R. Gaafar - Lung cancer - Guidelines and clinical case presentation (2-3 cases)

2,183 views
1,995 views

Published on

Published in: Health & Medicine, Business
0 Comments
3 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
2,183
On SlideShare
0
From Embeds
0
Number of Embeds
8
Actions
Shares
0
Downloads
0
Comments
0
Likes
3
Embeds 0
No embeds

No notes for slide
  • Kras and other biomarkers and metatanlsis wcclc 2009
  • Gefitinib significantly prolongs PFS (HR = 0.68); OS prolongation not significant, HR = 0.86 PFS benefit occurs late and is impressive at later time points Tarceva significantly prolongs PFS (HR = 0.71) and PFS benefit occurs relatively early and is prolonged Benefit is greatest in EGFR mutated patients but is independent of histology The ‘ n ’ s in the population represents the actually treated patients = safety population. There were a number of cases that progressed before tarceva therapy could be started, the baseline scan was reevaluated and re-classified as PD… etc. 20% censoring in erlotinib arm and 10% censoring in the placebo arm.
  • Pre-specified analyses in the statistical analysis plan for study BR.21 included stratifications on the basis of performance status, prior therapy (including platinum therapy), responsiveness to prior therapy, and HER1/EGFR status. Treatment of NSCLC patients with erlotinib resulted in a statistically significant improvement in the primary endpoint of overall survival versus placebo. In a univariate analysis of all patients, the hazard ratio was 0.72 (ie patients treated with erlotinib had a 28% better chance of survival compared with placebo) Patients treated with erlotinib (median survival=6.7 months) survived 30% longer than placebo-treated patients (median survival=4.7 months). One-year survival rates were increased 48% by treatment with erlotinib. Erlotinib is the only HER1/EGFR inhibitor proven to prolong the survival of patients with advanced, refractory NSCLC.
  • R. Gaafar - Lung cancer - Guidelines and clinical case presentation (2-3 cases)

    1. 1. Guidelines on the Treatment of Advanced Non-Small Cell Lung Cancer Rabab Gaafar, MD Prof. Medical Oncology NCI Cairo, Cairo University Board Member EORTC Lung EASO Amman , 2011
    2. 2. Guidelines on the Treatment of Advanced Non-Small Cell Lung Cancer <ul><li>1- First-line Therapy </li></ul><ul><li>2- Maintenance therapy </li></ul><ul><li>3- Therapy in pre-treated patients </li></ul>
    3. 4. NSCLC <ul><li>Generally, treatment should be initiated after interdisciplinary discussion, ideally at a tumour-board or conference involving different specialists (medical and radiation oncologist, pneumologist, thoracic surgeon, radiologist and pathologist). </li></ul><ul><li>Systemic treatment should be guided by an experienced medical oncologist and selection of agents should take into account the patient's situation, the treatment goal and potential side-effects of the different treatments. </li></ul>
    4. 5. “ Evidence – Based Medicine” Meta-Analysis of Phase III Trials Randomized Phase III Trial Phase II Clinical Trial (s) Anecdotes In Vitro/Vivo Data Phase I Clinical Trial (s)
    5. 6. Levels of Evidence <ul><li>Category 1 : Evidence is obtained from metaanalysis ,randomized trials with low false positive and low low false negative errors (high power) </li></ul><ul><li>Category 2: : Evidence is obtained from at least 1 well designed experimental study, randomized trials with high false positive and or negative errors (low power) </li></ul><ul><li>Category 3: Evidence obtained from well designed –quasi experimental studies, such as non randomized controlled single group , or matched case control series. </li></ul><ul><li>Category 4 : The recommendation is based on any level of evidence but reflects major disagreement . </li></ul><ul><li>Category 5 : Evidence from case reports and clinical examples . </li></ul>
    6. 7. Grades of Recommendation <ul><li>A Evidence of type I or consistent findings from multiple studies of types II, III, or IV. </li></ul><ul><li>B Evidence of type II, III, or IV and findings are generally consistent. </li></ul><ul><li>C Evidence of type II, III, or IV but findings are inconsistent. </li></ul><ul><li>D Little or no systematic empirical evidence. </li></ul>
    7. 8. First Line Therapy
    8. 9. Recommendation 1 <ul><li>Platinum-based combination chemotherapy prolongs survival, improves quality of life, and controls symptoms in patients with a good performance status (PS 0-2) [I, A]. </li></ul>
    9. 11. G.Giaccone, ESMO 2004 Doubling of RR, Doubling of MST and 4 times more in 1 year survival.
