Eribulin Research Articles

The Marine Pharmacology and Pharmaceuticals Pipeline in 2018

The ocean's organisms continue to deliver a chemical biodiversity that contributes to both the global preclinical and clinical pharmaceutical pipelines. Thus, in November 2018, the clinical marine pharmaceutical pipeline consisted of seven marine‐derived drugs approved by the United States Food and Drug Administration (FDA): for cancer, cytarabine (Cytosar‐U®, Depocyt®, FDA‐approved 1969); for Herpes Simplex Virus, vidarabine (Vira‐A®, FDA‐approved 1976); for pain, ziconotide (Prialt®, FDA‐approved 2004); for hypertriglyceridemia, omega‐3‐acid ethyl esters (Lovaza®, FDA‐approved 2004); for cancer, eribulin mesylate (Halaven®, FDA‐approved 2010), brentuximab vedotin (Adcetris®, FDA‐approved 2011), and trabectedin (Yondelis®, FDA‐approved 2015). The website www.clinicaltrials.gov was searched to determine marine‐derived pharmaceuticals that were in Phase I, Phase II and Phase III of clinical development in November 2018. Confirmation of our findings in the www.clinicaltrials.gov website was conducted by visiting the websites of all pharmaceutical companies supporting the development of compounds currently in Phase I, Phase II and Phase III of clinical development. Our clinical research determined that there were 25 marine‐derived compounds in active clinical trials in November 2018: 6 marine‐derived compounds were in Phase III, 10 compounds in Phase II, and at least 9 compounds in Phase I, many of them auristatin‐containing antibody drug conjugates or ADCs. Regular updates on the clinical marine pharmaceutical pipeline will be posted on the dedicated website: http://marinepharmacology.midwestern.edu/clinical_pipeline.html. Furthermore, it is important to note that the global preclinical marine pharmacology pipeline continues to generate considerable data on multiple pharmacological classes, as highlighted in a recent review: A. M. S. Mayer, A. D. Rodríguez, O. Taglialatela‐Scafati and N. Fusetani. Marine Pharmacology in 2012–2013: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti‐Inflammatory, Antiprotozoal, Antituberculosis, and Antiviral Activities; Affecting the Immune and Nervous Systems, and other Miscellaneous Mechanisms of Action. Marine Drugs 15 (9): 273, 2017. We thus conclude that in November 2018, both the marine pharmacology preclinical and clinical pharmaceutical pipelines continued to remain very active.Support or Funding InformationSupport by the College of Pharmacy, Vicki Sears, Pharmacology Department, College of Graduate Studies and Elizabeth Tallman, Information Technology Services, Midwestern University are gratefully acknowledged.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

EP-2167 Radiosensitizing effect of eribulin mesylate in human cervical carcinoma cells in vitro

EP-2167 Radiosensitizing effect of eribulin mesylate in human cervical carcinoma cells in vitro

Efficacy and tolerability of eribulin mesylate in the treatment of anthracycline and taksan resistance to metastatic breast cancer. Single central experience

Amac : Mikrotubul inhibitoru olan eribulin mesilat antrasiklin ve taksana rezistant metastatik meme kanserli hastalarda kullanimi kabul edilmistir. Amac eribulin mesilatin etkinligini arastirmak. Gerec ve Yontemler: Retrospektif calismada Istanbul Okmeydani egitim ve arastirma hastanesi tibbi onkoloji kliniginde metastatik meme kanseri nedeniyle tedavi gormekte olan ve oncesinde antrasiklin ve taksan dahil olmak uzere en az 2 seri kemoterapi almis olan hastalar alindi. Bulgular: Calismaya toplam 25 hasta alindi. Median yas 54,9 (range 36-73) idi. median takip suresi 11.6 aydi. Hastalarin %68 ER pozitif, %68 Pr pozitif, %8,3 HER2 pozitif ve %6,2 triple negatifti. Hastalardan %78 inde karaciger, %64 unde kemik,%36sinda akciger metastazi mevcuttu. Eribuli seri sayisi 4,4 (min3-max6) idi. Eribulin kur sayisi 6,6 (min 1-max 33) idi. Median PFS 6,6 (0-26) ay olup median OS 17 (0-30) aydi. %8 inde tam yanit (2 hasta), %12 (3hasta) sinde parsiyel yanit,%52 (13 hasta) stabil yanit ve %28 (7 hasta ) progresif hastalik mevcuttu. Hastalarin hormon reseptor durumu ve HER2 durumuna gore sag kalimda farklilik yoktu(P=0,187). Hastalardaki metastaz bolgelerine gore de sag kalim da farklilik tespit edilmedi(P=0,875). %12 (3 hasta ) hastada grade 3-4 hematolojik toksisite ve %4( 1 hasta )hastada grade 3-4 noropati gorulmusken %40 (10 hasta ) hastada grade 1-2 hematolojik toksisite, %24 (6hasta ) hastada grade 1-2 noropati gorulmustur. Sonuc: Eribulin mesilat antrasiklin ve taksan rezistans onceden coklu seri kemoterapi almis metastatik meme kanserli hastalarin tedavisinde 3. Seri ve daha sonraki serilerde etkin ve tolerabl bulunmustur.

