Efficacy Of Eribulin Research Articles

The clinical outcome of eribulin treatment in Japanese patients with advanced soft tissue sarcoma: a Tokai Musculoskeletal Oncology Consortium study.

The efficacy and safety of eribulin in Japanese patients with advanced soft-tissue sarcomas (STS) have not been evaluated in a large-scale cohort study. Thus, we aimed to investigate the clinical outcome of 82 Japanese patients with STS receiving eribulin across multiple study centers retrospectively. Of 82 STS patients receiving eribulin treatment, 13 were treated for locally unresectable tumor, 46 for metastasis, and 23 for both. The primary endpoint of this study was to evaluate the efficacy of eribulin against STS. The median age was 60years. Thirty-seven were diagnosed with L-sarcoma (leiomyosarcoma or liposarcoma) and 45 had non-L-sarcoma. The median progression-free survival (PFS) for all patients was 2.7months, with 3.4months in those with L-sarcoma and 2.2months in those with non-L-sarcoma. Patients with L-sarcoma showed a better PFS than those with non-L-sarcoma. Overall, the median survival time was 11.1months, and 12.3months and 7.9months in patients with L-sarcoma and non-L-sarcoma, respectively; however, there was no significant differences between the groups. The prognostic significance of PS = 0 and both existence of local and metastatic STS was evaluated by multivariate analysis. We also evaluated the overall survival (OS) in patients with undifferentiated pleomorphic sarcoma (UPS) and other non-L-sarcomas. Patients with UPS had better OS than those with the other non-L-sarcomas. In conclusion, there was a significant difference in PFS between patients with L-sarcoma and non-L-sarcoma following treatment with eribulin. The anti-tumor potential of eribulin was evident in patients with UPS.

Eribulin penetrates brain tumor tissue and prolongs survival of mice harboring intracerebral glioblastoma xenografts.

Glioblastoma is one of the most devastating human malignancies for which a novel efficient treatment is urgently required. This pre–clinical study shows that eribulin, a specific inhibitor of telomerase reverse transcriptase (TERT)‐RNA‐dependent RNA polymerase, is an effective anticancer agent against glioblastoma. Eribulin inhibited the growth of 4 TERT promoter mutation‐harboring glioblastoma cell lines in vitro at subnanomolar concentrations. In addition, it suppressed the growth of glioblastoma cells transplanted subcutaneously or intracerebrally into mice, and significantly prolonged the survival of mice harboring brain tumors at a clinically equivalent dose. A pharmacokinetics study showed that eribulin quickly penetrated brain tumors and remained at a high concentration even when it was washed away from plasma, kidney or liver 24 hours after intravenous injection. Moreover, a matrix‐assisted laser desorption/ionization mass spectrometry imaging analysis revealed that intraperitoneally injected eribulin penetrated the brain tumor and was distributed evenly within the tumor mass at 1 hour after the injection whereas only very low levels of eribulin were detected in surrounding normal brain. Eribulin is an FDA‐approved drug for refractory breast cancer and can be safely repositioned for treatment of glioblastoma patients. Thus, our results suggest that eribulin may serve as a novel therapeutic option for glioblastoma. Based on these data, an investigator‐initiated registration‐directed clinical trial to evaluate the safety and efficacy of eribulin in patients with recurrent GBM (UMIN000030359) has been initiated.

Discovery of Inhibitors of Membrane Traffic from a Panel of Clinically Effective Anticancer Drugs

