Management Of Breast Cancer:
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1 PRITER-FRIEDLY VERSI T CLIICLCLGY.CM and PHRMCYPRCTICEEWS.CM Management f Breast Cancer: dvanced Disease and ovel gents ll rights reserved. Reproduction in whole or in part without permission is prohibited. CREY K. DERS, MD Division of Medical ncology Department of Medicine Duke University Comprehensive Cancer Center Durham, orth Carolina KIMBERLY L. BLCKWELL, MD Division of Medical ncology Departments of Medicine and Radiation ncology Duke University Comprehensive Cancer Center Durham, orth Carolina For patients with metastatic breast cancer, the goal of therapy is to maximize quality of life while palliating cancer-related symptoms. Many factors must be considered when treatment strategies are selected in this setting, including type and timing of prior therapy; hormonal (estrogen receptor [ER] and progesterone receptor [PR]) status; ERBB2 (formerly HER2/neu) status; location and extent of disease; and patient characteristics, such as age and comorbidities. s the field of targeted biologic therapeutics expands, previous therapy with trastuzumab (Herceptin, Genentech) also becomes an important consideration. lthough the optimal strategy is still under debate, this article reviews the essential components of advanced breast cancer treatment, including endocrine therapy, chemotherapy, and novel targeted agents. Endocrine Therapy hormonal approach to treatment is determined by a patient s menopausal status and previous exposure to anti-estrogen agents. Premenopausal women who have not received prior anti-estrogen therapy should be offered tamoxifen with or without ovarian ablation (ie, luteinizing hormone-releasing hormone agonist or oophorectomy). For postmenopausal women, several Phase III randomized trials have demonstrated that type 1 (steroidal) and type 2 (nonsteroidal) aromatase inhibitors are at least equivalent, if not superior, to tamoxifen as first-line therapy in the metastatic setting (Table). 1-4 Fulvestrant (Faslodex, strazeneca), an antiestrogen agent that binds to and degrades the ER, has also shown benefit among patients previously treated with a third-generation aromatase inhibitor. 5 EFECT TRIL lthough therapy with third-generation aromatase inhibitors and fulvestrant clearly shows benefit in the treatment of hormone-sensitive metastatic breast cancer, the optimal sequencing of individual agents has been subject to debate. The EFECT (Evaluation of Fulvestrant vs Exemestane) trial evaluated both efficacy and tolerability of fulvestrant versus the type 1 aromatase inhibitor exemestane (romasin, Pfizer) IDEPEDETLY DEVELPED BY MCMH PUBLISHIG MRCH
2 Table. romatase Inhibitors Versus Tamoxifen s Initial Therapy for Metastatic Breast Cancer nastrozole 1 nastrozole 2 Letrozole 3 Exemestane 4 Patients, n (I vs tamoxifen) 170 vs vs vs vs 189 TTP/PFS, mo 11.1 vs vs vs vs 6.7 (I vs tamoxifen) (P=0.005) (P=0.941) (P=0.0001) (P=0.04) ll rights reserved. Reproduction in whole or in part without permission is prohibited. I, aromatase inhibitor; TTP/PFS, time to disease progression/progression-free survival R D M IZ TI n=693 E, exemestane; F, fulvestrant; HR, hazard ratio; TTP, time to progression Figure 1. EFECT Trial: schema and results. Based on reference 6. Fulvestrant 500 mg IM day 0; 250 mg IM days 14 and 28; 250 mg IM q28d thereafter Exemestane 25 mg P daily F E HR P Value TTP, mo in postmenopausal women with hormone-sensitive breast cancer whose disease progressed after therapy with a nonsteroidal aromatase inhibitor, either letrozole or anastrozole (Figure 1). 6 In this trial, 693 women were randomly assigned to receive fulvestrant (n=351; loading dose 500 mg intramuscularly on day 0, 250 mg on days 14 and 28, and 250 mg every 28-±3 days thereafter) or exemestane (n=342; 25 mg orally daily). The median time to progression (TTP) in both groups was 3.7 months (hazard ratio [HR], 0.963; 95% confidence interval [CI], ; P=0.65). Both treatments were similarly well tolerated, with no significant differences in adverse events including hot flashes, weight gain, nausea/vomiting, diarrhea, and injection-site reactions. Fulvestrant (given with a loading dose) and exemestane are well-tolerated, efficacious treatment options for postmenopausal women with hormone-sensitive breast cancer following treatment with nonsteroidal aromatase inhibitors. Chemotherapy Several cytotoxic agents have shown efficacy in the treatment of patients with metastatic breast cancer. The choice of agent(s) depends on individual patient characteristics, including previous chemotherapy exposure and comorbidities. Recent trials have shown improved response rates and survival in patients with metastatic disease treated with taxanes and capecitabine (Xeloda, Roche), either alone or in combination Each of the trials discussed below compared specific taxanes and their dosing schedules. TX311 The TX311 (Randomized Trial of Taxotere vs Taxol for Women with Metastatic Cancer) trial addressed the question, What is the optimal taxane in anthracyclineresistant breast cancer? In this trial, investigators randomly assigned 449 women to receive either docetaxel (Taxotere, Sanofi-ventis) 100 mg/m 2 every 3 weeks, or paclitaxel 175 mg/m 2 every 3 weeks. 11 In the docetaxel arm, there was an increase in TTP of 2.1 months (P=0.0001) and an increase in overall survival (S) of 2.7 months (P=0.03). Higher rates of toxicity, including significant increases in neutropenia, myalgia, and diarrhea, were reported in the patients receiving docetaxel. CLGB 9840 The CLGB (Cancer and Leukemia Group B) 9840 trial addressed the question, What is the optimal dosing schedule for taxanes in metastatic breast cancer? This Phase III trial sought to determine whether infusing paclitaxel 80 mg/m 2 weekly for 1 hour yields better results and causes fewer side effects than the standard 3-hour infusion of 175 mg/m 2 every 3 weeks (Figure 2). 12 While patients were enrolling in the study, trastuzumab became standard therapy for patients with HER2-positive metastatic breast cancer. Thus, patients with HER2 overexpression received trastuzumab, and those with 2 IDEPEDETLY DEVELPED BY MCMH PUBLISHIG