Use of a Healthcare Claims Database for Post-Marketing Safety Assessments of Eribulin in Japan: A Comparative Assessment with a Prospective Post-Marketing Surveillance Study.

BackgroundTo understand the extent to which a large-scale healthcare claims database (DB) captures the safety profile of eribulin mesylate (Halaven®, Eisai Co., Ltd., Japan), we compared patient characteristics, drug use, and adverse events (AEs) between data for patients treated with eribulin retrieved from a DB and data for metastatic breast cancer patients from a conventional prospective post-marketing surveillance (PMS).MethodsWe descriptively summarized patient characteristics and AEs of 551 and 951 patients retrieved from DB and PMS, respectively, during 2011‒2013. Using 2814 patient data from the DB during 2011‒2016, the drug use and AE incidence over time were assessed.ResultsIn both datasets, 99.8% were females, and the mean age was 57.8 ± 10.7 years. The mean number of eribulin administration was 11.1 ± 10.9 and 10.1 ± 7.8 in DB and PMS, respectively. Although, overall, the difference in AE incidence between the two datasets was moderate, gaps were larger for nausea (DB: 73.32% vs. PMS: 15.77%), neutropenia (20.87% vs. 66.67%), stomatitis (37.39% vs. 10.94%), and alopecia (0.36% vs. 12.09%). During 2011‒2016, the observed incidence of anemia or pyrexia significantly decreased (trend test, p = 0.0009 for both).ConclusionGenerally, patient characteristics, drug use, and AE incidence between the DB and PMS were comparable; however, AEs such as neutropenia may require defining based on the laboratory data to achieve more comparable results in DBs. Besides the usefulness of healthcare claims DBs for long-term assessments, they may also serve as a good complementary to PMS in the pharmacovigilance of eribulin.

Abstract OT2-07-05: A phase III trial to compare eribulin mesylate + trastuzumab (H) + pertuzumab (P) with paclitaxel or docetaxel + HP for HER2-positive advanced or metastatic breast cancer (JBCRG-M06/ EMERALD)

Abstract Background: Docetaxel + Trastuzumab (H) + Pertuzumab (P) provided progression-free survival (PFS) and overall survival (OS) benefits in HER2-positive advanced or metastatic breast cancer (AMBC) in the CLEOPATRA study as a first-line therapy. However, long-term administration of docetaxel at a dose of 75 mg/m2 every 3 weeks in AMBC patients (pts) is difficult due to the toxicities. Eribulin mesylate (E) is a well-tolerated microtubule inhibitor, and we have reported the efficacy and safety of EHP regimen as first- and second-line therapy for AMBC in a multicenter, phase II study (JBCRG-M03/UMIN000012232). In this M06 study, we address the clinical question as to which is the better chemotherapy partner for HP as first line regimen, in terms of efficacy, toxicity and QOL. Methods: JBCRG-M06 is a multicenter open-label randomized phase III study for HER2-positive AMBC pts who have received no prior chemotherapy except for the HER2- Antibody-Drug Conjugate (ADC). Pts will be randomized 1:1 to E (1.4mg/m2 on day 1 and 8) + H (8 mg/kg loading dose followed by 6 mg/kg) +P (840 mg loading dose followed by 420 mg) q3wks or standard taxanes (docetaxel 75mg/m2 on day1 or paclitaxel 80mg/m2 on day 1, 8 and 15) + HP q3wks. Stratification factors for randomization are; presence of visceral metastases, number of prior taxanes on perioperative adjuvant treatment, and treatment with prior anti-HER2-ADC. Primary endpoint is PFS and secondary endpoints include overall response rate, duration of response, OS, patient-reported outcomes (PRO) relating to QOL and peripheral neuropathy, new-metastases free survival, and safety. Translational research to search for biomarker for individual precision therapy will be performed. Main eligibility criteria are as follows: pts with HER2-positive AMBC, female aged 20-70 years old, ECOG PS of 0-1, LVEF ≥ 50% at baseline and adequate organ function. Pts who had progressive MBC within 6 months after the end of primary adjuvant systemic chemotherapy are excluded. The sample size was calculated by type1 error (2-sided) of 0.05 and 80% power to estimate the noninferiority margin 1.33 with an expected median PFS of 14.2 months. The target number of pts is 480 recruited over the duration of 3-years. The first patient in was achieved on August 2017. (ClinicalTrials.gov Identifier:NCT03264547). Citation Format: Masuda N, Yamashita T, Saji S, Araki K, Ito Y, Takano T, Takahashi M, Tsurutani J, Koizumi K, Kitada M, Kojima Y, Sagara Y, Tada H, Iwasa T, Kadoya T, Iwatani T, Hasegawa H, Morita S, Ohno S. A phase III trial to compare eribulin mesylate + trastuzumab (H) + pertuzumab (P) with paclitaxel or docetaxel + HP for HER2-positive advanced or metastatic breast cancer (JBCRG-M06/ EMERALD) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-07-05.

