BALKAN MCO 2011 - F. Cardoso - Chemotherapy options/management issues in metastatic breast cancer

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BALKAN MCO 2011 - F. Cardoso - Chemotherapy options/management issues in metastatic breast cancer

  1. 1. ESO BALKAN MASTERCLASS IN CLINICAL ONCOLOGY<br />Dubrovnik, Croatia, 11-15 May 2011<br />Chemotherapy options/management issues in (HER-2 NEG) metastatic breast cancer<br />F. Cardoso, MD<br />ESO Breast Cancer Program Coordinator<br />Head, Breast Cancer Unit - Champalimaud Cancer Center<br />Lisbon, Portugal<br />
  2. 2. 1st main question:CT or HT<br />TAILOR FOR THE DISEASE <br />TAILOR FOR THE PATIENT<br />
  3. 3. 2nd main question:If CT, combination or sequential use of monotherapy?<br />
  4. 4. AVAILABLE DATA<br />Most trials and meta-analysis compare single agent vs. combination and NOT sequential use of single agents vs. combination CT (no crossover)<br />The majority of trials show that combination CT yields higher RR, in some higher PFS, higher toxicity and no or quite small survival benefit<br />
  5. 5. Docetaxel vs. <br />Docetaxel + Capecitabine<br />Paclitaxel vs. <br />Paclitaxel + Gemcitabine<br />
  6. 6. COMBINATION vs. SEQUENTIAL SINGLE AGENTS<br /> BUT<br />Subsequent Chemotherapy<br />PG vs. P<br /> Docetaxel 10.5% 10.3%<br />Gemcitabine 3.8% 14.1%<br />T vs. TC<br />Capecitabine 17 % <br /> Docetaxel 20 %<br />NO OR MINIMAL CROSSOVER<br />BENEFIT OF COMBINATION IS ONLY LEVEL-2 EVIDENCE-BASED<br /><ul><li> Discuss with patients; new treatment option…
  7. 7. Consider combination in « high risk » fit patients</li></li></ul><li>RANDOMIZED STUDIES WITH CROSSOVER FOLLOWING PROGRESSION IN THE MONOTHERAPY ARM <br />*Denotes statistically significant result with P≤.05<br />Cardoso F, et al. J Natl Cancer Inst. 2009;101(17):1174-1181 <br />
  8. 8. A<br />T<br />AT<br />P Value<br />34<br />6.2<br />14<br />20.1<br />33<br />5.9<br />20 <br />22.2<br />46<br />8.0<br />-<br /> 22.4<br />S<br />S<br />S<br />NS<br />RR% first-line<br />MEDIAN TTF, mos<br />RR% second-line<br />MEDIAN OS, mos<br />Paclitaxel Versus Doxorubicin Versus BothCrossover Part of Trial Design<br />739 MBC patients<br />QOL Different toxicities, similar tolerability<br />Sledge W Jr, et al. Proc Am Soc Clin Oncol. 1997. Abstract 2<br />
  9. 9. COMBINATION<br />SEQUENTIAL SINGLE AGENTS<br /><Toxicity<br />Similar survival<br />Better overall QoL<br />Better management of resources<br />>RR<br />Faster symptom/disease control<br />>Toxicity<br />>Impact on daily life<br />No or very small gain in survival<br />Uses up “all weapons” faster<br /><RR<br />Slower symptom/disease control<br />
  10. 10. ESO-EBCC MBC Recommendations<br />9th REVISED STATEMENT<br />Sequential use of single cytotoxic drugs should be the preferred choiceexcept if:<br />Rapidly progressing disease<br /> Life threatening visceral metastases<br /> Need for rapid disease/symptom control<br />Define the subgroup of patients who need first-line combination because will not be able to rescued with second-line or third-line CT <br />Cardoso F, et al. J Natl Cancer Inst. 2009;101:1174-1181<br />Well-designed, prospective phase III trial in current chemotherapy era with mandated crossover is sorely needed <br />
  11. 11. 3rd main question:If CT, which agent?Alone or with targeted therapy?<br />
  12. 12. ADVANCED BREAST CANCER<br />MANY AVAILABLE OPTIONS <br />(inside and outside clinical trials)<br /><ul><li> CYTOTOXIC AGENTS
  13. 13. BIOLOGICAL AGENTS
  14. 14. COMBINATION OF “STANDARD” + BIOLOGICAL AGENTS