    10. 12. Recommendation 2 <ul><li>there is no standard platinum-based doublet for metastatic NSCLC (IA) </li></ul><ul><li>Pemetrexed is preferred to gemcitabine in patients with non-squamous histology according to a survival benefit demonstrated in a pre-planned subgroup analysis of one large randomized clinical trial [II, B]. </li></ul>
    11. 13. Kelly K, et al. J Clin Oncol 2001; 19:3210–3218; Schiller JH, et al. N Engl J Med 2002;346:92–98; Scagliotti GV, et al. J Clin Oncol 2002;20:4285–4291 1 st -line platinum-based CT: Efficacy plateau OS, overall survival Study arm OS (mo) 1 year (%) PCb 8.6 38 CV 8.1 36 Study arm OS (mo) 1 year (%) PC 7.8 31 GC 8.1 36 DC 7.4 31 PCb 8.1 34 Study arm OS (mo) 1 year (%) PCb 9.9 43 GC 9.8 37 CV 9.5 37 Pacli + carbo (PCb) Cis + vin (CV) Overall survival % 100 80 60 40 20 0 0 Months Months Overall survival 30 Pacli + cis (PC) Gem + cis (GC) Doc + cis (DC) Pacli + carbo (PCb) 5 10 15 20 25 Pacli + carbo (PCb) Gem + cis (GC) Cis + vin (CV) Months 0 1.0 0.9 0.6 0.5 0.4 0.3 0.8 0.7 0.2 0.1 0 1.0 0.9 0.6 0.5 0.4 0.3 0.8 0.7 0.2 0.1 0 Overall survival 30 5 10 15 20 25 0 30 5 10 15 20 25
    12. 14. Cisplatin/Pemetrexed versus Cisplatin/Gemcitabine Scagliotti G et al. JCO 2008, 26, 3543 Superiority of pemetrexed/cisplatin in non-squamous cell carcinomas p =0.011 p =0.051
    13. 15. Incidence of Histological Subtypes in the World Atlas of Cytogenetics in Oncology and Haematology. Available from: http://atlasgeneticsoncology.org/Tumors/LungNonSmallCellID5141.html Accessed January 26, 2011; Bryant A, Cerfolio RJ. Chest 2007;132:185–192 Ginsberg RJ, et al. Cancer: Principles and Practices of Oncology. 5th ed. 1997;858-911.
    14. 16. Recommendation 3 <ul><li>Platinum-based chemotherapy is preferred to non-platinum-based chemotherapy in eligible patients with metastatic NSCLC (I A). </li></ul>
    15. 17. <ul><li>According to results of Two meta-analyses, non-platinum-based combination chemotherapy of third-generation agents can be considered if platinum therapy is contraindicated. </li></ul><ul><li>Most trials show lower response rates for non-platinum combinations but similar survival rates [I, A]. </li></ul><ul><li>The absolute survival benefit for patients treated with platinum-based chemotherapy was 3% at 1 year, corresponding to a reduction in the risk of death within the first year with an HR of 0.88 (95% CI 0.78–0.99,  P  = 0.044 ). </li></ul>
    16. 18. EORTC 08975: Survival (n=480) (Platin-based vs Platin-free CT) (months) 0 3 6 9 12 15 18 21 24 27 30 0 10 20 30 40 50 60 70 80 90 100 v. Meerbeeck et al. ASCO 2001 Pac/Gem 6.9 mo 26.6% Gem/Cis 8.8 mo 32.6% Pac/Cis 8.1 mo 32.1% MS 1-yr-S
    17. 19. Recommendation 4 <ul><li>Cisplatin should be used in fit patients with PS 0-1 who have adequate organ function (I, B) </li></ul><ul><li>Several meta-analyses showed higher response rates for cisplatin combinations when compared with carboplatin combinations. </li></ul><ul><li>Overall survival was significantly superior for cisplatin in the subgroup of non-squamous histologies treated with third-generation regimens in one meta-analysis (I A) . </li></ul>
    18. 20. CISCA Meta-Analysis(3000 pts) Survival <ul><li>HR = 1.07 (95% CI: 0.99-1.15) </li></ul>Ardizzioni, JNCI 2007 p = 0.101 overall, But p < 0.05 with Cisplatin given with Newer or “3rd” Generation agents
    19. 21. Recommendation 5 <ul><li>  in PS 2 patients either single-agent chemotherapy or platinum-based combinations are valid options </li></ul><ul><li>(I B). </li></ul>