Abstract P1-14-02: A phase 2 study of low dose metronomic eribulin in metastatic breast cancer

Abstract Background: Eribulin mesylate is a non-taxane microtubule dynamics inhibitor approved by FDA in treatment of metastatic breast cancer (MBC) based on improvements in overall survival in the pivotal EMBRACE trial. Eribulin is approved at 1.4mg/m2 administered D1,8 of q21d cycle. However, this dose and schedule may have significant myelosuppression and peripheral neuropathy requiring dose reductions and treatment delays for some patients. We hypothesized that a low dose metronomic schedule will allow responding patients to remain on treatment, resulting in longer TTP (time to progression) and decreased incidence of toxicities and treatment-related discontinuations. Methods: A multi-site prospective open-label phase II trial of metronomic dosing of eribulin in patients with MBC has completed accrual of 60 patients, outcomes will be updated at presentation. Patients whose disease had progressed following 1-6 prior regimens with prior exposure to a taxane, ECOG performance status of 0 – 2, measurable disease per RECIST 1.1, with normal marrow and organ function were eligible. Eribulin was administered at 0.9mg/m2 weekly for 3 out of 4 weeks. For patients with HER2 positive disease, concurrent trastuzumab administration was allowed. Concurrent denosumab or bisphosphonates were allowed for patients with bone disease. Results: 60 patients were enrolled, average age 58 (range 34-83). Majority were postmenopausal Caucasian females, but the study included African American, Hispanic, native American, male patients. The majority of tumors were ER+, infiltrating ductal, but the study included 13 HER2+, and 12 TN tumors, with 5 ILC, and 5 mixed ILC/IDC. Nearly half of the enrolled patients had clinical benefit from the regimen, remaining on therapy for 6 months or longer, with stable disease or response; 50% had progression PD at 3 months 32% had stable disease and 18% had a partial or complete response (1, long term). Overall Survival, OS, for the entire group of heavily pre-treated patients was 1.2 years, with TN and HER2 positive patients faring better than ER+ in this small study. One HER2+ patient remains in long-term remission, off chemotherapy. The regimen was extremely well tolerated. The majority of the patients experienced grade 0 or 1 toxicity for alopecia (48/60) and peripheral neuropathy (7 with grade 2 neuropathy, 5 pre-existing, 2 with grade 3 neuropathy). There were few dose reductions (n=15), thrombocytopenia (11 grade 1 only), or use of G-CSF (14). Conclusions: Metronomic weekly low dose eribulin appears to be an active and tolerable regimen with less myelosuppression, alopecia and peripheral neuropathy than is seen with approved dose, allowing longer duration of use and disease control, with similar outcomes compared to the standard dose regimen. Outcomes will be updated at presentation. Citation Format: Chalasani P, Liu AJ, Khanjian JA, Peha M, Buening BJ, Gadi VK, Specht JM, Salazar L, Linden HM. A phase 2 study of low dose metronomic eribulin in metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-14-02.

Effect of High-dose Vitamin C Combined With Anti-cancer Treatment on Breast Cancer Cells.

The anti-cancer effect of high doses of intravenous vitamin C (high-dose vitamin C) remains controversial despite growing evidence that high-dose vitamin C exerts anti-tumorigenic activity by increasing the amount of reactive oxygen species in cancer cells without meaningful toxicities. Therefore, this study attempted to demonstrate the in vitro anti-cancer activity of high-dose vitamin C in combination with conventional treatment in breast cancer. The pro-apoptotic effects of high-dose vitamin C (1.25 to 20 mM) with or without anti-cancer agents (eribulin mesylate, tamoxifen, fulvestrant, or trastuzumab) were estimated using an MTT assay to measure the cell viability of a variety of breast cancer cell lines (MCF7, SK-BR3, and MDA-MB-231), as well as normal breast epithelial cells (MCF10A). High-dose vitamin C (≥10 mM) significantly decreased cell viability of all breast cancer cell lines, particularly of MCF-7 cells. The catalase activities of MCF7 and MDA-MD-231 cells were also lower than those of MCF10A cells. Moreover, cell viability of both MCF7 and MDA-MD-231 cells was decreased further when combining high-dose vitamin C and eribulin mesylate, and this was also true for MCF-7 cells when combining high-dose vitamin C with tamoxifen or fulvestrant and for SK-BR3 cells when combining high-dose vitamin C with trastuzumab in comparison with chemotherapy or endocrine therapy alone. Combining high-dose vitamin C with conventional anti-cancer drugs can have therapeutic advantages against breast cancer cells.

