Ixabepilone demonstrates marked synergistic activity in combination with capecitabine, which served as the rationale for the evaluation of this combination in the clinic. Ixabepilone plus capecitabine is currently approved for patients with locally advanced or metastatic breast cancer (MBC) progressing after treatment with an anthracycline and a taxane; approval was based on the results of two phase III trials comparing the combination with capecitabine monotherapy. An array of preclinical studies in multiple solid tumor types show that ixabepilone demonstrates therapeutic synergy with targeted therapies including trastuzumab, bevacizumab, brivanib, and cetuximab; with immune-modulating agents such as anti-CTLA-4 antibody; and with other chemotherapy drugs such as irinotecan and epirubicin. Notably, experiments in several xenograft models show that ixabepilone provides greater antitumor synergism when combined with bevacizumab than either paclitaxel or nab-paclitaxel combined with bevacizumab. These preclinical findings provide a foundation for ongoing phase II clinical trials using ixabepilone in combination with trastuzumab or lapatinib in HER2-positive breast cancer; with bevacizumab in breast cancer, endometrial cancer, renal cancer, and non-small cell lung cancer (NSCLC); with cetuximab in breast cancer, NSCLC, and pancreatic cancer; and with brivanib, dasatinib, sorafinib, sunitinib, or vorinostat in MBC. Preliminary results from several of these trials suggest that ixabepilone-based combinations have promising anticancer activity.
breast cancer; colon cancer; epothilones; ixabepilone; non-small cell lung cancer; synergism; targeted therapy
A simple oral combination of capecitabine and cyclophosphamide for the treatment of patients with metastatic breast cancer was evaluated. The addition of cyclophosphamide did not result in outcomes superior to those seen with capecitabine alone.
After completing this course, the reader will be able to:
Compare outcomes in patients treated with capecitabine plus CPA with those of capecitabine monotherapy and combination therapy with bevacizumab, sorafenib, or ixabepilone.Identify patients for whom single-agent capecitabine is recommended.
This article is available for continuing medical education credit at CME.TheOncologist.com
Interest in oral agents for the treatment of metastatic breast cancer (MBC) has increased because many patients prefer oral to i.v. regimens. We evaluated a simple oral combination of capecitabine with cyclophosphamide (CPA) for MBC.
The trial was designed to determine whether or not combination therapy would achieve a 42% response rate (RR) using the Response Evaluation Criteria in Solid Tumors (RECIST) in MBC. Patients with two or fewer prior chemotherapy regimens for MBC were eligible. Those with estrogen receptor–positive MBC had to have progressed on endocrine therapy. Patients had measurable disease or elevated mucin (MUC)-1 antigen and received CPA, 100 mg daily on days 1–14, and capecitabine, 1,500 mg twice daily on days 8–21, in 21-day cycles.
In 96 eligible patients, the median progression-free survival (PFS) interval was 5.9 months (95% confidence interval [CI], 3.7–8.0 months) and median overall survival (OS) time was 18.8 months (95% CI, 13.1–22.0 months). The RR was 36% (95% CI, 26%–48%) in 80 patients with measurable disease. The MUC-1 antigen RR was 33% (95% CI, 20%–48%), occurring in 15 of 46 patients with elevated MUC-1 antigen. Toxicity was mild, with no treatment-related deaths.
PFS, OS, and RR outcomes with capecitabine plus CPA compare favorably with those of capecitabine monotherapy and combination therapy with bevacizumab, sorafenib, or ixabepilone. The addition of these other agents to capecitabine does not improve OS time in MBC patients, and this single-arm study does not suggest that the addition of CPA to capecitabine has this potential in an unselected MBC population. When OS prolongation is the goal, clinicians should choose single-agent capecitabine.
Metastatic breast cancer; Capecitabine; Cyclophosphamide; Oral therapy
To date, blockade of growth factor receptors is the mainstay of targeted therapy in metastatic breast cancer (mBC). Monoclonal antibodies such as trastuzumab and bevacizumab represent the first generation of molecular-based therapies. Both the HER2 inhibitors and the vascular endothelial growth factor (VEGF) antagonists have shown synergism with a broad spectrum of established cytotoxins, thus being approved for first-line treatment of mBC in combination with taxanes. As a next step, tyrosine kinase inhibitors (TKIs) have been integrated into daily routine as an alternative approach for targeting HER2: The dual HER1/2 inhibitor lapatinib demonstrated activity in trastuzumab-pretreated mBC patients in combination with capecitabine. Furthermore, chemotherapy-free regimens (trastuzumab or lapatinib plus aromatase inhibitors) have been identified as additional options for hormone receptor (HR)- and HER2-positive patients. Recently published data indicate that a combination of two biologicals such as lapatinib and trastuzumab can be effective as a treatment beyond trastuzumab related progression. Multitarget TKIs have the potential to inhibit several signaling pathways involved in breast cancer-related angiogenesis. Until now, they have failed to show a clear benefit in mBC. On the other hand, poly(ADP-ribose) polymerase (PARP) inhibition, mediated by a new class of small molecules, is an interesting area of investigation. Future directions of research in HER2-positive breast cancer focus on the evaluation of novel antibodies (pertuzumab, T-DM1), and irreversible TKIs (neratinib, BIBW 2992) and inhibitors of HER2-related downstream signaling (mTOR, TORC 1/2, PI3K/Akt) and of receptor cross-talk (IGFR).
