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Highlights of Metastatic Breast Cancer Research

Highlights of Metastatic Breast Cancer Research. ASCO 2007 : Highlights of Metastatic Breast Cancer Research. Single-Agent First-Line Therapy New data show improved clinical activity of nab -paclitaxel compared with docetaxel in patients with advanced breast cancer.

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Highlights of Metastatic Breast Cancer Research

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  1. Highlights of Metastatic Breast Cancer Research

  2. ASCO 2007:Highlights of Metastatic Breast Cancer Research Single-Agent First-Line Therapy New data show improved clinical activity of nab-paclitaxel comparedwith docetaxel in patients with advanced breast cancer Combination Therapy for First-Line Treatment of Metastic Breast Cancer • First-line data for lapatinib in HER2-positive advanced breast cancer is encouraging • Adding a platinum to a taxane plus trastuzumab does not add to efficacy • Capecitabine plus nab-paclitaxel is highly active in first-line metastatic breast cancer

  3. Single-Agent First-Line Therapy

  4. New data show improved clinical activity of nab-paclitaxel compared with docetaxel Randomized comparison of weekly or every-3-week (q3w) nab-paclitaxel compared to q3w docetaxel as first-line therapy in patients (pts) with metastatic breast cancer (MBC) Gradishar W, et al. ASCO 2007: Abstract 1032.

  5. Background • First generation taxanes, paclitaxel and docetaxel, provide major improvements in treatment of early-stage and metastatic breast cancer, but contain required chemical solvents associated with toxicity • Response rates of 40% to 60% reported in chemotherapy-naïve patients with metastatic breast cancer treated with paclitaxel, and rates of 25% to 30% in patients refractory to anthracycline-containing regimens1 • Current studies are assessing whether nab-paclitaxel can offer the same antitumour effect as docetaxel • Previous phase III trial has demonstrated superiority of nab-paclitaxel over paclitaxel in MBC,in addition to its advantages, which include lack of premedication and shorter infusion time2,3 • William Gradishar and colleagues presented data from fourth interim analysis of randomized, open-label phase II study of QW or Q3W nab-paclitaxel compared to docetaxel Q3W as first-line therapy in patients with metastatic breast cancer4 1. Nabholtz JM, et al. Expert Open Pharmacother 2000. 2. Gradishar WJ, et al. J Clin Oncol 2005. 3. Jones SE, et al. J Clin Oncol 2005. 4. Gradishar W, et al. ASCO 2007: Abstract 1032. MBC = metastatic breast cancer QW = weekly Q3W = every 3 weeks

  6. Study design • This current four-arm trial compares toxicity and preliminary efficacy data for • Solvent-free nab-paclitaxel vs. solvent-based docetaxel • Nab-paclitaxel QW vs. Q3W • High-dose vs. low-dose QW nab-paclitaxel QW = weekly Q3W = every 3 weeks Gradishar W, et al. ASCO 2007: Abstract 1032.

  7. Study design(continued) • Patients had no prior chemotherapy for metastatic disease, Stage IV adenocarcinoma of the breast, and adequate liver function • Three hundred patients enrolled with mean age of 54 years; 75% were postmenopausal • Primary outcomes: antitumour response (evaluated every 8 weeks by RECIST criteria) and toxicity • Secondary outcome: PFS • Investigator-confirmed response assessments compared with secondary response assessments conducted by independent radiology review • Independent radiology reviewer blinded to treatment assignment, investigator assessment of response, and target lesions identified by investigator MBC = metastatic breast cancer PFS= progression-free survival RECIST = response evaluation criteria in solid tumours Gradishar W, et al. ASCO 2007: Abstract 1032.

