pancreatic) FDA 1997 Tarceva (pancreatic) FDA 2005 Avastin (CRC) FDA 2004 Irinotecan (CRC) FDA 2000 Oxaliplatin (CRC) FDA 2004 Approval based on PFS Sorafenib (RCC) FDA 2005; EMEA 2006 Sunitinib (RCC) FDA 2007; EMEA 2007 Avastin (RCC) EMEA 2007 Gemcitabine (Ovarian) FDA 2006 Herceptin (Breast) FDA 2006 Lapatinib (Breast) FDA 2007 Avastin (Breast) FDA 2008; EMEA 2007 Ixabepilone (Breast) FDA 2007 Panitumumab (CRC) FDA 2006

8. Evolving therapeutic landscape presents challenges in clinical trial endpoint selection

9. Tarceva and Avastin: targeting the tumour and the vasculature

10. Improved treatment approaches in NSCLC confer unprecedented survival duration Case studies to introduce the notion that survival outcomes that can now be achieved in advanced NSCLC were unheard of a few years ago.Case studies to introduce the notion that survival outcomes that can now be achieved in advanced NSCLC were unheard of a few years ago.

11. Meeting objectives Discuss key considerations when selecting first- and second-line therapy for advanced NSCLC patients, in order to ensure optimal outcomes for our patients consider how tumour histology influences treatment decision making assess the role of molecular markers in treatment selection review the importance of key clinical characteristics when selecting therapy Chair to review the scope of the meeting programme: in the face of the changing therapeutic landscape in NSCLC, we will examine and discuss practical aspects of patient management that are fundamental to daily treatment decision making, particularly the roles of tumour histology, molecular markers and clinical characteristics in optimising patient outcomes.Chair to review the scope of the meeting programme: in the face of the changing therapeutic landscape in NSCLC, we will examine and discuss practical aspects of patient management that are fundamental to daily treatment decision making, particularly the roles of tumour histology, molecular markers and clinical characteristics in optimising patient outcomes.

12. Programme Chair to briefly outline the meeting programme and then introduce the first speaker, Maurice Perol.Chair to briefly outline the meeting programme and then introduce the first speaker, Maurice Perol.

13. Importance of histology in NSCLC treatment decisions Prognostic importance of histology suggested adenocarcinoma = better outcome Histology often described, but predictive value for treatment selection unclear Looking ahead . . . analyse association between histology subtype and efficacy outcomes increased reliance on histology for determining optimal treatment Previous data have consistently shown adenocarcinoma histology to be a positive prognostic factor. However, the predictive value of histology in determining optimal outcomes for different treatments has only been defined in retrospective analyses of larger trials.Previous data have consistently shown adenocarcinoma histology to be a positive prognostic factor. However, the predictive value of histology in determining optimal outcomes for different treatments has only been defined in retrospective analyses of larger trials.

14. Audience question

15. Importance of histology in optimising NSCLC care Maurice Pérol Hôpital de la Croix-Rousse Lyon, France

16. Major NSCLC histology classifications: considerations for therapy Limitations of histology determining therapy1 diagnosis on cytological samples small biopsies in NSCLC not representative of the whole tumour misclassification of tumours limitations of available studies with no central pathological review This slide shows the major NSCLC histology classifications and some of the potential limitations of the classification process. Prof Perol: would you want to comment on whether there is any additional benefit of IHC analysis in differentiating tumour type? This slide shows the major NSCLC histology classifications and some of the potential limitations of the classification process. Prof Perol: would you want to comment on whether there is any additional benefit of IHC analysis in differentiating tumour type?

17. NSCLC: regulatory approved therapies

18. Avastin first-line, non-squamous histology: efficacy proven in two phase III trials

19. Avastin first-line, non-squamous histology: longest survival time in NSCLC

20. E4599 pre-planned subgroup analysis: unprecedented OS benefit in adenocarcinoma histology Avastin-based therapy (n=602) extends OS to 14.2 months 31% reduction in the risk of death (HR=0.69)

21. Avastin first-line, squamous histology: benefit unknown Squamous-cell tumours often centrally located and cavitated1–3 Patients with squamous histology: excluded from pivotal Avastin phase III trials safety signal in phase II study (all histologies):4 4/6 patients with severe bleeding had squamous histology

22. Cetuximab first-line: mixed results (therapy not approved)

23. Pemetrexed: three phase III trials show lack of efficacy in squamous histology

24. Tarceva: significant survival benefit, regardless of histology (BR.21 study)

25. First-line therapeutic options by histology

26. Second-line therapeutic options by histology

27. Summary Accurate determination of NSCLC tumour histology necessary before most appropriate therapy to improve survival can be prescribed In adenocarcinoma, Avastin extends survival by 4 months versus chemotherapy alone (E4599) Second-line Tarceva provides a significant survival benefit in NSCLC, regardless of histology