Breast cancer, metastatic; Anti-angiogenesis; Antibody; PARP inhibition; Multitargeting
The first results from a phase II, open-label study designed to evaluate the efficacy and safety of bevacizumab in combination with trastuzumab and capecitabine as first-line therapy for patients with human epidermal growth factor receptor-2–positive locally recurrent or metastatic breast cancer are reported.
We report the first results from a phase II, open-label study designed to evaluate the efficacy and safety of bevacizumab in combination with trastuzumab and capecitabine as first-line therapy for human epidermal growth factor receptor (HER)-2-positive locally recurrent (LR) or metastatic breast cancer (MBC). Patients were aged ≥18 years with confirmed breast adenocarcinoma, measurable LR/MBC and documented HER-2-positive disease. Patients received bevacizumab (15 mg/kg on day 1) plus trastuzumab (8 mg/kg on day 1 of cycle 1, 6 mg/kg on day 1 of each subsequent cycle) plus capecitabine (1,000 mg/m2 twice daily, days 1–14) every 3 weeks until disease progression, unacceptable toxicity, or consent withdrawal. Eighty-eight patients were enrolled; 40 (46%) are still on study treatment. The median follow-up was 8.8 months (range, 0.9–17.1 months). The overall response rate, the primary endpoint, was 73% (95% confidence interval [CI], 62%–82%), comprising 7% complete and 66% partial responses. The median progression-free survival interval was 14.4 months (95% CI, 10.4 months to not reached [NR]), with 35 events. The median time to progression was 14.5 months (95% CI, 10.5 months to NR), with 33 events. Treatment was well tolerated; main side effects were grade 3 hand–foot syndrome (22%), grade ≥3 diarrhea (9%), and grade ≥3 hypertension (7%). Overall, 44% of patients experienced grade ≥3 treatment-related adverse events and 13 patients discontinued capecitabine because of toxicity, but continued with bevacizumab and trastuzumab. Heart failure was seen in two patients. The combination of bevacizumab, trastuzumab, and capecitabine was clinically active as first-line therapy for patients with HER-2-positive MBC, with an acceptable safety profile and no unexpected toxicities.
Bevacizumab; Trastuzumab; Capecitabine; First-line; HER-2-positive; Metastatic breast cancer
Angiogenesis has a clear and definite role in the breast cancer progression process, making antivascular endothelial growth factor (VEGF) therapies an attractive option for the treatment of metastatic breast cancer (MBC). Bevacizumab is a potent humanized monoclonal antibody to VEGF, which has shown regression of breast cancer in preclinical and clinical setting, either alone or in combination with cytotoxic treatment. Additionally, bevacizumab potentially increases the effectiveness of other anticancer therapies through the normalization of tumor vasculature, reduction of intratumoral pressure and improved tumor oxygenation. Phase 1/2 trials showed significant antitumor effects of bevacizumab in MBC, in particular in tumors not expressing HER2 receptor. A first phase 3 trial in pre-treated MBC patients showed better response rates but no survival benefit from the addition of bevacizumab to capecitabine. However, in two phase 2 trial in first-line setting in patients with MBC, bevacizumab improved progression-free survival in combination with weekly paclitaxel in comparison to paclitaxel alone or in combination with 3-weekly docetaxel in comparison with docetaxel alone, respectively. Bevacizumab in combination with taxanes seems to be a highly effective first-line treatment for MBC patients. Future research will investigate bevacizumab in the neoadjuvant or adjuvant setting, where even more potential may exist for these patients.
bevacizumab; breast cancer; HER2; HER2-negative breast cancer
Metastatic breast cancer (MBC) is a major cause of death among women worldwide. Progress has been made in treating MBC with the advent of anti-estrogen therapies, potent cytotoxic agents, and monoclonal antibodies. Bevacizumab is a monoclonal antibody against circulating vascular endothelial growth factor (VEGF), which was approved in 2008 by the US Food and Drug Administration (FDA), for first-line treatment of HER-2 negative MBC in combination with paclitaxel. The FDA then reversed this decision in December 2010 by recommending removal of the MBC indication from bevacizumab, citing primarily safety concerns, and that these risks did not outweigh the ability of bevacizumab to significantly prolong progression-free survival. This decision was unexpected in the oncology community and remains controversial. This review looks at all available phase 3 data with bevacizumab in the MBC setting to determine whether the data support this decision by the FDA, and discusses the future of bevacizumab in breast cancer.