    20. 22. <ul><li>Subgroup analyses from several randomized trials suggest that several new-generation cytotoxic drugs are superior to BSC alone in this category of patients. </li></ul><ul><li>Taking into account the superiority shown by the carboplatin/paclitaxel combination compared with paclitaxel alone in a subgroup analysis of PS 2 patients,  platinum-based combinations may also be considered as an option for these patients. </li></ul><ul><li>  </li></ul>
    21. 23. Recommendation 6 <ul><li>platinum-based chemotherapy is preferred in fit elderly patients with PS 0–1 and adequate organ function. </li></ul><ul><li>Single-agent third-generation drugs are preferred in unfit elderly patients (I B) </li></ul>
    22. 24. Recommendation 7 Timing and duration of first line chemotherapy <ul><li>  four cycles of chemotherapy appear sufficient in most NSCLC patients but six cycles may be considered depending on response and toxicity (II B) </li></ul>
    23. 25. Phase III Randomized Trial of 3 Versus 6 Courses of MVP <ul><li>Smith IE et al. J Clin Oncol 19:1336, 2001 </li></ul><ul><li>Patient Population: 308 IIIB and IV </li></ul><ul><li>Mitomycin 8 mg/m 2 , Vinblastine 6 mg/m, 2 cisplatin 50 mg/m 2 </li></ul><ul><li>Cycle length 21 days </li></ul>
    24. 26. Recommendation 8 <ul><li>bevacizumab combined with platinum-based chemotherapy is a treatment option in eligible patients with nonsquamous NSCLC, in particular when carboplatin/paclitaxel combination is the chemotherapy back bone (I B). </li></ul>
    25. 27. Bevacizumab in advanced NSCLC ECOG 4599 Sandler A et al. NEJM 2006, 355, 2542 AVAiL Reck M et al. JCO 2009, 27, 1227 6.2 months HR=0.66 p<0.001 Median PFS 6.7 months HR=0.75 p=0.003 6.5 months HR=0.82 p=0.03 Significant PFS Benefit <ul><ul><li>21% improvement in OS, </li></ul></ul><ul><ul><li>34%improvement in PFS </li></ul></ul>
    26. 28. AVAPERL: PFS from induction a Bev+pem 10.2 months (81 events) Bev 6.6 months (104 events) HR, 0.50 (0.37–0.69); P <.001 Progression -free survival (%) Time (months) 128 126 103 66 25 4 0 125 122 73 38 12 2 0 100 75 50 25 0 0 3 6 9 12 15 18 Pts at risk Bev+pem Bev Bev, bevacizumab; HR, hazard ratio; Pem, pemetrexed; pts, patients. a Randomized pts, Intent-to-treat population Barlesi et al ASCO 2011 Cont. maintenance bev+pem (n=128) Cont. maintenance bev (n=125)
    27. 29. Recommendation 9 <ul><li>cetuximab added to platinum-based chemotherapy can be considered as a treatment option for patients with EGFR immunohistochemistry positive metastatic NSCLC, in particular when cisplatin/vinorelbine is the chemotherapy backbone (I B) </li></ul><ul><li>A meta-analysis of 2018 patients from two randomized phase II trials and the two phase III trials confirmed the efficacy of cetuximab when added to chemotherapy.  </li></ul><ul><li>The benefit of cetuximab was seen irrespective of either histological subtype or type of platinum-based chemotherapy. </li></ul><ul><li>The main cetuximab-related adverse event is an acne-like rash that has been shown to be associated with prolonged survival. </li></ul>
    28. 30. FLEX Overall Survival Months Overall Survival (%) HR = 0.871 (95% CI 0.762-0.996), P = 0.044 42 % 10.1 months <ul><li>CT (n = 568) </li></ul>47 % 11.3 months <ul><li>CT + Cetuximab (n = 557) </li></ul>1-year survival Median OS Pirker et al Lancet 2009 Cisplatin 80 mg/m 2 day 1 Vinorelbine 25 (30) mg/m 2 days 1, 8 Every 3 weeks, up to 6 cycles
