GASTRIC & PANCREATIC CANCER

Transcription

1 GASTRIC & PANCREATIC CANCER ASCO HIGHLIGHTS 2005 Fadi Sami Farhat, MD Head of Hematology Oncology Division Hammoud Hospital University Medical Center Saida Lebanon Tel: drfadi@drfadi.org

2 ADJUVANT CHEMOTHERAPY in GASTRIC CANCER

3 Peri-operative Chemotherapy in Operable Gastric And Lower Oesophageal Cancer Final results, randomised, controlled trial (the MAGIC trial, ISRCTN ) Cunningham, ASCO2005, Oral4001

4 DESIGN and PATIENTS Two arm, randomized trial 503 Patients Chemotherapy (ECF) Epirubicin = 50 mg/m2 iv bolus d1; Cisplatin = 60 mg/m2 infusion d1; 5-FU=200 mg/m2 continuous infusion d1 21 Cunningham, ASCO2005, Oral4001

5 STUDY DESIGN R CSC n=250 S n=253 Commenced ECF n=237 (95%) Completed ECF n=215 (86%) Proceeded to surgery n=219 (88%) Proceeded to surgery n=240 (95%) Cunningham, ASCO2005, Oral4001

6 STUDY DESIGN CSC n=250 Proceeded to surgery n=219 (88%) Commenced post-op ECF n=137 (55%) Completed post-op ECF n=104 (42%) Cunningham, ASCO2005, Oral4001

7 OVERALL SURVIVAL Percent of pts CSC 41 S 36 CSC Benefit to CSC arm: 2-yr: 9% (3 18) 5-yr: 13% (4 22) p=0.0001; HR= S 0 2-yr survival 5-yr survival Cunningham, ASCO2005, Oral4001

8 MEDIAN OVERALL SURVIVAL PFS benefit to CSC arm: p=0.0001; HR= Benefit to CSC arm: 4 mo (2 13) Months CSC S 5 0 Median OS Cunningham, ASCO2005, Oral4001

9 PATHOLOGY STAGING FOLLOWING SURGERY p= p=0.01 Percent of pts Extent of tumor T1/2 Extent of tumor T3/4 Nodal status N0/N1 Nodal status N2/N3 CSC S Gastric only Cunningham, ASCO2005, Oral4001

10 Post-operative Morbidity/Mortality Post-operative deaths Post-operative complications Median duration of post-operative hospital stay CRC 6% 46% 13 d S 6% 46% 13 d Cunningham, ASCO2005, Oral4001

11 Tolerability hematological toxicities Percent of pts Post-op Pre-op 3 1 Granulocytes Lymphocytes WBC count Hb Platelets Cunningham, ASCO2005, Oral4001

12 Tolerability Non-Hematological Toxicities No significant difference in toxicity between pre-operative or post-operative chemotherapy Percent of pts Pre-op Post-op Nausea Vomiting Neurological max Skin Stomatitis Diarrhea Cunningham, ASCO2005, Oral4001

13 CONCLUSIONS In operable gastric and lower esophageal cancer, peri-operative chemotherapy Leads to downsizing of primary tumor Significantly improves PFS Significantly improves overall survival Cunningham, ASCO2005, Oral4001

14 PALLIATIVE CHEMOTHERAPY in GASTRIC CANCER

15 Docetaxel + Cisplatin + 5-FU vs. Cisplatin + 5-FU in metastatic gastric carcinoma R TAX325 Final results Phase III Randomized, controlled Docetaxel (75 mg/m 2 iv 1 h, d1) Cisplatin (75 mg/m2 iv 1 3 h, d1) 5-FU 750 mg/m 2 /d civ over 5 d) q3w (n=227) Cisplatin (100 mg/m 2 iv 1 3 h, d1) 5-FU 1000 mg/m 2 civ over 5 d) q4w (n=230) Moiseyenko,ASCO2005, Oral4002

16 EFFICACY RESULTS Relative risk reduction HR 32.1% % p-value TCF 8 Months CF 2 0 TTP Moiseyenko,ASCO2005, Oral4002 OS

17 EFFICACY RESULTS Percent of pts Any TTP event 1-yr survival 2-yr survival Overall RR PD TCF CF Moiseyenko,ASCO2005, Oral4002