Bevacizumab; metastatic breast cancer; randomized control (phase 3) trials; review; chemotherapy; anti-angiogenesis
The available evidence for the use of capecitabine as a single agent in the first-line treatment of patients with human epidermal growth factor receptor 2–negative metastatic breast cancer is reviewed.
The goals of treatment for metastatic breast cancer (MBC) are to prolong overall survival (OS) while maximizing quality of life, palliating symptoms, and delaying tumor progression. For many years, anthracyclines and taxanes have been the mainstay of treatment for MBC, but these agents are now commonly administered earlier in the course of the disease. A recent meta-analysis revealed adverse effects on OS and overall response rates in patients with MBC receiving first-line anthracycline-based chemotherapy following relapse on adjuvant chemotherapy. Noncrossresistant cytotoxic agents and combinations that combine high clinical activity and acceptable tolerability while being convenient for patients are therefore needed for the first-line treatment of MBC patients. Capecitabine has substantial antitumor activity in the first-line treatment of patients with MBC in prospective, randomized, phase II/III clinical trials as monotherapy and in combination with biologic and novel agents. First-line capecitabine monotherapy has a favorable safety profile, lacking myelosuppression and alopecia, and does not compromise the administration of further lines of chemotherapy. Capecitabine is suitable for long-term administration without the cumulative toxicity that can limit the prolonged use of other chemotherapy agents. Here, we review the available data on capecitabine as a single agent for first-line treatment of patients with human epidermal growth factor receptor 2–negative MBC.
Metastatic breast cancer; Capecitabine; First-line therapy; Chemotherapy
The article presents final analyses of overall survival from a phase III trial of lapatinib and capecitabine in patients with human epidermal growth factor receptor 2–positive locally advanced or metastatic breast cancer that progressed following prior therapy including trastuzumab.
A planned interim analysis of study EGF100151 prompted early termination of enrollment based on a longer time to progression with lapatinib and capecitabine than with capecitabine alone in patients with human epidermal growth factor receptor (HER)-2+ previously treated advanced breast cancer or metastatic breast cancer (MBC). Here, we report final analyses of overall survival.
Patients and Methods.
Women with HER-2+ MBC who progressed after regimens that included, but were not limited to, anthracyclines, taxanes, and trastuzumab, were randomized to lapatinib (1,250 mg/day) plus capecitabine (2,000 mg/m2) or capecitabine monotherapy (2,500 mg/m2) on days 1–14 of a 21-day cycle.
At enrollment termination, 399 patients were randomized, and nine were being screened and were offered combination treatment. In total, 207 and 201 patients were enrolled to combination therapy and monotherapy, respectively. Thirty-six patients receiving monotherapy crossed over to combination therapy following enrollment termination. The median overall survival times were 75.0 weeks for the combination arm and 64.7 weeks for the monotherapy arm (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.71–1.08; p = .210). A Cox regression analysis considering crossover as a time-dependent covariate suggested a 20% lower risk for death for patients treated with combination therapy (HR, 0.80; 95% CI, 0.64–0.99; p = .043). The low incidence of serious adverse events was consistent with previously reported rates.
Although premature enrollment termination and subsequent crossover resulted in insufficient power to detect differences in overall survival, exploratory analyses demonstrate a trend toward a survival advantage with lapatinib plus capecitabine. These data continue to support the efficacy of lapatinib in patients with HER-2+ MBC.
Breast cancer; Lapatinib; Metastatic; Capecitabine; Survival; HER-2
This review discusses recent findings from clinical studies of antiangiogenic agents for metastatic breast cancer, as well as challenges facing clinicians as the role of antiangiogenics in metastatic breast cancer evolves.
Angiogenesis has become an important target in the treatment of several solid tumors, including breast cancer. As monotherapy, antiangiogenic agents have demonstrated limited activity in metastatic breast cancer (MBC); therefore, they have generally been developed for use in combination with chemotherapies. Thus far, the experience with antiangiogenic agents for MBC has been mixed. The results from one study assessing addition of the monoclonal antibody bevacizumab to paclitaxel led to approval of bevacizumab for MBC. However, the modest improvement of progression-free survival rates in subsequent MBC studies has led to reappraisal of bevacizumab. Phase III studies have not produced evidence supporting use of the multikinase inhibitor sunitinib alone or in combination with MBC chemotherapy. Experience with sorafenib in a phase IIb program indicates potential when used in select combinations, particularly with capecitabine; however, phase III confirmatory data are needed. Although antiangiogenic therapies combined with chemotherapy have increased progression-free survival rates for patients with MBC, increases in overall survival times have not been observed. Some studies have tried to combine antiangiogenic agents such as bevacizumab and sunitinib or sorafenib, but that approach has been limited because of toxicity concerns. Sequential use of antiangiogenic agents with differing mechanisms of action may be an effective approach. Despite setbacks, angiogenesis will likely remain an important target of treatment for selected patients with MBC.
Angiogenesis; Metastatic breast cancer; Bevacizumab; Sunitinib; Sorafenib; Everolimus
This review summarizes some of the key signaling pathways involved in tumor progression and some of the novel therapies that are in development for the treatment of metastatic breast cancer patients.