29. Pathways successfully targeted in NSCLC (based on positive phase III trials)

30. Targeted drugs are effective in NSCLC

31. Audience question

32. Value of molecular markers in NSCLC: an update Jürgen Wolf Center for Integrated Oncology University Hospital of Cologne Cologne, Germany To verbally introduce: We are now at the beginning of a process in which we are able to extract clinically relevant, molecularly-defined subgroups from the heterogeneous spectrum of NSCLC. This process will allow us to define the disease more precisely, and to tailor treatments accordingly. This talk will consider two molecularly-defined subsets that have emerged recently as being clinically important, especially with respect to targeted therapies: EGFR-mutant NSCLC and KRAS-mutant NSCLCTo verbally introduce: We are now at the beginning of a process in which we are able to extract clinically relevant, molecularly-defined subgroups from the heterogeneous spectrum of NSCLC. This process will allow us to define the disease more precisely, and to tailor treatments accordingly. This talk will consider two molecularly-defined subsets that have emerged recently as being clinically important, especially with respect to targeted therapies: EGFR-mutant NSCLC and KRAS-mutant NSCLC

33. EGFR mutations as predictive biomarkers for EGFR-TKI therapy 90% of mutations in exons 18–24 most commonly exon 19 deletions exon 21 point mutation (L858R) Functional consequence: ligand-independent activation of downstream pathways not by EGFR amplification

34. Epidemiology of EGFR mutations Mitsudomi T, et al. Int J Clin Oncol 2006;11:190–208Mitsudomi T, et al. Int J Clin Oncol 2006;11:190–208

35. First-line Tarceva in patients with EGFR mutations: high response rate and long OS What cannot be answered in a phase II trial: predictive or prognostic?

36. IPASS study First-line gefitinib versus CP in highly selected patients (Asian, adeno, never- or light ex-smokers, predominantly female)

37. EGFR mutations and clinical characteristics (IPASS) Mok T, et al. Ann Oncol 2008;19(Suppl. 8) Abs. LBA2Mok T, et al. Ann Oncol 2008;19(Suppl. 8) Abs. LBA2

38. Clinical relevance EGFR mutations are predictive for EGFR-TKI treatment Patients with EGFR mutations should receive first-line EGFR-TKI Epidemiological preselection (never smoker etc.) is not sufficient (60% mutation frequency in IPASS) EGFR mutation status must be determined before choosing between chemotherapy and EGFR-TKI treatment Share data with Prof Wolf: CR rate SLCG vs IPASS EGFR mutations meta-analysisShare data with Prof Wolf: CR rate SLCG vs IPASS EGFR mutations meta-analysis

39. What about EGFR wild-type and Tarceva? Prof Wolf to verbally discuss personal experience of long term SD in patients with wild-type EGFR Prof Wolf to verbally discuss personal experience of long term SD in patients with wild-type EGFR

40. Conclusions for second-line treatment In unselected patients, Tarceva has similar efficacy to chemotherapy Patients with EGFR mutations should receive an EGFR-TKI, if they did not receive first line Further efforts are needed to identify the subgroup of patients with wild-type EGFR who do not obtain clinical benefit from an EGFR-TKI

41. EGFR-TKIs in KRAS-mutant NSCLC KRAS mutations occur in 15–30% cases of NSCLC (exons 12, 13 and 61) Predominant mutation type differs between tumours CRC: G12D NSCLC: G12C KRAS mutations predict lack of benefit from anti-EGFR MAbs in CRC Can these findings be translated to NSCLC?

42. Are KRAS mutations a negative predictor for clinical benefit with anti-EGFR treatment? Meta-analysis only considered CR/PR, not stable disease To date, no data from prospective randomised trials in NSCLC SATURN KRAS data to be shared with Prof Wolf Linardou et al, Lancet Oncology Oct 2008 SATURN KRAS data to be shared with Prof Wolf Linardou et al, Lancet Oncology Oct 2008

43. Summary Patients with EGFR mutations should be treated with an EGFR-TKI test in never- or light ex-smokers with adenocarcinoma Some patients with wild-type EGFR obtain clinical benefit from EGFR-TKIs treatment option in unselected relapsed patients KRAS mutations seem to be a negative predictor for response to EGFR-TKIs investigation ongoing; SATURN data expected at ASCO

45. Patient characteristics: considerations for optimising treatment outcomes The two previous talks have looked at the importance of considering histology and molecular markers in the treatment decision process. A number of clinical characteristics are also important and these will be presented shortly.The two previous talks have looked at the importance of considering histology and molecular markers in the treatment decision process. A number of clinical characteristics are also important and these will be presented shortly.

