1 / 46

PROF. FRANCESCO COGNETTI REGINA ELENA NATIONAL CANCER INSTITUTE, ROME

TAXANES, GEMCITABINE AND MONOCLONAL ANTIBODIES ANTI-HER-2 AND THEIR COMBINED USE: WHAT IS THE BENEFIT IN TERMS OF RESPONSE QUALITY AND SURVIVAL?. PROF. FRANCESCO COGNETTI REGINA ELENA NATIONAL CANCER INSTITUTE, ROME. Rome, 16-18 December 2004. INTRODUCTION.

brennan-lopez
Download Presentation

PROF. FRANCESCO COGNETTI REGINA ELENA NATIONAL CANCER INSTITUTE, ROME

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. TAXANES, GEMCITABINE AND MONOCLONAL ANTIBODIES ANTI-HER-2 AND THEIR COMBINED USE: WHAT IS THE BENEFIT IN TERMS OF RESPONSE QUALITY AND SURVIVAL? PROF. FRANCESCO COGNETTI REGINA ELENA NATIONAL CANCER INSTITUTE, ROME Rome, 16-18 December 2004

  2. INTRODUCTION • TAXANES (Paclitaxel and Docetaxel) are anticancer drugs that has shown significance efficacy against metastatic breast cancer. • PACLITAXEL is an anticancer agent that stabilizes microtubules. • Single-agent Paclitaxel: Response Rate ranges between 30 to 60% when given every three weeks and between 20 to 50% when given weekly. Perez BA, JCO 2001 Seidman AD, JCO 1998

  3. INTRODUCTION • DOCETAXEL is a new semisintetic taxane with a significant antineoplastic activity and toxicity consisting in myelosuppression primarily. • It acts by disruption of mitosis, promotion of microtubular assembly, and suppression of depolymerization of microtubular bundles to free tubulin. • Single-agent Docetaxel: Response Rate of 59% in first-line treatment and 46% in second-line treatment in patients with metastatic breast cancer. Response rate of 41% in patients progressing after prior anthraciclines therapy. Bissery MC, Cancer Research 1991 Ravdin, Semin Oncol,1997

  4. INTRODUCTION • GEMCITABINE, a nucleotide analog, upon entering the cells, is phosphorilated by deoxycytidine kinase and both diphosphate and triphosphate contribute to its citotoxicity. • Diphospate is an inhibitor of ribonucleotide reductase, essential for the intracellular synthesis of deoxynucleotide triphosphates for normal DNA production. • Triphosphate is a fraudolent base that, once incorporetad into the DNA, leads to halting of DNA chain enlogation. Perez BA, JCO 2001

  5. INTRODUCTION • Single-agent Gemcitabine: Response Rate ranges between 14 to 37% in first and subsequent lines, with very low toxicity. Perez BA, JCO 2001

  6. COMBINATION DOC/GEM

  7. COMBINATION DOC/GEM

  8. Paclitaxel/gemcitabine background • In Non small cell lung camcer (NSCLC) cell lines the combination of Paclitaxel and Gemcitabine has at least additive cytotoxicity, with paclitaxel leading to the accumulation of difluorodeoxycytidine triphosphate (dFdCTP), the active metabolite of Gemcitabine. Kroep JR, Br J Cancer 2000 Paclitaxel did not affect the pharmacokinetics of Gemcitabine, nor did gemcitabine affect the pharmacokinetics of paclitaxel, but paclitaxel increase dFdCTP accumulation. Kroep JR, JCO 1999

  9. Paclitaxel/gemcitabine background In NSCLC cell lines, paclitaxel administered immediatly before gemcitabine, significantly improves dFdCTP accumulation, gemcitabine accumulation into RNA and apoptotic index. Kroep JR, JCO 1999 • In mouse model the maximum effect was obtained when paclitaxel was administered on day 1 and 15, with gemcitabine every three days. Cividalli A, J Canc Res Clin Onc, 2000