Greater understanding of the underlying etiology and biology of breast cancer is enabling the clinical development of targeted therapies for metastatic breast cancer (MBC). Following the successful introduction of trastuzumab, the first human epidermal growth factor receptor (HER) biologically targeted therapy to become widely used in MBC patients, other agents have been developed. Novel agents include monoclonal antibodies such as pertuzumab, which bind to receptors on the cell surface, and tyrosine kinase inhibitors (TKIs) such as lapatinib, which target intracellular pathways such as that of the epidermal growth factor receptor. There is also growing clinical experience with antiangiogenic agents, particularly in combination with chemotherapy. These include the monoclonal antibody bevacizumab, which targets vascular endothelial growth factor receptor, and multitargeted TKIs with antiangiogenic and antiproliferative activities, such as sunitinib. Combination treatment with multiple agents targeting both the HER family and angiogenic pathways (e.g., trastuzumab plus bevacizumab) is also showing activity in the clinical setting. Despite recent advances, there are unanswered questions regarding the management of MBC with targeted agents. Future studies are necessary to determine the optimal combinations, doses, and schedules required to maximize clinical activity while minimizing toxicity. Despite the temptation to use a targeted agent in all patients, identification of patient subgroups most likely to benefit must be a key goal and will be critical to the successful future use of these treatments. The aim of this review is to summarize some of the key signaling pathways involved in tumor progression and some of the novel therapies that are in development for MBC.
Human epidermal growth factor receptor; Metastatic breast cancer; Signaling pathways; Vascular endothelial growth factor; Tyrosine kinase inhibitors
Preclinical and clinical trials suggest that tyrosine kinase inhibitors (TKI) could supplement current therapies in metastatic breast cancer (MBC). HER-2 inhibition is still a main focus. Numerous agents targeting the epidermal growth factor receptors EGFR and HER-2 are currently tested after previous trastuzumab treatment. Lapatinib targets HER-2 and EGFR. As monotherapy, clinical activity was low. Combined with cytotoxic agents, lapatinib showed good activity (overall response rate (ORR) 24-27%) and moderate toxicity. Neratinib, a pan-ErbB TKI, showed an ORR of 26%. Neratinib combined with trastzumab was well tolerated and active (ORR = 27%). After bevacizumab's proof-of-concept studies, anti-angiogenesis remains of importance. Sunitinib inhibits the vascular endothelial growth factor receptor (VEGFR), the platelet-derived growth factor receptor (PDGFR), c-kit and the colony-stimulating factor 1 (CSF-1) receptor. Monotherapy is tolerated and moderately active in MBC. Combination trials are ongoing. Toxicities of docetaxel ± sunitinib were manageable (ORR 72.2%). Pazopanib targets VEGFR, PDGFR and c-kit. Pazopanib ± lapatinib was superior in combination (progression-free survival (PFS) = 27% vs. 19%). Axitinib has similar targets. Combined with docetaxel, it was superior compared to placebo (ORR 40% vs. 23%), with manageable toxicity. Imatinib inhibits PDGFR and c-kit. As monotherapy, it showed no clinical activity. Combination trials with chemotherapy are ongoing.
Metastatic breast cancer; Tyrosine kinase inhibitor; Her-2/neu; Anti-angiogenesis; Intracellular kinase pathways
The epothilone B analog, ixabepilone, demonstrates low susceptibility to drug resistance mechanisms and has demonstrated clinically meaningful efficacy in patients refractory to other chemotherapeutic options. Ixabepilone is approved by the FDA for treatment of patients with metastatic breast cancer (MBC) progressing after taxanes and anthracyclines, either in combination with capecitabine or as monotherapy if the patient has already progressed on capecitabine. Ixabepilone is generally well tolerated at the approved dose and administration schedule of 40 mg/m2 every 3 weeks. The most commonly observed dose-limiting adverse events (AEs) associated with ixabepilone are myelosuppression and peripheral neuropathy. Dose modification including dose reduction and dosing schedule modification may be utilized to manage toxicities, but this must be based on careful hematologic, neurologic, and liver function monitoring. Other ixabepilone dose schedules are being evaluated to further improve the risk/benefit profile. Weekly and daily schedules of ixabepilone have shown useful efficacy and reasonable tolerability. A recent phase II trial compared the tolerability of ixabepilone dosed once weekly (16 mg/m2 on Days 1, 8, and 15 of each 28-day cycle) or every 3 weeks (40 mg/m2 on Day 1 of each 21-day cycle) in patients with MBC. Preliminary data showed that both dosing schedules had an acceptable safety profile; however, more AEs were reported in patients receiving ixabepilone every 3 weeks. Ixabepilone is also being evaluated in combination with other anticancer agents (e.g., bevacizumab and lapatinib), in earlier breast cancer settings and in other indications.