46. Audience question

47. Practical approach to treatment decisions Egbert Smit Vrije Universiteit Medical Centre Amsterdam, The Netherlands

48. Giving the best approved first-line treatment in advanced NSCLC Significantly prolongs PFS vs platinum doublets (E4599, AVAiL) Longest OS for non-squamous: 12.3 mos (E4599)1; 13.6 mos (AVAiL)2 adenocarcinoma: 14.2 mos (E4599)3

49. Non-squamous NSCLC patients will benefit from first-line Avastin

50. SAiL study schema

51. Avastin-based therapy in patients with hypertension Almost one third of patients enrolled in SAiL had a cardiovascular condition requiring cardiovascular medication at baseline. In spite of this high risk population, only 3.4% of patients experienced severe hypertension during the trial.Almost one third of patients enrolled in SAiL had a cardiovascular condition requiring cardiovascular medication at baseline. In spite of this high risk population, only 3.4% of patients experienced severe hypertension during the trial.

52. Avastin-based therapy in patients with central tumour location Diagnosis: adenocarcinoma right upper lobe (central lesion?) 07/07–09/07 carboplatin/vinorelbine (x 4) + Avastin 15mg/kg Stable disease No bleeding complications during or beyond treatment Information provided by Dr Reck: The ? followed the difficulties in the definition of central tumour lesions with infiltration of central vessels. Looking at this tumour one could argue that this might a central tumour invading a central vessel but on the other hand you also could say that this might be a tumour in the upper lobe just touching (not invading) the central vessels. I put up this case just to discuss the issue of central tumour and treatment with Avastin (we do have a more liberal way to classify a tumour as a central tumour with vessel invasion).Information provided by Dr Reck: The ? followed the difficulties in the definition of central tumour lesions with infiltration of central vessels. Looking at this tumour one could argue that this might a central tumour invading a central vessel but on the other hand you also could say that this might be a tumour in the upper lobe just touching (not invading) the central vessels. I put up this case just to discuss the issue of central tumour and treatment with Avastin (we do have a more liberal way to classify a tumour as a central tumour with vessel invasion).

53. Avastin-based therapy in patients receiving anticoagulation therapy (ACT)

54. ATLAS and PASSPORT: study designs Chemotherapy included carboplatin/paclitaxel, carboplatin/gemcitabine, carboplatin/docetaxel, cisplatin/gemcitabine, cisplatin/vinorelbine or cisplatin/docetaxel. Chemotherapy included carboplatin/paclitaxel, carboplatin/gemcitabine, carboplatin/docetaxel, cisplatin/gemcitabine, cisplatin/vinorelbine or cisplatin/docetaxel.

55. Avastin-based therapy in patients with treated CNS metastases Patients were treated on protocols for ATLAS or PASSPORT. The ATLAS phase III study allows chemotherapy + bevacizumab, followed by Avastin +/- Tarceva to disease progression, for patients with advanced non-squamous or peripherally located squamous NSCLC. Treatment for brain metastases was whole brain radiotherapy (WBRT). The PASSPORT phase II study tests bevacizumab in combination with first- or second-line systemic therapy in patients with non-squamous NSCLC and treated brain metastases. Treatment for brain metastases includes radiosurgery, neurosurgery or whole brain radiotherapy. As at ASCO 2008, 41 patients with brain metastases are enrolled in ATLAS, and 111 in PASSPORT. The findings presented by Akerley et al are based on data collected from March 2006 through October 2007. As of October 12, 2007, a total of 83 patients with brain metastases were treated with Avastin. The median number of Avastin doses (15 mg/kg/q3w) was 3 (range 1-16) in PASSPORT and 4 (1-17) in ATLAS; 6 patients were non-Avastin treated. No CNS haemorrhages were reported on either study during the main study treatment (95% CI: 0, 4.2). One Grade 2 CNS bleed was observed in a patient on post-progression therapy in ATLAS after 14 cycles of Avastin; the patient’s only site of disease progression was at the site of NS metastases. This new metastasis did not receive any additional localised radiotherapy/neurosurgery.Patients were treated on protocols for ATLAS or PASSPORT. The ATLAS phase III study allows chemotherapy + bevacizumab, followed by Avastin +/- Tarceva to disease progression, for patients with advanced non-squamous or peripherally located squamous NSCLC. Treatment for brain metastases was whole brain radiotherapy (WBRT). The PASSPORT phase II study tests bevacizumab in combination with first- or second-line systemic therapy in patients with non-squamous NSCLC and treated brain metastases. Treatment for brain metastases includes radiosurgery, neurosurgery or whole brain radiotherapy. As at ASCO 2008, 41 patients with brain metastases are enrolled in ATLAS, and 111 in PASSPORT. The findings presented by Akerley et al are based on data collected from March 2006 through October 2007. As of October 12, 2007, a total of 83 patients with brain metastases were treated with Avastin. The median number of Avastin doses (15 mg/kg/q3w) was 3 (range 1-16) in PASSPORT and 4 (1-17) in ATLAS; 6 patients were non-Avastin treated. No CNS haemorrhages were reported on either study during the main study treatment (95% CI: 0, 4.2). One Grade 2 CNS bleed was observed in a patient on post-progression therapy in ATLAS after 14 cycles of Avastin; the patient’s only site of disease progression was at the site of NS metastases. This new metastasis did not receive any additional localised radiotherapy/neurosurgery.