Low-dose eribulin reduces lung metastasis of osteosarcoma in vitro and in vivo.

Lung metastasis markedly reduces the prognosis of osteosarcoma. Moreover, there is no effective treatment for lung metastasis, and a new treatment strategy for the treatment of osteosarcoma lung metastasis is required. Therefore, in this study, we investigated the suppressive effect of the microtubule inhibitor eribulin mesylate (eribulin) on lung metastasis of osteosarcoma. At concentrations >proliferation IC50, eribulin induced cell cycle arrest and apoptosis in a metastatic osteosarcoma cell line, LM8. However, at concentrations <proliferation IC50, (low dose), eribulin changed cell morphology and decreased LM8 migration. Low eribulin concentrations also reduced directionality during migration, peripheral localization of adenomatous polyposis coli protein, and turnover of focal adhesions. In a three-dimensional collagen culture system, low eribulin concentrations inhibited tumor cell proliferation and colony formation. Higher doses of eribulin administered on a standard schedule inhibited lung metastasis and primary tumor growth in a murine osteosarcoma metastasis model. Frequent low-dose eribulin administration (0.3 mg/kg every 4 days × 4) effectively inhibited lung metastasis but had little effect on primary tumor growth. Overall, our results indicate that eribulin could reduce osteosarcoma lung metastasis.

Eribulin mesylate use as third-line therapy in patients with metastatic breast cancer (VESPRY): a prospective, multicentre, observational study.

Background:In real-world practice, eribulin mesylate provides significant survival benefit, with a manageable safety profile in heavily pretreated patients with metastatic breast cancer (MBC).Methods:In this prospective, open-label, multicentre, observational study we evaluated the effectiveness and tolerability of eribulin as third-line treatment in a homogeneous population. The primary endpoints were the safety profile and response in metastatic sites; secondary endpoints included the response in different subtypes, overall response rate (ORR), progression-free survival (PFS) and overall survival (OS).Results:From 2013 to 2016, 118 women were treated in 21 Sicilian institutions; the median age was 58 years (range 29–79), with 69% of patients under 65. The median cycles of eribulin were 5.5 (range 1–26). The most common adverse event was neutropenia (9.3%, 3 cases of grade 3, 4 of grade 4); only 1 case of QT prolongation was reported. Eribulin was effective in controlling metastatic disease in all sites, and it achieved the highest ORR in brain (16%) and liver (14.9%). Median OS was 31.8 months (95% CI 27.9–34.4) and median PFS 5.5 months (95% CI 4.2–6.6). PFS was 5.2 months (95% CI 2.8–8.4) in patients with triple-negative subtype. Median PFS was longer in patients over 65 years (6.1 months, 95% CI 4.4–8.3). In patients who had visceral metastases PFS was 5.5 months (95% CI 95% 3.5–6.6) and OS 33.9 months (95% CI 29.8–40.8).Conclusions:Eribulin as third-line treatment shows an acceptable safety profile and a substantial antitumour activity in the treatment of MBC, even in elderly patients and in those with visceral disease.

Uterine leiomyosarcoma well-controlled with eribulin mesylate

Uterine leiomyosarcoma is a rare type of malignant gynecological tumor and has a poor prognosis; therefore, this tumor is often difficult to treat. Some new drugs have been approved during the past several years in Japan and are expected to be efficacious. Eribulin, one of these drugs, is a natural product of halichondrin B, which is isolated from a marine sponge. A recent clinical trial comparing eribulin with dacarbazine to target liposarcoma and leiomyosarcoma indicated that overall survival (OS) was prolonged by treatment with eribulin. We report a case of uterine progressive leiomyosarcoma that responded to eribulin. A 57-year-old woman was suspected of having leiomyosarcoma based on an endometrial biopsy and imaging examinations. Although the tumor grew toward the uterine artery on the right side of the uterine cervix, we performed a total abdominal hysterectomy and bilateral salpingo-oophorectomy to obtain an outcome of no gross residual disease. However, the margin of the right side of the uterine cervix was histologically positive, so leiomyosarcoma stage IIB (pT2bcN0cM0, FIGO2008) was diagnosed. Gemcitabine and docetaxel therapy was administered postoperatively. However, after three cycles, the residual tumor progressed. Other anticancer drugs were administered but were ineffective. We administered eribulin (1.4mg/m2) as a fourth-line regimen, and the mass decreased by 32% after four cycles. However, the residual tumor continued to grow after eight cycles. The only adverse event associated with eribulin treatment was mild, grade 2 neutropenia. For our patient, eribulin was effective for her recurrent leiomyosarcoma. In selecting chemotherapy, there are currently no fixed guidelines; we should consider the characteristics and adverse events associated with each drug and patient performance status and comorbidities. In this patient, eribulin was associated with few adverse events, an easy route of administration and a good quality of life. Therefore, eribulin is expected to be efficacious for the treatment of gynecologic sarcoma.