3 R D Paclitaxel 175 mg/m 2 q3wk HER2+ nonoverexpressing with weekly trastuzumab (4-mg/kg loading dose, then 2 mg/kg weekly until disease progression) R D M IZ M IZ TI Paclitaxel 80 mg/m 2 weekly HER2+ nonoverexpressing without weekly trastuzumab (4-mg/kg loading dose, then 2 mg/kg weekly until disease progression) ll rights reserved. Reproduction in whole or in part without permission is prohibited. TI n=735 n=228 Paclitaxel Paclitaxel q1wk q3wk P Value TTP, mo S, mo Grade 3/4 granulocytopenia, % Grade 3/4 neurosensory, % HER2+ HER2+ onover- onoverexpressing with expressing w/o Trastuzumab Trastuzumab P Value TTP, mo S, mo S, overall survival; TTP, time to disease progression Figure 2. CLGB 9840: schema and results. Based on reference 12. normal HER2 expression were randomly assigned to receive paclitaxel with or without trastuzumab. Women in the weekly paclitaxel arm showed an increased TTP (9 vs 5 months; P=0.0008) and a trend toward increased S (24 vs 16 months; P=0.17). Weekly dosing of paclitaxel caused less granulocytopenia (5% vs 15%; P=0.013) but worsened neurosensory toxicity (23% vs 12%; P=0.001). The addition of trastuzumab did not increase TTP (7 vs 6 months; P=0.09) or S (22 vs 20 months; P=0.67) in patients who did not overexpress HER2. GL-CELTIC IV In the CLGB 9840 trial, a higher total dose was given in the weekly paclitaxel arm. This observation left many unsure as to whether or not paclitaxel given on a weekly schedule was truly superior to every-3-week administration. Therefore, the nglo-celtic IV trial was designed to determine superiority of paclitaxel given weekly at the same total dose as the every-3-week regimen. 13 Between 2002 and 2006, 569 patients were randomly assigned to receive either paclitaxel 90 mg/ m 2 weekly for 12 weeks, or paclitaxel 175 mg/m 2 every 3 weeks for 6 cycles. Response rates ([RR], 43% vs 27%, P=0.002) and TTP (24 vs 22 weeks; HR, 0.92; P=0.06) favored the weekly paclitaxel arm. The CLGB 9840 and nglo-celtic IV results support the hypothesis that total dose and schedule of paclitaxel are important. Furthermore, these results support the widespread adoption of weekly paclitaxel as the standard administration schedule in the setting of metastatic breast cancer. BRXE anoparticle albumin-bound (ab) paclitaxel (braxane, braxis ncology), was approved by the FD in 2005 for the treatment of metastatic breast cancer after failure of combination chemotherapy or relapse within 6 months after adjuvant chemotherapy. pproval was based on the results of a Phase III study that illustrated superior efficacy of ab paclitaxel 260 mg/m 2 administered over 30 minutes (no premedications) compared with paclitaxel 175 mg/m 2 administered over 3 hours (standard premedication), both given every 3 weeks. 14 More recently, results of a trial comparing ab paclitaxel, dosed both weekly and every 3 weeks, compared with docetaxel were updated in a fourth interim analysis (Figure 3). 15,16 In the first-line setting, 300 women with metastatic breast cancer were randomly assigned to 1 of 4 arms: docetaxel 100 mg/m 2 every 3 weeks, ab paclitaxel 300 mg/m 2 every 3 weeks, and either 150 mg/m 2 or 100 mg/m 2 of ab paclitaxel weekly for 3 out of 4 weeks. The confirmed response rate was higher for both doses of weekly ab paclitaxel (RR, 62%, 100 mg/m 2 ; RR, 70%, IDEPEDETLY DEVELPED BY MCMH PUBLISHIG 3
4 R D rm : braxane 300 mg/m 2 q3wk M IZ rm B: braxane 100 mg/m 2 weekly (3 of 4) TI rm C: braxane 150 mg/m 2 weekly (3 of 4) ll rights reserved. Reproduction in whole or in part without permission is prohibited. rm D: Docetaxel 100 mg/m 2 q3wk n=300 B C D RR, % P Values vs B vs C B vs D C vs D P=0.016 P=0.007 P=0.002 P=0.003 RR, response rate Figure 3. braxane as first-line therapy for metastatic breast cancer: schema and results. Based on reference 15, mg/m 2 ) than for docetaxel (RR, 38%; P=0.002 and P=0.003 [vs 100 mg/m 2 and 150 mg/m 2, respectively]) and ab paclitaxel every 3 weeks (RR, 43%; P=0.016 and P=0.007 [vs 100 mg/m 2 and 150 mg/m 2, respectively]). Progression-free survival (PFS) was statistically superior among patients who received ab paclitaxel 300 mg/m 2 every 3 weeks (HR, 0.63; P=0.046) or ab paclitaxel 150 mg/m 2 weekly (HR, 0.46; P=0.002) compared with every-3-week docetaxel. There was no significant difference in PFS between weekly ab paclitaxel 100 mg/m 2 and docetaxel. Finally, PFS was superior for weekly ab paclitaxel dosed at 150 mg/m 2 compared with 100 mg/m 2 (HR, 0.55; P=0.009). ab paclitaxel resulted in significantly lower rates of grade 4 neutropenia (P<0.001) and shorter duration of peripheral neuropathy compared with docetaxel. Based on these results, the authors have decided to proceed with a large, Phase III trial comparing the efficacy of weekly ab paclitaxel 150 mg/m 2 with every-3-week docetaxel 100 mg/m 2. Combination Chemotherapy Sequential single-agent chemotherapy versus combination chemotherapy remains controversial. 17 In general, combination chemotherapy yields a higher response rate and a longer TTP, but it also increases toxicity. In 2002, a large study showed a survival benefit for the combination of docetaxel and capecitabine compared with docetaxel alone. 