In addition to their major targets, clinically effective drugs may have unknown off-targets. By identifying such off-targets it may be possible to repurpose approved drugs for new indications. We are interested in the Golgi apparatus as a novel target for cancer therapy, but there is a paucity of candidate Golgi-disrupting drugs. Here, we aimed to identify Golgi-disrupting compounds from a panel of 34 approved anticancer drugs by using HBC-4 human breast cancer cells and immunofluorescence microscopy to visualize the Golgi apparatus. The screen identified five drugs having Golgi-disrupting activity. Four of them were vinca alkaloids (vinorelbine, vindesine, vincristine and vinblastine), and the fifth drug was eribulin. This is the first study to demonstrate that vinorelbine, vindesine and eribulin possess Golgi-disrupting activity. The 5 drugs are known to inhibit tubulin polymerization and to induce microtubule depolymerization. Interestingly, a microtubule-stabilizer paclitaxel did not induce Golgi-disruption, suggesting that the three-dimensionally preserved microtubules are partly responsible for maintaining the Golgi complex. Concerning eribulin, a noteworthy drug because of its high clinical efficacy against advanced breast cancer, we further confirmed its Golgi-disrupting activity in 3 different human breast cancer cell lines, BSY-1, MDA-MB-231 and MCF-7. Golgi-disruption may contribute to anticancer efficacy of eribulin. In conclusion, the present study revealed that 4 vinca alkaloids and eribulin possessed potential Golgi-disrupting activity among a panel of 34 approved anticancer drugs. Other drugs covering various molecular-targeted drugs and classical DNA-damaging drugs showed no Golgi-disrupting effect. These results suggest that tubulin polymerization-inhibitors might be promising candidate drugs with Golgi-disrupting activity.

Selectively high efficacy of eribulin against high-grade invasive recurrent and/or metastatic squamous cell carcinoma of the head and neck.

Patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) have a poor prognosis. Over the past decade, a major development in the first-line treatment of R/M SCCHN was the introduction of cetuximab in combination with platinum plus 5-fluorouracil chemotherapy. Currently, a promising novel treatment option in R/M SCCHN has emerged, termed immune checkpoint inhibitors. However, only a few patients presenting with R/M SCCHN have exhibited meaningful tumor regression with these agents. Therefore, novel agents are required to order improve the overall survival of patients with R/M SCCHN. Recently, we demonstrated that R/M SCCHN cells are highly sensitive to eribulin. In the present study, the effects of eribulin, paclitaxel and vinblastine were investigated in R/M SCCHN (OLC-01 and OSC-19) and locally advanced SCCHN (OSC-20) cells. Tumour-inhibitory activities of eribulin against R/M SCCHN were evaluated in orthotopic xenograft models. The data revealed that eribulin has sub-nM growth inhibitory activities in vitro against OLC-01 cells, and that it is more potent than paclitaxel and vinblastine. The reduced expression of Tubulin Beta 3 Class III (TUBB3) following treatment was correlated with a high sensitivity to eribulin. Histological analysis of OLC-01 cells in NOD-SCID mice demonstrated that they had a higher invasiveness in the tissue around the alveolar cancer when compared with the histology of OSC-19 cells, which has been reported in our previous study. Treatment with eribulin revealed marked inhibitory activities in vivo at 0.125 mg/kg against OLC-01 cells orthotopic xenografts. In conclusion, the results highlight the existence of invasive-type heterogeneity in R/M SCCHN with respect to eribulin sensitivity. Eribulin is already an approved clinical agent; therefore, the continued investigation of its preclinical antitumor attributes may contribute significantly to the future process of identifying novel uses of eribulin against R/M SCCHN.

P139 - Efficacy of eribulin in patients with metastatic breast cancer with brain metastases in routine practice in Russian Federation

P139 - Efficacy of eribulin in patients with metastatic breast cancer with brain metastases in routine practice in Russian Federation

1650P - The efficacy of eribulin for patients with taxane-resistant cutaneous angiosarcoma: Interim result of multi-center, prospective observational study

1650P - The efficacy of eribulin for patients with taxane-resistant cutaneous angiosarcoma: Interim result of multi-center, prospective observational study

317P - Clinical efficacy of eribulin as first- or second-line treatment for patients with recurrent HER2-negative breast cancer: A phase II randomized study (JBCRG-19)

317P - Clinical efficacy of eribulin as first- or second-line treatment for patients with recurrent HER2-negative breast cancer: A phase II randomized study (JBCRG-19)

