Combination Of Eribulin Research Articles

Eribulin Synergistically Increases Anti-Tumor Activity of an mTOR Inhibitor by Inhibiting pAKT/pS6K/pS6 in Triple Negative Breast Cancer

Unlike other breast cancer subtypes, patients with triple negative breast cancer (TNBC) have poor outcomes and no effective targeted therapies, leaving an unmet need for therapeutic targets. Efforts to profile these tumors have revealed the PI3K/AKT/mTOR pathway as a potential target. Activation of this pathway also contributes to resistance to anti-cancer agents, including microtubule-targeting agents. Eribulin is one such microtubule-targeting agent that is beneficial in treating taxane and anthracycline refractory breast cancer. In this study, we compared the effect of eribulin on the PI3K/AKT/mTOR pathway with other microtubule-targeting agents in TNBC. We found that the phosphorylation of AKT was suppressed by eribulin, a microtubule depolymerizing agent, but activated by paclitaxel, a microtubule stabilizing agent. The combination of eribulin and everolimus, an mTOR inhibitor, resulted in an increased reduction of p-S6K1 and p-S6, a synergistic inhibition of cell survival in vitro, and an enhanced suppression of tumor growth in two orthotopic mouse models. These findings provide a preclinical foundation for targeting both the microtubule cytoskeleton and the PI3K/AKT/mTOR pathway in the treatment of refractory TNBC.

TAK228 enhances antitumor activity of eribulin in triple negative breast cancer.

Background: Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) negatively regulates the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway. Triple negative breast cancers (TNBC) are often PTEN-deficient, making mTOR a compelling target. We evaluated the efficacy of catalytic mTOR inhibitor TAK228 alone and in combination with eribulin in TNBC. Results: Five of eight triple negative breast cell lines were sensitive to TAK228, independent of PIK3CA/PTEN status. Western blotting demonstrated inhibition of mTORC1/2 signaling as demonstrated by decreased phospho-AKT, phospho-S6 and phospho-4EBP1. In vitro, TAK228 was synergistic with eribulin in all eight TNBC cell lines. The combination of TAK228 and eribulin did not enhance apoptosis but increased G2/M growth arrest. In vivo, TAK228 led to modest growth inhibition in TNBC patient-derived xenografts (PDXs) with no tumor regression observed. In two TNBC PDXs with PTEN loss, one with intrinsic eribulin sensitivity, another eribulin resistance, TAK228 in combination with eribulin did not enhance in vivo efficacy. In a third PTEN-negative TNBC model, eribulin alone achieved disease stabilization, but the combination of TAK228 and eribulin led to significantly smaller tumor volumes compared to eribulin alone (p < 0.001). Methods: We tested in vitro efficacy of TAK228 in a panel of TNBC cell lines with cell proliferation assays. In vivo antitumor efficacy of TAK228 was evaluated alone and in combination with eribulin. Conclusion: TAK228 enhances the antitumor efficacy of eribulin in TNBC models in vitro, and enhanced in vivo activity in selected models. Further study is needed to determine the potential of this combination, and optimal patient selection strategies.

Abstract 4089: Antitumor activity of eribulin in combination with anti-PD1 antibody in a mouse syngeneic breast cancer model