    29. 31. Response rate by EGFR expression levels CT CT + cetuximab High EGFR expression (≥200) n=345 (31%) Low EGFR expression (<200) n=776 (69%) Response rate (%) p=0.36 p=0.002 Treatment interaction test p=0.040 CT, chemotherapy 0 50 40 30 20 10 44.4 28.1 0 50 40 30 20 10 29.6 32.6
    30. 32. Recommendation 10 <ul><li>an EGFR TKI is the preferred first-line treatment in patients whose tumor harbors an activating EGFR mutation (I A). </li></ul>
    31. 33. IPASS Phase III Study: First-line Gefitinib vs CP in Advanced NSCLC Untreated Asian patients* with stage IIIb/IV NCSLC and PS 0-2 (N = 1217) Gefitinib 250 mg/day (n = 609) Carboplatin AUC 5-6 + Paclitaxel 200 mg/m 2 3 every wks † (n = 608) Fukuoka M, et al. ASCO 2009. Abstract 8006. Primary endpoint: PFS Secondary endpoints: OS, ORR, QoL, disease-related symptoms, safety, tolerability Biomarker analysis: EGFR mutation, expression, and gene copy number *Never smokers or ex-light smokers. † ≤ 6 cycles. Gefitinib as first line
    32. 34. <ul><ul><ul><li>EGFR mutant patients had a response rate to </li></ul></ul></ul><ul><ul><ul><li>Gefitinib of 71% (versus 47% with chemo), while those who were EGFR wild-type had an ORR of 1.1% with Gefitinib versus 23.5% with chemo </li></ul></ul></ul>
    33. 35. EGFR mutation positive 12 mo prog-free: HR: 0.74; p<0.0001 GEF: 25% PC: 7%
    34. 36. 230 patients with EGFR mutated tumors
    35. 38. OPTIMAL: confirmed superiority of erlotinib vs chemotherapy in EGFR Act Mut+ NSCLC HR=0.16 (0.10–0.26) Log-rank p<0.0001 13.1 4.6 PFS probability 1.0 0.8 0.6 0.4 0.2 0 0 5 10 15 20 Time (months) Zhou, et al. ESMO 2010 Cut-off date 16 August 2010 8.5 months difference in PFS Gem/carbo (n=72) Erlotinib (n=82)
    36. 39. PFS in ITT population (updated analysis 26 Jan 2011) PFS probability Erlotinib (n=86) Chemotherapy (n=87) HR=0.37 (0.25–0.54) Log-rank p<0.0001 Time (months) 0 3 6 9 12 15 18 21 24 27 30 33 Patients at risk Erlotinib 86 63 54 32 21 17 9 7 4 2 2 0 Chemo 87 49 20 8 5 4 3 1 0 0 0 0 Data cut-off: 26 Jan 2011 1.0 0.8 0.6 0.4 0.2 0 9.7 5.2 EURTAC study 4.5 months difference in PFS
    37. 40. Overall survival in ITT population (interim analysis 2 Aug 2010) EURTAC study OS probability 1.0 0.8 0.6 0.4 0.2 0 Erlotinib (n=77; 35% with event) Chemotherapy (n=76; 36% with event) HR=0.80 (0.47–1.37) Log-rank p=0.4170 Time (months) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Patients at risk Erlotinib 77 61 53 41 34 22 14 11 9 2 1 1 1 0 Chemo 76 59 43 35 25 18 14 7 3 2 2 2 0 0 Data cut-off: 2 Aug 2010 N.B. 59 pts in chemotherapy arm had PFS event; 51 of these had second-line treatment, of whom 49 had EGFR TKI
    38. 41. Maintenance Therapy
    39. 42. Recommendation 11 <ul><li>Poor performance status (PS3–4) patients should be offered best supportive care [II, B]. </li></ul><ul><li>In PS3 patients with EGFR-mutated NSCLC TKI treatment (erlotinib or gefitinib) may be justified </li></ul><ul><li>[V, D]. </li></ul><ul><li>To date, other molecular markers (except for activating EGFR mutation for consideration of first-line use of gefitinib and erlotinib) should not be used for treatment decisions </li></ul>
    40. 43. Recommendation 12 Maintenance Therapy <ul><li>  'switch maintenance ' treatment with erlotinib or pemetrexed following completion of first-line chemotherapy is an option. </li></ul><ul><li>Decision factors for the use of 'switch maintenance' include histology, type and response to first-line chemotherapy, residual toxicity, patient's symptoms and preference. </li></ul><ul><li>Any patient whose tumor harbors an activating EGFR mutation should receive an EGFR TKI as maintenance, if not yet received as first line (I B). </li></ul>
