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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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2. Chairs welcome and introduction Johan Vansteenkiste
University Hospital GasthuisbergLeuven, 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 valuefor 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 Prol
Hpital de la Croix-RousseLyon, 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 cavitated13
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 Jrgen Wolf
Center for Integrated OncologyUniversity Hospital of CologneCologne, 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 1824most 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;11:190208Mitsudomi T, et al. Int J Clin Oncol 2006;11:190208
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-typeand 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 efficacyto 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 1530% 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 CentreAmsterdam, 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?)
07/0709/07 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 patients 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 patients 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. Chairs conclusion and close Johan Vansteenkiste
University Hospital GasthuisbergLeuven, 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 sequentialTarceva in unresectable NSCLC
75. Conclusions
76. Thank you for your participation