9 More recently, the studies described below showed improved efficacy with the addition of gemcitabine (Gemzar, Eli Lilly) to taxane therapy. GEMCITBIE-PCLITXEL In a Phase III study, 529 women with metastatic disease were randomly assigned to receive first-line paclitaxel (175 mg/m 2 on day 1, every 21 days), or paclitaxel (175 mg/m 2 on day 1, every 21 days) plus gemcitabine (1,250 mg/m 2 on days 1 and 8, every 21 days), until disease progression. 18 Women in the gemcitabine-paclitaxel arm showed an increased 1-year survival rate compared with those in the paclitaxel arm (70.7% vs 60.9%; P=0.019) and an increased median S (18.5 vs 15.8 months; P=0.018). Grade 3/4 toxicities, including febrile neutropenia (5% vs 1%), thrombocytopenia (1.9% vs 0%), and anemia (2.7% vs 0.8%), were increased in the gemcitabine-paclitaxel arm. This study was significant because it was the second Phase III study showing a survival benefit for a combination of agents versus a single agent for metastatic disease. Sub sequent ongoing trials have been designed to determine which patients benefit from combination therapy and to develop regimens with greater efficacy. GEMCITBIE-DCETXEL In a Phase III trial, 305 women with metastatic breast cancer were randomly assigned in the firstor second-line setting to 21-day cycles of gemcitabine (1,000 mg/m 2 on days 1 and 8) plus docetaxel 4 IDEPEDETLY DEVELPED BY MCMH PUBLISHIG
5 R D Ixabepilone 40 mg/m 2 day 1 + capecitabine 2,000 mg/m 2 day 1-14 (21-d cycle) M IZ TI Capecitabine 2,500 mg/m 2 day 1-14 (21-d cycle) ll rights reserved. Reproduction in whole or in part without permission is prohibited. n=752 Ixabepilone + Capecitabine Capecitabine P Value RR, % < PFS, mo RR, overall response rate; PFS, progression-free survival Figure 4. Ixabepilone and capecitabine combination therapy: schema and results. Based on reference 21. (75 mg/m 2 on day 1), or capecitabine (2,500 mg/m 2 on days 1-14) plus docetaxel (75 mg/m 2 on day 1). 19 Patients had been pretreated with an anthracycline in either the adjuvant or first-line metastatic setting. Efficacy results were similar, including overall response rates (27% in the gemcitabine-docetaxel arm vs 31% in the capecitabine-docetaxel arm; P=0.4537). Toxicity was lower in the gemcitabine-docetaxel arm: febrile neutropenia (7% gemcitabine-docetaxel vs 12% capecitabine-docetaxel), grade 3/4 diarrhea (7% vs 17%), grade 3/4 mucositis (4% vs 16%), and grade 3/4 hand foot syndrome (0% vs 24%). This study suggests that gemcitabine-docetaxel is an active combination that should be considered in women who will be receiving combination chemotherapy. CMPRIS F GEMCITBIE-PCLITXEL WITH GEMCITBIE-DCETXEL More recently, gemcitabine-paclitaxel (gemcitabine 1,250 mg/m 2 on days 1 and 8 plus paclitaxel 175 mg/ m 2 on day 1) was compared to gemcitabine-docetaxel (gemcitabine 1,000 mg/m 2 on days 1 and 8 plus docetaxel 75 mg/m 2 on day 1), both on a 21-day cycle. 20 In this Phase II trial of 50 patients with metastatic breast cancer, overall response rates were similar: 39% for gemcitabine-paclitaxel and 40% for gemcitabinedocetaxel. Hematologic toxicity was more frequent in the gemcitabine-docetaxel group. Febrile neutropenia occurred in 16% of patients in the gemcitabine-docetaxel group vs 0% in the gemcitabine-paclitaxel group. These results indicate that both gemcitabine-paclitaxel and gemcitabine-docetaxel are efficacious in the treatment of metastatic breast cancer. Careful attention should be paid to the hematologic effects of docetaxel, and growth factor support should be strongly considered when selecting this regimen. ewer Chemotherapeutic gents IXBEPILE Ixabepilone (Ixempra, Bristol-Myers Squibb), a novel epothilone B analog that stabilizes microtubule dynamics leading to apoptotic cell death, has shown activity in resistant breast cancer. In ctober 2007, the FD approved ixabepilone as combination therapy with capecitabine for patients with incurable breast cancer resistant to both an anthracycline and a taxane, and as monotherapy for patients whose breast cancer is resistant or refractory to anthracyclines, taxanes, and capecitabine. Ixabepilone is a novel agent for patients whose options are limited following pro gression after an anthracycline, taxane, and/or capecitabine therapy. IXBEPILE D CPECITBIE To evaluate the advantage of adding ixabepilone to capecitabine, 752 patients with anthracycline and taxane-resistant, advanced breast cancer were randomly assigned to receive ixabepilone 40 mg/m 2 on day 1 plus capecitabine 2,000 mg/m 2 on days 1-14 of a 21-day cycle, or capecitabine 2,500 mg/m 2 alone on the same schedule (Figure 4). 21 bjective response rates (35% IDEPEDETLY DEVELPED BY MCMH PUBLISHIG 5
6 ERLLMET RR n=126* * Resistant to anthracycline, taxane, and capecitabine IV, investigator; IRF, independent radiology faculty Figure 5. Ixabepilone monotherapy. Based on reference 22. vs 14%; P<0.0001) and PFS (5.8 vs 4.2 months; HR, 0.75; P=0.0003) were superior with combination therapy. Toxicities including grade 3/4 neuropathy (21% vs 0%), fatigue (9% vs 3%), neutropenia (68% vs 11%), and the rate of death due to toxicity, particularly among those with grade 2 or higher liver dysfunction (3% vs 1%), were also more common with combination therapy and should be taken into account when selecting this therapeutic option. IXBEPILE MTHERPY multicenter, Phase II study illustrated efficacy of ixabepilone monotherapy in the setting of anthracycline, taxane, and capecitabine-resistant metastatic breast cancer. 22 In this study, 126 heavily pretreated patients (88% with 2 or more lines of treatment in the metastatic setting) were treated with ixabepilone 40 mg/m 2 on day 1 of a 21-day cycle, yielding an investigator-assessed overall response rate of 18.3% (95% CI, ) and stable disease among 50% of patients (Figure 5). 