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Chicago 2008: Post - ASCO Analysis Advanced and Metastatic NSCLC

Chicago 2008: Post - ASCO Analysis Advanced and Metastatic NSCLC. CONTENT. Take Home Message . . . . . 2 First-Line treatment with Navelbine . . . 4 First-Line treatment – Other Agents . . . 12 Targeted Treatments . . . . . 16 Maintenance Therapy . . . . . 21

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Chicago 2008: Post - ASCO Analysis Advanced and Metastatic NSCLC

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  1. Chicago 2008: Post - ASCO AnalysisAdvanced and Metastatic NSCLC CONTENT • Take Home Message . . . . . 2 • First-Line treatment with Navelbine . . . 4 • First-Line treatment – Other Agents . . . 12 • Targeted Treatments . . . . . 16 • Maintenance Therapy . . . . . 21 • Elderly or PS 2 patients . . . . . 32 • Second Line Treatments . . . . . 40 • New Developments . . . . . 45

  2. ASCO 2008 - Advanced NSCLC:Take Home Message • EGFR-targeted therapies deeply developed ... • Navelbine + CDDP as Reference treatment and … • FLEX NP+Cetuximab • The first combination confirming effectiveness of targeted Therapy as front line CT • Maintenance treatment improves PFS and…maybe OS: • The opportunity for Navelbine Oral ! • More data to differenciate treatment between Adeno & Squamous • Second Line Treatment: • Chemotherapy or targeted therapy? • … and now Third line treatments under development!

  3. Prediction of survival benefit:Correlation with RR, PFS and OS • Mandrekar, #8021p: • PFS is more predictive of OS than best/confirmed OR (BR/CR) for PS2 • PFS 6m is significantly associated with survival than BR or CR p<0.001 • DC (CR,PR, SD) 8 w is a better predictor of OS than tumour response • Hotta, #8022p • TTP useful surrogate marker as an alternative to OS • Buyse # 8019o • In 2838 pts, 7 trials, PFS correlated to OS (R2=0.68 CI 0.67-0.68) • Median PFS 5.5m MOS 10 m

  4. ASCO 2008:First-Line Treatment: Navelbine

  5. First-Line Treatment - FLEX TrialPhase III Navelbine-CDDP + Cetuximab (Pirker, #3o) Primary endpoint : Overall survival (845 events, 1100 pts) NSCLC wet IIIB/IV EGFR + expressing Maintenance Arm A: NVB/CDDP + Cetuximab Cetuximab until PD or untolerable toxicity Arm B: NVB/CDDP Chemotherapy (CT) Cetuximab Cisplatin 80 mg/m2 day 1 Loading dose 400 mg/m2 Vinorelbine 25 (30) mg/m2 day 1, 8  250 mg/m2 weekly Every 3 weeks, up to 6 cycles # = N Abstract; O = Oral presentation; P = Poster; NP + Cetuximab : the winner doublet in 1st line

  6. OS Race/Histology CT + Cetuximab CT HR [95% CI] 9,1 0,803 Caucasian (n=946) 10,5 [0,694 - 0,928] 10,3 Adeno (n=413) 12,0 [0,649 - 1,023] 0,815 8,9 Squamous cell (n=347) 10,2 [0,626 - 1,007] 0,794 0,807 [0,584 - 1,115] 8,2 9,0 Other (n=185) FLEX Trial Overall Efficay by race and histology (Pirker, #3o) # = N Abstract; O = Oral presentation; P = Poster; Superior overall survival compared to chemotherapy alone in patients with advanced EGFR-expressing NSCLC

  7. FLEX Trial Efficay and Safety Data (Pirker, #3o) Toxicity G3-4 (% pts) # = N Abstract; O = Oral presentation; * p < 0.05; ** There was no grade 4 acne-like rask Expected and manageable side effects with acne-like rash as the main cetuximab related side effect

  8. FLEX Trial Subset Analysis – Asian Subgroup (Pirker, #3o) CT + Cetuximab CT p Baseline prognostic factors: Adenocarcinoma 65% 80% Post-study treatment: EGFR TKls 50% 73% OS (months) 17,6 months 20,4 months ns OR % 50% 44% ns # = N Abstract; O = Oral presentation; P = Poster; Small sample size (10%) and difference in histology and post-study EGFR TKl treatment do not allow to draw definitive conclusions

  9. Treatment # pts RR (%) PFS (mo) OS (mo) IHC Cis/VNR 66 28% 4,6 7,3 YES Cis/VNR/C225 65 35% 5,0 8,3 YES Plat/Gem 66 18 4,2 9,3 NO Plat/Gem/C225 65 28 5,1 12,0 NO Cb/Pac/C225 106 34% 4,0 11,0 NO Cb/Pac=>C226 119 31% 4,0 10,0 NO FLEX Trial How should Cetuximab be used? (Linch, General discussion) Single Agent NO Second or Third Line NO Squamous Cell NSCLC YES Bevacizumab « Ineligible » YES Bevacizumab « Eligible » Not Yet Maintenance YES Chemo other than Cis/VNR YES Statement not in line with current results since POSITIVE only with NP!