  8. Key findings • The nab-paclitaxel Q3W regimen significantly improved PFS compared with docetaxel Q3W (Figure 1) • Nab-paclitaxel 300 mg/m2 Q3W vs. docetaxel, HR = 0.63, p = 0.046 • The nab-paclitaxel QW high-dose regimen significantly improved PFS compared with docetaxel Q3W • Nab-paclitaxel 150 mg/m2 QW vs. docetaxel, HR = 0.46, p = 0.002 • Nab-paclitaxel 100 mg/m2 QW vs. docetaxel, HR = not significant • The higher dose of weekly nab-paclitaxel (150 mg/m2 QW) was significantly better than the lower QW dose (100 mg/m2); HR = 0.55, p = 0.009 HR = hazard ratio PFS= progression-free survival QW = weekly Q3W = every 3 weeks Gradishar W, et al. ASCO 2007: Abstract 1032.

  9. Figure 1: Progression-free survival PFS= progression-free survival QW = weekly Q3W = every 3 weeks Gradishar W, et al. ASCO 2007: Abstract 1032.

  10. Figure 2: Objective response rates • Nab-paclitaxel QW (100 and 150 mg/m2) significantly increased tumour response rate compared with docetaxel Q3W (Figure 2 above) • nab-paclitaxel 100 mg/m2 QW vs. docetaxel 100 mg/m2 Q3W (p = 0.002) • nab-paclitaxel 150 mg/m2 QW vs. docetaxel 100 mg/m2 Q3W (p = 0.003) CRR = complete response rate QW = weekly Q3W = every 3 weeks RECIST = response evaluation criteria in solid tumours Gradishar W, et al. ASCO 2007: Abstract 1032.

  11. Safety • Low-dose QW arm appeared to be the most tolerable of the three nab-paclitaxel arms • All nab-paclitaxel arms had significantly less neutropenia than docetaxel arm • Neutropenia (all grades) significantly more common in Q3W arm and high-dose QW arm of nab-paclitaxel compared with low-dose QW arm (Table 1) • Rate of febrile neutropenia lower in all nab-paclitaxel arms compared with docetaxel • Lower incidence of fatigue with all schedules of nab-paclitaxel compared with docetaxel (Table 2) QW = weekly Q3W = every 3 weeks Gradishar W, et al. ASCO 2007: Abstract 1032.

  12. Incidence of fatigue among treatment arms QW = weekly Q3W = every 3 weeks Gradishar W, et al. ASCO 2007: Abstract 1032.

  13. Incidence of neutropenia and febrile neutropeniaamong treatment arms QW = weekly Q3W = every 3 weeks Gradishar W, et al. ASCO 2007: Abstract 1032.

  14. Safety(continued) • No difference observed in peripheral neuropathy rates between nab-paclitaxel arms and docetaxel • The 100 mg/m2 arm of nab-paclitaxel associated with least peripheral neuropathy • Grade 1 and 2 arthralgias significantly more common in Q3W arm and high-dose QW arm of nab-paclitaxel compared with low-dose QW arm • Grade 1 and 2 arthralgias more common in Q3W arm (p = 0.021) and high-dose (150 mg/m2) QW (p = 0.048) nab-paclitaxel arms compared with docetaxel QW = weekly Q3W = every 3 weeks Gradishar W, et al. ASCO 2007: Abstract 1032.

  15. Key conclusions • Response rate observed to be superior for both 100 mg/m2 and 150 mg/m2 QW doses of nab-paclitaxel compared with docetaxel in metastatic breast cancer • PFS significantly improved with QW nab-paclitaxel 150 mg/m2 and nab-paclitaxel 300 mg/m2 Q3W compared with docetaxel • PFS superior for QW nab-paclitaxel 150 mg/m2 compared with QW nab-paclitaxel 100 mg/m2 • Fewer AEs such as neutropenia and fatigue with all schedules of nab-paclitaxel compared with docetaxel • Large randomized phase III trial to begin shortly comparing QW (3 weeks out of 4) nab-paclitaxel 150 mg/m2 vs. docetaxel 100 mg/m2 Q3W in metastatic breast cancer AE = adverse event PFS = progression-free survival QW = weekly Q3W = every 3 weeks Gradishar W, et al. ASCO 2007: Abstract 1032.