  10. PHASE II TRIALS OF PTX/GEM • A. M. Murad et al., PHASE II TRIAL OF THE USE OF PACLITAXEL AND GEMCITABINE AS A SALVAGE TREATMENT IN METASTATIC BREAST CANCER. Am J Clin Oncol:264-268, 2001. • Sanchez F., RESULTS FROM A PHASE II STUDY OF GEMCITABINE IN COMBINATION WITH PACLITAXEL IN METASTATIC BREAST CANCER. Ann Oncol 9:16, 1998 (abs 77P) • P Vici et al.,BIWEEKLY PACLITAXEL/GEMCITABINE (P/G) AS SALVAGE TREATMENT IN BREAST CANCER PATIENS : PRELIMINARY RESULTS. Proc Am Soc Clin Oncol: 2002 (abs 2054)

  11. PHASE II TRIALS OF PTX/GEM • J. O’Shaughnessy et al, GEMCITABINE PLUS PACLITAXEL (GT) VERSUS PACLITAXEL (T) AS FIRST-LINE TREATMENT FOR ANTHRACYCLINE PRE-TREATED METASTATIC BREAST CANCER (MBC).Proc Am Soc Clin Oncol: 2003 (abs 25) • C. Delfino et al, GEMCITABINE PLUS PACLITAXEL AS FIRST-LINE CHEMOTHERAPY FOR PATIENTS WITH ADVANCED BREAST CANCER. Oncology 2004, 66 (1): 18-23. • R. Colomer et al., BIWEEKLY PACLITAXEL PLUS GEMCITABINE IN ADVANCED BREAST CANCER: PHASE II TRIAL AND PREDICTIVE VALUE OF HER2 EXTRACELLULAR DOMAIN. Annals of Oncology 15:201-206, 2004.

  12. GEMCITABINE PLUS PACLITAXEL (GT) VERSUS PACLITAXEL (T) AS FIRST-LINE TREATMENT FOR ANTHRACYCLINE PRE-TREATED METASTATIC BREAST CANCER (MBC). • SECOND OR SUBSEQUENT LINES • T (135 mg/mq) g1, G (1000 mg/mq) gg 1, 8, (15* in the first 5 patients, interrupted because of inacceptable thrombocitopenia). Cycles every 3 weeks. • 29 PATIENTS. • 137 MEDIAN CYCLES. A. M. Murad et al, Am J Clin Oncol:264-268, 2001

  13. GEMCITABINE PLUS PACLITAXEL (GT) VERSUS PACLITAXEL (T) AS FIRST-LINE TREATMENT FOR ANTHRACYCLINE PRE-TREATED METASTATIC BREAST CANCER (MBC). RESULTS A. M. Murad et al, Am J Clin Oncol:264-268, 2001.

  14. RESULTS FROM A PHASE II STUDY OF GEMCITABINE IN COMBINATION WITH PACLITAXEL IN METASTATIC BREAST CANCER. • SECOND OR SUBSEQUENT LINES (93%PRIOR ANTHRACICLINES AND 20%PRIOR PACLITAXEL) • T (135 mg/mq) g1, G (2500 mg/mq) gg 1, 15. Cycles every 4 weeks. • 44 PATIENTS. • 137 MEDIAN CYCLES. • EMATOLOGIC TOXICITY IN 15% OF PATIENTS, WITH 34% REQUIRING G-CSF. Sanchez F., et al, Ann Oncol 9:16, 1998 (abs 77P)

  15. RESULTS FROM A PHASE II STUDY OF GEMCITABINE IN COMBINATION WITH PACLITAXEL IN METASTATIC BREAST CANCER. RESULTS Sanchez F., et al, Ann Oncol 9:16, 1998 (abs 77P)

  16. BIWEEKLY PACLITAXEL/GEMCITABINE (P/G) AS SALVAGE TREATMENT IN BREAST CANCER PATIENS : PRELIMINARY RESULTS. • T (150 mg/mq) g1, G (1500 mg/mq) gg 1, 15. Cycles every 4 weeks. • 27 PATIENTS HEAVILY PRETREATED. • 137 MEDIAN CYCLES. P Vici et al., Proc Am Soc Clin Oncol: 2002 (abs 2054)