A Randomized Phase II Study of Eribulin/Cyclophosphamide or Docetaxel/Cyclophosphamide as Neoadjuvant Therapy in Operable HER2-negative Breast Cancer

BackgroundEribulin mesylate is a non–taxane microtubule inhibitor effective in the treatment of metastatic breast cancer refractory to anthracyclines and taxanes. In preclinical studies, additional mechanisms of eribulin included reversal of epithelial mesenchymal transition and tumor vascular remodeling. The present study compared the safety and efficacy of eribulin plus cyclophosphamide (ErC) to docetaxel plus cyclophosphamide (TC) as neoadjuvant therapy for operable HER2− breast cancer. Patients and MethodsWomen with invasive HER2− breast adenocarcinoma with no distant metastases were eligible. After a 10-patient safety lead-in, the patients were randomized 2:1 to receive either ErC (eribulin 1.4 mg/m2 on days 1 and 8 plus cyclophosphamide 600 mg/m2 on day 1) or TC (docetaxel 75 mg/m2 plus cyclophosphamide 600 mg/m2 on day 1) administered every 21 days for 6 cycles, followed by surgery. The pathologic complete response (pCR) rate was the primary endpoint. Tumor samples collected at baseline and at surgery were assayed for select epithelial mesenchymal transition and vascular density markers: E-cadherin, vimentin, and CD31 expression. ResultsA total of 76 patients were enrolled. Of the 76 patients, 10 received ErC in the lead-in phase and 66 were randomized to ErC (n = 44) or TC (n = 22). The pCR rates with ErC and TC were 13% and 9%, respectively. Both regimens produced frequent neutropenia and peripheral neuropathy. Both regimens increased vascular density as measured by CD31 staining. ConclusionThe neoadjuvant regimens of ErC and TC resulted in relatively low pCR rates in this patient population. No unexpected toxicities were observed. Our results also provided no suggestion that ErC is a neoadjuvant treatment with greater efficacy than that of standard regimens.

Higher efficacy and complete response with administration of eribulin for recurrent squamous cell breast carcinoma: A case report.

Squamous cell carcinoma is a rare histological type of breast cancer classified as metaplastic carcinoma. Metaplastic carcinoma involves differentiation of the breast glandular duct cells into mesenchymal tissues. While the chemotherapy regimen for metaplastic carcinoma is often similar to that for invasive ductal carcinoma, recurrence is associated with a poor prognosis due to the inadequate therapeutic efficacy of the regimen. We herein present the case of a 42-year-old female patient who underwent mastectomy of the right breast and right axillary node lymphadenectomy for T4N3aM0 breast cancer stage. The cancer was histopathologically diagnosed as squamous cell carcinoma of the breast. Adjuvant cyclophosphamide-epirubicin-fluorouracil (CEF) postoperative chemotherapy was administered, and lymphadenectomy of right-sided parasternal lymphatic metastases with pleural drainage was subsequently performed. Radiotherapy was administered to the thoracic wall and supraclavicular lymph nodes at 60 Gy. Positron emission tomography (PET)-computed tomography (CT) examination 3 months after the radiotherapy identified accumulation of fluorodeoxyglucose (FDG) in a supraclavicular lymph node and the thoracic wall; hence, a chemotherapeutic regimen with eribulin was initiated. At 11 months after initiation of eribulin, complete response was achieved, indicated by the absence of FDG accumulation in both the supraclavicular lymph node and the thoracic wall on PET-CT. The treatment efficacy of eribulin is considered to be a result of the mixed morphology of squamous cell carcinoma, including the presence of an epithelial component, such as adenocarcinoma cells, and a mesenchymal component, in the form of sarcomatoid cells. Eribulin displayed an effect similar to that of adriamycin against malignant soft tissue tumors and was shown to effectively target mesenchymal components. In cases of reduced expression of the DNA repair pathway components, such as in metaplastic carcinomas, eribulin may be more effective compared with adriamycin, the mechanism of action of which involves inhibition of DNA synthesis. A superior therapeutic effect was obtained with eribulin in squamous cell carcinoma. Therefore, eribulin appears to be a promising, effective therapeutic choice for the management of metaplastic carcinomas, including squamous cell carcinomas.