18 Tolerability Hematological Percent of pts TCF CF Neutropenia Anemia Thrombocytopenia Moiseyenko,ASCO2005, Oral4002

19 Tolerability Non-Hematological Lethargy Stomatitis Diarrhea Infection Nausea Vomiting Anorexia Neurosensory Venous Alopecia Moiseyenko,ASCO2005, Oral4002 % of patients

20 CONCLUSIONS Benefit of adding D to Cddp/5-FU in 1 st line metastatic and locally recurrent gastric ca Better efficacy in terms of TTP, OS, RR Expected and manageable toxicity TCF - new therapeutic option in this disease Moiseyenko,ASCO2005, Oral4002

21 Docetaxel, Carboplatin, 5-FU vs. Epirubicin, Cisplatin, 5FU for Locally Advanced Gastric Cancer Docetaxel (75 mg/m 2 ) 5-FU (1200 mg/m 2 ) Carboplatin (AUC6) (n=30) DF-carbo R SWOG arm randomized, Phase III Final results Epirubicin Cisplatin 5-FU (n=34) ECF G-CSF support provided to both groups Elsaid, ASCO2005, PosterD4014

22 RESPONSE TO TREATMENT DF-carbo ECF p (n=30) (n=34) ORR (%) 67% 46% Median survival (mo) 12.4m 8.7m yr survival (%) 20% 14% 0.03 (Comparable tolerability between both groups) Elsaid, ASCO2005, PosterD4014

23 TOLERABILITY Elsaid, ASCO2005, PosterD Alopecia ECF DF-carbo Anemia Fatigue Nausea/vomiting Myalgia Neuropathy Diarrhea Thrombocytopenia Neutrogena Percent of pts

24 CONCLUSIONS Response Rate And Survival Advantage compared with ECF chemotherapy The high RR supports its use in neoadjuvant setting The results of this study confirm the value of Docetaxel-based chemotherapy in advanced gastric cancer Elsaid, ASCO2005, PosterD4014

25 CPT FU/folinic acid vs. CDDP + 5-FU in 1 st -line Advanced Gastric Cancer R FA 500 mg/m 2 ; 5-FU 2000 mg/m 2 as 22 h ci Irinotecan 80 mg/m 2 Weekly for 6 weeks q7w n=172 (FAP n=170) IF Randomized Phase III 5-FU 1000 mg/m 2 as 24h ci x 5 d CDDP 100 mg/m 2 d1) q4w n=165 (FAP n=163) Dank, ASCO2005, Oral4003 CF

26 OUTCOMES 10 8 HR: 1.23 ( ) Log rank p=0.088 HR: 1.43 ( ) Log rank p=0.002 HR: 1.08 ( ) Log rank p= Months TTP TTF OS IF CF Dank, ASCO2005, Oral4003

27 EFFICACY RESULTS 80 Percent of pts CR PR ORR Tumor control IF CF Dank, ASCO2005, Oral4003

28 Tolerability Hematological (Grade 3 4) IF CF Dank, ASCO2005, Oral Neutropenia Febrile neutropenia Leukopenia Anemia Thrombocytopenia Percent of pts

29 CONCLUSIONS This trial failed to meet its primary endpoint of TTP This trial failed to show a survival advantage for the IF arm Dank, ASCO2005, Oral4003

30 PANCREAS Erlotinib and Gemcitabine vs Gemcitabine (#1) Gemcitabine + FU + LF vs Gemcitabine (#4009) Gemcitabine + Capecitabine vs Gemcitabine (#4010)

31 TARGETED THERAPY in PANCREATIC CANCER

32 ERLINOTAB + GEMCITABINE Compared With GEMCITABINE ALONE A Phase III Trial National Cancer Institute In Canada Clinical Trials Group (NCIC-CTG) Moore, ASCO2005 PlenarySession1

33 Rationale for Targeting HER1/EGFR in Pancreatic Cancer Her1/EGFR over expression is common HER1/EGFR & EGF - more aggressive disease: Increased tumor size, late clinical stage, poor patient prognosis, reduced sensitivity to chemotherapy Preclinical models, HER1/EGFR-TK inhibitors enhance gemcitabine-induced tumor apoptosis Moore, ASCO2005 PlenarySession1

