Elsevier

Clinical Breast Cancer

Volume 15, Issue 1, February 2015, Pages 8-15
Clinical Breast Cancer

Original Study
Ixabepilone Alone or With Cetuximab as First-Line Treatment for Advanced/Metastatic Triple-Negative Breast Cancer

https://doi.org/10.1016/j.clbc.2014.07.007Get rights and content

Abstract

Background

Despite high initial sensitivity to chemotherapy, TNBC is associated with a poor prognosis, highlighting the need for novel therapeutic strategies. The aim of this multicenter, randomized, open-label phase II trial was to assess the efficacy of ixabepilone as monotherapy, and the combination of ixabepilone with cetuximab, as first-line treatment in patients with triple-negative locally advanced nonresectable and/or metastatic breast cancer.

Patients and Methods

Women were randomly assigned to receive either ixabepilone (40 mg/m2) every 21 days (n = 40), or ixabepilone (40 mg/m2) every 21 days with cetuximab (400 mg/m2 loading dose, followed by 250 mg/m2) once weekly (n = 39). The primary end point of the trial was to estimate the response rates of ixabepilone monotherapy and ixabepilone with cetuximab combination therapy.

Results

Of 79 randomized patients, 77 were treated. Based on an intent-to-treat analysis, an objective response rate of 30% (95% confidence interval [CI], 16.6-46.5) was observed in the monotherapy arm, and 35.9% (95% CI, 21.2-52.8) in the combination arm. Median progression-free survival was 4.1 months in both treatment groups. Safety findings were consistent with the known individual toxicity profiles of ixabepilone and cetuximab. Skin and subcutaneous tissue disorders were more common with combination therapy, as were discontinuations because of adverse events.

Conclusion

Ixabepilone monotherapy and the ixabepilone and cetuximab combination demonstrated similar levels of clinical activity in first-line treatment of advanced TNBC, with a predictable safety profile. Further investigation of novel therapies for TNBC is required to improve patient outcomes.

Introduction

Triple-negative (TN) breast cancer (TNBC) refers to tumors that do not express estrogen receptor, progesterone receptor, or HER2, and accounts for approximately 15% of breast cancers.1, 2, 3 In a retrospective analysis of biomarker data from a Cancer and Leukemia Group B (CLGB) study, 44 of 136 metastatic cases were TN.4 TNBC is increasingly recognized as a heterogeneous disease, not only on the molecular level, but also on the pathological and clinical levels.5 Tumors of this type are associated with a relatively aggressive clinical course and poor prognosis, because of increased likelihood of treatment failure, early recurrence, and distant metastases (especially visceral) compared with non-TN tumors.6, 7 Breast cancer metastases might be more likely to have the TN phenotype than nondisseminated tumors.

Management of TNBC is problematic because of a lack of evidence-based treatment options outside of conventional chemotherapy. No standard therapeutic regimen for TNBC exists, and so patients are managed according to general guidelines that do not account for the specific nature of TN disease. Despite greater sensitivity to chemotherapy compared with other breast tumor types, particularly in the neoadjuvant setting,8, 9, 10 TN tumors progress more quickly than non-TN tumors, leading to significantly worse overall survival (OS).4, 8, 9 This highlights the need for improved medical therapy in TNBC, particularly because of the heterogeneity of the disease. Various novel approaches are currently undergoing clinical evaluation.

Ixabepilone, a semisynthetic analogue of epothilone B, is a novel microtubule-targeting agent with established antitumor activity in taxane-refractory tumors.11, 12 In phase II studies, ixabepilone monotherapy demonstrated activity in women with locally advanced or metastatic breast cancer (MBC) resistant to taxanes,13, 14 and also in earlier treatment lines in the metastatic setting.15, 16 Combination therapy with ixabepilone and capecitabine has proven efficacy in patients with MBC, including the non-TN and TN phenotypes.17, 18 In a subset analysis of 443 TN patients included in phase III studies, ixabepilone/capecitabine treatment showed observed progression-free survival (PFS) benefit compared with capecitabine monotherapy (4.1 vs. 2.1 months; hazard ratio [HR], 0.63), an increased objective response rate (ORR; 31% vs. 15%), and a trend toward extended OS (10.3 vs. 9.0 months; HR, 0.87), although not significant.19 In the United States and other countries ixabepilone is indicated in combination with capecitabine for the treatment of metastatic or locally advanced breast cancer in patients after failure of an anthracycline and a taxane. It is also indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients after failure of an anthracycline, a taxane, and capecitabine.