Eribulin in the treatment of advanced breast cancer: real-world scenario from 39 Italian centers - ESEMPiO study.

We performed a multicenter retrospective cohort study of eribulin mesylate (EM) use in Italy, to describe the current practice for metastatic breast cancer patients (ESEMPiO) in the real-world. Baseline characteristics, treatment administration and safety were summarized using descriptive statistics. No safety concerns were raised in the population enrolled in the ESEMPiO database and treated in a real-life practice. Median progression-free survival and overall survival were 3.2 and 10.1 months, respectively. EM activity was similar between breast cancer subtypes. In metastatic breast cancer patients treated with EM in 'real-world' setting, the clinician-registered outcomes were comparable to those reported in pivotal trials. Furthermore, EM maintained clinical activity and a tolerable safety profile.

Eribulin Mesylate as Third or Subsequent Line Chemotherapy for Elderly Patients with Locally Recurrent or Metastatic Breast Cancer: A Multicentric Observational Study of GIOGer (Italian Group of Geriatric Oncology)-ERIBE.

Metastatic breast cancer (MBC) is highly prevalent in middle-aged or elderly patients. Eribulin is a nontaxane microtubule inhibitor, approved for the treatment of pretreated MBC. This multicentric study (sponsored by GIOGer, Italian Group for Geriatric Oncology) was designed to assess the efficacy and tolerability of eribulin, according to parameters usually used in geriatric oncology. An observational study was conducted on 50 consecutive elderly patients with MBC. The primary endpoint was to evaluate the change in items score of comprehensive geriatric assessment (CGA) and health-related quality of life (HRQL). Italian versions of the CGA and HRQL questionnaires were administered at baseline, before the third and fifth cycles, and then every three cycles until treatment discontinuation. Secondary endpoints were efficacy and safety. Overall, both EQ-5D scores and EQ-5D-3 L visual analogic scale did not significantly change from baseline; the percentage of subjects without problems doing usual activities tended to decrease during treatment (p for linear trend .018), and the percentage of patients with minor problems performing usual activities tended to increase (p for linear trend.012). Among CGA items, Instrumental Activities of Daily Living tended to decrease during treatment and Geriatric Depression Scale tended to increase. After 12 months follow-up, 24 patients (out of 47) showed clinical benefits; median progression-free survival was 4.49 months (2.10-10.33) and median OS was 7.31 months (3.70-14.03). The treatment was associated with mild toxicity. Eribulin treatment preserved quality of life and geriatric parameters included in the CGA, except for instrumental functioning and geriatric depression, in elderly patients with MBC. A collaboration between oncologist and geriatric specialists is essential in the management of patients with metastatic breast cancer, who are frequently elderly or frail. The assessment of geriatric parameters in the decision-making process can contribute to direct toward the most appropriate therapeutic plan and preserve the quality of life of patients. Eribulin does not seem to affect quality of life or worsen the overall geriatric status; therefore, it can be considered a suitable option for elderly patients with metastatic breast cancer.

Predictive impact of absolute lymphocyte counts for progression-free survival in human epidermal growth factor receptor 2-positive advanced breast cancer treated with pertuzumab and trastuzumab plus eribulin or nab-paclitaxel