Ixabepilone; Breast cancer; Metastatic; Advanced; Epothilones; Treatment schedules
To evaluate the efficacy and toxicity of erlotinib plus bevacizumab in patients with metastatic breast cancer (MBC), targeting the epidermal growth factor receptor (EGFR/HER1) and the vascular endothelial growth factor (VEGF) pathway.
Thirty-eight patients with MBC were enrolled and treated at two institutions with erlotinib, a small molecule EGFR tyrosine kinase inhibitor (150 mg orally daily) plus bevacizumab, an anti-VEGF antibody (15 mg/kg intravenously every 3 weeks). Patients had 1-2 prior chemotherapy regimens for metastatic disease. The primary end point was response rate by RECIST criteria using a Simon 2-stage design. Secondary end points included toxicity, time to progression (TTP), response duration, and stabilization of disease ≥ 26 weeks. Correlative studies were performed on tumor tissue, including EGFR expression and mutation analysis.
One patient achieved a partial response for 52+ months. Fifteen patients had stable disease at first evaluation at 9 weeks; 4 of these patients had stable disease beyond 26 weeks. Median TTP was 11 weeks (95% confidence interval [CI] 8-18 weeks). Diarrhea of any grade was observed in 84% of patients (grade 3 in 3%); 76% experienced grade 1 or 2 skin rash, and 18% developed hypertension (grade 3 in 11%). The level of EGFR expression was not predictive of response to therapy.
The combination of erlotinib and bevacizumab was well tolerated, but had limited activity in unselected patients with previously treated MBC. Biomarkers are needed to identify those MBC patients likely to respond to anti-EGFR/HER1 plus anti-VEGF therapy.
Bevacizumab and the antimetabolites capecitabine and gemcitabine have been shown to improve outcomes when added to taxanes in patients with metastatic breast cancer. The primary aims of this trial were to determine whether the addition of capecitabine or gemcitabine to neoadjuvant chemotherapy with docetaxel, followed by doxorubicin plus cyclophosphamide, would increase the rates of pathological complete response in the breast in women with operable, human epidermal growth factor receptor 2 (HER2)–negative breast cancer and whether adding bevacizumab to these chemotherapy regimens would increase the rates of pathological complete response.
We randomly assigned 1206 patients to receive neoadjuvant therapy consisting of docetaxel (100 mg per square meter of body-surface area on day 1), docetaxel (75 mg per square meter on day 1) plus capecitabine (825 mg per square meter twice a day on days 1 to 14), or docetaxel (75 mg per square meter on day 1) plus gemcitabine (1000 mg per square meter on days 1 and 8) for four cycles, with all regimens followed by treatment with doxorubicin–cyclophosphamide for four cycles. Patients were also randomly assigned to receive or not to receive bevacizumab (15 mg per kilogram of body weight) for the first six cycles of chemotherapy.
The addition of capecitabine or gemcitabine to docetaxel therapy, as compared with docetaxel therapy alone, did not significantly increase the rate of pathological complete response (29.7% and 31.8%, respectively, vs. 32.7%; P = 0.69). Both capecitabine and gemcitabine were associated with increased toxic effects — specifically, the hand–foot syndrome, mucositis, and neutropenia. The addition of bevacizumab significantly increased the rate of pathological complete response (28.2% without bevacizumab vs. 34.5% with bevacizumab, P = 0.02). The effect of bevacizumab on the rate of pathological complete response was not the same in the hormone-receptor–positive and hormone-receptor–negative subgroups. The addition of bevacizumab increased the rates of hypertension, left ventricular systolic dysfunction, the hand–foot syndrome, and mucositis.
The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response, which was the primary end point of this study. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00408408.)
A better understanding of tumor biology has led to the development of a number of antibody-based targeted therapies in breast cancer. Several of these newer agents, such as trastuzumab and bevacizumab have demonstrated clinical activity and have improved the treatment of patients with metastatic breast cancer (MBC). Trastuzumab is a monoclonal antibody that binds to the extracellular domain of the HER2 receptor. The addition of trastuzumab to chemotherapy and also to endocrine therapy has enhanced efficacy of treatment. New antibody-based strategies directed against HER2 are under development. These new approaches include pertuzumab, an antibody with a different binding epitope that inhibits dimerization of HER2 with other members of the HER receptor family and TDM1, a trastuzumab-based antibody chemotherapeutic conjugate. Another approach to the treatment of solid tumors is inhibition of angiogenesis. The anti-VEGF antibody bevacizumab has been approved for treatment of MBC. Although the mechanism of action is still under investigation, bevacizumab is tested in other clinical settings such as adjuvant therapy, maintenance therapy, and in combination with both chemotherapy and other targeted agents. In this review, we will summarize the most important studies on trastuzumab and bevacizumab, and describe new antibodies currently under clinical development.