22 Toxicities were manageable, with grade 3/4 peripheral neuropathy occurring in 14% of patients, fatigue in 13%, myalgia in 8%, and stomatitis in 6%. Ixabepilone monotherapy provides an efficacious and tolerable option for patients with advanced breast cancer having received multiple prior therapies. Management of ERBB2-Positive Metastatic Breast Cancer Ixabepilone 40 mg/m 2 day 1 (21-d cycle) Ixabepilone monotherapy IRF-assessed 11.5% (95% CI 6.3%-18.9%) IV-assessed 18.3% (95% CI 11.9%-26.1%) TRSTUZUMB Trastuzumab, an immunoglobulin G monoclonal antibody directed against the extracellular domain of the HER2 protein, has been shown to have activity both as a single agent and in combination with chemotherapy. 23,24 Recent data show that the addition of trastuzumab to chemotherapy provides a survival advantage in comparison with chemotherapy alone in patients with either amplification of the HER2 gene or overexpression of the HER2/neu protein. Moreover, the addition of trastuzumab to hormonal therapy has shown benefit in the setting of hormone-sensitive, HER2-positive advanced breast cancer. ll rights reserved. Reproduction in whole or in part without permission is prohibited. TRSTUZUMB D TXES The taxanes are the most common chemotherapeutic agents used in combination with trastuzumab. In cell lines, paclitaxel has been shown to have additive cytotoxicity and docetaxel has been shown to have synergistic cytotoxicity when combined with trastuzumab. 25 Weekly paclitaxel-trastuzumab is the only FD-approved combination regimen with trastuzumab in the metastatic setting. 26 recent Phase II study evaluated the pharmacokinetics, safety, and efficacy of every-3-week administration of this regimen and found comparable drug trough levels and clinical response rates. 27 Based on these data, it can be expected that many clinicians will administer the drug regimen on a 3-week dosing schedule. dditionally, a Phase II study has illustrated superiority of docetaxel-trastuzumab compared with docetaxel alone in the setting of HER2-positive metastatic breast cancer (Figure 6). 28 Finally, a large, nonrandomized, community-based Phase IV trial illustrated no difference in overall response rate, median survival, and cardiac toxicity between first-line docetaxel-trastuzumab and paclitaxel-trastuzumab. 29 Further follow-up will determine if the responses to docetaxel-trastuzumab and paclitaxel-trastuzumab remain equivalent over time. TRSTUZUMB D THER CYTTXIC GETS Recent trials have shown efficacy and tolerability with vinorelbine and trastuzumab as first-line therapy for metastatic breast cancer, with overall response rates ranging from 68% to 84% Trastuzumab has also been evaluated in combination with gemcitabine and with capecitabine, yielding response rates of up to 62% in both combinations. 34,35 Recent Phase II studies have shown benefit when a platinum agent was added to trastuzumab-taxane regimens with respect to overall response rates and TTP. 36,37 Furthermore, a Phase III trial demonstrated improved TTP with the addition of a platinum agent to the combination of trastuzumab and a taxane (Figure 7). 38 In another trial, the Breast Cancer International Research Group (BCIRG 007) found equivalence with regard to overall response rates, TTP, and S (36.4 vs 36.6 months) when a platinum agent was added to trastuzumab-taxane combination therapy. 39,40 6 IDEPEDETLY DEVELPED BY MCMH PUBLISHIG
7 R D Docetaxel 100 mg/m 2 q3wk 6 cycles Crossover design if progression M IZ TI Docetaxel 100 mg/m 2 q3wk 6 cycles Trastuzumab (4 mg/kg loading dose, then 2 mg/kg weekly until disease progression) ll rights reserved. Reproduction in whole or in part without permission is prohibited. n=188 Docetaxel Docetaxel + Trastuzumab P Value* RR, % TTP, mo Median S, mo *57% of patients in docetaxel arm crossed over to combination therapy. RR, overall response rate; S, overall survival; TTP, time to disease progression Figure 6. M77001: schema and results. Based on reference 28. TRSTUZUMB D EDCRIE THERPY ER and/or PR expression occurs in approximately 50% of HER2-positive breast cancers. In a recent Phase III study, investigators reported the efficacy of adding trastuzumab to the aromatase inhibitor anastrozole (rimidex, strazeneca) in the treatment of advanced breast cancer. 41 In total, 207 patients with co-expression of ER and/or PR as well as HER2 by immunohistochemistry (IHC 3+) and/or fluorescence in situ hybridization (FISH+) were randomly assigned to receive anastrozole (1 mg orally daily) or anastrozole plus trastuzumab (4 mg/kg on day 1, 2 mg/kg weekly thereafter; Figure 8). 41 Significant improvements in overall response rates (20.3% vs 6.8%; P=0.018) and PFS (4.8 vs 2.4 months; P=0.0016) were observed in the combination-therapy arm. trend toward an S advantage was observed with the addition of trastuzumab (28.5 vs 23.9 months; P=0.325) despite crossover of more than half of patients in the anastrozole arm to receive trastuzumab on progression of disease. BEYD TRSTUZUMB: LPTIIB D VEL HER2-TRGETED GETS Lapatinib (Tykerb, GlaxoSmithKline) is an orally active, reversible inhibitor of the tyrosine kinase activity of epidermal growth factor receptor (EGFR; ERBB1) and HER2 (ERBB2). In March 2007, the FD approved lapatinib for use in combination with capecitabine in women with advanced HER2-positive breast cancer that is refractory to anthracycline, taxane, and trastuzumab therapy. Previously reported Phase II trials had demonstrated the efficacy of lapatinib monotherapy with respect to PFS and overall response rate among women with HER2-positive, trastuzumab-refractory, metastatic breast cancer. 