Abstract 5847: A histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth with apoptosis in triple-negative breast cancer cells

Abstract Purpose: Triple negative breast cancer (TNBC) is the most aggressive subtype in breast cancer. Eribulin is one of the well-tolerated chemotherapeutic drugs for the treatment of metastatic breast cancer. We usually administer eribulin or eribulin with anti-HER2 antibodies. Eribulin was approved for metastatic breast cancer refractory to anthracyclins and taxanes through EMBRACE trial, and the subgroup analysis indicated the efficacy of eribulin was effective in patients with TNBC. However, the prognosis of patients with TNBC is still poor because of the various molecular characteristics. Therefore, there is an urgent need for more effective treatment for the management of TNBC. Methods: We investigated the effect of eribulin in several TNBC cell lines. Eribulin inhibited the cell growth of TNBC cells in a dose-dependent manner. However, eribulin increased the expression of survivin, known to inhibit apoptosis. To counteract the up-regulation of survivin by eribulin, we used OBP-801, a novel histone deacetylase (HDAC) inhibitor, because HDAC inhibitors were reported to suppress the expression of survivin. Results: Co-administration of OBP-801 with eribulin showed a synergistic inhibition of cell growth in TNBC cells. The mechanism of this combination is due to the enhancement of apoptosis. The apoptosis was partially dependent on caspase, and it was via the suppression of not only survivin as expected, but also Bcl-xL. OBP-801 could suppress the survivin expression induced by eribulin at both protein and mRNA level. Interestingly, the combination more potently suppressed a MAPK pathway than each agent. Conclusion: We found that the combination of eribulin and OBP-801 synergistically inhibits the growth with apoptosis in TNBC cells, raising the possibility that the combination might be a novel promising strategy against TNBC patients. Citation Format: Hisako Ono, Yoshihiro Sowa, Yosuke Iizumi, Mano Horinaka, Tetsuya Taguchi, Toshiyuki Sakai. A histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth with apoptosis in triple-negative breast cancer cells [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 5847.

Outcome of eribulin as a late treatment line for Thai metastatic breast cancer patients.

BackgroundWe report the safety and efficacy of eribulin as a late treatment line in Thai metastatic breast cancer (MBC) patients.Patients and methodsA total of 30 MBC patients treated with eribulin between January 2014 and January 2017 were retrospectively analyzed. The patients were scheduled to receive 1.4 mg/m2 of eribulin on day 1, day 8 and subsequently every 21 days. All patients had previously received at least three chemotherapy regimens including anthracycline and taxane. Response rate and progression-free survival (PFS) were analyzed.ResultsThe median age was 56 years (range, 40–74 years), with a median follow-up time of 5.7 months (range, 0.2–25 months). The overall response rate was 30% (nine patients): four patients had triple-negative breast cancer, three patients had luminal B breast cancer and two patients had luminal A breast cancer. The median PFS was 2.9 months (range, 0.2–14 months). The median number of previous chemotherapy regimens was 4 (range, 3–9). Univariate analysis showed that the number of regimens (four or fewer) prior to eribulin was statistically associated with superior PFS (P = 0.009). Multivariate analysis also showed similar statistical association between number of prior regimens (four or fewer) and better PFS adjusted by age group (≥50 years; hazard ratio = 1.29; 95% CI: 1.0–1.65; P = 0.046). There were no toxic deaths or grade 4 toxicities. Nine (30%) patients had grade 3 anemia toxicities, and the other common toxicities were leukopenia and neutropenia. Four (13%) patients required dose reduction and 16 (53%) patients required dose delay because of toxicities.ConclusionEribulin is an effective drug for heavily pretreated MBC patients with tolerable toxicities. The benefit was superior in patients who received fewer than four previous chemotherapy regimens.