    41. 44. Historical approach to NSCLC treatment <ul><li>As a result of cumulative toxicity, patients receive a limited number of cycles of chemotherapy </li></ul><ul><li>According to ASCO guidelines 1 , those with stable disease or better will be observed, with regular follow up to check for disease progression – ‘watch and wait’ approach </li></ul>Diagnosis CR/PR/SD First-line treatment Platinum doublet chemotherapy (4–6 cycles) ‘ Watch and wait’ PD Second and further lines of treatment PD 1 Pfister DG, et al. J Clin Oncol 2004;22:330–53
    42. 45. Double-blind, Placebo-controlled, Multicenter, Phase III Trial JMEN Overall Survival (Intent-to-treat Population) Belani, et al. Presented at: Annual Meeting of the American Society of Clinical Oncology, 2009. MAINTENANCE ALIMTA ® (PEMETREXED) AFTER PRIOR PLATINUM IN STAGE IIIB/IV NSCLC Pemetrexed 13.4 mos Placebo 10.6 mos Survival Probability Time (months) HR=0.79 (95% CI: 0.65–0.95) p=0.012 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
    43. 46. Overall Survival by Histology JMEN Pemetrexed 9.9 mos Placebo 10.8 mos Squamous (n=182) HR=1.07 (95% CI: 0.77–1.50) p =0.678 Time (months) Non-squamous Pemetrexed 15.5 mo Placebo 10.3 mo HR=0.70 (95% CI: 0.56-0.88) p=0.002 Survival Probability Time (months) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Survival Probability Belani, et al. Presented at: Annual Meeting of the American Society of Clinical Oncology, 2009. 5 months difference in Non squamous histology
    44. 47. Investigator Assessed PFS (from Maintenance) PARAMOUNT (Continuous Maintenance) Pemetrexed: median =4.1 mos (3.2-4.6) Placebo: median =2.8 mos (2.6-3.1) Log-rank P =0.00006 Unadjusted HR: 0.62 (0.49-0.79) Patients at Risk Pem + BSC N=359 132 57 21 4 0 Placebo + BSC N=180 52 15 5 0 0 Pem + BSC Placebo + BSC
    45. 48. Independently Reviewed Tumor Response* (Maintenance) - All randomized patients PARAMOUNT * Response represents a further tumor reduction from the baseline response to induction therapy Pemetrexed (N=316) n (%) Placebo (N=156) n (%) P-value CR 0 0 PR 9 (2.8) 1 (0.6) RR: CR+PR 9 (2.8) 1 (0.6) 0.176 SD 218 (69.0) 92 (59.0) DCR: CR+PR+SD 227 (71.8) 93 (59.6) 0.009 PD 88 (27.8) 61 (39.1) Other / ND 1 (0.3) 2 (1.3)
    46. 49. Phase III Studies of EGFR TKI Maintenance 1. Cappuzzo F, et al. ASCO 2009. Abstract 8001. 2. Cappuzzo F, et al. Lancet Oncol. 2010;11:521-529. 3. Miller VA, et al. ASCO 2009. Abstract LBA8002. 4. Kabbinavar FF, et al. ASCO 2010. Abstract 7526. 5. Perol M, et al. ASCO 2010. Abstract 7507. 6 . Gaafar RM, et al. ASCO 2010. Abstract 7518 . Trial Treatment Comparison N PFS OS HR (95% CI) P Value HR (95% CI) P Value SATURN [1,2] Erlotinib vs placebo 1949 0.71 (0.62-0.82) < .0001 0.81 (0.70-0.95) 0.009 ATLAS [3,4] Bev + erlotinib vs bev + placebo 1160 0.72 (0.59-0.88) .0012 0.92 (0.70-1.21) .5604 IFCT-GFPC 0502 [5] Erlotinib vs observation 834 0.82 (0.73-0.93) .002 0.91 (0.80-1.04) NS EORTC 08021 [6 ] Gefitinib vs placebo 173 0.61 (0.45-0.83) .0015 0.83 (0.60-1.15) .2
    47. 50. Tarceva maintenance therapy after first-line chemotherapy treatment SATURN Cappuzzo et al. Lancet Oncology 2010 Probability Time (weeks) PFS OS 0 8 16 24 32 40 48 56 64 72 80 88 96 Time (weeks) 0 8 16 24 32 40 48 56 64 72 80 88 96 Erlotinib (n=438) Placebo (n=451) Erlotinib (n=437) Placebo (n=447) HR=0.71 (0.62–0.82) Log-rank p<0.0001 HR=0.81 (0.70–0.95) Log-rank p=0.0088 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0