42,43 In those trials, therapy was well tolerated, with rash, fatigue, and diarrhea being the most common side effects. Serious, irreversible declines in cardiac ejection fraction were not observed in either of the studies. More recently, the Phase III study, on which FD approval was based, showed safety and benefit of adding lapatinib to capecitabine therapy in patients with trastuzumab-refractory disease. 44 The results of Phase II trials evaluating lapatinib in the challenging settings of central nervous system (CS) metastasis and recurrent inflammatory breast cancer, and in combination with paclitaxel, have also been reported and will be reviewed below. LPTIIB PLUS CPECITBIE In an international, open-label, Phase III trial, 324 patients were randomly assigned to receive either oral lapatinib 1,250 mg once daily continuously plus capecitabine 2,000 mg/m 2 per day on days 1 to 14 of a 21-day cycle, or capecitabine alone at a dosage of 2,500 mg/m 2 per day on days 1 to 14 of a 21-day IDEPEDETLY DEVELPED BY MCMH PUBLISHIG 7
8 RDMIZTI n=196 Trastuzumab + Paclitaxel Day 1: trastuzumab 4 mg/kg (first dose); 2 mg/kg thereafter Day 2: paclitaxel 175 mg/m 2 Day 8, 15: trastuzumab 2 mg/kg Cycles q21d until progression Trastuzumab + Paclitaxel + Carboplatin Day 1: trastuzumab 4 mg/kg (first dose); 2 mg/kg thereafter Day 2: paclitaxel 175 mg/m 2 + carboplatin UC=6 Day 8, 15: trastuzumab 2 mg/kg Cycles q21d until progression ll rights reserved. Reproduction in whole or in part without permission is prohibited. TP TPC P Value TTP, mo S, mo TP TPC (HER2 3+) (HER2 3+) P Value TTP, mo S, mo UC, area under the curve; S, overall survival; TP, trastuzumab + paclitaxel; TPC, trastuzumab + paclitaxel + carboplatin; TTP, time to disease progression Figure 7. Trastuzumab-paclitaxel with or without carboplatin as first-line therapy for metastatic breast cancer: schema and results. Based on reference 38. cycle (Figure 9). 44 Eligible women had HER2-positive, locally advanced, or metastatic breast cancer and had previously been exposed to anthracycline, taxane, and trastuzumab therapy. verall response rate (22% vs 14%; P=0.09) and median PFS (8.4 months vs 4.4 months; HR, 0.49; 95% CI, ; P<0.001) significantly favored lapatinib combination therapy over capecitabine monotherapy. Relapse within the CS was less frequent in the combination arm than with capecitabine alone (4 vs 11 events, respectively). verall, the side-effect profile was similar between groups. Diarrhea (60% vs 39%) and rash (27% vs 15%) were more common with com bination therapy than among those receiving capecitabine monotherapy. This probably reflects the longer exposure time to capecitabine in the combination-therapy arm. Four women on combination therapy experienced an asymptomatic decline in cardiac ejection fraction, but all recovered with discontinuation of study drug. Survival data are not yet significant; longer follow-up is required. LPTIIB FR CS METSTSES Phase II trial was recently reported evaluating the safety and efficacy of lapatinib in patients with HER2-positive breast cancer with progressive CS metastasis. 45,46 Eligible patients (n=241) received oral lapatinib 750 mg twice daily. f these, 19 (7%) had a 50% or greater reduction in volumetric tumor burden (the study s primary objective); 46 (19%) had a 20% or greater reduction in volumetric tumor burden. By RE- CIST (Response Evaluation Criteria in Solid Tumors), 15 (6%) patients achieved a partial response and 102 (42%) had stable disease at no less than 8 weeks. Median time to treatment failure was 15.1 weeks (95% CI, ) among all patients and 25.3 weeks among responders (95% CI, 16.1; not yet reached). Lapatinib was well tolerated. lthough this study failed to show hypothesized efficacy ( 20% CS response), it provides evidence that lapatinib penetrates the CS. Furthermore, an extension arm to this trial indicates that the addition of capecitabine to lapatinib at the time of CS progression yields response rates of 20% (8 of 40; 50% volumetric tumor reduction) and 40% (16 of 40; 20% volu metric tumor reduction), providing an option in patients who have CS progression with lapatinib monotherapy. 47 LPTIIB I RECURRET IFLMMTRY BREST CCER EGF is a Phase II trial evaluating lapatinib monotherapy in patients with relapsed, refractory 8 IDEPEDETLY DEVELPED BY MCMH PUBLISHIG
9 inflammatory breast cancer. 48 Forty-seven patients were assigned to 1 of 2 cohorts: 32 in cohort (ERBB2 overexpressors: 2 of 3 IHC+/FISH+) and 15 in cohort B (ERBB1+/ERBB2 non-overexpressors). In all, 16 of 32 (50%) cohort patients responded (2 complete responses and 14 partial responses), whereas 1 of 15 (7%) cohort B patients responded. The researchers concluded that inflammatory breast cancer that overexpresses HER2 (ERBB2, FISH+/IHC 3+) with evidence of HER2 (ERBB2) activation (phospho-erbb2) was more likely to respond to lapatinib monotherapy. This trial illustrates that selecting patients by tumor biology, rather than histology, is necessary to maximize the clinical efficacy of ERBB2 tyrosine kinase inhibitors. LPTIIB D PCLITXEL In a Phase III, randomized, double-blind study of patients with HER2-negative (0-1+ via IHC /FISH ) or HER2-unknown advanced breast cancer, 579 trastuzumab-naïve patients were randomly assigned to receive either lapatinib 1,500 mg daily plus paclitaxel 175 mg/m 2 every 3 weeks or placebo daily plus paclitaxel 175 mg/m 2 every 3 weeks. 49 lthough overall the response rate was improved among patients who R D M IZ TI n=207, anastrozole; RR, overall response rate; PFS, progression-free survival; T, trastuzumab; TnDEM, Trastuzumab in Dual HER2 ER-positive Metastatic Breast Cancer Figure 8. TnDEM Study: schema and results. Based on reference 41. nastrozole 1 mg P daily nastrozole 1 mg P daily Trastuzumab 4 mg/kg day 1, 2 mg/kg weekly thereafter +T P value RR, % PFS, mo S, mo ll rights reserved. Reproduction in whole or in part without permission is prohibited. RDMIZTI n=324 Lapatinib 1,250 mg P daily Capecitabine 2,000 mg/m 2 daily, days 1-14 (21-d cycle) Capecitabine 2,500 mg/m 2 daily, days 1-14 (21-d cycle) Lapatinib + capecitabine Capecitabine P Value RR, % PFS, mo CS metastases 4 11 n/a CS, central nervous system; RR, overall response rate; PFS, progression-free survival Figure 9. Capecitabine with or without lapatinib to treat HER2-positive trastuzumab-refractory metastatic disease: schema and results. Based on reference 44. IDEPEDETLY DEVELPED BY MCMH PUBLISHIG 9