34 STUDY DESIGN Stratify by Center PS (0-1 vs 2) 569 patients Primary end-point: OS Gemcitabine 1000 mg/m2 IV + Erlonitib 100/150 mg/day PO (n=285) Gemcitabine 1000 mg/m2 IV + Placebo 100/150 mg/day PO (n=285) Moore, ASCO2005 PlenarySession1

35 TUMOR RESPONSE (%) Complete Response Partial Response OR (CR + PR) Stable Disease Tumor Control (CR + PR + SD) Median Duration of response in days (95% CI) Erlotinib / GEM ( ) Placebo / GEM ( ) Moore, ASCO2005 PlenarySession1

36 Moore, ASCO2005 PlenarySession1

37 Moore, ASCO2005 PlenarySession1

38 Selected adverse events 100 mg cohort Moore, ASCO2005 PlenarySession1

39 Moore, ASCO2005 PlenarySession1

40 CONCLUSION Erlinotab + Gemcitabine Compared With Gemcitabine Alone The addition of erlotinib [TarcevaTM, OSI- 774] to gemcitabine significantly improves Survival and Progression Free Survival in Advanced Pancreatic Cancer

41 Gemcitabine plus Capecitabine versus Gemcitabine Locally advanced or Metastatic Pancreatic cancer A Randomized Phase III Study of the Swiss Group for Clinical Cancer Research (SAKK) and the Central European Oncology Group (CECOG) Hermann, ASCO2005 ORAL[4010]

42 GC vs. G in advanced PC Stratify by : KPS:90-100% vs % Extent: Locally advanced vs. Metastatic Pain: Presence vs. absence Center Primary end-point: OS Improve OS from 5 to 7 m overall p-.05 at 80% Total events 284 R A N D O M I Z E Hermann, ASCO2005 ORAL[4010] Gemcitabine 1g/m2-30 d1+8 q 3w Capecitabine 650 mg/m2 bid. x 14 days q 3w Gemcitabine 1g/m2 30 weekly x7 rest 1w then weeklyx3/4

43 Progression Free Survival 1.0 Proportion not progressing Month At risk Hermann, ASCO2005 ORAL[4010]

44 Overall Survival 1.0 Proportion surviving Month At risk Hermann, ASCO2005 ORAL[4010]

45 RESPONSE RECIST Criteria CR PR CR + PR GC 148 pts (10%) G 152 pts (8%) Median Duration 95% interval 7.4 months months Hermann, ASCO2005 ORAL[4010]

46 Overall Survival for Treatment Arm in Subgroups GC better G better Hazard Ratio Hermann, ASCO2005 ORAL[4010] All Pain No pain Metastatic Not metastatic KPS KPS Hazard Ratio with 95% confidence Interval

47 Overall Survival : KPS Proportion surviving Month At risk Hermann, ASCO2005 ORAL[4010]

48 Overall Survival : KPS Proportion surviving Month At risk Hermann, ASCO2005 ORAL[4010]

49 TOXICITY Grade III-IV (%) GC G GC G 155 pts 153 pts 155 pts 153 pts Neutropenia Diarrhea Anemia Nausea Vomiting Thrombocytopenia Stomatitis Febrile Neutropenia Hand-Foot Syndrome Hermann, ASCO2005 ORAL[4010]

50 CONCLUSION Overall this trial failed to show a significant survival advantage for GC over G GC is well tolerated, can be easily administered In advanced pancreatic cancer, good KPS : GC - good alternative to G alone Hermann, ASCO2005 ORAL[4010]

51 Gemcitabine, 5-FU (24 h infusion) with Folinic Acid (GFF) versus Gemcitabine Alone (Gem) in Advanced and Inoperable Pancreatic Cancer Phase III Study CONKO 002 Reiss ASCO2005. Oral [4009]

52 CONKO-002: GFF vs. G Stratification KPS 60-80% % Tumor Stage III IVa IVb G 1000 mg/m 2 /wk FA 200 mg/m 2 /wk FU ci 750 mg/m 2 /wk x 4 wks q 6 wks Centralized Randomization Primary End-point : OS Improve S 6-8 month A 0.05 at power 80% 394 events G 1000mg/m2/wk x 7 wks 1000 mg/m2/wk x3wks q 4 wks Reiss ASCO2005. Oral [4009]