    48. 51. PFS WITH MAINTENANCE TARCEVA IN EGFR MUTATION+ and WILD-TYPE SATURN 1.0 0.8 0.6 0.4 0.2 0 Time (weeks) 1.0 0.8 0.6 0.4 0.2 0 Time (weeks) 0 8 16 24 32 40 48 56 64 72 80 88 96 0 8 16 24 32 40 48 56 64 72 80 88 96 Interaction p<0.001 PFS probability Log-rank p<0.0001 HR=0.10 (0.04–0.25) Log-rank p=0.0185 HR=0.78 (0.63–0.96) EGFR mutation+ EGFR wild-type Brugger et al ASCO 2009 abstr 8020 Tarceva (n=199) Placebo (n=189) Tarceva (n=22) Placebo (n=27)
    49. 52. OS probability 1.0 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) 9.6 11.9 1.0 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) 12.0 12.5 Log-rank p=0.0019 HR=0.72 (0.59–0.89) Log-rank p=0.6181 HR=0.94 (0.74–1.20) SD CR/PR OS is measured from time of randomisation into the maintenance phase Coudert et al. ELCC 2010 OS according to response to 1 st line chemotherapy SATURN Erlotinib (n=252) Placebo (n=235) Erlotinib (n=184) Placebo (n=210)
    50. 53. Hazard Ratio(95% CI) = 0.81 (0.59,1.12 ) Median in months (95% CI) Placebo : 9.4 (6.6,13.8) Gefitinib : 10.9 (9.2,13.8) Gaafar RM, et al. ASCO 2010. Abstract 7518 EORTC 08021 A double-blind, randomized, placebo-controlled phase III intergroup study of gefitinib (G) in patients (pts) with advanced NSCLC, non-progressing after first line platinum-based chemotherapy (EORTC 08021- ILCP 01/03). Number of patients = 173 Started 2004 Ended 2009 40% reduction in developing PD
    51. 55. PFS by EGFR mutation status (unknown) INFORM † Estimated using the Kaplan-Meier method HR <1 implies a lower risk of progression on gefitinib EGFR mutation-unknown Time (weeks) 0 20 40 60 80 100 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 PFS (%) 109 64 36 20 11 8 5 3 2 1 1 1 0 0 0 108 80 62 53 49 44 39 34 31 22 15 12 5 1 0 Placebo Gefitinib No. of patients at risk 27 centers China 296 patients HR (95% CI) = 0.40 (0.29, 0.54) Gefitinib (n=108) Median PFS † , 6.0 months No. events, 90 (83.3%) Placebo (n=109 ) Median PFS † , 2.7 months No. events, 105 (96.3%)
    52. 56. Progression-free survival by EGFR mutation status † Estimated using the Kaplan-Meier method HR <1 implies a lower risk of progression on gefitinib 0 20 40 60 80 100 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 PFS (%) Time (weeks) 15 9 5 3 3 2 1 1 1 1 1 1 0 0 0 15 15 14 14 13 11 10 18 7 7 5 3 1 0 0 Placebo Gefitinib No. of patients at risk 0 20 40 60 80 100 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 PFS (%) Time (weeks) 24 9 5 3 2 0 0 0 0 0 0 0 0 0 0 25 14 6 3 3 1 0 0 0 0 0 0 0 0 0 Placebo Gefitinib No. of patients at risk 83% reduction of PD in mutated cases HR (95% CI) = 0.17 (0.07, 0.42) Gefitinib (n=15) Median PFS † , 16.6 months No. events, 9 (60.0%) Placebo (n=15) Median PFS † , 2.8 months No. events, 15 (100.0%) EGFR mutation-positive HR (95% CI) = 0.86 (0.48, 1.51) Gefitinib (n=25) Median PFS † , 2.7 months No. events, 25 (100.0%) Placebo (n=24) Median PFS † , 1.5 months No. events, 24 (100.0%) EGFR mutation-negative
    53. 57. Objective response rate and disease control rate (RECIST; ITT population) INFORM ORR (%) (n=148) (n=148) Odds ratio >1 implies a greater chance of response on gefitinib Odds ratio and p-value from logistic regression with covariates ITT, intent-to-treat; RECIST, Response Evaluation Criteria In Solid Tumors Odds ratio (95% CI) = 54.1 (7.17, 408); p= 0.0001 (n=148) (n=148) DCR (%) Odds ratio (95% CI) = 2.69 ( 1.62 , 4.46); p= 0.0001
