Novel anti-tubulin cytotoxic agents for breast cancer.

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1: Expert Rev Anticancer Ther. 2009 Feb;9(2):175-85. Links

Novel anti-tubulin cytotoxic agents for breast cancer.

Morris PG, Fornier MN.
Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Regardless of stage of disease, cytotoxic chemotherapy remains an important part of the treatment paradigm for breast cancer. Anthracyclines and taxanes are the most active agents; however, limitations with their use exist. These include a maximum lifetime dose and tumor resistance with anthracycline, hypersensitivity reactions and cumulative toxicity with taxanes. Therefore, to meet these challenges, the development of new cytotoxics and novel taxane formulations is an important area of active research. Several recent advances have been made. Epothilones represent a novel group of cytotoxic agents, with proven activity in breast cancer. Nanoparticle drug delivery systems have led to the development of ABI-007, which has demonstrated superior response rates than 3-weekly paclitaxel, with a lower risk of hypersensitivity reactions. To circumvent the problem of taxane resistance, larotaxel, a semisynthetic taxoid, and vinflunine, a synthetic vinca alkaloid, have been developed with encouraging clinical results to date. Eribulin, a synthetic derivative of halichondrin has recently entered Phase III trials based on encouraging activity in heavily pretreated patients. A further novel approach is the conjugation of cytotoxic agents to targeted agents, such as with trastuzumab-MCC-DM1. Elucidating the relative importance of these agents and incorporating them into existing treatment paradigms is a significant challenge for the future.

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larotaxel
A semi-synthetic derivative of the taxane 10-deacetylbaccatin III with potential antineoplastic activities. Larotaxel binds to tubulin, promoting microtubule assembly and stabilization and preventing microtubule depolymerization, thereby inhibiting cell proliferation. As it represents poor substrate for P-glycoprotein-related drug resistance mechanisms, this agent may be useful for treating multi-drug resistant tumors. Larotaxel penetrates the blood brain barrier. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

Code names:

RPR 109881 RPR 109881A XRP9881

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1: Ann Oncol. 2008 Jul;19(7):1255-60. Epub 2008 Apr 1. Links

Phase II multicenter study of larotaxel (XRP9881), a novel taxoid, in patients with metastatic breast cancer who previously received taxane-based therapy.

Diéras V, Limentani S, Romieu G, Tubiana-Hulin M, Lortholary A, Kaufman P, Girre V, Besenval M, Valero V.
Department of Medical Oncology, Institut Curie, Paris, France. veronique.dieras@curie.net
BACKGROUND: Treatment options are limited for patients with refractory metastatic breast cancer (MBC). Larotaxel (XRP9881) is a novel taxoid with preclinical activity against taxane-resistant breast cancer. The current phase II trial of larotaxel was conducted in women with taxane-treated MBC. PATIENTS AND METHODS: Patients were stratified by response to prior taxane therapy (resistant or nonresistant). Larotaxel 90 mg/m(2) was administered as a 1-h infusion every 3 weeks. Patients were evaluated for tumor response every two cycles. A blinded external response review committee determined the overall response rate (ORR), duration of response (DOR), and time to progression (TtP) of the disease. Median survival time (MST) and safety were also evaluated. RESULTS: One hundred and thirty patients were treated. In the nonresistant group, the ORR was 42%; median DOR 5.3 months; median TtP 5.4 months; and MST 22.6 months. In the resistant group, the ORR was 19%; median DOR 5.0 months; median TtP 1.6 months; and MST 9.8 months. The most common grade 3/4 adverse events were neutropenia (82%), fatigue (15%), diarrhea (12%), febrile neutropenia (9%), neutropenic infection (8%), and sensory neuropathy (7%). CONCLUSIONS: Larotaxel has good activity, manageable toxicity, and a favorable therapeutic index in women with taxane-pretreated MBC.
PMID: 18381372 [PubMed - indexed for MEDLINE

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Eribulin prolongs survival in women with metastatic breast cancer
Will Boggs, MD


Last Updated: 2009-04-22 16:42:07 -0400 (Reuters Health)

NEW YORK (Reuters Health) - Eribulin, a nontaxane microtubule dynamics inhibitor, prolongs survival in heavily pretreated women with metastatic breast cancer, according to a report in the April Journal of Clinical Oncology.

"Eribulin is a very active drug with a good toxicity profile," Dr. Linda T. Vahdat from Weill Cornell Medical College, New York, told Reuters Health. "It is a great drug and needs to get approved."

Dr. Vahdat and colleagues evaluated the efficacy and tolerability of eribulin in heavily pretreated women with metastatic breast cancer who had already received anthracycline and a taxane.

The overall objective response rate (all partial responses) was 11.5% in the per protocol group, 13.6% in the intention-to-treat analysis, and 16.5% by investigator assessment, the authors say. Eribulin appeared to show activity across a range of patient subgroups.

Median progression-free survival was 79 days, and median overall survival was 275 days, the authors report. Among the 10 responders in the per protocol group, however, median progression-free survival was 264 days and median overall survival was 560 days.

The incidence of febrile neutropenia was low, and only 5 patients experienced grade 3 peripheral neuropathy. Gastrointestinal adverse effects were generally mild.

Eribulin "is probably as active as the taxanes when used in similar settings (which means it is probably as good as ixabepilone)," Dr. Vahdat said. "I think its big advantage is the near lack of alopecia and low rate of peripheral neuropathy."

"My concern is that if we get too caught up in sequence of administering drug in metastatic breast cancer we can miss an opportunity to have another drug available which ultimately extends the survival in increments (by this I mean the obsession with making sure patients have anthracyclines and taxanes before they administer capecitabine, etc.)," she continued. "As you know, sequence doesn't matter with regard to survival when picking a drug for the treatment of advanced breast cancer, but side effects do."

J Clin Oncol 2009.