Abstract 4402: MiR-195 potentiates the efficacy of microtubule-targeting agents in non-small cell lung cancer

Abstract Introduction: microRNAs (miRNAs) are a family of small noncoding RNAs (18-24 nt) that post-transcriptionally repress gene expression by direct binding to the 3' untranslated regions (UTRs) of their targets. By targeting cancer-related genes, miRNAs have been shown not only to regulate cancer growth/progression, but also to modulate the response of cancer cells to chemotherapy. Such miRNAs are potential candidates for therapeutic intervention. Aiming to identify functional miRNAs in non-small cell lung cancer (NSCLC), we performed a high-throughput screen and found that miR-195 inhibits the growth of NSCLC cells and sensitizes them to microtubule-targeting agents (MTAs), a family of chemotherapeutic drugs widely used for NSCLC treatment. The function and mechanism of miR-195 in NSCLC were demonstrated both in vitro and in vivo. Results: We demonstrated that miR-195 synergizes with both a traditional MTA (paclitaxel) and a recently discovered one (eribulin) to repress the growth of NSCLC cells. Overexpression of miR-195 sensitizes NSCLC cells to paclitaxel and eribulin, while knockout of miR-195 confers resistance to paclitaxel and eribulin. Importantly, lung tumors with miR-195 overexpression are more sensitive to eribulin treatment than control tumors. Induced expression of miR-195 in lung tumors potentiates the efficacy of eribulin to repress tumor growth. Additionally, we showed that miR-195 directly targets CHEK1 to regulate the response of NSCLC cells to paclitaxel and eribulin. The direct and specific binding of miR-195 to the 3'UTR of CHEK1 was confirmed by luciferase reporter assay. Repression of CHEK1 using siRNAs and chemical inhibitor synergizes with paclitaxel and eribulin to repress the growth of NSCLC cells. Overexpression of CHEK1 contributes to the resistance to paclitaxel and eribulin in NSCLC cells. Analysis of TCGA data shows that CHEK1 is significantly upregulated in lung tumors compared to adjacent normal tissues and that its upregulation is associated with worse recurrence-free and overall survival. Conclusions: We report the identification of miR-195 as a sensitizer to microtubule-targeting agents in NSCLC, mediated by its repression of CHEK1. Mouse xenografts with induced or constitutive overexpression of miR-195 show that tumors with high miR-195 expression are more sensitive to drug treatment and that induction of miR-195 potentiates the efficacy of eribulin in repressing tumor growth. These results highlight the possible application of miR-195 expression as a biomarker to predict patient response to MTAs and the potential for delivery of miR-195 mimic as an adjuvant to chemotherapy. Citation Format: Xiaojie Yu, Yiqiang Zhang, Xiuye Ma, Alexander Pertsemlidis. MiR-195 potentiates the efficacy of microtubule-targeting agents in non-small cell lung cancer [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 4402.

Abstract 5872: Pediatric Preclinical Testing Consortium (PPTC) of eribulin in osteosarcoma (OS) patient-derived xenograft (PDX) models