  17. BIWEEKLY PACLITAXEL/GEMCITABINE (P/G) AS SALVAGE TREATMENT IN BREAST CANCER PATIENTS : PRELIMINARY RESULTS. RESULTS P Vici et al., Proc Am Soc Clin Oncol: 2002 (abs 2054)

  18. GEMCITABINE plus PACLITAXEL (GT) versus PACLITAXEL (T) as first-line treatment for anthracyclne pre-treated metastatic breast cancer (MBC): Quality of life (QoL) and pain palliation results from the global phese III study. RANDOMI ZE GT (G 1250mg/mq d 1, 8; T 175 g/mq d1) T (175 mq/mq d1 q 21) END POINT: OVERALL SURVIVAL (os), Progression free-survival (PFS), overall response rate (ORR), QoL, Palliation of pain, time to progressive disease (TTP). Oshaughnessy J, C. Moinpour, ASCO 2003-2004

  19. Paclitaxel/gemcitabine • 529 patients randomized: 267 GT arm and 262 T arm. • Median cycles: 6 for GT (range 0-20) • 5 for T (range 0-16). P= 0.0013 P= 0.0007 Oshaughnessy J, C. Moinpour, ASCO 2003-2004

  20. Time to disease progression GT 100 T 80 • Log-rank test p-value 0.0013 • Hazard ratio 0.73 (0.61-0.89) 60 % Progression-free 40 20 0 0 3 6 9 12 15 18 21 24 TTP (months) Oshaughnessy J, C. Moinpour, ASCO 2003-2004

  21. Paclitaxel/Gemcitabine • EMATOLOGIC TOXICITY CTC GRADE 4 Oshaughnessy J, C. Moinpour, ASCO 2003-2004

  22. Paclitaxel/gemcitabine • The Rotterdam Symptoms checklist (RSCL) global QoL score for patients receiving GT was significantly and significantly better than that reported by T arm patients. • This difference was clinically significant. • Of patients requiring analgesic at baseline, more GT pts were able to reduce analgesic level for >1 cycle (25 vs 15%) Oshaughnessy J, C. Moinpour, ASCO 2003-2004

  23. Rotterdam Symptoms checklist: overall evaluation of life item BETTER QoL 80 GT (n=152) T (n=162) 75 * * Mean Score 70 65 60 0 1 2 3 4 5 6 WORSE QoL Cycle *Statistical improvement within the GT arm, as compared to baseline Oshaughnessy J, C. Moinpour, ASCO 2003-2004

  24. Paclitaxel/gemcitabine • The Rotterdam Symptoms checklist (RSCL) global QoL score for patients receiving GT was significantly and significantly better than that reported by T arm patients. • This difference was clinically significant. • Of patients requiring analgesic at baseline, more Gt pts were able to reduce analgesic level for >1 cycle (25 vs 15%) Oshaughnessy J, C. Moinpour, ASCO 2003-2004

  25. GEMCITABINE PLUS PACLITAXEL AS FIRST-LINE CHEMOTHERAPY FOR PATIENTS WITH ADVANCED BREAST CANCER • FIRST LINE (60% PATIENTS PRIOR ADJUVANT). • T (175 mg/mq) g1, G (1200 mg/mq) gg 1, 8. Cycles every 3 weeks. • 45 PATIENTS. C. Deflfino et al., Oncology 2004, 66 (1): 18-23

  26. GEMCITABINE PLUS PACLITAXEL AS FIRST-LINE CHEMOTHERAPY FOR PATIENTS WITH ADVANCED BREAST CANCER RESULTS • Grade3/4 leukopenia, neutropenia and thrombocitopenia developed in 13.3%, and 15.5% developed mucositis grade 3/4. C. Delfino et al., oncology 2004, 66 (1): 18-23