  16. Canadian perspective by Dr. Chia • Data in this second analysis for large phase II trial interesting as it appears more nab-paclitaxel (450 mg/m2) can be delivered with acceptable toxicity and improved PFS compared to docetaxel • One has to be cautious about placing too much emphasis on the results of randomized phase II trials • Current data reaffirm nab-paclitaxel may be equivalent, if not superior, to docetaxel in the metastatic breast cancer setting; this finding warrants further testing of this agent in larger phase III studies, which is set to begin • Current analysis may change schedule of nab-paclitaxel used in phase III trials (i.e., choosing the weekly nab-paclitaxel arm of 150 mg/m2 QW for 3 weeks out of 4) PFS = progression-free survival QW = weekly Gradishar W, et al. ASCO 2007: Abstract 1032.

  17. Combination Therapy for First-Line Treatment

  18. First-line data for lapatinib in HER2-positive advanced breast cancer is encouraging Lapatinib (L) with paclitaxel compared to paclitaxel as first-line treatment for patients with metastatic breast cancer: a phase III randomized, double-blind study of 580 patients Di Leo A, et al. ASCO 2007: Abstract 1011.

  19. Background • In tumours of 20% to 25% of women with breast cancer HER2 gene amplified; as many as 50 or 100 gene copies per cell generated1 • Overexpression of HER2 shown to be associated with a more aggressive disease with a poorer prognosis1 • Lapatinib showed promising results in preclinical and early clinical studies as an orally active small molecule tyrosine kinase inhibitor that targets both HER2 and EGFR (HER1)2 • Lapatinib given as a single agent results in RR of 5% to 10% in patients with refractory disease (i.e., those who have received multiple prior chemotherapy regimens and trastuzumab), as demonstrated in two separate trials • Response rate appears to be approximately 25%in patients who have not received prior treatment in the metastatic setting and who are trastuzumab-naïve2 EGFR = epidermal growth factor receptor HER = human epidermal growth factor receptor RR = response rate 1. Jørgensen JT, et al. Oncologist 2007. 2. Nelson HM, et al. Ann Pharmacother 2006.

  20. Background(continued) • Combination of lapatinib and capecitabine has received regulatory approval by the U.S. FDAas treatment for metastatic HER2-positive breast cancer in patients for whom other treatments have failed • This follows positive data from a pivotal open-label phase III trial in which TTP almost doubled in patients with HER2-positive advanced breast cancer treated with lapatinib in combination with capecitabine vs. capecitabine alone1 • Combination of lapatinib and cytotoxic capecitabine resulted in • RR 22%, while RR to capecitabine alone was 14% (p = 0.09) • TTP significantly better in the combination arm (8.4 mos) compared with the single arm (4.4 mos) (p <0.001, HR = 0.47) • At ASCO 2007, Angelo Di Leo and colleagues presented a planned subset analysis of HER2 subgroups of the phase III randomized, double-blind, placebo-controlled, multicentre trial evaluating efficacy and tolerability of lapatinib plus paclitaxel2 EGFR = epidermal growth factor receptor FDA = U.S. Food and Drug Administration HR = hazard ratio RR = response rate TTP = time to progression 1. Geyer CE, et al. N Engl J Med 2006. 2. Di Leo A, et al. ASCO 2007: Abstract 1011.

  21. Study design • Trial enrolled 580 patients with • Incurable HER2-negative or unknown breast cancer, Stage III or IV • No prior treatment for metastatic disease • Median age 51 years in paclitaxel plus lapatinib arm; 52 years in paclitaxel plus placebo arm • Majority of patients had Stage IV disease (87% and 86%, respectively) • Patients randomly assigned to receive paclitaxel 175 mg/m2 Q3W plus either lapatinib 1,500 mg daily by mouth (n = 293) or a placebo (n = 286); 2 patients on paclitaxel plus placebo arm received both paclitaxel and lapatinib • Primary endpoint was TTP; study designed with 90% power to detect 40% proportional increase in median TTP of ITT population • Secondary endpoints included EFS, OS, ORR, clinical benefit rate, ORR plus SD ≥6 months, duration of response, and safety EFS = event-free survival ITT = intent to treat ORR = overall response rate OS = overall survivalQ3W = every 3 weeks RR = response rate SD = stable disease TTP = time to progression Di Leo A, et al. ASCO 2007: Abstract 1011.