Abstract Introduction: Eribulin is a synthetic analogue of halichondrin B and inhibits cancer cell proliferation via blockade of microtubule function. It is FDA approved for patients with breast cancer with two prior chemotherapy regimens for the treatment of metastatic disease and for previously treated patients with inoperable or metastatic liposarcoma. In vivo testing of eribulin against osteosarcoma (OS) Pediatric Preclinical Testing Program (PPTP) PDX models, developed from primary tumors, demonstrated significant single-agent activity. However, a Children's Oncology Group (COG) phase 2 trial of eribulin in patients with relapsed OS did not demonstrate significant antitumor activity of single-agent eribulin. In the current study the efficacy of eribulin in PDX models generated from primary and relapsed tumors, as well as dose-response, were assessed. Methods: Eribulin was evaluated in 6 PPTC models, 4 from primary OS specimens (OS46, OS51, OS55, OS56) and 2 from relapsed specimens (OS39R, OS60). Eribulin was administered via intraperitoneal (IP) injection at a dose of 1mg/kg on days 1 and 4, repeated every 21 days. Response to treatment was determined based on PPTP-established endpoints (1). In addition, 3 dose levels of eribulin were evaluated in 3 PPTP models developed from primary tumors (OS1, OS17, OS33) and 1 model developed from a relapsed tumor (OS60). In the dose-response studies, eribulin was administered IP at 1mg/kg, 0.5mg/kg and 0.25mg/kg on days 1 and 4, repeated every 21 days with follow-up through day 42. Results: Eribulin at a dose level of 1mg/kg induced stable disease (SD) or partial response (PR) in 4/9 and 3/9 OS xenografts, respectively. SD/PR responses were observed in PDX models generated from primary tumors (5/7) as well as PDX models generated from relapsed tumors (2/2). Eribulin demonstrated maximal antitumor activity at the highest dose level, 1mg/kg (SD/PR in 3/4). At 0.5 mg/kg 1/4 models achieved SD/PR, and at 0.25mg/kg all 4 models showed progressive disease within the 6-week testing period. Minimum relative tumor volumes also showed a dose-response effect from 0.25 to 1.0 mg/kg. Conclusions: Eribulin demonstrated antitumor activity against OS PDX models generated from primary and relapsed tumors at a dose level of 1mg/kg. Eribulin showed a clear dose-response effect in terms of its ability to induce SD/PR responses, highlighting the importance of dose selection. This dose-response effect suggests that an inability to achieve comparable serum drug concentrations in human clinical trials may explain the limited tumor responses observed in the COG phase 2 trial of eribulin. Pharmacokinetic studies from the COG phase 2 study are ongoing in an effort to understand the disparate tumor responses seen in the in vivo studies and the phase 2 clinical trial. Reference: 1. Houghton PJ et al. Pediatr Blood Cancer 2007;49:928-40. Supported by NCI Grants: CA199222, CA199221. Citation Format: Wendong Zhang, E. Anders Kolb, Richard Gorlick, Michael Roth, Jonathan Gill, Sudie Rowshan, Stephen Erickson, Raushan Kurmasheva, Peter Houghton, Beverly Teicher, Malcolm A. Smith. Pediatric Preclinical Testing Consortium (PPTC) of eribulin in osteosarcoma (OS) patient-derived xenograft (PDX) models [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 5872.

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.

The histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth of triple-negative breast cancer cells with the suppression of survivin, Bcl-xL, and the MAPK pathway

PurposeTriple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Eribulin was approved for the treatment of metastatic breast cancer through the EMBRACE trial, and a subgroup analysis in this clinical trial indicated the efficacy of eribulin in patients with TNBC. However, the prognosis of patients with TNBC is still poor due to various molecular characteristics. Therefore, there is an urgent need for a more effective treatment for the management of TNBC.MethodsWe investigated the synergistic effect of a novel histone deacetylase (HDAC) inhibitor, OBP-801, and eribulin in TNBC cell lines because OBP-801 has been known to enhance the anti-tumor activities of other chemotherapeutic agents. The cell growth was analyzed, and the flow cytometry analysis was conducted to evaluate the effects on cell cycle and the induction of apoptosis. The mechanism underlying the enhancement of inhibition of TNBC cell growth was investigated through Western blot analyses.ResultsThe combination treatment of OBP-801 with eribulin showed the synergistic inhibition of the growth in TNBC cells, involved with the enhancement of apoptosis. We, for the first time, found that eribulin upregulated survivin and also that OBP-801 could remarkably suppress the upregulation of survivin by eribulin. Moreover, this combination potently suppressed Bcl-xL and the MAPK pathway compared with either agent alone.ConclusionWe found that the combination of OBP-801 and eribulin synergistically inhibited the growth with apoptosis in TNBC cells, suggesting that this combination might be a promising novel strategy for treating TNBC patients.

Eribulin Promotes Antitumor Immune Responses in Patients with Locally Advanced or Metastatic Breast Cancer.