  15. 15. COMBINATION OF BIOLOGICAL AGENTS</li></ul>MAIN RULE: Whenever possible, always put your MBC patients in clinical trials)<br />
  16. 16. NEW CYTOTOXIC AGENTS<br /><ul><li> NEW CYTOTOXIC AGENTS
  17. 17. Targeting microtubules:Eribulin, Epothilones
  18. 18. Targeting cell cycle: Polo-like kinase &Aurora-kinase inhibitors
  19. 19. “OLD” AGENTS IN NEW FORMULATIONS
  20. 20. Capecitabine
  21. 21. Liposomal anthracyclines
  22. 22. New formulations of anti-microtubules:Abraxane , EndoTAG-1, T-DM1
  23. 23. “OLD” AGENTS IN NEW INDICATIONS
  24. 24. Platinum & Alkylating agents for TN</li></li></ul><li>E7389 (Eribulinmesylate) : Halichondrin B analogue<br />Broad antiproliferative activity and a unique profile of tubulin interaction<br />Phase II study in MBC patients previously treated with anthracycline and taxane (N=87):1RR: 11.5%, CB: 17.2%, median duration of response: 5.6 months<br />Main toxicity1: Neutropenia grade 3/4 (64 %); febrile neutropenia (4%); peripheral neuropathy grade 3 (5%)<br />Two pivotal phase III trials recently closed to accrual<br />Eribulin vs best choice of investigator Median of 4 prior chemotherapy regimens<br />Eribulin vs capecitabine (prior anthracycline and taxane)<br />Eribulin : 1.4 mg/m2 IV d 1+8<br />1. Vahdat L, et al. J Clin Oncol. 2009;27(18):2954-2961.<br />
  25. 25. EMBRACE – A phase III study of eribulin in MBC pts previously treated with anthracyclines and taxanes<br />Eribulin (E)<br />1.4 mg/m2, 2-5 min IV, days 1 and 8 q 21 days n = 508<br /><ul><li> n = 762
  26. 26. locally recurrent or MBC
  27. 27. 2-5 prior chemotherapies
  28. 28. progression ≤ 6 months of last chemotherapy
  29. 29. neuropathy ≤ 2
  30. 30. ECOG ≤ 2</li></ul>2:1<br />R<br />Treatment of physician’s choice<br />(TPC) - Any monotherapy (chemotherapy, hormonal, biological) or supportive care only – n = 254<br /><ul><li>Primary endpoint: overall survival
  31. 31. Secondary endpoints: PFS, ORR, safety
  32. 32. 96% of patients in TPC arm received chemotherapy</li></ul>Twelves C. et al. ASCO 2010, abstract 1004<br />
  33. 33. EMBRACE: Overall Survival (ITT)<br /> 1-Year Survival<br />Eribulin (n = 508) 53.9%<br />TPC (n = 254) 43.7%<br />1.0<br />0.8<br />Eribulinmedian 13.12 months<br />0.6<br />Survival Probability<br />HR* 0.81 (95% CI: 0.66, 0.99)P value† = 0.041<br />TPCmedian 10.65 months<br />0.4<br />0.2<br />2.47 months<br />0.0<br />14<br />12<br />10<br />16<br />18<br />20<br />8<br />6<br />4<br />2<br />0<br />22<br />24<br />26<br />28<br />Overall Survival, months<br />*HR Cox model including geographic region, HER2/neu status, and prior capecitabine therapy as strata<br />†P value from stratified log-rank test (predefined primary analysis), HR, hazard ratio; CI, confidence intervals<br />Twelves C, et al. J Clin Oncol. 2010;28(15s): Abstract CRA1004.<br />
  34. 34. Epothilones<br />Epothilones bind to the protein tubulin and disturb the equilibrium of microtubule and disassembling<br />Best studied: Ixabepilone (BMS-247550)<br />Important antitumor activity in taxane-resistant (preclinical & clinical studies)<br /><ul><li>Single-agent ixabepilone
  35. 35. No prior taxane (n = 65): RR = 42%</li></ul>Roche H et al. J Clin Oncol. 20071<br /><ul><li>Taxane-resistant (n = 49): RR = 12%</li></ul>Thomas E et al. J Clin Oncol. 20072<br /><ul><li>“Triple-refractory” (n = 113): RR = 19%</li></ul>Perez E et al. J Clin Oncol. 20073<br />NOT APPROVED IN EUROPE<br />1. Roche H, et al. J Clin Oncol. 2007;25(23):3415-3420. 2. Thomas ES, et al. J Clin Oncol. 2007;25(23):3399-3406. 3. Perez E, et al. J Clin Oncol. 2007;25(23):3407-3414.<br />