56. Appropriate patient selection reduces the risk of haemoptysis The incidence of haemoptysis with Avastin-based therapy is now within the range of spontaneous incidence in non-Avastin-treated patients. The incidence of haemoptysis with Avastin-based therapy is now within the range of spontaneous incidence in non-Avastin-treated patients.

57. Non-squamous NSCLC patients will benefit from first-line Avastin

58. First-line treatment considerations for patients with squamous NSCLC

59. Giving the best first-line treatment in advanced non-squamous NSCLC Significantly better outcomes vs platinum doublets1,2 Longest OS for non-squamous: 13.6 mos2 adenocarcinoma: 14.2 mos3 Majority of patients eligible

60. Second-line Tarceva OS*

61. All patient subgroups derive survival benefit from Tarceva (BR.21 study)

62. Giving the best second-line treatment in advanced NSCLC Tarceva Similar survival Better tolerability Effective across all subgroups of patients

63. Summary Patient characteristics can significantly impact on treatment selection in first-line and second-line Avastin-based therapy: proven to deliver the longest survival time in NSCLC First-line Avastin-based therapy: benefit in non-squamous NSCLC patients Second-line Tarceva: offers survival benefit across all subgroups of patients similar efficacy to chemotherapy better tolerated than chemotherapy Trials of Avastin and Tarceva are ongoing Avastin: different patient subgroups Tarceva: first-line and first-line maintenance

65. Chair’s conclusion and close Johan Vansteenkiste University Hospital Gasthuisberg Leuven, Belgium

66. Patient characteristics: considerations for optimising treatment outcomes

67. Avastin-based therapy provides clinical benefit regardless of chemotherapy regimen No survival benefit for Bevacizumab in combination with Cis/Gem Benefit for highly selected patient group only Exclusion criteria: squamous cell, hemoptysis, brain metastases, uncontrolled hypertension High risk of pulmonary bleedingNo survival benefit for Bevacizumab in combination with Cis/Gem Benefit for highly selected patient group only Exclusion criteria:squamous cell, hemoptysis, brain metastases, uncontrolled hypertension High risk of pulmonary bleeding

68. E4599 pre-planned subgroup analysis: unprecedented OS benefit in adenocarcinoma histology Avastin-based therapy (n=602) extends OS to 14.2 months 31% reduction in the risk of death (HR=0.69)

69. Tarceva: randomised data in relapsed advanced NSCLC (BR.21)

70. Role of molecular markers in NSCLC Molecular markers may play a role in treatment decision making Tarceva is effective against both mutant and wild-type EGFR1,2 particularly impressive clinical outcomes in patients with EGFR mutation-positive tumours Predictive value of KRAS mutations across tumour types cannot be extrapolated role as a predictive marker for Tarceva unclear3

71. Importance of clinical characteristics in NSCLC to optimise outcomes

72. BRIDGE: evaluating first-line Avastin-based therapy in squamous histology

73. ATLAS: phase III trial of first-line Avastin with or without Tarceva Chemotherapy included carboplatin/paclitaxel, carboplatin/gemcitabine, carboplatin/docetaxel, cisplatin/gemcitabine, cisplatin/vinorelbine or cisplatin/docetaxel. Chemotherapy included carboplatin/paclitaxel, carboplatin/gemcitabine, carboplatin/docetaxel, cisplatin/gemcitabine, cisplatin/vinorelbine or cisplatin/docetaxel.

74. SATURN: phase III trial of sequential Tarceva in unresectable NSCLC

75. Conclusions

76. Thank you for your participation

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