sBackgroundAlthough peripheral blood-based parameters (PBBPs) are reported as prognostic indicators in patients with breast cancers, their utility has not been studied in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC). Tumor-infiltrating lymphocytes (TILs) might be a predictive factor in patients with HER2-positive ABC treated with pertuzumab and trastuzumab (PT) plus docetaxel. We aimed to evaluate whether PBBPs could have predictive value in HER2-positive ABC treated with pertuzumab and trastuzumab (PT) combined with eribulin (ERI) or nab-paclitaxel (Nab-PTX).MethodsData from 51 patients included in two single-arm, phase II trials were included in this retrospective-prospective study; the ERI + PT (N = 30) and Nab-PTX + PT (N = 21) combinations were registered under clinical trials number UMIN000012375 and UMIN000006838, respectively. We assessed PBBPs using prospectively collected data and investigated the association with progression-free survival (PFS); we evaluated absolute lymphocyte count (ALC), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR). The cutoff values for ALC, NLR, and PLR were set at 1000 or 1500 cells/μL, 2, and 250, respectively.ResultsPFS was significantly improved in patients with ALC ≥1500/μL compared to those with ALC 1000–, <1500/μL or ALC < 1000/μL (P = 0.0106). High baseline ALC was significantly associated with improved PFS (≥1500/μL; hazard ratio [HR]: 0.3715; 95% confidence interval [CI]: 0.1735–0.7955; P = 0.0108). In contrast, improved PFS was not significantly associated with NLR or PLR. Improved PFS in patients with ALC ≥1500/μL was observed irrespective of visceral metastasis or chemotherapy regimen.ConclusionsOur results showed that baseline ALC was a predictive factor for PFS in HER2-positive ABC treated with PT irrespective of combined chemotherapy regimen. Anti-tumor effects might be mediated not only by the tumor microenvironment, but also by systemic peripheral circulating lymphocytes. Baseline systemic parameters such as peripheral lymphocyte count might be beneficial in addition to disease extent for predicting the efficacy of PT treatment.Trial registrationUMIN000012375, registration date: 21NOV2013, and UMIN000006838, registration date: 6DEC2011.

311P - Early results from an open-label phase 1b/II study of eribulin mesylate (EM) + pegvorhyaluronidase alfa (PEGHP20) combination for the treatment of patients with HER2-negative, high-hyaluronan (HA) metastatic breast cancer (MBC)

311P - Early results from an open-label phase 1b/II study of eribulin mesylate (EM) + pegvorhyaluronidase alfa (PEGHP20) combination for the treatment of patients with HER2-negative, high-hyaluronan (HA) metastatic breast cancer (MBC)

P-gp Inhibition by the Anti-psychotic Drug Pimozide Increases Apoptosis, as well as Expression of pRb and pH2AX in Highly Drug-resistant KBV20C Cells.

The present study was designed to identify drugs that could sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells to treatment with Halaven (HAL) or vincristine (VIC). Using relatively low doses or IC50 concentrations of drugs to sensitize anti-mitotic drug-resistant KBV20C cells, pimozide (PIM) sensitized HAL-resistant KBV20C cancer cells, with higher P-gp inhibitory activity than another anti-psychotic drug, fluphenazine (FLU). The first-generation P-gp inhibitor verapamil required a dose that was similar to that of PIM for P-gp inhibition, suggesting that PIM has a similar specificity for binding P-gp to prevent efflux of anti-mitotic drugs. Furthermore, co-treatment with PIM and another anti-mitotic drug, VIC, also increased sensitization of KBV20C cells, suggesting that PIM can be combined with other anti-mitotic drugs to sensitize resistant cancer cells. PIM caused a reduction in cell viability and an increase in the number of cells arresting at the G2 phase of the cell cycle. PIM induced both early and late apoptosis in KBV20C cells in response to HAL treatment. Furthermore, the DNA damage marker pH2AX, the cell-cycle protein pRb, and the pro-apoptotic protein C-PARP levels increased after HAL-PIM co-treatment, indicative of a mechanism involving G2 phase arrest and an increase in the number of cells undergoing apoptosis. PIM may be a promising therapeutic agent for the treatment of cancers that are resistant to anti-mitotic drugs.

Aging-related Repositioned Drugs, Donepezil and Sildenafil Citrate, Increase Apoptosis of Anti-mitotic Drug-resistant KBV20C Cells Through Different Molecular Mechanisms.

The study focused on identifying the mechanisms or drugs that could sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells to halaven (HAL) or vincristine (VIC) treatment. Based on the relatively low dose or IC50 values for sensitizing anti-mitotic drug-resistant KBV20C cells, the aging-related drugs donepezil (DON) and sildenafil citrate (SID) were selected. Fluorescence-activated cell sorting (FACS), western blotting, and annexin V analyses were performed to investigate the mechanism of action of DON and SID in HAL-treated KBV20C cells. DON or SID reduced cell viability, increased G2 arrest, and up-regulated the expression of the DNA damaging protein pH2AX when used as co-treatment with HAL. DON and SID induced both early and late apoptosis in KBV20C cells in response to HAL treatment, without increasing autophagy. VIC-DON and VIC-SID co-treatments increased sensitization of KBV20C cells, suggesting that DON and SID can be combined with other anti-mitotic drugs for sensitizing resistant cancer cells. When the sensitization efficacies of DON and SID were compared to that of the anti-psychotic repositioned drug fluphenazine (FLU), HAL-SID or HAL-FLU co-treatments were found to have better sensitization effects than HAL-DON suggesting that HAL-SID sensitization mechanism is different from that of HAL-DON. In addition, DON was found to have higher P-gp inhibitory activity than FLU or SID. These results suggest that HAL-FLU or HAL-SID sensitization in KBV20C cells involves both cytotoxic and P-gp inhibitory effects, whereas HAL-DON sensitization may involve only P-gp inhibitory activity of DON.

