halichondrin-b and Neoplasm-Metastasis

Metastatic soft tissue sarcoma, a devastating disease, has a median overall survival of only 12-18 months. Treatment options remain scarce. However, eribulin mesylate, a first-in-class halichondrin B-based microtubule dynamics inhibitor, has recently been approved for the management of patients with advanced liposarcoma. Areas covered: Based on a review of the literature between 2005 and 2017, we present a summary of eribulin mesylate's mechanism of action and the studies showing its clinical efficacy in locally advanced or metastatic sarcomas. Expert commentary: Future development includes the definition of a biomarker signature related to patient outcome with eribulin. Further investigation via controlled clinical trials is needed to identify combination regimens that can optimize the efficacy of eribulin while providing an acceptable safety profile in sarcoma patients.

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Disease-Free Survival; Epithelial-Mesenchymal Transition; Ethers, Cyclic; Female; Furans; Humans; Ketones; Macrolides; Neoplasm Metastasis; Sarcoma; Tubulin Modulators

The pharmacology, pharmacokinetics, clinical efficacy, safety, and administration of eribulin in patients with metastatic breast cancer are reviewed.. Classical chemotherapeutic agents for breast cancer have dominated treatment regimens even in the era of targeted therapy. Disease progression through these agents is often due to the development of resistance or lack of efficacy with these agents. Recently, a new nontaxane agent, eribulin mesylate, was approved for the treatment of metastatic breast cancer in patients who have received at least two prior chemotherapeutic agents. Eribulin is a member of a new class of synthetic cytotoxic agents derived from the Japanese sea sponge Halichondria okadai. Eribulin differs from other antimicrotubule agents in that it can bind to the microtubule cap and inhibit tubulin polymerization, leading to microtubule arrest. In Phase II clinical trials, eribulin demonstrated activity in extensively pretreated patients who had previously received an anthracycline, taxane, and capecitabine and had shown disease progression within the last six months of treatment. In a pivotal Phase III clinical trial of heavily pre-treated patients, patients who received eribulin versus the physician's treatment of choice showed a significant increase in overall and progression-free survival. Eribulin has a manageable adverse-effect profile, consisting mainly of neutropenia and fatigue. Eribulin has been associated with a low incidence of peripheral neuropathy.. Eribulin, a novel synthetic antimicrotubule agent that binds to the vinca domain of tubulin and inhibits the polymerization of tubulin, offers a new treatment option for metastatic breast cancer or locally advanced breast cancer.

Topics: Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Ethers, Cyclic; Female; Furans; Humans; Ketones; Macrolides; Neoplasm Metastasis

Eribulin is a synthetic analog of halichondrin B, a non-taxane microtubule inhibitor extracted from the marine sponge, Halichondria okaida. It presents a novel mechanism of action and is active on cancer cells resistant to other antimicrotubule agents. It was granted approval in the USA and Europe for the treatment of heavily pretreated metastatic breast cancer. Early trials had shown activity in this setting with main toxicities being neutropenia and neuropathy in patients where quality of life is essential. Approvals were granted after a phase 3 trial demonstrated overall survival benefit in metastatic breast cancer previously treated with anthracyclines, taxanes, and capecitabine, in a setting where most treatments are failing to demonstrate a survival benefit. Recent data suggest that this survival benefit is also consistent in the elderly with no excess toxicity. Future strategies of eribulin are being tested in ongoing trials, evaluating this drug in earlier metastatic lines as well as in the adjuvant and the neoadjuvant settings.

Topics: Adult; Aged; Antineoplastic Agents; Breast; Breast Neoplasms; Clinical Trials as Topic; Drug Monitoring; Ethers, Cyclic; Female; Furans; Humans; Ketones; Macrolides; Microtubules; Neoplasm Metastasis; Neutropenia; Treatment Outcome

Despite advances in cancer biology, chemotherapy remains the backbone of treatment approaches for many patients with metastatic breast cancer (MBC). Halichondrins, derived from marine sponges, have significant potential as potent antimicrotubule agents. Eribulin, with proven preclinical activity, is a synthetic halichondrin analog with novel actions on tubulin including suppression of microtubule polymerization. Phase I and II studies in MBC identified neutropenia as the dose-limiting toxicity and a maximum tolerated dose of 1.4 mg/m2 on days 1 and 8 of a 21-day cycle. An encouraging response rate of 11.5% in refractory MBC led to the launch of the phase III Eisai Metastatic Breast Cancer Study Assessing Physician's Choice versus Eribulin trial, in which heavily pretreated patients with MBC were randomized 2 : 1 to intravenous eribulin or monotherapy of the investigator's choice. Recently, it was reported that this important study of 762 patients met its primary endpoint of overall survival: eribulin was associated with an improvement in median overall survival from 10.65 months to 13.12 months (hazard ratio 0.8; 95% confidence interval 0.66-0.99) and a response rate of 12.2%. In general, the side effect profile of eribulin seems to be acceptable, as although neutropenia occurred in 45% of the patients, febrile neutropenia was rare and the incidence of neuropathy was low. These findings show that eribulin is potentially a new active agent for MBC, although results of ongoing studies are awaited to confirm the reported benefit. Future studies will investigate the potential role of eribulin in other settings, including for early breast cancer, to ascertain how to optimally incorporate this new agent into current treatment paradigms.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Breast Neoplasms; Clinical Trials, Phase III as Topic; Ethers, Cyclic; Female; Furans; Humans; Infusions, Intravenous; Ketones; Macrolides; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neutropenia; Randomized Controlled Trials as Topic; Survival Rate; Treatment Outcome; Tubulin Modulators

Eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analog of the marine natural product halichondrin B. This open-label, single-arm, phase II study evaluated efficacy and tolerability of eribulin in heavily pretreated patients with metastatic breast cancer (MBC).. MBC patients who were previously treated with an anthracycline and a taxane received eribulin mesylate (1.4 mg/m(2)) as a 2- to 5-minute intravenous (IV) infusion on days 1, 8, and 15 of a 28-day cycle. Because of neutropenia (at day 15), an alternative regimen of eribulin on days 1 and 8 of a 21-day cycle was administered. The primary end point was overall response rate.. Of the 103 patients treated, the median number of prior chemotherapy regimens was four (range, one to 11 regimens). In the per-protocol population (n = 87), eribulin achieved an independently reviewed objective response rate (all partial responses [PRs]) of 11.5% (95% CI, 5.7 to 20.1) and a clinical benefit rate (PR plus stable disease > or = 6 months) of 17.2% (95% CI, 10.0 to 26.8). The median duration of response was 171 days (5.6 months; range, 44 to 363 days), the median progression-free survival was 79 days (2.6 months; range, 1 to 453 days), and the median overall survival was 275 days (9.0 months; range, 15 to 826 days). The most common drug-related grades 3 to 4 toxicities were as follows: neutropenia, 64%; leukopenia, 18%; fatigue, 5%; peripheral neuropathy, 5%; and febrile neutropenia, 4%.. Eribulin demonstrated activity with manageable tolerability (including infrequent grade 3 and no grade 4 neuropathy) in heavily pretreated patients with MBC when dosed as a short IV infusion on days 1 and 8 of a 21-day cycle.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Ethers, Cyclic; Female; Furans; Humans; Ketones; Macrolides; Microtubules; Middle Aged; Neoplasm Metastasis; Taxoids; Treatment Outcome

Topics: Antineoplastic Agents; Breast Neoplasms; Drug Approval; Ethers, Cyclic; Female; Furans; Humans; Ketones; Macrolides; Mesylates; Microtubules; Neoplasm Metastasis