  27. BIWEEKLY PACLITAXEL PLUS GEMCITABINE IN ADVANCED BREAST CANCER: PHASE II TRIAL AND PREDICTIVE VALUE OF HER-2 EXTRACELLULAR DOMAIN (ECD). • FIRST LINE (51% PATIENTS PRIOR ADJUVANT, 32% WITH ANTHRACICLINES) • T (150 mg/mq) g1, 14; G (2500 mg/mq) gg 1, 14. • 43 PATIENTS • ASSESSEMENT OF HER2 ECD SERUM LEVELS BY ELISA R. Colomer et al, Annals of Oncol 2004, 15: 201-206

  28. BIWEEKLY PACLITAXEL PLUS GEMCITABINE IN ADVANCED BREAST CANCER: PHASE II TRIAL AND PREDICTIVE VALUE OF HER-2 EXTRACELLULAR DOMAIN (ECD). TOXICITY R. Colomer et al, Annals of Oncol 2004, 15: 201-206

  29. BIWEEKLY PACLITAXEL PLUS GEMCITABINE IN ADVANCED BREAST CANCER: PHASE II TRIAL AND PREDICTIVE VALUE OF HER-2 EXTRACELLULAR DOMAIN (ECD). RESULTS R. Colomer et al, Annals of Oncol 2004, 15: 201-206

  30. BIWEEKLY PACLITAXEL PLUS GEMCITABINE IN ADVANCED BREAST CANCER: PHASE II TRIAL AND PREDICTIVE VALUE OF HER-2 EXTRACELLULAR DOMAIN (ECD). RESULTS: Response Rate according to baseline HER-2 ECD level (n=41) R. Colomer et al, Annals of Oncol 2004, 15: 201-206

  31. BIWEEKLY PACLITAXEL PLUS GEMCITABINE IN ADVANCED BREAST CANCER: PHASE II TRIAL AND PREDICTIVE VALUE OF HER-2 EXTRACELLULAR DOMAIN (ECD). RESPONSE DURATION stratified by HER2 ECD status R. Colomer et al, Annals of Oncol 2004, 15: 201-206

  32. CONCLUSIONS • The combination Ptx/Gem is higly active and well tolerated regimen as first-line therapy. • HER2 ECD levels correlated inversely with objective response (p=0.02) and with response duration (p=0.04). • A Study with Gem/Tax/Herceptin is ongoing. Colomer R, Ann Onc 2004

  33. TRASTUZUMAB IN BREAST CANCER • HER-2 • Discovered in 1980 • Member of EGFR family • Overexpressed in 25 to 30% of breast cancers • Shortened survival and relative resistance to therapies. • TRASTUZUMAB • Binds to the EC domain of HER2 • FDA approved (1998) • Only in IHC 3+ or FISH +

  34. erbB Receptor Family erbB-1(EGFR) erbB-4(HER4) erbB-2(HER2/neu) erbB-3(HER3) EGFTGF-AmphiregulinBetacellulinHB-EGF NRG2NRG3HeregulinsBetacellulin Heregulins Tyrosine Kinase Domain Tyrosine Kinase Domain Tyrosine Kinase Domain Fernandes et al, 1999. Moghal et al, 1999.

  35. HERCEPTIN MONOTHERAPY

  36. HerceptinInteractions with Cytotoxic Agents Pegram et al. Oncogene 1999:18:2241. Konecny et al. Breast Cancer Res Treat 1999;57:114a.

  37. HERCEPTIN AND TAXANES

  38. Paclitaxel/Gemcitabine/Trastuzumab • The addition of Trastuzumab to chemotherapy improves response rate as well as duration of response and overall median survival. The combination is well tolerated. • Gemcitabine and Trastuzumab exhibit additive or sinergistic antitumor effect when combined in Her-2 positive human cancer cell lines. Slamon D, JCO 2001 Sledge GW, Sem Onc, 2003