Low-dose eribulin mesylate exerts antitumor effects in gastric cancer by inhibiting fibrosis via the suppression of epithelial&amp;ndash;mesenchymal transition and acts synergistically with 5-fluorouracil

BackgroundCharacterized by aggressive proliferation, extensive stromal fibrosis, and resulting drug resistance, peritoneal dissemination in gastric cancer remains associated with poor prognosis. Interaction between cancer and stromal cells accelerates tumor progression via epithelial–mesenchymal transition (EMT), which is one of the major causes of tissue fibrosis, and human peritoneal mesothelial cells (HPMCs) play important roles as cancer stroma in peritoneal dissemination. Transforming growth factor-β (TGF-β) has a pivotal function in the progression of EMT, and Smad proteins play an important role in the TGF-β signaling pathway. Eribulin mesylate (eribulin), a nontaxane microtubule dynamics inhibitor used for the treatment of advanced breast cancer, inhibits EMT changes in triple-negative breast cancer cells. We examined its ability to inhibit tumor progression and EMT changes resulting from the interaction between gastric cancer cells and HPMCs and to act synergistically with 5-fluorouracil (5-FU), a key drug for gastric cancer.Materials and methodsProliferation of gastric cancer cells and HPMCs isolated from healthy omentum was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Following gastric cancer cell/HPMC coculture, EMT markers were detected by immunofluorescence, immunohistochemistry, and Western blotting; invasion assays were performed; and TGF-β and Smad phosphorylation were assessed by Western blotting and enzyme-linked immunosorbent assay. A mouse fibrotic tumor xenograft model was established using gastric cancer cell/HPMC cocultures. The effect of eribulin and/or 5-FU was tested in each case.ResultsEribulin significantly suppressed gastric cancer cell proliferation and EMT changes in MKN-45 gastric cancer cells and HPMCs induced by their interaction in vitro. Eribulin inhibited EMT at much lower concentrations (≥0.5 nM for MKN-45 and ≥0.1 nM for HPMCs) than its half maximal inhibitory concentrations (2.2 nM for MKN-45 and 8.1 nM for HPMCs), and this resulted, at least partly, from the downregulation of TGF-β/Smad signaling. Eribulin administration of ≥0.1 mg/kg suppressed tumor progression (0.1 mg/kg, p=0.02), and fibrosis was inhibited by lower dose (0.05 mg/kg, p=0.008) in the xenograft model. Furthermore, 0.05 mg/kg administration with 5-FU brought about synergistic antitumor effects (p=0.006).ConclusionLow-dose eribulin combined with 5-FU might be a promising therapy for peritoneal dissemination in gastric cancer.

Clinical benefit of treatment with eribulin mesylate for metastatic triple-negative breast cancer: Long-term outcomes of patients treated in the US community oncology setting.

IntroductionReal‐world data are critical to demonstrate the consistency of evidence and external generalizability of randomized controlled trials (RCTs). This study examined characteristics and outcomes of metastatic triple‐negative breast cancer (mTNBC) patients treated with eribulin mesylate at community oncology practices in the United States.MethodsPhysicians identified mTNBC patients initiating eribulin between 1 January 2011 and 1 January 2014 and abstracted data into an electronic case report form (eCRF). Eribulin treatment in the metastatic setting was categorized as early use (EU, first‐/second‐line) and late use (LU, third‐line or later). Patient characteristics, overall survival (OS), disease response (per treating physician), and adverse events (AEs) rates in each group, respectively, are reported.ResultsOverall 252 eCRFs were completed: 125 (49.6%) EU and 127 (50.4%) LU. The median age at metastatic diagnosis was 53 years and 42.1% were stage IV at their initial diagnosis. The median duration of follow‐up from the initiation of first‐line treatment was 24 months. Rates of disease response (complete or partial per treating physician) were 69.9% in the EU group and 48.8% in the LU group. The five most commonly reported adverse events during eribulin were as follows: fatigue (65.1%), weakness (40.1%), decreased appetite (32.5%), neutropenia (31.0%), and leukopenia (27.4%). Discontinuation of eribulin due to AE was observed in 4.0% of patients. Median OS from initiation of eribulin was 23.0 months (95% CI: 18.7‐27.3) among EU and 14.7 (95% CI: 12.6‐16.9) among LU.ConclusionIn the real‐world eribulin‐treated mTNBC, patients have more sites of metastatic disease and exposure to greater numbers of prior therapies compared to RCTs. The median OS of 14.7 months among LU patients is consistent with, and slightly longer than the 13.1 months and 14.4 months reported in the EMBRACE and Study 301 clinical trials, respectively.