  10. First Line: Triplet of CTNavelbine and CDDP-based Triplet (Yamaguchi, #13552) • Phase II . 83 pts . Stages IIIB-IV . KPS 60-70: 13.2 %; 80-100: 86.6 % • Age <60: 52.9 %; 60-69: 31.3 %; > 70: 14.4 % • NVB 30 + Gem 1500 + CDDP 60 q3w 4 cycles • ORR : 54.2 % • Clinical Benefit : 78.9 % (CR+PR+SD) • Median OS: 17.3 m • Toxicity was tolerable and fully recoverable Interesting Median Survival in this relative young population

  11. First Line Doublets:Navelbine i.v./oral + Oxaliplatin in PS > 2 (Mir, #19064) • Phase II in 30/55 PS>2 pts, 21 eval,60 yrs [43-84]. NVB 25 D1 and ORAL NVB 60 D8 + OLP 85 D1 q 2w • 288 cycles . MC 4[1-11]. • ORR : 25 %; M PFS : 3.5 months • Median OS : 9.5 months / 1 Y Survival : 24 % • TOX Gr3-4 : Neutropenia 27 %, Anemia 22 %, F. Neutro 5.5 % • P. Neuropathy 15 %; Elev ASAT3.7 % Effective doublet with Navelbine Oral/i.v. in poor prognosis patients

  12. ASCO 2008:First-Line Treatment - Other Agents

  13. Gemcitabine 1st Line Mono vs Doublet vs Triplet: Randomized Phase III trial (Fink, # 19008) # = N Abstract; O = Oral presentation; P = Poster; Similar Efficacy with pronounced Hematotoxicity in Arms B & C Role of triplets ?

  14. Gemcitabine + Oxaliplatin (GemOx) First Line GemOx vs Txl – CBDCA (Weissman, #8024p) # = N Abstract; O = Oral presentation; P = Poster; Similar Efficacy and safety profile in favour of GemOx

  15. Docetaxel + Gemcitabine First Line :Alternate schedules with NVB/CDDP (Lopez-Castro #19120) • Phase II: 21/27 evaluable; Age 58 y; ADK 48.1 % • TXT 35 + Gem 800 D1D8 and NVB 25 + CDDP 35 D21D29 every 6 weeks • Clinical Benefit : 81 % (CR 4.8 %/PR 61.9 %/SD 14.3 %) • PFS 9.7 m • TOX Gr3-4 : Neutropenia 11% / Elev ASAT3.7 % Do we need a sequential approach with NVB/CDDP?

  16. ASCO 2008:Targeted Treatment

  17. Targeted Treatment:Epidermal Growth Factor Receptor (EGFR) as a target • EGFR expression reported in >80% of NSCLC pts • EGFR expression is associated with tumor growth, metastasis and poor prognosis • Blocking EGFR has the potential to improve outcome in NSCLC

  18. Targeted Therapy: Current Phase III Trials in NSCLC • MMPI Negative x 4 • EGFR-TKIs Negative x 4 • EGFR MoAb Positive • PKC Antisense Negative x 1-1.5 • FTIs Negative x 1 • Anti VEGF Negative x1* • Sorafenib Negative x 1 • Retinoids Negative x 2 • PF35112676 Negative x 2 * Clinically selected pts, with a second study showing only PFS improvement New targeted therapy frequently disappointing !