Several proteins involved in immune regulation and the relationship among these, the tumor microenvironment, and clinical outcomes of eribulin treatment were evaluated in advanced or metastatic breast cancer patients. This retrospective cohort study comprised 52 eribulin-treated locally advanced or metastatic breast cancer patients. Cancer tissue samples were obtained before and after treatment in 10 patients. Immunohistochemistry was performed to determine programmed death (PD)-1, CD8, and forkhead box P3 (FOXP3) expression by stromal tumor-infiltrating lymphocytes, and PD-ligand (L1) and PD-L2 expression by cancer cells. Of the 10 patients, 5 were responders (partial response) and 5 were non-responders (stable disease, 2; progressive disease, 3) to eribulin. PD-1, PD-L2, and FOXP3 expression became negative in 5 patients, PD-L1 expression became negative in 6 patients, and CD8 expression became positive in 3 patients after treatment. The response to eribulin was significantly associated with PD-L1 and FOXP3 negative conversion (p=0.024 and 0.004, respectively). The change in E-cadherin expression (positive or negative) was also correlated with the changes in PD-L1 and FOXP3 (p=0.024 and 0.004, respectively). Kaplan-Meier analysis with log-rank tests revealed that progression-free survival and time-to-treatment failure were significantly longer in patients with PD-L1 and FOXP3 negative conversion (p=0.012 and 0.001; p=0.049 and 0.018, respectively). The efficacy of eribulin may be attributed to its biological effects on the immune system (reduction of PD-L1 and FOXP3 expression) through epithelial-mesenchymal transition suppression, and vascular remodeling and improvement of the tumor microenvironment.

Significant Association Between Low Baseline Neutrophil-to-Lymphocyte Ratio and Improved Progression-free Survival of Patients With Locally Advanced or Metastatic Breast Cancer Treated With Eribulin But Not With Nab-Paclitaxel

IntroductionAlthough eribulin and nab-paclitaxel are chemotherapy agents widely used for locally advanced or metastatic breast cancer (MBC), their predictive factors remain unknown. Because the absolute neutrophil-to-lymphocyte ratio (NLR) is a significant prognostic factor for early-stage breast cancer, we investigated its usefulness in terms of the eribulin or nab-paclitaxel treatment efficacy for MBC. Patients and MethodsA total of 85 patients with MBC treated with eribulin (n = 59) or nab-paclitaxel (n = 26) were recruited. NLR values were collected at baseline, after 1 cycle, after 2 cycles, and at the end of treatment. The NLR cutoff value was set at 3. ResultsThe progression-free survival (PFS) of patients with an NLR < 3 at baseline (median, 242 days; n = 24) was significantly better than that of patients with an NLR of ≥ 3 (median, 98 days; n = 35; hazard ratio, 0.37, 95% confidence interval, 0.18-0.71; P = .0032). Similarly, the overall survival was marginally significantly better in patients with an NLR < 3 who were treated with eribulin (P = .058). However, the NLR was not significantly associated with PFS or overall survival for patients treated with nab-paclitaxel. No significant association was found between the NLR during treatment and PFS in the eribulin group. The significance of the NLR for the efficacy of eribulin was consistent, irrespective of estrogen receptor status, previous anthracycline or endocrine use, and the number of previous chemotherapy regimens. ConclusionA low NLR at baseline was significantly associated with improved PFS in patients treated with eribulin but not in those treated with nab-paclitaxel. Therefore, the baseline NLR might be clinically useful for selecting patients who would benefit from eribulin.