Abstract 1770: Morab-202, a folate receptor alpha-targeted antibody-drug conjugate, shows a highly potent activity against a panel of FRA-expressing tumors

Abstract Folate receptor alpha (FRA) is a membrane protein with high affinity for binding and transporting folate into cells. Overexpression of FRA may confer a growth advantage to tumors by increasing folate uptake and affecting cell proliferation via alternative cell signaling pathways (1). FRA levels have been found to be elevated in tumors of epithelial origin compared to normal tissue as cancers of the breast (including TNBC (2)), colon, lungs and ovary (3). In this study, we report the development of MORAb-202, an anti-FRA antibody-drug conjugate (ADC), consisting of a FRA-binding antibody (MORAb-003, farletuzumab) with a cathepsin-cleavable form of eribulin (eribulin mesylate, marketed as Halaven®), a highly potent anti-mitotic agent that induces cell-cycle arrest and cell death by targeting microtubules. We first study expression of FRA on a large panel of tumors patient-derived xenograft (PDX) and Cancer Cell Line-derived Xenograft (CDX). Then, we performed in vitro and in vivo anti-proliferation assays and compare antitumor activity of MORAb-202 with free eribulin accordingly to the FRA expression level. FRA expression was found to be determinant in the sensitivity of tumor cells to the cytotoxic effect of the ADC. Moreover, in case of high expression of FRA, MORAb-202 showed a higher antitumor activity compared with free eribulin. These results suggest that FRA expression could be used as a response-predictive biomarker for this targeted therapy. The ability to identify and treat patients with an effective therapy based on the known expression of the tumor marker is a key point in predictive medicine progress. These findings support the clinical development of MORAb-202 ADC as a novel targeted therapy for patients with FRA-expressing tumors. The ADC described in this abstract is investigational, as efficacy and safety have not been established. There is no guarantee that this ADC will be available commercially. 1-Siu MK et al., PLoS One. 2012;7(11) 2-Nacela BM. et al., PLoS One. 2015, 10(3) 3-Cheung A. et al., Oncotarget. 2016 7(32), 52553-52574 4-Arrowsmith J. &amp; Miller P. 2011-2012. Nat. Rev. Drug Discov. 12, 569 (2013). 5-Paul S.M. et al. Nat. Rev. Drug Discov. 9, 203-214 (2010). 6-Hidalgo, M. et al. Cancer Discov. 4, 998-1013 (2014). Citation Format: Caroline Mignard, Coralie DURIX, Katherine Rybinski, Xin Cheng, Keiji Furuuchi, Earl Albone, Toshimitsu Uenaka, Marc Hillairet de Boisferon. Morab-202, a folate receptor alpha-targeted antibody-drug conjugate, shows a highly potent activity against a panel of FRA-expressing tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1770.

Phase II trial of eribulin mesylate as a first- or second-line treatment for locally advanced or metastatic breast cancer: a multicenter, single-arm trial

BackgroundEribulin mesylate is currently indicated as a sequential monotherapy to be administered after two chemotherapeutic regimens, including anthracycline and taxane treatments, for treatment of metastatic breast cancer. This open-label, multicenter phase II study was designed to evaluate the efficacy and safety of eribulin as a first- or second-line treatment for patients with metastatic breast cancer.MethodsThe primary objective was to determine the overall response rate. Secondary objectives were to evaluate progression-free survival and the safety profile. Patients were scheduled to receive eribulin mesylate 1.4 mg/m2 intravenously on days 1 and 8 of a 21-day cycle. Patients received the study treatment unless disease progression, unacceptable toxicity, or a request to discontinue from the patient and/or investigator eventuated.ResultsBetween December 2012 and September 2015, 32 patients with metastatic breast cancer were enrolled at 10 participating clinical institutions in Japan, and toxicity and response rates were evaluated. The overall response rate was 43.8% (95% confidence interval [CI] 26.5–61.0). The clinical benefit and tumor control rates were 56.3% (95% CI 39.0–73.5) and 78.1% (95% CI 63.8–92.5), respectively. Median progression-free survival was 8.3 months (95% CI 7.1–9.4). A subgroup analysis did not identify any factors affecting the efficacy of eribulin. The most common adverse events were neutropenia (71.9%), alopecia (68.7%), and peripheral neuropathy (46.9%). As a first- or second-line therapy, eribulin showed sufficient efficacy for metastatic breast cancer compared with taxane and capecitabine treatment in previous clinical trials. The safety profile of eribulin was acceptable.ConclusionsEribulin may be another option for first-line chemotherapeutic regimens for metastatic breast cancer.Trial registrationsThis trial was retrospectively registered at the University Hospital Medical Information Network (UMIN) Clinical Trial Registry (ID number: UMIN000010334).Date of trial registration: April 1st, 2013.