  36. 36. Capecitabine in Taxane-Pretreated MBC: ConsistentEfficacy Data<br />ONLY DRUG CONSIDERED STANDARD IN MBC PRE-TREATED WITH A & T<br />ALSO BEING EVALUATED IN ADJUVANT SETTING<br />1. Blum JL, et al. Eur J Cancer. 2001;37(Suppl. 6): Abstract 693. 2. Blum JL, et al. Cancer. 2001;92(7):1759-1768. 3. Reichardt P, et al. Ann Oncol. In press. 4. Updated from Fumoleau P, et al. Proc Am Soc Clin Oncol. 2002;21: Abstract 247. 5. Maung K. Clin Breast Cancer. 2003;3:375-377. <br />
  37. 37. The Evolution ofLiposomal Technology<br />Pegylated <br />liposomal doxorubicin<br />Liposomal doxorubicin<br />Doxorubicin<br /><ul><li>MAY ALSO ALLOW COMBINATION WITH ANTI-HER2 AGENTS
  38. 38. CAUTION: NO LONG-TERM EXPERIENCE</li></ul>increased solubility<br />prolonged duration of exposure<br />selective drug delivery<br />improved tx index<br />
  39. 39. NAB-PACLITAXEL<br /><ul><li>Nab-paclitaxel is albumin-bound, polyethoxylated castor oil–free paclitaxel -> NO STEROIDS PREMEDICATION AND SHORT DURATION INFUSION
  40. 40. Previous study testing nab-paclitaxel in taxane pretreated advanced breast cancer patients 1
  41. 41. Compared with paclitaxel (Ph 3): Higher RR, Higher TTPand Slight better OS 2
  42. 42. Compared with docetaxel (Ph 2): Better RR and PFS, specially the weekly regimens 3</li></ul> 1 Blum JL, et al. ClinBreastCancer. 2007;7(11):850-856<br />2 Gradishar, W. et al. J Clin Oncol. 2005;23(31):7794-7803.<br />3 Gradishar WJ, et al. J Clin Oncol. 2009;27(22):3611-3619<br />
  43. 43. A few words on biological agents for HER-2 negative disease<br />
  44. 44. <ul><li>To assess the efficacy and tolerability of oral olaparib in BRCA1/ BRCA2 mutation carriers with breast cancer
  45. 45. Proof-of-concept phase II study, single-arm sequential cohort design</li></ul>Confirmed BRCA1 or BRCA2 mutation<br />Advanced refractory breast cancer(stage IIIB/IIIC/IV) after failure of ≥1 prior chemotherapy for advanced disease<br />Cohort 1 (enrolled first)<br />Cohort 2<br />Olaparib 400 mg po bid (MTD)<br />28-day cycles; n = 27<br />Olaparib 100 mg po bid<br />28-day cycles; n = 27<br />Tutt et al The Lancet 2010 376(9737):235-44 <br />
  46. 46. O’Shaughnessy et al, ESMO 2010<br />Iniparib (BSI-201) Study Design Multi-center, open-label, randomized Phase II <br />Metastatic TNBC -about 70% had prior chemotherapy for early BC <br />Measurable disease -median number of metastatic sites = 3<br />0-2 prior chemotherapy regimens for metastatic disease - no prior chemo~60%<br />No prior gemcitabine, carboplatin, cisplatin, PARP inhibitor<br />Stable brain metastases allowed<br />ECOG PS 0–1 - two thirds PS = 0 <br />Randomization (1:1)<br />Gemcitabine1000 mg/m2, IV, d 1, 8<br />CarboplatinAUC 2, IV, d 1, 8<br />21 day cycles<br />Iniparib5.6 mg/kg, IV, d 1, 4, 8, 11<br />Gemcitabine1000 mg/m2, IV, d 1, 8<br />CarboplatinAUC 2, IV, d 1, 8<br />21 day cycles<br />N=62*<br />N=61<br />RESTAGING: Every 2 Cycles (RECIST)<br />PRIMARY ENDPOINTS: CBR = CR + PR + SD ≥6mo, Safety<br />SECONDARY ENDPOINTS: DFS, ORR, Toxicity<br />*30 patients randomized to gem/carbo crossed over to receive gem/carbo + Iniparib (BSI-201) at disease progression<br />
  47. 47. O’Shaughnessy et al, ESMO 2010<br />Iniparib: Progression-Free and Overall Survival (ITT Population)<br />Progression Free Survival<br />Overall Survival-Exploratory<br />OS<br />+ 4.6 months<br />PFS<br />+ 2.3 months<br />*P-values were not adjusted for multiple interim analyses.<br />
  48. 48. Phase II Study of the PARP Inhibitor Iniparib (BSI-201)<br /><ul><li>WORDS OF CAUTION + PRAISE
  49. 49. Small Phase 2 trial
  50. 50. Late side effects?