53 Second-line Therapies Regimen GFF G Oxaliplatin/FU?FA Oxaliplatin/Capecit. Oxaliplatin/Gemcit. Gemcitabine/FU/FA Gemcitabine FU/FA FU mono Paclitaxel Doxo/MMC/FU/FA Others 15 (17%) 4 (5%) 6 (7%) 11 (13%) 6 (7%) 2 (2%) 2 (2%) 21 (23%) 7 (8%) 14 (16%) 25 (29%) 4 (5%) 4 (5%) 12 (14%) 20 (23%) 5 (6%) 2 (2%) 0 2 (2%) 12 (14%) Reiss ASCO2005. Oral [4009]

54 Tumor Response Rates CR PR SD PD GFF (%) G (%) Reiss ASCO2005. Oral [4009]

55 Time to Tumor Progression Log Rank P= Reiss ASCO2005. Oral [4009]

56 Overall Survival Log Rank P= Reiss ASCO2005. Oral [4009]

57 Subgroup Analysis Stage IV B KPS 60-80% KPS % Log Rank P= Log Rank P= Reiss ASCO2005. Oral [4009]

58 TOXICITIES CONKO-002 Adverse event Grade 3-4(%) Leukopenia Thrombocytopenia Anemia Diarrhea Nausea Infection Bleeding GFF 220 pts 11.3 / / / / / / / 0.9 GEM 225 pts 11.1 / / / / / / / 1.8 Reiss ASCO2005. Oral [4009]

59 CONCLUSION CONKO-002 Gemcitabine, 5-FU and Folinic acid did not result in improved survival as compared with Gemcitabine standard therapy Single agent Gemcitabine remains the standard of care for patients with advanced pancreatic cancer Reiss ASCO2005. Oral [4009]

60

61 Author Listing for "Farhat" [673] Vinorelbine (N)-capecitabine (C) combination in advanced breast cancer (ABC): Long-term results of two multicentric phase II trials M. Ghosn, G. Chahine, J. Kattan, F. Farhat, F. Nasr, W. Moukadem, J. Dagher, F. Younes, J. Gasmi, [4094] Encouraging preliminary results of FOLFOX-6 in first-line therapy of locally advanced or metastatic pancreatic cancer (APC). F. Farhat, J. Kattan, G. Chahine, W. Moukadem, F. Nasr, F. Younes, M. Ghosn, [5585] The triplet docetaxel, carboplatin and capecitabine in recurrent or metastatic squamous cell carcinoma of head and neck (SCCHN). J. Kattan, F. Farhat, G. Chahine, F. Nasr, W. Moukadem, F. Younes, M. Ghosn, [7330] Phase II trial of weekly docetaxel and carboplatin as first line chemotherapy in advanced or metastatic non small cell lung cancer (NSCLC). G. Y. Chahine, F. L. Nasr, J. G. Kattan, F. S. Farhat, M.-E. El Seoudi, M. Bachour, W. T. Moukadem, F. C. Younes, M. G. Ghosn,

62 Encouraging Preliminary Results of FOLFOX-6 in First-line Therapy Locally Advanced or Metastatic Pancreatic Cancer Gemcitabine is the only approved drug to be used as single agent in APC Recent publications - promising results of the combination of Oxaliplatin and 5-FU (Ducreux et al Ann Oncol 2004) [4094 ASCO 2005 ] F. Farhat

63 METHODS January November eligible patients Objectives : RR, PFS and toxicity profile Treatment plan : Oxaliplatin 100 mg/m2 Folinic Acid 400 mg/m2 on day 1 5-FU bolus 400 mg/m2 and 3 g/m2 46-h infusion q2ws Patients - RECIST criteria.

64 RESULTS 176 cycles delivered -mean of 5.9 cycles/patient (extremes: 1-12) PR 8/23, SD 11/23, Clinical benefit - 63 %. Decrease in CA 19-9 ( 60 %) -8 pts/12 FN - 2 pts, anemia and thrombocytopenia - 2 pts each, diarrhea - 1 pt, mucositis - 1 pt Neurosensory toxicity (grade II - 2 pts) Median Survival - not reached yet [4094 ASCO 2005 ] F. Farhat

65 CONCLUSION In APC patients, FOLFOX-6 regimen achieved an interesting response rate Toxicity profile acceptable Regimen is still recruiting patients to confirm our encouraging results [4094 ASCO 2005 ] F. Farhat