  22. Key findings • Addition of lapatinib to paclitaxel significantly improved RR compared with paclitaxel alone in the entire study population (35% vs. 25%, respectively) (Table 1) • Median duration of response, OS, and EFS similar between both treatment arms for entire study population of HER-2 negative or unknown breast cancers • Ninety-one patients were retrospectively identified as having HER2-positive disease by FISH or IHC analysis of tumour samples, 52 in the lapatinib-paclitaxel arm and 39 in the paclitaxel-placebo arm EFS = event-free survival FISH = fluorescence in situ hybridization IHC = immunohistochemistry OS = overall survival RR = response rate Di Leo A, et al. ASCO 2007: Abstract 1011.

  23. Overall outcomes of lapatinib plus paclitaxel vs. paclitaxel alone CI = confidence interval CR = complete response EFS = event-free survival HR = hazard ratio ORR = overall response rate OS = overall survival PR = partial response SD = stable disease Di Leo A, et al. ASCO 2007: Abstract 1011.

  24. Key findings(continued) • Findings for HER2-positive patients showed that 60% of patients administered lapatinib plus paclitaxel experienced CR or PR, compared to 36% given paclitaxel alone (Figure 1 below) CR = complete response HER = human epidermal growth factor receptor PR = partial response Di Leo A, et al. ASCO 2007: Abstract 1011.

  25. Key findings(continued) • Median EFS significantly longer for HER2-positive patients who received the lapatinib combination (7.9 months compared with 5.2 months in those who received paclitaxel alone); TTP was 8.1 months compared with 5.8, respectively (Table 2 below) EFS = event-free survival OS = overall survival TTP = time to progression Di Leo A, et al. ASCO 2007: Abstract 1011.

  26. Safety • Patients who received combination of lapatinib and paclitaxel had higher incidence of diarrhea than those receiving paclitaxel alone, as well as higher rate of nonprogression-related death (2.7% vs. 0.6%) (Table 3) LVEF = left ventricular ejection fraction Di Leo A, et al. ASCO 2007: Abstract 1011.

  27. Key conclusions • Lapatinib in combination with paclitaxel increased PFS and EFS in first-line treatment of patients with metastatic HER2-positive breast cancer, compared with paclitaxel alone in this relatively small subgroup of patients • Patients with metastatic HER2-negative breast cancer do not appear to derive additional benefit from lapatinib added to paclitaxel compared with paclitaxel alone • Improvement in TTP came at expense of increased toxicity, particularly diarrhea, mucositis, and rash; the latter may be related to pharmacokinetic interactions between drugs • Authors suggest that results warrant further trials to assess predefined molecular subtypes of breast cancer in larger randomized trials EFS = event-free survival HER = human epidermal growth factor receptor PFS = progression-free survival TTP = time to progression Di Leo A, et al. ASCO 2007: Abstract 1011.

  28. Canadian perspective by Dr. Chia • This study examined the combination of lapatinib with paclitaxel in HER2-negative breast cancer for patients with metastatic breast cancer who had no prior chemotherapy • Paclitaxel commonly used in many parts of the world where there is no access to drugs like trastuzumab or the ability to test for HER2 status • Lapatinib blocks both HER1 and HER2 signals, so it doesn’t intrinsically make a lot of sense to give it to HER2-negative patients. However some HER2-negative patients have EGFR/HER1 overexpression, and that formed the rationale for this particular study • Addition of lapatinib to paclitaxel increased RR when the whole patient population was observed, but didn’t change TTP or OS • Benefit in EFS and TTP with lapatinib in the HER2-positive cohort,and a trend to OS benefit EGFR = epidermal growth factor receptor EFS = event-free survival HER = human epidermal growth factor receptor OS = overall survival RR = response rate TTP = time to progression Di Leo A, et al. ASCO 2007: Abstract 1011.