Breast cancer; Metastasis; Antibody; Therapy
Ixabepilone (Ixempra®; Bristol-Myers Squibb) is a novel microtubule stabilizing agent recently approved for the treatment of metastatic breast cancer (MBC). This article focuses on considerations for ixabepilone administration and adverse event (AE) management, drawing from the biomedical literature indexed in PubMed, published abstracts from the American Society of Clinical Oncology annual meetings, and the manufacturer’s prescribing information for ixabepilone. Administered as monotherapy or in combination with capecitabine in clinical studies, ixabepilone demonstrated positive clinical response rates, prolonged progression-free survival, and a favorable safety profile in patients with MBC. Treatment-related AEs were predictable and manageable with dose modification, treatment interruption, and active management. As ixabepilone undergoes development in earlier lines of breast cancer therapy and in other solid tumors, oncology nurses will encounter more and more patients receiving ixabepilone therapy. If nurses are acquainted with the unique management strategies associated with ixabepilone treatment, as detailed herein, patients are more likely to receive the full benefit of therapy.
breast cancer; chemotherapy; microtubule-stabilizing agent; ixabepilone; adverse events; patient management
We sought to determine whether the combination of ixabepilone plus capecitabine improved overall survival (OS) compared with capecitabine alone in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes.
Patients and Methods
A total of 1,221 patients with MBC previously treated with anthracycline and taxanes were randomly assigned to ixabepilone (40 mg/m2 intravenously on day 1) plus capecitabine (2,000 mg/m2 orally on days 1 through 14) or capecitabine alone (2,500 mg/m2 on the same schedule) given every 21 days. The trial was powered to detect a 20% reduction in the hazard ratio (HR) for death.
There was no significant difference in OS between the combination and capecitabine monotherapy arm, the primary end point (median, 16.4 v 15.6 months; HR = 0.9; 95% CI, 078 to 1.03; P = .1162). The arms were well balanced with the exception of a higher prevalence of impaired performance status (Karnofsky performance status 70% to 80%) in the combination arm (32% v 25%). In a secondary Cox regression analysis adjusted for performance status and other prognostic factors, OS was improved for the combination (HR = 0.85; 95% CI, 0.75 to 0.98; P = .0231). In 79% of patients with measurable disease, the combination significantly improved progression-free survival (PFS; median, 6.2 v 4.2 months; HR = 0.79; P = .0005) and response rate (43% v 29%; P < .0001). Grade 3 to 4 neuropathy occurred in 24% treated with the combination, but was reversible.
This study confirmed a previous trial demonstrating improved PFS and response for the ixabepilone-capecitabine combination compared with capecitabine alone, although this did not result in improved survival.
Breast Cancer is the most prevalent cancer in the world with 4.4 million survivors up to 5 years following the diagnosis.1 In the US alone approximately forty thousand women die annually of metastatic breast cancer (MBC). Despite many effective systemic treatment options approximately 50% of women with MBC succumb to the disease within 24 months of the diagnosis.2 Ixabepilone is a novel, first in class member of the epothilone class of antineoplastic agents. Ixabepilone is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and Capecitabine. Ixabepilone is also indicated in combination with Capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. Ixabepilone was extensively studied as a single agent in patients with MBC and was found to be effective and well tolerated with a predictable and manageable safety profile. Not surprisingly prior exposure to anthracyclines and taxanes affects significantly the potential for response to therapy with single agent Ixabepilone in metastatic setting. MBC patients with taxane resistant MBC have objective response rate (RR) of 12%, patients with prior low exposure to taxanes and/or resistance RR = 22%, Ixabepilone treatment after adjuvant anthracycline therapy exposure renders RR = 42% and in Taxane naïve patients RR = 57%. In two large phase III studies of Ixabepilone + Capecitabine versus Capecitabine alone, progression free survival (PFS) and overall response rates (RR) were higher in the combination treatment arms, but no survival advantage was seen overall. Treatment with Ixabepilone + Capecitabine in a phase II study resulted in an overall response rate (ORR) of 23% in ER/PR/HER2 negative, triple-negative breast cancer patients (TNBC) while ORR of 31% was seen in a preplanned pooled analysis of TNBC in the phase III trials of Ixabepilone + Capecitabine. Significantly prolonged median PFS was seen for TNBC treated with the combination of Ixabepilone + Capecitabine compared to Capecitabine alone 4.2 vs. 1.7 months respectively. Ixabepilone as single agent appears to show excellent antitumor activity in patients with TNBC MBC. Addition of Ixabepilone to Capecitabine results in approximately doubling in median PFS for TNBC versus Capecitabine alone. Single agent Ixabepilone is generally well tolerated, and its toxicity profile does not overlap with that of Capecitabine and therefore depending on prior exposure to chemotherapy both single agent Ixabepilone or in combination with Capecitabine can be used safely and effectively for treatment of advanced breast cancer.
Ixabepilone; metastatic breast cancer; monotherapy; in combination with capecitabine; triple negative breast cancer
The addition of bevacizumab to cytotoxic chemotherapy has demonstrated a progression free survival (PFS) benefit in the first line and second line treatment of advanced or metastatic breast cancer (MBC). However, the addition of bevacizumab to capecitabine in heavily pretreated MBC patients did not show a PFS benefit (AVF2119g phase three trial). The aim of this study was to evaluate the expression of novel putative biomarkers as predictors of benefit from bevacizumab in retrospective subset analyses of the AVF2119g trial.