  51. 51. Need confirmation: phase 3 (>500 pts) finished accrual
  52. 52. Predictive biomarker evaluation under way
  53. 53. FUTURE/ONGOING RESEARCH
  54. 54. Not all PARPi were born equal
  55. 55. Is PARP really the main/only target?</li></ul>PHASE 3 TRIAL IS NEGATIVE! <br />(Will be presented at ASCO 2011)<br />
  56. 56. Bevacizumab in MBC<br />Meta-Analysis (O’Shaughnessy et al ASCO 2010) <br />PFS: 2.5 months, OS: 0.3 months<br />1. Miller K, et al. N Eng J Med. 2007;357(26):2666-2676. 2. Miles D, et al. J Clin Oncol. 2008;26:(May 20 Suppl): Abstract LBA1011. 3. Robert NJ, et al. J Clin Oncol. 2009;27(15S): Abstract 1005.<br />
  57. 57. <ul><li> FDA revoked approval
  58. 58. EMA kept only for 1st line & only with paclitaxel</li></ul> Urgent need for :<br /><ul><li> PREDICTIVE BIOMARKERS
  59. 59. Reasonable PRICES for new agents!</li></li></ul><li>4th main question:If CT, for how long?<br />
  60. 60. Gennari et al, ESMO 2010<br />Prolonging CT until disease progression improves Progression Free and Overall Survival in MBC: results of a systematic review<br />Alessandra Gennari, Oriana Nanni, Matteo Puntoni, Mariapia Sormani, Mauro D'Amico, Dino Amadori, Andrea De Censi, Paolo Bruzzi <br />DivisionofMedicalOncology, Galliera Hospital, Genoa <br />IRST, Meldola (FC)<br />DepartmentofHealthSciences, Universityof Genoa<br />National CancerResearchInstitute, Genoa, Italy<br />
  61. 61. 30<br />Gennari et al, ESMO 2010<br />Longer CT duration: <br /><ul><li>36% reduction in the risk of progression (HR 0.64; 95% CI 0.55 – 0.76)
  62. 62. 9% reduction in the risk of death (HR 0.91; 95% CI 0.84-0.99)
  63. 63. These results provide support to the clinical approach of prolonging 1st line CT in the absence of significant toxicity and disease progression (when CT is the only option…)
  64. 64. Role of biologics, HT, metronomic CT?!</li></li></ul><li>FINAL THOUGHTS<br />
  65. 65. ADVANCED BREAST CANCER: Summary<br />MANY AVAILABLE OPTIONS BUT VERY FEW STANDARDS!<br />1st LINE<br /><ul><li>If CT naïve: Anthracyclines or taxanes (specially if HER-2+ to give concomitant anti-HER2 therapy)
  66. 66. If A-based in adjuvant: Taxanes
  67. 67. If A and T-based in adjuvant: Capecitabine</li></ul>2nd LINE<br /><ul><li> If A, T and Capecitabine pre-treated: NO STANDARD! Clinical trial is the best option . If not available, some of the available options are:abraxane, eribulin, liposomal anthracycline, CMF, vinorelbine, Cisplatin + 5-FU…</li></li></ul><li>MBC PATIENTS’ SURVIVAL OVER TIME<br />Chia et al, Cancer 110:973–9, 2007<br />FROM 1991 TO 2001<br />Giordano SH, et al, Cancer 100:44-52, 2004<br />FROM 1974 TO 2000<br />
  68. 68. Prognosis in MBC by HER2 Statusand by Therapy with Trastuzumab<br />Dawood et al, ASCO abstract 1018, 2008<br />Courtesy A Wolf<br />
  69. 69. ER and/or PR positive tumours <br />The median survival was 22 months <br />and has not increase over time<br />Should be a research priority!<br />Trends in survival in metastatic breast cancer. Sundquist et al . EBCC 2010, abst # 453<br />
  70. 70. POTENTIAL SOLUTIONS TO IMPROVE MBC OUTCOME<br /><ul><li>New treatments
  71. 71. New strategies with “old” treatments
  72. 72. More pts in clinical trials </li></ul>(Less than 5-10% of cancer patients participate in clinical trials in the western countries!!)<br /><ul><li>Biomarkers (predictive, pharmacogenetics, pharmacogenomics…)
  73. 73. International GUIDELINES (that are followed!) (implementation of guidelines such as St Gallen increased survival EBC)</li></li></ul><li>The “St Gallen” of MBC<br />PLEASE JOIN US!!<br />

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