    54. 58. Overall survival (ITT population) INFORM 0 16 40 56 72 96 112 0 10 40 60 80 100 Overall survival (%) 20 30 50 70 90 8 24 32 48 64 80 88 104 120 128 Time (weeks) Placebo Patients at risk: 148 136 97 78 37 0 0 147 115 107 91 66 13 6 0 148 129 102 84 39 0 0 141 114 108 90 75 18 4 0 47 56 127 119 Gefitinib HR (95% CI) = 0.84 (0.62, 1.14); p=0.2608 Gefitinib (n=148) Placebo (n=148) Median OS, months 6-month survival rate, % 12-month OS rate, % No. events, n (%) 18.7 82.2 68.8 79 (53.4) 16.9 84.9 66.0 93 (62.8) HR <1 implies a lower risk of death on gefitinib
    55. 59. Second Line Therapy
    56. 60. Recommendation 13 Second or third-line therapy should be offered to patients with good PS who present with signs of disease progression (radiological and/or clinical) after first or second-line therapy (I A)
    57. 61. <ul><li>Second-line treatment improves disease-related symptoms and survival in patients with PS0–2 [docetaxel, pemetrexed (non-squamous histology only), gefitinib]; the same is true for erlotinib in second-line patients who cannot tolerate chemotherapy and third-line patients with PS0–3 [I, A]. </li></ul><ul><li>Second-line combination regimens have demonstrated higher response and progression-free survival but no improvement of overall survival compared with single-agent treatments in a recent meta-analysis [I, A]. </li></ul>
    58. 62. Survival (ITT) Pemetrexed (n=283 ) Docetaxel (n=288) Survival Distribution Function Months ITT = intent to treat HR = hazard ratio CI = confidence interval MST = median survival time 0.00 0.25 0.50 0.75 1.00 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 MST 8.3 mos 1-yr OS: 29.7% HR 0.99 95% CI of HR (0.82, 1.20) MST 7.9 mos 1-yr OS: 29.7% Hanna et al, ASCO 2003 Docetaxel vs Pemetrexed in Second line Therapy Equal Efficacy and less Toxicity
    59. 63. The Canadian NCIC BR.21 Trial : 731 Patients Significantly improved survival with Tarceva * HR and P -value adjusted for stratification factors at randomization plus HER1/EGFR status. Shepherd et al. N Engl J Med. 2005;353:123-132 HR= 0.70 (95% CI, 0.58-0.85); P < 0.001 21% 31% 1-year Survival 4.7months 6.7 months Median Survival Placebo n= 243 Erlotinib n= 488 45% increase in 1-year survival rate 27% reduction in risk of death with tarceva 42.5% increase in median OS 21% 31% Survival time (months) Survival distribution function 0 5 10 15 20 25 30 1.00 0.75 0.50 0.25 0 Erlotinib Placebo
    60. 64. BR.21: Survival by Smoking Status Shepherd et al. J Clin Oncol. 2005;353:123-132; Shepherd et al. Proc Am Soc Clin Oncol. 2004 Never Smokers Erlotinib Placebo Response Rate 24.7% 2.9% Median Survival 12.3 mos 5.6 mos HR= 0.42 (95% CI: 0.28 to 0.64) Survival distribution function 1.00 0.75 0.50 0.25 0 Months 0 5 10 15 20 25 Placebo (n= 42 ) Erlotinib (n= 104) Placebo (n= 187 ) Erlotinib (n= 358) Months 0 5 10 15 20 25 30 1.00 0.75 0.50 0.25 Current/Ex Smokers Erlotinib Placebo Response Rate 3.9% <1% Median Survival 5.5 mos 4.6 mos HR= 0.87 (95% CI: 0.71 to 1.05)
    61. 65. HORG : phase III study of erlotinib vs pemetrexed (≥second-line) <ul><li>Primary endpoint = TTP </li></ul><ul><li>Secondary endpoints = RR, OS, safety </li></ul>Erlotinib 150mg/day (n=166) Pemetrexed (n=166) R <ul><li>Stage IIIB/IV NSCLC </li></ul><ul><li>1–2 prior chemotherapy regimens </li></ul><ul><li>ECOG PS 0–2 </li></ul><ul><li>(n=332) </li></ul>HORG = Hellenic Oncology Research Group Vamvakas, et al. ASCO 2010 (Abs. 7519)