10 received lapatinib (35.1% vs 25.3%; P=0.008), there was no difference in TTP (HR, 0.87; P=0.142), eventfree survival (HR, 0.90; P=0.24), or S (HR, 0.86; P=0.22) in this HER2- negative patient population, illustrating the importance of HER2 positivity when selecting lapatinib as a therapeutic option. LPTIIB: FUTURE DIRECTIS Several Phase III studies have either been completed or are underway evaluating combination therapy with lapatinib and trastuzumab and lapatinib and letrozole (Femara, ovartis). The combination of paclitaxel, trastuzumab, and lapatinib as first-line treatment for HER2-positive metastatic breast cancer is also under investigation. The next few years hold promise for the use of lapatinib in patients with HER2-positive metastatic breast cancer. dditionally, it appears that lapatinib will be a clinically useful agent for the treatment of inflammatory breast cancer and among patients with CS metastases. ovel HER2-Targeted gents In addition to lapatinib, several other novel HER2- targeted agents, specifically pertuzumab (Genentech) and HKI-272 (Wyeth), are being tested in Phase II clinical trials. Pertuzumab, a humanized antibody, is the first in a new class of agents known as HER dimerization inhibitors (HDIs). HDIs block the ability of the HER2 receptor to collaborate with other HER receptor family members (HER1/EGFR, HER3, and HER4). Phase II multicenter trial evaluated the efficacy of pertuzumab when combined with trastuzumab among 42 patients with advanced HER2-positive (IHC 3+ or FISH+), trastuzumabrefractory metastatic breast cancer in a 2-stage study design. 50 t the time of presentation, 35% of patients were enrolled in the second stage. The overall response rate was 18.2%, with a 39.4% clinical benefit rate. The most common adverse events included diarrhea, skin toxicity, nausea/vomiting, and mucositis. ne patient had a decline in left ventricular ejection fraction (>10% to <50%). Further studies are ongoing in both early and advanced breast cancer to further define the benefit of pertuzumab when it is added to trastuzumab. HKI-272 is a potent, low-molecular-weight, orally active, irreversible pan-erbb receptor tyrosine kinase inhibitor shown to inhibit the growth of tumor cells that express ERBB1 (EGFR) and ERBB2 (HER2). Phase I trial reported on 73 patients (23 breast primary), defining the maximum tolerated dose and diarrhea as the dose-limiting toxicity. 51 f the responders, 4 breast cancer patients had partial responses, 2 confirmed and 2 unconfirmed. dditional Phase I/II trials combining HKI-272 with trastuzumab and paclitaxel are under way, with exciting results anticipated in 2008 in the treatment of advanced HER2-positive breast cancer. ll rights reserved. Reproduction in whole or in part without permission is prohibited. ovel Therapeutic pproaches: Targeted Therapies Promising advances for the treatment of metastatic breast cancer are emerging in the arena of targeted biologic therapeutics. ngoing research is focusing on the optimization of available therapies in combination with targeted biologic therapies. This section highlights the recent developments and exciting results observed within the arena of targeted therapeutics, including agents targeting vascular endothelial growth factor (VEGF) and EGFR. ngiogenesis is thought to play a key role in tumor development and metastasis. VEGF is a potent activator of angiogenesis. Bevacizumab (vastin, Genentech) is a humanized monoclonal antibody that acts as a VEGF inhibitor by blocking VEGF from binding to endothelial cells. Bevacizumab has been FD approved for first-line therapy for metastatic colon cancer and nonsquamous cell, non small-cell lung cancer; in February 2008, it received approval for use in combination with paclitaxel as first-line therapy in the setting of HER2-negative metastatic breast cancer. Sunitinib (Sutent, Pfizer) is an oral multitargeted, tyrosine kinase inhibitor that targets VEGF, platelet-derived growth factor receptor, c-kit, and FLT3. It is FD approved for treatment of gastrointestinal stromal tumor after progression on imatinib mesylate (Gleevec, ovartis) and for advanced renal cell cancer. More recently, axitinib (Pfizer), an oral tyrosine kinase inhibitor and selective inhibitor of VEGF receptors 1, 2, and 3 that has shown activity in lung, thyroid, and possibly pancreatic cancers, has shown promise when combined with docetaxel in the setting of metastatic breast cancer. Phase II studies on the use of bevacizumab, sunitinib, and axitinib in the treatment of metastatic breast cancer are showing promise. E2100 The results of E2100, a randomized Phase III trial, initially presented at the 2005 San ntonio Breast Cancer Symposium, have been updated (Figure 10). 52,53 The goal of this study was to evaluate the addition of bevacizumab to paclitaxel among chemotherapy-naïve patients with metastatic breast cancer. pproximately 722 women were randomly assigned to receive either 10 IDEPEDETLY DEVELPED BY MCMH PUBLISHIG