Epidermal growth factor receptor (EGFR) has an established role in the pathogenesis of malignant disease,20 and is linked with an aggressive phenotype and poor prognosis. EGFR is overexpressed more often in TNBC than in unselected breast cancer series (60% vs. 25%).21 EGFR immunoreactivity has also shown significant correlation with worse prognosis in patients with TN invasive ductal carcinomas of the breast.22 This evidence suggests that patients with TNBC might benefit from treatment with cetuximab,23, 24 a chimeric monoclonal antibody specific for EGFR currently undergoing clinical evaluation in combination regimens in TN MBC. Early clinical data indicate promising activity with cetuximab in various combination regimens in patients with TNBC.25, 26, 27, 28, 29 In a recent prospective study, cetuximab in combination with carboplatin was associated with 17% ORR in TN MBC patients at various lines of treatment.26, 27 Blockade of EGFR promoted chemosensitization in breast cancer cell lines, providing an additional rationale for the combination of cetuximab with cytotoxic agents in breast cancer.30

Preclinical data obtained in GEO human colon and L2987 human lung carcinoma xenografts indicate synergistic antitumor efficacy between ixabepilone and cetuximab,31, 32 providing a rationale for further investigation of this combination. The aim of this phase II study was to assess the efficacy of ixabepilone monotherapy, and the combination of ixabepilone with cetuximab, as first-line treatment in patients with TN locally advanced nonresectable and/or MBC.

Section snippets

Patients

Eligible patients included women aged ≥ 18 years with histologic or cytologic confirmed diagnosis of TN, invasive adenocarcinoma of the breast, with evidence of locally advanced nonresectable and/or metastatic disease. At least 1 target lesion was required as per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0 criteria. Patients were confirmed as HER2-negative using fluorescence in situ hybridization, chromogenic in situ hybridization, or immunohistochemistry staining of 0 or

Patient Characteristics

Seventy-nine patients were randomized, of whom 77 were treated. Forty patients were treated with ixabepilone monotherapy and 37 with ixabepilone with cetuximab. Two patients in the ixabepilone with cetuximab treatment arm were not treated; 1 patient was randomized because of an error and the other no longer met study criteria. All 77 treated patients discontinued study therapy. Reasons for treatment not related to the study included disease progression (n = 52; 67.5%), study drug toxicity (n =

Discussion

Despite high initial sensitivity to chemotherapy, TNBC is associated with a poor prognosis, highlighting the need for novel therapeutic strategies. The aim of this randomized phase II study was to assess the efficacy of ixabepilone, either as monotherapy or in combination with cetuximab, as first-line treatment in patients with TN locally advanced nonresectable and/or MBC. Ixabepilone demonstrated activity in TNBC, with a similar ORR observed in the monotherapy (12 patients/40) and combination

Conclusion

Ixabepilone monotherapy and the combination of ixabepilone and cetuximab demonstrated similar levels of clinical activity, measured according to tumor response in first-line treatment of advanced TNBC. The safety profile of the combination was acceptable and consistent with the known individual toxicity profiles of ixabepilone and cetuximab. However, more patients treated with ixabepilone with cetuximab discontinued treatment because of AEs than with ixabepilone monotherapy, and skin and

Acknowledgments

The authors take full responsibility for the content of this publication and confirm that it reflects their viewpoint and scientific expertise. They wish to acknowledge Clair Thomas of StemScientific for providing writing and editorial support, funded by Bristol-Myers Squibb.

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