  19. First Line Erlotinib:Sequential treatment (Lee, #8031p) GEM + CDDP/CBDCA Erlotinib vs GEM + CDDP/CBDCA # = N Abstract; O = Oral presentation; P = Poster; Promising results with increase in PFS and OR and similar toxicity

  20. Gefitinib:First or Second Line? Nokihara, # 8069p • (A) Taxol + CBDCA (TCb) Gefitinib vs (B) Gefitinib  TCb • Arm A chosen for Phase III: ORR 32.7 % vs 29 % . MS idem. Kobayaschi, # 8070p • First line Gefitinib for poor PS Pts and EGFR ++

  21. ASCO 2008:Maintenance Therapy

  22. Maintenance at ASCO 2008:Current Results • Maintenance with Pemetrexed • Ciuleanu, #8011o • Zelinsky, #8060p: Increased PFS • Continued Platinum Doublet CT or Gefitinib • Hida, #8012o • Duration of Chemotherapy in NSCLC • Systematic review and meta-analysis (Soon, #8013o) • Cetuximab (C) • TXL weekly + CBDCA + C maintenance = Highly active in a little population (Borghaei, #810p) • Pemetrexed + Bevacizumab • 49 eval pts . ORR 55%. MS 13.5 m. Non squamous population (Patel, #8044p)

  23. ASCO 2008:Maintenance Therapy (Ciuleanu, #8011o) • Stage IIIB/IV NSCLC • PS 0-1 • 4 prior cycles of gem • doc or tax + cis or carb • with CR, PR or SD • Randomization factors • Gender • PS • Stage • Best tumor response to • induction • Non-platinum induction • drug • Brain mets Placebo (d1, q21d) + BSC (N=222)* 2 : 1 Randomization Primary Endpoint = PFS Pemetrexed 500mg/m2(d1, q21d) + BSC (N=441)* # = N Abstract; O = Oral presentation; P = Poster; *B12, folate, and dexamethasone given in both arms

  24. Maintenance Therapy Main Results (Ciuleanu, #8011o) # = N Abstract; O = Oral presentation; P = Poster; Improved PFS with Strong Trend in OS

  25. Prelim Median Median PFS, mos CR+PR+SD* % OS, mos Pem Plac p- value Pem Plac p- value Pem Plac p- value Nonsquamous (n=482) 4,37 1,84 <0,00001 54,3 26,6 <0,001 14,4 9,4 0,005 Adeno (n=329) 4,60 2,66 <0,00001 58,2 29,6 <0,001 16,4 11,7 0,091 Large cell (n=20) 4,53 1,45 0,104 30,0 25,0 0,999 9,1 5,5 0,154 Other (n=133) 4,11 1,58 0,0001 47,5 18,9 0,004 11,3 7,0 0,005 Squamous (n=181) 2,43 2,50 0,896 33,3 34,5 0,999 9,6 11,9 0,231 Maintenance Therapy Efficacy by Histologic Groups (Ciuleanu, #8011o) # = N Abstract; O = Oral presentation; P = Poster; Improved efficacy in Non-Squamous and Adenocarcinoma Histologies

  26. Chemotherapy regimens: % A % B carboplatin + paclitaxel 64 65 cisplatin + vinorelbine 14 15 cisplatin + gemcitabine 15 14 cisplatin + irinotecan 2 3 cisplatin + docetaxel 2 2 Sample size n = 600 (n = 300 per Arm) Maintenance Therapy: GefitinibContinued CDDP-Doublet vs Gefitinib (Hida, #8012o) R A N D O M I Z E • NSCLC • Stage III B/IV • Balancing by • Histology • Stage • Gender • CT regimen Arm A: Chemotherapy alone >= 3 cycles (up to 6 cycles) Arm B: Chemotherapy followed by gefitinib 3 cycles => gefitinib 250 mg until PD # = N Abstract; O = Oral presentation; P = Poster Primary End Point: Survival…and NVB/CDDP among the most used regimen!

  27. Chemotherapy Chemotherapy p alone  gefitinib CR 2 (0,7%) 4 (1,3%) PR 85 (28,6%) 98 (32,9%) SD 124 (41,8%) 123 (41,3%) PD 73 (24,6%) 52 (17,4%) NE 13 (4,4%) 21 (7,0%) Total 297 298 Response rate 87 (29,3%) 102 (34,2%) P=0,19 Maintenance Therapy: Gefitinib (GEF)Therapeutic Response (Hida, #8012o) # = N Abstract; O = Oral presentation; P = Poster CDDP Doublets  GEF improved PFS but not OS even if…

  28. Maintenance Therapy: Pre-planned subset analysisAdenocarcinoma & Smoking patients (Hida, #8012o) CDDP Doublets  GEF improved OS in smokers with adenocarcinoma