  29. Canadian perspective(continued) • Lapatinib has only been tested in patients who have already received trastuzumab, so this study supports the idea that lapatinib may have similar clinical benefit as trastuzumab when combined with a taxane in the treatment of HER2 positive MBC, but without the associated cardiotoxicity • A positive study, overall; it will be interesting to see this drug move forward in clinical trials and in practice • Lapatinib will be good addition to the armamentarium of agents for metastatic breast cancer once it is approved in Canada • Cost is the issue with all new agents HER = human epidermal growth factor receptor MBC = metastatic breast cancer Di Leo A, et al. ASCO 2007: Abstract 1011.

  30. Adding a platinum to a taxane plus trastuzumab does not add to efficacy First overall survival analysis of a multicenter phase III randomized trial comparing docetaxel and trastuzumab as first-line chemotherapy for patients with metastatic breast cancer containing the HER2/neu alteration Pegram M, et al. ASCO 2007: Abstract LBA1008.

  31. Background • Trastuzumab slows the growth and spread of breast cancer cells by binding to HER2 protein receptors and interrupting the growth signal.In this way, trastuzumab, a monoclonal antibody, targets breast cancer cells that overexpress the HER2 protein • Pivotal study by Dennis Slamon and colleagues compared chemotherapy alone vs. chemotherapy plus trastuzumab1 • Study demonstrated that addition of trastuzumab to chemotherapy, either doxorubicin/cyclophosphamide (AC) or paclitaxel, improved RR, TTP, median survival, and one-year survival rate • Improvement in survival was seen in spite of the fact that 65% of women in the control arm ultimately received trastuzumab HER = human epidermal growth factor receptor RR = response rate TTP = time to progression 1. Slamon DJ, et al. N Engl J Med 2001.

  32. Background(continued) • Results of BCIRG-007 study presented at ASCO 2006 compared docetaxel (100 mg/m2) plus trastuzumab (TH) vs. docetaxel (75 mg/m2) plus carboplatin plus trastuzumab (TCH) in first-line treatment of metastatic breast cancer1 nn AUC = area under curve BCIRG = Breast Cancer International Research Group FISH = fluorescence in situ hybridization HER = human epidermal growth factor receptor RR = response rate TTP = time to progression 1. Forbes JF, et al. J Clin Oncol 2006.

  33. Background(continued) • No difference across the two arms in • RR (TH 72.5 % vs. TCH 72.7%) • TTP (TH 11 months vs. TCH 10.3 months) • Both regimens appear to be acceptable • Study raised important questions about the role of platinum salt in combination with taxane in treatment of HER2-positive metastatic breast cancer • First overall survival analysis of the BCIRG-007 trial presented at ASCO 20071 BCIRG = Breast Cancer International Research Group HER = human epidermal growth factor receptor RR = response rate TCH = carboplatin/docetaxel/trastuzumab TH = docetaxel/trastuzumab TTP = time to progression 1. Pegram M, et al. ASCO 2007: Abstract LBA1008.

  34. Study design • BCIRG-007 trial enrolled 263 women with FISH–confirmed, HER2-positive metastatic breast cancer (Table 1) • Median follow-up was 39 months • Primary endpoint: TTP • Secondary endpoints: RR, duration of OR, clinical benefit, toxicity, OS, and pathologic and molecular markers • No crossover allowed between arms • Power of the trial set to 80%, to detect 50% improvement in median TTP • Number of events required for final analysis set at 204 (significance = 0.05, power = 0.8) BCIRG = Breast Cancer International Research Group FISH = fluorescence in situ hybridization HER = human epidermal growth factor receptor OR = overall response OS = overall survival RR = response rate TTP = time to progression Pegram M, et al. ASCO 2007: Abstract LBA1008.

