halichondrin-b and Breast-Neoplasms

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

In the new era of 'precision' cancer medicine, new drug development has shifted from cytotoxic chemotherapy to molecularly targeted agents. Eribulin mesylate, a microtubule-destabilizing agent, is the only 'classical' cytotoxic agent approved for the treatment of breast cancer in the last 7 years. This synthetic analogue of halichondrin B, isolated from the marine sponge 'Halicondria Okaida', was responsible for prolonging overall survival of heavily pretreated metastatic breast cancer patients in a large Phase III trial. Eribulin is now under clinical development in earlier settings such as the neo-adjuvant and adjuvant settings. Furthermore, its unique mechanism of action and the absence of cross-resistance with taxanes have led to the design of clinical trials in multiple indications: bladder cancer, lung cancer, prostate cancer… The main adverse events are neutropenia, fatigue and peripheral neuropathy.

Topics: Alopecia; Antineoplastic Agents; Breast Neoplasms; Carcinoma; Chemotherapy, Adjuvant; Clinical Trials as Topic; Drug Approval; Drug Resistance, Neoplasm; Drugs, Investigational; Ethers, Cyclic; Fatigue; Female; Furans; Humans; Ketones; Macrolides; Molecular Targeted Therapy; Multicenter Studies as Topic; Neoadjuvant Therapy; Neutropenia; Peripheral Nervous System Diseases; Tubulin Modulators; United States; United States Food and Drug Administration

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

The activity and safety of eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor with a novel mechanism of action, were evaluated in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline, taxane, and capecitabine.. Eligible patients in this single-arm, open-label phase II study received eribulin mesylate (1.4 mg/m(2)) administered as a 2- to 5-minute intravenous infusion on days 1 and 8 of a 21-day cycle. The primary end point was objective response rate (ORR) assessed by independent review.. Of 299 enrolled patients who had received a median of four prior chemotherapy regimens, 291 received eribulin (for a median of four cycles). Of these, 269 patients met key inclusion criteria for the primary efficacy analysis. The primary end point of ORR by independent review was 9.3% (95% CI, 6.1% to 13.4%; all partial responses [PRs]), the stable disease (SD) rate was 46.5%, and clinical benefit rate (complete response + PR + SD > or = 6 months) was 17.1%. The investigator-reported ORR was 14.1% (95% CI, 10.2% to 18.9%). Median duration of response was 4.1 months, and progression-free survival was 2.6 months. Median overall survival was 10.4 months. The most common treatment-related grade 3 or 4 toxicities were neutropenia (54%; febrile neutropenia, 5.5%), leukopenia (14%), and asthenia/fatigue (10%; no grade 4); grade 3 neuropathy occurred in 6.9% of patients (no grade 4).. Eribulin demonstrated antitumor activity in extensively pretreated patients who had previously received an anthracycline, taxane, and capecitabine, with a manageable tolerability profile.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Breast Neoplasms; Disease-Free Survival; Drug Administration Schedule; Ethers, Cyclic; Female; Furans; Humans; Ketones; Macrolides; Middle Aged; Peripheral Nervous System Diseases; Retreatment

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

Despite their outstanding antitumour activity in mice, the limited supply from the natural sources has prevented drug discovery/development based on intact halichondrins. We achieved a total synthesis of C52-halichondrin-B amine (E7130) on a >10 g scale with >99.8% purity under GMP conditions. Interestingly, E7130 not only is a novel microtubule dynamics inhibitor but can also increase intratumoural CD31-positive endothelial cells and reduce α-SMA-positive cancer-associated fibroblasts at pharmacologically relevant compound concentrations. According to these unique effects, E7130 significantly augment the effect of antitumour treatments in mouse models and is currently in a clinical trial. Overall, our work demonstrates that a total synthesis can address the issue of limited material supply in drug discovery/development even for the cases of complex natural products.

Topics: Actins; Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Breast Neoplasms; Cancer-Associated Fibroblasts; Carcinoma, Squamous Cell; Cetuximab; Drug Discovery; Endothelial Cells; Ethers, Cyclic; Female; Gene Expression; Head and Neck Neoplasms; Humans; Macrolides; Mice; Mice, Inbred BALB C; Platelet Endothelial Cell Adhesion Molecule-1; Survival Analysis; Tubulin Modulators; Tumor Burden; Xenograft Model Antitumor Assays

Topics: Animals; Antineoplastic Agents; Biological Products; Breast Neoplasms; Ethers, Cyclic; Furans; Humans; Ketones; Macrolides; Marine Biology; Porifera; United States; United States Food and Drug Administration

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

Eisai is developing eribulin mesilate (E-7389), a synthetic macrocyclic ketone analogue of the tubulin inhibitor halichondrin B, for the treatment of a variety of solid tumors that include but are not limited to breast and lung cancer. In this context, eribulin is in phase III clinical trials in breast cancer; however, it has also progressed to phase II for nonsmall cell lung cancer, soft tissue sarcomas, pancreatic, prostate, head and neck cancer, bladder and ovarian and related gynecological tumors. Eribulin has shown synergistic in vitro antiproliferative activity in combination with the breast cancer drugs gemcitabine, epirubicin, trastuzumab, docetaxel and vinorelbine. Clinical trials have established efficacy, safety and a distinct survival advantage of 2.5 months with eribulin as compared to other treatments of physician's choice in metastatic breast cancer patients with heavy pretreatment and taxane resistance. It has a manageable side effect profile, consisting mostly of neutropenia and fatigue, with distinct tolerance at full doses in renal dysfunction, a lower incidence of peripheral neuropathy, minimal chances of drug-drug interactions and hypersensitivity. It appears to be a suitable candidate for third-line monotherapy and beyond for locally advanced and metastatic breast cancer. This review will focus on published and peer-reviewed data on breast cancer.

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

Topics: Animals; Antineoplastic Agents; Biological Products; Breast Neoplasms; Clinical Trials as Topic; Drug Approval; Ethers, Cyclic; Furans; Humans; Ketones; Macrolides; Porifera; Stereoisomerism; Tubulin Modulators

The synthesis of a simplified analogue of the potent, cytotoxic tubulin-depolymerizing agent spongistatin 1, based on the AB spiroketal framework, is presented. The new structural analogue is an extension of a recently described spongistatin congener reported to disrupt microtubules in breast cancer cells in vitro and to alter the microtubule assembly reaction. Cytotoxicity data on the new structural analogue, as well as the parent congener, are reported. We found no significant cytotoxic or antitubulin activity with either compound.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cattle; Ethers, Cyclic; Guanosine Triphosphate; Humans; Lactones; Macrolides; Spiro Compounds; Structure-Activity Relationship; Tubulin; Tumor Cells, Cultured