In the AVF2119g trial, 462 patients with MBC were randomly assigned to receive capecitabine or capecitabine plus bevacizumab. Primary tumor tissue and outcome data were available for 223 patients. Biomarker expression was assessed by in situ hybridization (VEGF-A, VEGF-B, thrombospondin-2 and Flt4) or immunohistochemistry (VEGF-C, PDGF-C, neuropilin-1, delta like ligand (Dll)4, Bv8, p53 and thymidine phosphorylase) on formalin fixed paraffin embedded tissue. PFS was associated with these variables in retrospective subset analyses.
Patients with low scores for Dll4, VEGF-C and neuropilin-1 showed trends toward improvement in PFS associated with the addition of bevacizumab to capecitabine (p values 0.01, 0.05 and 0.07, respectively). These observations were not statistically significant following correction for multiple hypothesis testing.
These retrospective subset analyses suggest that expression of Dll4, VEGF-C and neuropilin-1 may predict benefit from bevacizumab. Such observations are not conclusive but warrant additional testing.
The heterogeneity of metastatic breast cancer mandates the need to select therapies taking into account tumor and patient characteristics. Chemotherapy is indicated in the palliative setting especially when the disease is unresponsive to hormonal therapy or is hormone-receptor negative. The main chemotherapeutic agents are anthracyclines, taxanes, and capecitabine. The knowledge of the effects of currently approved agents and of the biology of breast cancer have paved the way for the evaluation of new treatment options, among which are anti-angiogenic agents. Angiogenesis inhibition has resulted in clinically significant improvements in the outcome of a variety of malignancies, including breast cancer. Bevacizumab, a monoclonal antibody anti-vascular endothelial growth factor (VEGF), is the most extensively studied anti-angiogenic compound. According to the results of a phase III trial in patients with untreated metastatic breast cancer, bevacizumab increases both objective response rate and median progression-free survival when combined with standard chemotherapy vs chemotherapy alone. The combination of anti-angiogenic drugs and other biologic agents is also being explored in an attempt to improve efficacy.
angiogenesis; bevacizumab; breast cancer; monoclonal antibody
The epothilone analog ixabepilone exhibits reduced susceptibility to several important tumor survival mechanisms that limit the efficacy of taxanes and anthracyclines. As a single agent, ixabepilone has shown promise in metastatic breast cancer when anthracyclines, taxanes, or capecitabine have failed; and in early-stage breast cancer that is taxane-naïve or has previously received taxanes in the adjuvant or metastatic setting. Compared with capecitabine alone, ixabepilone used in combination with capecitabine in patients previously treated with and resistant to anthracyclines and taxanes produced a 25% reduction in the risk of disease progression. Triple-negative tumors showed particular susceptibility to this doublet. Ixabepilone has also demonstrated efficacy as first-line therapy in combination with targeted agents such as bevacizumab and trastuzumab. Ongoing investigations should provide insight as to how this agent could be integrated into treatment of early-stage disease. In clinical studies, toxicities with ixabepilone were manageable and reversible through dose reduction or delay, even in patients with extensive or heavily-pretreated disease. Thus, ixabepilone represents a useful addition to the therapeutic options available for advanced breast cancer, and it may extend progression-free survival in patients with limited treatment options.
ixabepilone; breast cancer; efficacy; metastasis; adjuvant
Combinations of capecitabine and a taxane are highly active in metastatic breast cancer, and synergy between capecitabine and docetaxel has also been demonstrated. Such combinations potentially would provide a promising non–anthracycline-based alternative for patients with early breast cancer. Non-anthracycline preoperative regimens are a particularly interesting proposition in human epidermal growth factor receptor 2 (HER2)-positive breast cancer, as they offer less cardiotoxicity and thus can be used concomitantly with preoperative trastuzumab therapy. Capecitabine plus docetaxel (XT) and trastuzumab with XT (HXT) are promising non-anthracycline regimens for the preoperative treatment of women with HER2-negative and HER2-positive breast cancer, respectively. The Xeloda in Neoadjuvant (XeNA) trial, an open-label, multicenter, phase II study, independently assesses the efficacy of preoperative XT in HER2-negative and HXT in HER2-positive breast cancer. A particularly important feature of the XeNA study is the use of pathologic complete response (pCR) plus near pCR (npCR) as the primary endpoint. pCR is associated with long-term survival, and although it is valuable as a surrogate marker, pCR has some limitations. Measurement of residual breast cancer burden (RCB) has been proposed as a more practical alternative to predict survival after preoperative chemotherapy. The combination of RCB-0 and RCB-I (npCR) expands the subset of patients shown to benefit from preoperative chemotherapy, and achievement of pCR or npCR is associated with long disease-free survival. In XeNA, the sum of pCR and npCR will facilitate correlative studies designed to identify patients most likely to benefit from XT and HXT and may expedite the clinical evaluation of these novel preoperative regimens.