  35. Patient characteristics KPS = Karnofsky Performance Status TCH = carboplatin/docetaxel/trastuzumab TH = docetaxel/trastuzumab Pegram M, et al. ASCO 2007: Abstract LBA1008.

  36. Key findings • No difference after 39 months of follow-upin survival rate of either TH or TCH arms (39.1 months vs. 39.2 months, p = 0.65) • More patients given TCH received maximum number of chemo-therapy cycles (79% versus 64%) • Grade 3 and 4 toxicities occurred with similar frequency in both treatment arms, with the exception of thrombocytopenia, nausea, and emesis, more common with the carboplatin-containing regimen (Table 2, 3) • All grade sensory neuropathy, rash, myalgia, and nail changes significantly more common in trastuzumab plus docetaxel arm vs carboplatin-containing arm (Table 3) TCH = carboplatin/docetaxel/trastuzumab TH = docetaxel/trastuzumab Pegram M, et al. ASCO 2007: Abstract LBA1008.

  37. Reported hematological adverse events TCH = carboplatin/docetaxel/trastuzumab TH = docetaxel/trastuzumab Pegram M, et al. ASCO 2007: Abstract LBA1008.

  38. Reported non-hematological adverse events TCH = carboplatin/docetaxel/trastuzumab TH = docetaxel/trastuzumab Pegram M, et al. ASCO 2007: Abstract LBA1008.

  39. Key conclusions • Addition of carboplatin to docetaxel and trastuzumab combination failed to improve outcomes from docetaxel plus trastuzumab alone • No statistical differences in RR, TTP, or survival between the two treatments, though the study was underpowered to detect modest differences • Both therapies effectively treat HER2-positive metastatic breast cancer, with a TTP >10 months and an OS of more than 36 months • More grade 3 or 4 thrombocytopenia, nausea, and emesis in carboplatin-containing arm • Myalgia, rash, and nail changes more common with the docetaxel-trastuzumab regimen • Because of asymmetry in the docetaxel doses (TH 100 mg/m2 vs. TCH 75 mg/m2), it cannot be ruled out that carboplatin played a role in response in the lower-dose docetaxel arm HER = human epidermal growth factor receptor OS = overall survival RR = response rate TCH = carboplatin/docetaxel/trastuzumab TH = docetaxel/trastuzumab TTP = time to progression Pegram M, et al. ASCO 2007: Abstract LBA1008.

  40. Canadian perspective by Dr. Chia • Application of platinum-based chemotherapy in clinical practice has been hampered by concerns about toxicity and lack of proven survival effects1 • Some recent interest shown in combining platinums with trastuzumab, given observed synergistic interactions in preclinical studies2 • BCIRG-007 designed to study incremental effect of adding carboplatin to proven doublets such as docetaxel and trastuzumab • First analysis of BCIRG-007 trial showed no difference in RR or PFS; updated results show no difference in OS • Slight differences in toxicity between carboplatin-containing and non-carboplatin–containing arm suggest that women are better able to tolerate docetaxel and trastuzumab when combined with a platinum than without it because of the ability to deliver a lower dose of docetaxel when combined with carboplatin BCIRG = Breast Cancer International Research Group OS = overall survival PFS = progression-free survival RR = response rate 1. Martin M. Clin Breast Cancer 2001. 2. Pegram MD, et al. J Natl Cancer Inst 2004.

  41. Capecitabine plus nab-paclitaxel is highly active in first-line metastatic breast cancer Phase II trial of nab-paclitaxel (nanoparticle albumin-bound paclitaxel (ABX)) + capecitabine (XEL) in first-line treatment of metastatic breast cancer (MBC) Somer B, et al. ASCO 2007: Abstract 1053.