    62. 66. HORG : comparable TTP and OS with second-line erlotinib and pemetrexed in NSCLC Probability 1.0 0.8 0.6 0.4 0.2 0 0 5 10 15 20 25 30 35 40 45 Time (months) 1-year survival rate (%) 35.7% Erlotinib 38.5% Pemetrexed Time (months) 1.0 0.8 0.6 0.4 0.2 0 Erlotinib (n=166) Pemetrexed (n=166) p=0.916 Erlotinib (n=163) Pemetrexed (n=161) p=0.299 TTP OS 0 5 10 15 20 25 30 35 40 45 Vamvakas, et al. ASCO 2010 (Abs. 7519)
    63. 67. Gefitinib vs Docetaxel; second-line treatment for advanced NSCLC INTEREST <ul><li>Gefitinib is </li></ul><ul><li>as effective as docetaxel </li></ul><ul><li>in all subgroups </li></ul><ul><li>GEF is a valid option for second-line treatment with improvement in QoL </li></ul>N: 1466; Non-inferiority Strtf: histology (adeno ca vs others ) Douillard et al. WCLC 2007
    64. 68. Recommendation 14 <ul><li>Choice of Treatment in Second or Third-line NSCLC With Regard to Histology? (II B) </li></ul><ul><li>for nonsquamous tumors, data support the use of pemetrexed or EGFR TKIs. </li></ul><ul><li>  for squamous tumors, data support the use of docetaxel or EGFR TKIs. </li></ul><ul><li>in the presence of EGFR sensitizing mutations, the use of an EGFR TKI is recommended if not received previously. </li></ul>
    65. 69. Conclusion <ul><ul><li>Platinum-based doublets with a 3 rd generation drug </li></ul></ul><ul><ul><ul><li>pemetrexed preferred to gemcitabine in patients with non-squamous cell NSCLC in doublet platinum combination. </li></ul></ul></ul><ul><ul><ul><li>plus bevacizumab in selected patients with non-squamous NSCLC </li></ul></ul></ul><ul><ul><ul><li>plus cetuximab in EGFR-expressing NSCLC ( Cetuximab not yet approved) </li></ul></ul></ul><ul><ul><li>Gefitinib or Erlotinib in patients with EGFR-activating mutations may be alternative to chemotherapy </li></ul></ul><ul><li>Adequate biopsy tissue is required for molecular diagnosis of NSCLC </li></ul><ul><li>Pathology is required to differentiate Squamous from Adenocarcinoma </li></ul><ul><li>Maintenance treatment is approved and should be discussed with the patient. </li></ul><ul><li>Second line therapy may be chemotherapy (Pemetrexed or Docetaxel) or TKI . </li></ul><ul><li>Treatment based on molecular diagnosis is becoming the emerging standard </li></ul>
    66. 70. First step : Clinical criteria Third step : Molecular Criteria Second step : Histological criteria Asian Erlotinib Female Light or never smoker Gefitinib Untreated CNS metastasis Uncontrolled hypertension bevacizumab, No hemoptysis Adenocarcinoma = Erlotinib Gefitinib Non squamous = Bevacizumab Pemetrexed EGFR mutated = Gefitinib EML4 ALK = Crizotinib The Change from an Empiric Treatment to Personalized Treatment Occurred in Different Steps
    67. 71. NSCLC Guidelines according to NCCN (current and expected approval status considered) 2 nd Line Adapted and simplified from NSCLC NCCN Guidelines (version 3.2011) * For PS 3–4 best supportive care only; ‡ If eligible for bevacizumab § Approval expected in 2011 ¶ Bevacizumab is not licensed for second-line use in NSCLC Maintenance 1 st Line Erlotinib or pemetrexed or docetaxel, based on prior therapy Histologic assessment Erlotinib Platinum doublet* Erlotinib or docetaxel, based on prior therapy Platinum doublet Bevacizumab ‡¶ Post - platinum Start erlotinib or pemetrexed Continuation of bevacizumab EGFR mut- or unknown EGFR TKI (Erlotinib § ) EGFR mut+ Platinum doublet * Bevacizumab ‡ Squamous cell Non-squamous EGFR mutation testing

    ×