  29. Duration of Chemotherapy in NSCLC:A systematic review and meta-analysis (Soon, #8013o) • Memento Asco Guidelines • Limit to 6 cycles • Stop 4 cycles for Non Responders • Is it preferable to continue ? Effects on PFS and OS ? • Randomized Trials : 4 cycles and continue… • Systematic Review (3 independent reviewers): • 13 trials 2416 pts • with third generation of drugs : 9 trials • With old CT : 2 trials

  30. Duration of Chemotherapy in NSCLC:Updated results with PEM maintenance (Soon, #8013o) Hazard Outcome Patients Ratio 95% CI P value PFS 1907 0,78 0,72 0,86 < 0,00001 PFS (Ciuleanu) 2570 0,75 0,69 0,81 < 0,00001 OS 2416 0,94 0,87 1,01 0,10 OS (Ciuleanu) 3079 0,92 0,86 0,99 0,03 # = N Abstract; O = Oral presentation; P = Poster Extending CT improvement with significant PFS but little effect on OS

  31. Maintenance Therapy in Advanced NSCLC:Is more better ? (Eberhardt, Discussion) • Pemetrexed YES • In Non Squamous cell carcinomas +++ • Gefitinib YES • In Smokers with Adenocarcinoma +++ ASCO 2003 Guidelines still valid as far as unselected patients are concerned!

  32. ASCO 2008:Elderly or PS 2 Patients

  33. Elderly PatientsCurrent approaches with Chemotherapy • Tang, #8090p: • Chemotherapy or not ? Combination or Single agent • Hang, #20630: • Combination or Single agent ? Which doublet ? • Gridelli, #8117p: • New approach with new drugs • AMOROSO #19085: • NVB Oral • Firvida GLCG #19068: • NVB Oral + GEM : Non platin doublet ! • Vasile, #19092: • Sequential GEMTXT in elderly pts E. VASILE # 19092

  34. Elderly PatientsMeta-analysis on 21441 pts (Tang, #8090p) • Pts > 66 yrs & Adjusted Survival, According for poor PS • CT>Non CT (BSC) (p<0.0001) but most elderly pts did not receive CT • Platinum Doublet (PD) > Non Platinum Doublet (p<0.0001) • Non Platinum Doublet > Single Agent (SA) (p=0.04) • NS in OS TXN-P vs Other drugs-P  NVB–P (p=0.7)! # = N Abstract; O = Oral presentation; P = Poster CT improves OS in patients aged > 75 yrs with acceptable toxicity PD = TXN D 50.9% - GEM 9.6% - VP 16 3.8% - NVB 2.3% SA = NVB 10.1% - TXN 6.1% - GEM 4.2%

  35. Elderly Patients:Combination or Single agent ?(Zhang #20630) # = N Abstract; O = Oral presentation; P = Poster In this study single agent CT reported similar efficacy as combination CT Single agents = TXN, GEM, NVB

  36. Elderly Patients or PS 2 : New approaches with new drugs(Gridelli, #8117p) # = N Abstract; O = Oral presentation; P = Poster Cetuximab as sequential option seems to be the better for PS 2 pts

  37. Navelbine Oral in Elderly Patients:Single Agent oral CT in poor PS (Amoroso, #19085) Toxicity No Grade 3-4 Toxicity Febrile Neutropenia: 1 pat Nausea & Vomiting 50 % Sensorial neuropathy 10 % Fatigue 30 % Leuco/Neutropenia 25 % No Treatment-related death # = N Abstract; O = Oral presentation; P = Poster NVB Oral achieves efficacy with optimal tolerance in this poor population But Elderly patients and poor PS : is it our target ?

  38. Navelbine Oral and GEM in Elderly Patients:A non platinum Doublet(Firvida, #19068) Toxicity G 3/4 Anemia 4pts Neutropenia 4 pts Thrombopenia 2pts Asthenia Gr3 3pts Emesis Gr3 1 pt # = N Abstract; O = Oral presentation; P = Poster NVB Oral + Gem effective and well tolerated in elderly patients

  39. Gemcitabine and Docetaxel (TXT) in Elderly Patients:Sequential GEM  TXT (Vasile, #19092) • Phase II: 56 Patients > 70 y • GEM 1200 D1D8 q3w 3 cycles followed TXT 37.5 D1D8 q3w 3 cycles • PS 0: 7/1: 38 /2: 11. M Age 76[70-84]. • ORR : 16 % - SD : 41 % . M TTP : 4.8 m[3.6-6.6] . M OS : 8 m [5.6-10.5] • 1 Y Survival : 34 % Toxicity Gr 3-4 : • Febrile Neutropenia : 5.4 %. Thrombocytopenia : 3.6 %. • Fatigue : 8.9 % . Diarrhea/mucositis 3.6 % ccc Standard results in elderly with TXT used at fractionated doses