  39. GEMCITABINE, PACLITAXEL AND TRASTUZUMAB IN METASTATIC BREAST CANCER • FIRST LINE (ADJUVANT TAXANES PERMITTED) • HER-2 OVEREXPRESSION DETECTED BY IMMUNOHYSTOCHEMISTRY OR FLUORESCENCE IN SITU HYBRIDIZATION. • T (175 mg/mq) g1, G (1200 mg/mq) gg 1, 8. Cycle every 3 weeks. • TRASTUZUMAB 4 mg/Kg loading dose and 2 mg/Kg once weekly after. • 46 PATIENTS ENROLLED. • MEDIAN CYCLES ADMINISTERED: 6. Miller KD, Oncology, 2001

  40. GEMCITABINE, PACLITAXEL AND TRASTUZUMAB IN METASTATIC BREAST CANCER • TOXICITY Miller KD, Oncology, 2001

  41. GEMCITABINE, PACLITAXEL AND TRASTUZUMAB IN METASTATIC BREAST CANCER • RESULTS (41 PATIENTS AVALUABLE) Miller KD, Oncology, 2001

  42. NEOADJUVANT SETTING • P. Sanchez-Rovira, DOSE-DENSE AND SEQUENTIAL COMBINATION OF EPIRUBICIN AND CYCLOPHOSPHAMIDE FOLLOWED BY PACLITAXEL AND GEMCITABINE +-TRASTUZUMAB AS NEOADJUVANT CHEMOTHERAPY IN STAGE II AND III BREAST CANCER. Proc Am Soc Clin Oncol: 2004 (abs 608) • A. Schneeweiss et al., DOSE DENSE GEMCITABINE AND EPIRUBICIN (GE) FOLLOWED SEQUENTIALLY BY DOSE DENSE DOCETAXEL (Doc) AS PRIMARY SISTEMIC THERAPY OF PATIENTS WITH EARLY BREAST CANCER: FIRST RESULTS OF A PHASE I/II TRIAL. Proc Am Soc Clin Oncol: 2004 (abs 734)

  43. DOSE-DENSE AND SEQUENTIAL COMBINATION OF EPIRUBICIN AND CYCLOPHOSPHAMIDE FOLLOWED BY PACLITAXEL AND GEMCITABINE +-TRASTUZUMAB AS NEOADJUVANT CHEMOTHERAPY IN STAGE II AND III BREAST CANCER.. • EPIRUBICIN (90 mg/mq) and CYCLOPHOSPHAMIDE (600 mg/mq) for III cyclesPACLITAXEL (150 mg/mq) and GEMCITABINE (2500 mg/mq) for VI Cycles (with profilactic G-CSF). • In patients with HER2-neu overexpression: weekly TRASTUZUMAB concomitant with GT. • 30 PATIENTS. Sanchez F., et al, Ann Oncol 9:16, 1998 (abs 77P)

  44. DOSE-DENSE AND SEQUENTIAL COMBINATION OF EPIRUBICIN AND CYCLOPHOSPHAMIDE FOLLOWED BY PACLITAXEL AND GEMCITABINE +-TRASTUZUMAB AS NEOADJUVANT CHEMOTHERAPY IN STAGE II AND III BREAST CANCER.. • TOXICITY Sanchez F., et al, Ann Oncol 9:16, 1998 (abs 77P)

  45. DOSE-DENSE AND SEQUENTIAL COMBINATION OF EPIRUBICIN AND CYCLOPHOSPHAMIDE FOLLOWED BY PACLITAXEL AND GEMCITABINE +-TRASTUZUMAB AS NEOADJUVANT CHEMOTHERAPY IN STAGE II AND III BREAST CANCER. • PATHOLOGICAL RESPONSE (available only for 21 pts) • CLINICAL RESPONSE • (available only for 26 pts) Of 5 pts overexpressing HER2, 1 pCR and 1microscopical residual disease Sanchez F., et al, Ann Oncol 9:16, 1998 (abs 77P)

  46. CONCLUSIONS • Combination of taxanes, especially paclitaxel and gemcitabine are: • Safe : Haematologic toxicity is common (ANC) but mild. • Active : RR – 40-70%, with durable responses with high level complete remissions • Combination of both with trastuzumab is promising. Randomized trial are needed to test this combination.

More Related