11 RDMIZTI n=722 Paclitaxel 90 mg/m 2 days 1, 8, 15 Paclitaxel 90 mg/m 2 days 1, 8, 15 Bevacizumab 10 mg/kg days 1 and 15 ll rights reserved. Reproduction in whole or in part without permission is prohibited. Bevacizumab + Paclitaxel Paclitaxel P Value RR, % <0.001 PFS, mo <0.001 S, mo RR, overall response rate; S, overall survival; PFS, progression-free survival Figure 10. E2100: schema and results. Based on reference 52, 53. paclitaxel 90 mg/m 2 on days 1, 8, and 15 plus bevacizumab 10 mg/kg on days 1 and 15, or paclitaxel alone on the same dosing schedule. Women were ineligible if they had CS metastases or were receiving long-term anticoagulation therapy. The primary end point was PFS. The overall response rate was superior in the bevacizumab arm (36.9% vs 21.2%; P<0.001), as was PFS (11.8 vs 5.9 months; HR, 0.60; P<0.001). S, however, was similar between the 2 treatment groups (median 26.7 months vs 25.2 months; HR, 0.88, P=0.16). Grade 3 and 4 hypertension (P<0.001), proteinuria (P<0.001), headache (P=0.008), and cerebrovascular ischemia (P=0.02) were more common in the bevacizumab arm. Febrile neutropenia was uncommon in both arms (<1%). EXCLIBUR The primary objective of the single-arm, Phase II study Excalibur was to evaluate PFS among patients with metastatic breast cancer treated in the first-line setting with the combination of capecitabine 1,000 mg/m 2 twice daily on days 1 to 15 and bevacizumab 15 mg/kg on day 1 of a 21-day cycle. 54 mong 106 patients with HER2-negative advanced disease, the overall response rate was 38%, median TTP was 5.7 months, and median S was 16 months or longer. The median prespecified end point was met because TTP was prolonged from 4 to 5.6 months. utcome was even more favorable among patients with ERpositive disease, who had overall response rates of 47%, median TTP of 8.9 months, and median S of 16.6 months. METRMIC CHEMTHERPY PLUS BEVCIZUMB Low-dose, repetitive, metronomic chemotherapy has been shown to effectively inhibit tumor growth in preclinical models. Phase II trial reports efficacy of metronomic chemotherapy in combination with bevacizumab. 55 Patients with advanced disease were randomly assigned to receive metronomic chemotherapy alone (cyclophosphamide 50 mg daily and methotrexate 2.5 mg twice daily for 2 days each week), or the same treatment plus bevacizumab (10 mg/kg every 14 days). verall response rates (29% vs 10%) and TTP (5.5 months vs 2.2 months) were better in combination chemotherapy-bevacizumab arm. verall, therapy was well tolerated, with hypertension more commonly observed among patients receiving bevacizumab. SUITIIB In a Phase II trial evaluating efficacy of sunitinib, 64 patients with advanced breast cancer were treated with sunitinib in 6-week cycles, 50 mg daily for 28 days, followed by 14 days of rest. 56 verall clinical benefit (partial response/stable disease) was 16% (10 of 64 patients). o grade 4 hematologic toxicities were observed. Grade 3 nonhematologic toxicities included fatigue (14%), hand foot syndrome (11%), diarrhea (6%), and nausea (8%). Patients in this trial were heavily pretreated with both a taxane and an anthracycline. XITIIB recent Phase II study evaluated the addition of axitinib to docetaxel (Figure 11). 57 In the study, 168 IDEPEDETLY DEVELPED BY MCMH PUBLISHIG 11
12 R D xitinib 5 mg twice a day + docetaxel 80 mg/m 2 q3wk M IZ TI Placebo twice a day + docetaxel 80 mg/m 2 q3wk ll rights reserved. Reproduction in whole or in part without permission is prohibited. n=168 xitinib + Placebo + docetaxel docetaxel P Value RR, % <0.038 TTP, mo RR, overall response rate; TTP, time to progression Figure 11. xitinib plus docetaxel: schema and results. Based on reference 57. patients with no prior therapy for advanced breast cancer were randomly assigned in a 2:1 fashion to receive either docetaxel 80 mg/m 2 every 3 weeks plus axitinib 5 mg twice daily or docetaxel (same dose) plus a placebo. verall response rate was superior for the axitinib/docetaxel compared with placebo/ docetaxel (40% vs 23% respectively; P=0.038). The primary objective, TTP, was also improved in the axitinib-doectaxel arm compared with the placebodocetaxel arm (8.2 months vs 7.0 months, respectively; HR, 0.73 [prespecified, one-sided; P=0.052]). Grade 3/4 toxicities were noted to be more common in the axitinib group; these included febrile neutropenia (16% for axitinib vs 7% for placebo), fatigue (13% vs 5%), stomatitis (13% vs 2%), diarrhea (11% vs 0%), and hypertension (5% vs 2%). Based on this report, the combination of axitinib and docetaxel as first-line therapy for advanced breast cancer has an acceptable safety profile and promising antitumor activity. Further studies are awaited to confirm these findings. VEGF Inhibitors: Future Directions These results support a role for therapies targeting angiogenesis among patients with advanced breast cancer. Studies combining bevacizumab with other chemotherapeutic agents, hormonal therapy, and trastuzumab are ongoing. dditionally, the use of bevacizumab beyond the first-line setting, and in patients with CS metastases, is being studied in active trials. Finally, multiple studies evaluating the efficacy of sunitinib plus weekly paclitaxel, sunitinib plus trastuzumab, and sunitinib versus standard chemotherapy in the metastatic setting are under investigation. Triple-egative Metastatic Breast Cancer The evaluation of breast tumors through geneexpression profiling has led to an ability to subclassify breast tumors into distinct subgroups, including basal-like, ERBB2-overexpressing and luminal and B breast cancers. 58 The basal-like breast cancer has low expression of ER, PR, and HER2, and is often termed triple-negative breast cancer. Preclinical studies suggest that triple-negative breast cancer may be dependent on EGFR/HER1 for proliferation. TBCRC 001 TBCRC 001 is a multicenter randomized Phase II study of cetuximab (Erbitux, Bristol-Myers Squibb/ Imclone Systems, Inc), a monoclonal antibody that binds the extracellular portion of EGFR, in combination with carboplatin in the setting of triple-negative 12 IDEPEDETLY DEVELPED BY MCMH PUBLISHIG
