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ESO BALKAN MASTERCLASS ON CLINICAL ONCOLOGY
1. ESO BALKAN MASTERCLASS IN CLINICAL ONCOLOGY Dubrovnik, Croatia, 11-15 May 2011 Chemotherapy options/management issues in (HER-2 NEG) metastatic breast cancer F. Cardoso, MD ESO Breast Cancer Program Coordinator Head, Breast Cancer Unit - Champalimaud Cancer Center Lisbon, Portugal
4. AVAILABLE DATA Most trials and meta-analysis compare single agent vs. combination and NOT sequential use of single agents vs. combination CT (no crossover) The majority of trials show that combination CT yields higher RR, in some higher PFS, higher toxicity and no or quite small survival benefit
5. Docetaxel vs. Docetaxel + Capecitabine Paclitaxel vs. Paclitaxel + Gemcitabine
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8. A T AT P Value 34 6.2 14 20.1 33 5.9 20 22.2 46 8.0 - 22.4 S S S NS RR% first-line MEDIAN TTF, mos RR% second-line MEDIAN OS, mos Paclitaxel Versus Doxorubicin Versus BothCrossover Part of Trial Design 739 MBC patients QOL Different toxicities, similar tolerability Sledge W Jr, et al. Proc Am Soc Clin Oncol. 1997. Abstract 2
9. COMBINATION SEQUENTIAL SINGLE AGENTS <Toxicity Similar survival Better overall QoL Better management of resources >RR Faster symptom/disease control >Toxicity >Impact on daily life No or very small gain in survival Uses up “all weapons” faster <RR Slower symptom/disease control
10. ESO-EBCC MBC Recommendations 9th REVISED STATEMENT Sequential use of single cytotoxic drugs should be the preferred choiceexcept if: Rapidly progressing disease Life threatening visceral metastases Need for rapid disease/symptom control Define the subgroup of patients who need first-line combination because will not be able to rescued with second-line or third-line CT Cardoso F, et al. J Natl Cancer Inst. 2009;101:1174-1181 Well-designed, prospective phase III trial in current chemotherapy era with mandated crossover is sorely needed
36. Capecitabine in Taxane-Pretreated MBC: ConsistentEfficacy Data ONLY DRUG CONSIDERED STANDARD IN MBC PRE-TREATED WITH A & T ALSO BEING EVALUATED IN ADJUVANT SETTING 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.
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38. CAUTION: NO LONG-TERM EXPERIENCEincreased solubility prolonged duration of exposure selective drug delivery improved tx index
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40. Previous study testing nab-paclitaxel in taxane pretreated advanced breast cancer patients 1
41. Compared with paclitaxel (Ph 3): Higher RR, Higher TTPand Slight better OS 2
42. Compared with docetaxel (Ph 2): Better RR and PFS, specially the weekly regimens 3 1 Blum JL, et al. ClinBreastCancer. 2007;7(11):850-856 2 Gradishar, W. et al. J Clin Oncol. 2005;23(31):7794-7803. 3 Gradishar WJ, et al. J Clin Oncol. 2009;27(22):3611-3619
43. A few words on biological agents for HER-2 negative disease
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45. Proof-of-concept phase II study, single-arm sequential cohort designConfirmed BRCA1 or BRCA2 mutation Advanced refractory breast cancer(stage IIIB/IIIC/IV) after failure of ≥1 prior chemotherapy for advanced disease Cohort 1 (enrolled first) Cohort 2 Olaparib 400 mg po bid (MTD) 28-day cycles; n = 27 Olaparib 100 mg po bid 28-day cycles; n = 27 Tutt et al The Lancet 2010 376(9737):235-44
46. O’Shaughnessy et al, ESMO 2010 Iniparib (BSI-201) Study Design Multi-center, open-label, randomized Phase II Metastatic TNBC -about 70% had prior chemotherapy for early BC Measurable disease -median number of metastatic sites = 3 0-2 prior chemotherapy regimens for metastatic disease - no prior chemo~60% No prior gemcitabine, carboplatin, cisplatin, PARP inhibitor Stable brain metastases allowed ECOG PS 0–1 - two thirds PS = 0 Randomization (1:1) Gemcitabine1000 mg/m2, IV, d 1, 8 CarboplatinAUC 2, IV, d 1, 8 21 day cycles Iniparib5.6 mg/kg, IV, d 1, 4, 8, 11 Gemcitabine1000 mg/m2, IV, d 1, 8 CarboplatinAUC 2, IV, d 1, 8 21 day cycles N=62* N=61 RESTAGING: Every 2 Cycles (RECIST) PRIMARY ENDPOINTS: CBR = CR + PR + SD ≥6mo, Safety SECONDARY ENDPOINTS: DFS, ORR, Toxicity *30 patients randomized to gem/carbo crossed over to receive gem/carbo + Iniparib (BSI-201) at disease progression
47. O’Shaughnessy et al, ESMO 2010 Iniparib: Progression-Free and Overall Survival (ITT Population) Progression Free Survival Overall Survival-Exploratory OS + 4.6 months PFS + 2.3 months *P-values were not adjusted for multiple interim analyses.
55. Is PARP really the main/only target?PHASE 3 TRIAL IS NEGATIVE! (Will be presented at ASCO 2011)
56. Bevacizumab in MBC Meta-Analysis (O’Shaughnessy et al ASCO 2010) PFS: 2.5 months, OS: 0.3 months 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.
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60. Gennari et al, ESMO 2010 Prolonging CT until disease progression improves Progression Free and Overall Survival in MBC: results of a systematic review Alessandra Gennari, Oriana Nanni, Matteo Puntoni, Mariapia Sormani, Mauro D'Amico, Dino Amadori, Andrea De Censi, Paolo Bruzzi DivisionofMedicalOncology, Galliera Hospital, Genoa IRST, Meldola (FC) DepartmentofHealthSciences, Universityof Genoa National CancerResearchInstitute, Genoa, Italy
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62. 9% reduction in the risk of death (HR 0.91; 95% CI 0.84-0.99)
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…)
68. Prognosis in MBC by HER2 Statusand by Therapy with Trastuzumab Dawood et al, ASCO abstract 1018, 2008 Courtesy A Wolf
69. ER and/or PR positive tumours The median survival was 22 months and has not increase over time Should be a research priority! Trends in survival in metastatic breast cancer. Sundquist et al . EBCC 2010, abst # 453