Pathologic complete response; Breast-conserving surgery; Taxane; Anthracycline-induced cardiotoxicity
Lapatinib, an oral, reversible inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2) tyrosine kinase, has proven antitumor activity in HER2-positive metastatic breast cancer (MBC). Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. This was an open-label, single-arm, multicenter, Phase II study to evaluate the efficacy and safety of nab-paclitaxel plus lapatinib in women with HER2 over-expressing MBC who had received no more than one prior chemotherapeutic regimen. The primary efficacy endpoint was the overall response rate (ORR). This was defined as the percentage of patients having either a complete response (CR) or partial response (PR). Secondary efficacy endpoints included progression-free survival (PFS), overall survival, duration of response (DoR), time to response (TTR), and time to progression (TTP). Investigator-assessed ORR was 53 % (n = 32, 95 % confidence interval (CI): 40.7–66.0) with the majority of patient responses demonstrating a PR (47 %). Four (7 %) patient responses demonstrated a CR, and ten (17 %) a stable disease. The median Kaplan–Meier estimate of investigator-assessed PFS, DoR, TTR, and TTP was 39.7 weeks (95 % CI 34.1–63.9), 48.7 weeks (95 % CI 31.7–57.1), 7.8 weeks (95 % CI 7.4–8.1), and 41 weeks (95 % CI 39.1–64.6), respectively. Lapatinib 1,000 mg with nab-paclitaxel 100 mg/m2 IV is feasible with manageable and predictable toxicity and an ORR of 53 % comparing favorably with other HER2-based combinations in this setting.
Breast cancer; HER2; Lapatinib; Nab-paclitaxel
Inhibition of the HER-2 pathway via the monoclonal antibody trastuzumab has had a major impact in treatment of HER-2 positive breast cancer, but de novo or acquired resistance may reduce its effectiveness. The known interplay between the epidermal growth factor receptor (EGFR) and HER-2 receptors and pathways creates a rationale for combined anti-EGFR and anti-HER-2 therapy in HER-2 positive metastatic breast cancer (MBC), and toxicities associated with the use of multiple chemotherapeutic agents together with biological therapies may also be reduced. We conducted a prospective, single arm, phase I/II trial to determine the efficacy and toxicity of the combination of trastuzumab with the EGFR inhibitor gefitinib and docetaxel, in patients with HER-2 positive MBC. The maximum tolerated dose (MTD) was determined in the phase I portion. The primary end point of the phase II portion was progression-free survival (PFS). Immunohistochemical analysis of biomarker expression of the PKA-related proteins cAMP response element-binding protein (CREB), phospho-CREB and DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32 kDa) plus t-DARPP (the truncated isoform of DARPP-32); PTEN; p-p70 S6K; and EGFR was conducted on tissue from metastatic sites. Nine patients were treated in the phase I portion of the study and 22 in the phase II portion. The MTD was gefitinib 250 mg on days 2–14, trastuzumab 6 mg/kg, and docetaxel 60 mg/m2 every 21 days. For the 29 patients treated at the MTD, median PFS was 12.7 months, with complete and partial response rates of 18 and 46%, and a stable disease rate of 29%. No statistically significant correlation was found between response and expression of any biomarkers. We conclude that the combination of gefitinib, trastuzumab, and docetaxel is feasible and effective. Expression of the biomarkers examined did not predict outcome in this sample of HER-2 overexpressing metastatic breast cancer.
Breast cancer; HER2; Gefitinib; Phosphatase and tensin homolog; Protein kinase A; Trastuzumab
Taxanes are a standard first-line option for metastatic breast cancer (MBC), but their utility may be limited by primary or acquired resistance. New microtubule-targeting agents have been developed to overcome taxane resistance and provide additional options for improving patient outcomes. This article reviews these alternative microtubule-targeting agents and their potential clinical benefits for MBC patients. Relevant clinical data were compiled through searches within PubMed and congress abstract databases. Ixabepilone, a novel microtubule-stabilizing drug approved by the US Food and Drug Administration (FDA), has proven efficacy across multiple lines of therapy, including patients with taxane-resistant/refractory disease. In phase III trials, ixabepilone plus capecitabine significantly improved progression-free survival compared with capecitabine alone in anthracycline/taxane-pretreated patients. Eribulin has recently been approved by the FDA and by the European Medicines Agency for the treatment of patients with MBC who have received at least two prior chemotherapy regimens for late-stage disease. In a phase III trial, eribulin extended overall survival compared with the physician’s treatment choice in heavily pretreated MBC patients. In addition, several investigational microtubule-targeting agents may have therapeutic potential in MBC. The development of new microtubule-targeting agents helps to address the need for additional effective regimens for patients progressing after standard treatment with anthracycline- and taxane-containing regimens.
Taxanes; Microtubule-targeting agents; Epothilones; Ixabepilone; Eribulin