Eribulin inhibits the growth of small cell lung cancer cell lines alone and with radiotherapy

ObjectivesSmall cell lung cancer (SCLC) patients of all stages are treated with etoposide and cisplatin or carboplatin with or without surgery or chest radiotherapy. Initial response rates are ≥70% however the majority of patients relapse and are resistant to additional therapies due to pan-resistance to these salvage therapies. Therefore, new treatments are urgently needed. The non-taxane microtubule inhibitor eribulin has produced responses in heavily pretreated breast cancer patients. We evaluated the efficacy of eribulin alone and in combination with radiation in a panel of SCLC cell lines established from patients prior to or after receiving chemotherapy and or radiation. Material and methodsGrowth inhibition by eribulin alone, radiation alone and the combination was assessed by MTS assay and clonogenic survival. Eribulin induced cell cycle arrest was evaluated by FACS. Apoptosis was evaluated by using the Caspase-GLO 3/7 luminescent plate assay and by the Vybrant apoptosis assay with analysis by FACS. ResultsEribulin mesylate inhibited the growth of all 17-SCLC lines at concentrations of ≤10 nM which is a clinically achievable dose. Growth inhibition was not significantly different between cell lines established prior to or after chemotherapy (p = .5). Concurrent eribulin + radiation induced a greater G2-M arrest, an increase in apoptotic cells and increased growth inhibition over radiation alone. ConclusionsEribulin was highly active alone and in combination with radiation in treatment naïve SCLC lines and lines established from previously treated patients. In vivo pre-clinical studies of eribulin alone and in combination with radiation should be considered in SCLC cell lines.

Metastatic Liposarcoma: A Case of Partial Remission with Eribulin in Late Treatment Lines

Liposarcoma, a type of soft tissue sarcoma, represents a therapeutic challenge, in particular in the metastatic setting. This case describes a patient with retroperitoneal liposarcoma that was first treated by surgery and, upon manifestation of metastatic disease, with a series of chemotherapy regimens comprising doxorubicin (line 1), doxorubicin plus ifosfamide (line 2), trabectedin (lines 3 and 4) and dacarbazine (line 5). While transient partial remission was achieved in the first three lines, rapid disease progression was observed in subsequent therapies. After failure of the previous chemotherapy regimens, eribulin was administered (line 6), and partial remission was achieved within five months. However, the occurrence of grade 3 polyneuropathy led to temporary discontinuation of therapy. Overall, metastatic liposarcoma was controlled for twelve months with eribulin treatment in a heavily pre-treated patient. This case underscores the efficacy of eribulin in treatment-refractory advanced/metastatic liposarcoma.

Safety Results and Analysis of Eribulin Efficacy according to Previous Microtubules-Inhibitors Sensitivity in the French Prospective Expanded Access Program for Heavily Pre-treated Metastatic Breast Cancer

PurposeEribulin is approved for advanced breast cancers refractory to anthracyclines and taxanes. Efficacy according to sensitivity to previous therapies has been poorly explored.Materials and MethodsSafety data were collected prospectively and we retrospectively collected efficacy data from the five French centres that participated in the Eribulin E7389-G000-398 expanded access program. Our main objectives were exploration of safety and analysis of eribulin efficacy (progression-free survival [PFS] and overall survival [OS]) according to sensitivity to the last microtubule-inhibiting agent administered.ResultsMedian eribulin treatment duration was 3.3 months for the 250 patients included in this prospective single-arm study. Two hundreds and thirty-nine patients (95.6%) experienced an adverse event (AE) related to treatment including 129 (51.6%) with grade ≥ 3 AEs. The most frequently observed toxicities were cytopenias (59.6% of included patients), gastro-intestinal disorders (59.2%), and asthenia (56.4%). The most frequent grade 3-4 AE was neutropenia (37.2% with 4.8% febrile neutropenia). Median PFS and OS were 4.6 and 11.8 months, respectively. Patients classified as responders to the last microtubule-inhibiting therapy had a longer OS (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.51 to 0.94; p=0.017), and tended to display a better PFS (HR, 0.78; 95% CI, 0.58 to 1.04; p=0.086). OS improvement was still significant in multivariate analysis (adjusted HR, 0.53; 95% CI, 0.35 to 0.79; p=0.002).ConclusionThis work based on a prospective study suggests that identification of patients likely to be more sensitive to eribulin could be based on their previous response to microtubules inhibitors.