13 breast cancer. 59 Patients (n=21) with ER-, PR-, and HER2-negative breast cancer were treated in 1 of 2 arms: cetuximab (400 mg/m 2, then 250 mg/m 2 weekly) with carboplatin (area under curve 2 weekly, 3 of 4 weeks) added upon progression, or upfront cetuximab and carboplatin (same dosing strategy). lthough single-agent cetuximab (arm 1) did not meet prespecified response criteria, among 14 evaluable patients in whom carboplatin was added at progression, 28% had a partial response and 28% had stable disease. Continued follow-up and biomarker analysis is anticipated to determine the efficacy of the exciting combination of upfront cetuximab and carboplatin in the setting of aggressive, triple-negative metastatic breast cancer. Conclusion lthough metastatic breast cancer remains a difficult disease to treat, recent advances in the field of novel biologic therapeutics are setting the stage for exciting advances in the life expectancy of patients with metastatic breast cancer. Continued emphasis on enrolling all patients in clinical trials is crucial and offers the promise of improved and better-tolerated therapies for women with metastatic breast cancer. References 1. abholtz JM, Buzdar, Pollak M, et al. nastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a orth merican multicenter randomized trial. rimidex Study Group. J Clin ncol. 2000;18(22): , PMID: Bonneterre J, Thurlimann B, Robertson JF, et al. nastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or rimidex Randomized Group Efficacy and Tolerability study. J Clin ncol. 2000;18(22): , PMID: Mouridsen H, Gershanovich M, Sun Y, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. 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14 21. Thomas ES, Gomez HL, Li RK, et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin ncol. 2007;25(33): , PMID: Perez E, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS ) in a Phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin ncol. 2007;25(23): , PMID: Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. Engl J Med. 2001; 344(11): , PMID: Vogel CL, Cobleigh M, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin ncol. 2002;20(3): , PMID: Pegram MD, Konecny GE, Callaghan C, Beryt M, Pietras R, Slamon DJ. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J atl Cancer Inst. 2004;96(10): , PMID: Burstein HJ, Kuter I, Campos SM, et al. Clinical activity of trastuzumab and vinorelbine in women with HER2-over-expressing metastatic breast cancer. J Clin ncol. 2001;19(10): , PMID: Burstein HJ, Harris L, Marcom PK, et al. Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter Phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin ncol. 2003;21(15): , PMID: Chan, Martin M, Untch M, et al. Vinorelbine plus trastuzumab combination as first-line therapy for HER 2-positive metastatic breast cancer patients: an international Phase II trial. Br J Cancer. 2006;95(7): , PMID: Stein S, DeMichele, Domchek S, et al. Gemcitabine and trastuzumab combinations for patients with metastatic breast cancer overexpressing HER2/neu. Clin Breast Cancer. 2004;4(suppl 3):S117-S120, PMID: Biganzoli L, Martin M, Twelves C. Moving forward with capecitabine: a glimpse of the future. ncologist. 2002;7(suppl 6): 29-35, PMID: ; Erratum in: ncologist. 2003;8(1):127. ll rights reserved. Reproduction in whole or in part without permission is prohibited. 26. Seidman D, Fornier M, Esteva FJ, et al. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin ncol. 2001;19(10): , PMID: Leyland-Jones B, Gelmon K, youb JP, et al. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel. J Clin ncol. 2003;21(21): , PMID: Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin ncol. 2005;23(19): , PMID: Reddy JC, Berker C, Lim D, et al. utcome of patients treated with docetaxel vs paclitaxel in a non-randomized Phase IV trial of first-line taxane/trastuzumab therapy in patients with HER2+ metastatic breast cancer [poster]. Presented at: San ntonio Breast Cancer Symposium; December 3-6, 2003; San ntonio, Texas. Poster Jahanzeb M, Mortimer J, Yunus F, et al. Phase II trial of weekly vinorelbine and trastuzumab as first-line therapy in HER2 (+) metastatic breast cancer. ncologist. 2002;7(5): , PMID: Pegram MD, Pienkowski T, orthfelt DW, et al. Results of two, open-label, multicenter Phase II studies of docetaxel, platinum salts, and trastuzumab in HER2 positive, advanced breast cancer. J atl Cancer Inst. 2004;96(10): , PMID: Perez E, Suman VJ, Rowland KM, et al. Two concurrent Phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every- 3-week schedule) as first-line therapy in women with HER2- overexpressing metastatic breast cancer: CCTG study Clin Breast Cancer. 2005;6(5): , PMID: Robert J, Leyland-Jones B, smar L. Randomized Phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2 overexpressing metastatic breast cancer. J Clin ncol. 2006:24(18): , PMID: Forbes JF, Kennedy J, Pienkowski T, et al. BCIRG 007: randomized Phase III trial of trastuzumab plus docetaxel with or without carboplatin first line in HER2 positive metastatic breast cancer (MBC). J Clin ncol. 2006;24(18S). bstract LB Pegram M, Forbes J, Pienkowski V, on behalf of the BCIRG007 investigators. BCIRG 007: First overall survival analysis of randomized phase III trial of trastuzumab plus docetaxel with or without carboplatin as first line therapy in HER2 amplified metastatic breast cancer (MBC). J Clin ncol. 2007;25(18S): bstract LB IDEPEDETLY DEVELPED BY MCMH PUBLISHIG
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