  42. Background • Nab-paclitaxel and capecitabine are both highly effective single agents for the treatment of metastatic breast cancer1,2 • Combination of capecitabine and taxane has been shown to improve RR and TTP compared to singlet therapy3 • Preclinical and clinical research suggests that paclitaxel enhances activity of capecitabine4,5 • Study by Somer and colleagues designed to test safety and efficacy of nab-paclitaxel and capecitabine in novel combination schedule6 1. Gradishar WJ, et al. J Clin Oncol 2005. 2. O'Shaughnessy JA, et al. Ann Oncol 2001. 3. Miles D, et al. Clin Breast Cancer 2004. 4. Sawada N, et al. Clin Cancer Res 1998. 5. O'Shaughnessy JA, et al. Clin Breast Cancer 2006. 6. Somer B, et al. ASCO 2007: Abstract 1053. RR = response rate TTP = time to progression

  43. Study design • Trial was a phase II, multicentre open-label study • Patients (n = 50) enrolled in the study (Table 1) had • Metastatic breast cancer, measurable by RECIST criteria, ECOG PS 0–2, and HER2/neu negative status • No prior capecitabine therapy or chemotherapy for metastatic disease • No adjuvant fluoropyrimidine and/or paclitaxel treatment unless more than 6 months before enrolling in the trial if they received these agents in the adjuvant setting • Primary objective: evaluate RR • Secondary objectives: PFS, safety, and OS • Patients received 125 mg/m2 IV nab-paclitaxel on days 1 and 8 with no premedication, and 825 mg/m2 PO BID capecitabine on days 1–14 Q3W ECOG = Eastern Cooperative Oncology Group HER = human epidermal growth factor receptor OS = overall survival PFS = progression-free survival PS = performance status RECIST = response evaluation criteria in solid tumours RR = response rate Somer B, et al. ASCO 2007: Abstract 1053.

  44. Patient baseline Somer B, et al. ASCO 2007: Abstract 1053.

  45. Key findings • Data were available from complete sample of 50 patients • Median PFS of 270 days was observed with this combination regimen (Figure 1) • ORR was 60.9%, with 21.5% patients exhibiting SD, and 17.4% patients with progressive disease (Table 2) • Eight patients required a dose reduction in capecitabine; 4 patients required a dose reduction in nab-paclitaxel • Combination relatively well tolerated; most frequent grade 3 events fatigue, neutropenia, mucositis, and hand-foot syndrome (Table 3) ORR = overall response rate PFS = progression-free survival SD = stable disease Somer B, et al. ASCO 2007: Abstract 1053.

  46. Figure 1: Median progression-free survival Somer B, et al. ASCO 2007: Abstract 1053.

  47. Antitumour activity of nab-paclitaxel plus capecitabine Somer B, et al. ASCO 2007: Abstract 1053.

  48. Most frequent adverse events by Common Toxicity Criteria grade Somer B, et al. ASCO 2007: Abstract 1053.

  49. Key conclusions • Capecitabine plus nab-paclitaxel is highly active combination regimen in first-line treatment of metastatic breast cancer, with an ORR of 61% • Median PFS of 9 months observed with this combination • Dose of 125 mg/m2nab-paclitaxel on days 1 and 8, plus 825 mg/m2 capecitabine BID on days 1−14 Q3W appears to be well tolerated ORR = overall response rate PFS = progression-free survival Q3W = every three weeks Somer B, et al. ASCO 2007: Abstract 1053.

  50. Canadian perspective by Dr. Chia • Doublet therapy with taxanes (capecitabine or gemcitabine) appears to be superior to monotherapy with taxanes for RR and TTP in metastatic breast cancer (MBC) • This phase II trial demonstrated safety and efficacy for the combination of nab-paclitaxel and capecitabine • A larger phase II trial may be needed to ensure this is a relatively well-tolerated and active regimen in treatment of MBC, particularly in patients already exposed to adjuvant taxane • This combination may have greater yield in the adjuvant or neoadjuvant setting; phase III trials in these settings needed to address whether this combination can reduce toxicity and/or gain efficacy RR = response rate TTP = time to progression Somer B, et al. ASCO 2007: Abstract 1053.

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