  40. ASCO 2008:Second Line Treatments

  41. Chemotherapy in Second Line:Poly- or Single Agent (SA) CT ? • Di Maio #8052p • Six studies analysed: 608 pts, 72% CDDP-based CT • Better MS of Mono- vs Poly-CT in 2nd line: 37.9 vs 35 w • Better ORs of PolyCT (p=0.01) but more toxicity • Hemato 45 vs 31 %; Non hemato 33 vs 24 % • Smit, #8050p • Pemetrexed vs Pemetrexed + CDDP • Limited Role of CDDP in 2nd line with increased toxicity: • Gr 3-4 : 44 % vs 29 %. Single agent CT allows similar survival and better tolerance

  42. Chemotherapy in Second Line:Analyses of Single agent CT • Tassinari, #19058: • No significant differences between Chemotherapies for 1 Year Survival and RR in 8 trials with 2671 pts • De Marinis, #8087p: • Meta analysis of 7 trials with 4291 pts • Taxotere, the reference standard for second Line • Neutropenia, the worst toxicity, limits its use

  43. Second Line Treatment:Targeted Therapies • EVEROLIMUS vs Erlotinib Papadimitrakopoulou # P • 72 pts. ORR: 11pts . Main tox : rash,stomatis/mucositis and diarrhea. Too early for survival rates. • Pemetrexed + Bevacizumab (Adjei, #8080) • 48 pts eval. The results are very good in second line. DC 50 % . MS 8.6 m. # = N Abstract; O = Oral presentation; P = Poster

  44. Second Line Treatment:Targeted Therapies • Gefitinib vs Docetaxel (Txt) (Lee #8025p) • PFS and OS longer with Gefitinib • ORR significantly improved with TXT • QOL similar in the 2 arms. # = N Abstract; O = Oral presentation; P = Poster Gefitinib vs Gem vs Txt  Txt vs Gefitinib (Morere, #8046p) • Trend in favour of first line Txt regarding OR, CD and overall survival in the entire population and in the subgroup of PS2 • Tox Gr3-4 higher with Txt 43 vs 12 % # = N Abstract; O = Oral presentation; P = Poster

  45. ASCO 2008:New Developments

  46. ASCO 2008:New Developments • More and more trials … • Alone or in combination with other targeted therapy • Often disappointing ! • Sometimes interesting… • SORAFENIB in third or fourth line • Targeting IGF R1 • TOLL-Receptor 9 agonist

  47. New Drugs in First Line CT : Enzastaurine* (ENZ)R Phase II PEM/Carbo + E vs Txt/Carbo (Kocs, #8061p) * Enzastaurine: Oral serine/ Threonine Inhibitor # = N Abstract; O = Oral presentation; P = Poster Preliminary results : Pemetrexate + Carbo + ENZ appear to be well tolerated

  48. New Drugs in First Line CT : PF 3512676 (TLR9*)Two trials vs TCb(Hirsch, #8016o)or GP (Manegold, #8017o) *TL R9 Agonist (Toll like receptor /plasmocyt) CT-related AE: TCb 14 %; GP10 % Neutro Gr3-4 : TCb 51 %; GP 58 %; + TLR9 73 % vs # = N Abstract; O = Oral presentation; P = Poster Disappointing results: PF3512676 did not improve outcome

  49. New Drugs in Third Line: Sorafenib (SOR)R Phase II Sorafenib vs Placebo - Interest (Schiller, #8014o) 342 pts received 400 mg of Sorafenib orally 2X /day for 2 cycles Pts in response continue SOR . Pts with stable disease were rando SOR or Placebo Results : Rando 107 - 83 analysed • N° Abstract : O = Oral presentation ; P = Poster ; E = Educational # = N Abstract; O = Oral presentation; P = Poster Preliminary results suggest Sorafenib may prolong PFS in pretreated Pts

  50. New Drugs in Third line CT: IgF - CP 75 18 71 MoAb (I) (Karp #8015o) Rando 2:1 ratio 150 pts 1) TXL200+CarboAUC6 (TC) + I (10-20mg/Kg)  I 2) TC  I vs TCI Most common adverse event : Neutropenia Gr3-4: 30 vs 16 % Hyperglycemia Gr3-4 : 20 vs 8 % # = N Abstract; O = Oral presentation; P = Poster High activity of TCI in squamous NSCLC

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