Abstract Eribulin is a synthetic analog of halichondrin B, which is isolated from the marine sponge natural product, as the first halichondrin class of microtubule dynamics inhibitors. Its clinical formulation is currently approved for advanced breast cancer (BC) and advanced liposarcoma in numerous countries. Eribulin shows antitumor activity through cell death induction by an antimitotic effect, and modulation of tumor microenvironment that include vascular remodeling, and reversal of EMT in some of preclinical subcutaneous xenograft models. Effects of eribulin on tumor microenvironment led us to test combination of eribulin with anti-PD1 blockades, and Phase2 clinical study of eribulin in combination with pembrolizumab for metastatic BC patients is in progress. In this study, we investigated antitumor activity of eribulin in combination with anti-PD1 mAb in preclinical mouse BC model using 4T1 cells. Because parent 4T1 cells express P-glycoprotein (Pgp) and eribulin is a substrate of Pgp, we established Pgp-knockout (Pgp-KO) mouse 4T1 BC cells to examine combination antitumor activity of eribulin with anti-PD1 antibody. We used a clone 31 of Pgp-KO 4T1 (#31) cells, which maintains similar tumor phenotypes to parent 4T1 orthotropic transplantation (OT) models, such as growth rate and formation of metastasis. Eribulin inhibited in vitro proliferation of Pgp-KO 4T1 (#31) cells with a lower concentration compared to parent 4T1 cells. Eribulin were intravenous administered at 1 mg/kg with either Q7Dx2 or Q4Dx3 in the combination with anti-PD1 mAb, 200 µg/head, Q3Dx10 in the Pgp-KO 4T1 (#31) OT model (6 mice per a treatment group). Anti-PD1 mAb did not clearly show in vivo antitumor activity. Treatments of eribulin by Q4Dx3 showed enhanced antitumor activity in the combination compared to each single treatment, and all tumors became non-palpable in the combination group. On the other hand, weekly treatments of eribulin did not enhance antitumor activity in the combination with anti-PD1 mAb, although eribulin single treatment significantly inhibited in vivo tumor growth of Pgp-KO 4T1 (#31) tumors. These preclinical results provide preclinical rationale for clinical testing of eribulin in combination with anti-PD1 blockades in patients with BC, and further preclinical analysis of MOA of combination antitumor activity of eribulin with anti-PD1 antibody is warranted. Citation Format: Taro Semba, Kimiyo Tabata, Yoichi Ozawa, Saori Watanabe Miyano, Junji Matsui, Yasuhiro Funahashi. Antitumor activity of eribulin in combination with anti-PD1 antibody in a mouse syngeneic breast cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4089.

Abstract 3965: Circulating levels of IFN gammaand neutrophil counts in breast cancer patients who received balixafortide and eribulin combination therapy

Abstract Background: Balixafortide (B) is a highly selective antagonist of the chemokine receptor CXCR4. Clinical proof-of-concept in combination with eribulin (E) was achieved in a recent Phase 1 single arm dose-escalation trial in patients with metastatic HER2-negative breast cancer (NCT01837095). Safety and tolerability of B in combination with E was similar to that of B or E monotherapy. Anti-cancer effects of CXCR4 antagonists include sensitization of tumor cells to chemotherapy, suppression of metastatic spread, inhibition of angiogenesis, and activation of immune cells. Methods: Plasma samples from patients who received initial E monotherapy (1.4 mg/m2, run-in cycle) or combination of B and E (escalating doses of B intravenous up to 5.5 mg/kg plus E 1.4 mg/m2 in 21 days cycles) were immediately processed and stored at -80°C. Circulating levels of IFN-γ, an important marker of anti-tumor immune response, were determined by a high-sensitive S-Plex assay (Meso Scale Diagnostics). Absolute neutrophil counts (ANC) were measured by automated hematology instruments. Results: E monotherapy did not increase IFN-γ levels in the first 8 hours post dosing, but led to an increase after 24 hours. Combination with B modulated IFN-γ levels and led to a sustained ANC increase 5 days post dosing. The increase pre vs post treatment can be up to 100-fold and receded prior to the next treatment cycle. Conclusions: E treatment led to a strong, transient increase of plasma IFN-γ levels in breast cancer patients modulated by B. The ANC increase by B may balance possible neutropenic actions of E. Citation Format: Johann Zimmermann, Garry Douglas, Barbara Romagnoli, Debra Barker, Daniel Obrecht. Circulating levels of IFN gammaand neutrophil counts in breast cancer patients who received balixafortide and eribulin combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3965.

PI3K inhibition enhances the anti-tumor effect of eribulin in triple negative breast cancer

Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) is commonly observed in triple negative breast cancer (TNBC), leading to activation of the phosphoinositide 3-kinase (PI3K) signaling to promote tumor cell growth and chemotherapy resistance. In this study, we investigated whether adding a pan-PI3K inhibitor could improve the cytotoxic effect of eribulin, a non-taxane microtubule inhibitor, in TNBC patient-derived xenograft models (PDX) with loss of PTEN, and the underlying molecular mechanisms. Three TNBC-PDX models (WHIM6, WHIM12 and WHIM21), all with loss of PTEN expression, were tested for their response to BKM120 and eribulin, alone or in combination in vivo. In addition, the effect of drug treatment on cell proliferation and cell cycle progression were also performed in vitro using a panel of TNBC cell lines, including 2 derived from PDX models. The combination of eribulin and BKM120 led to additive or synergistic anti-tumor effect in 2 of the 3 PDX models, accompanied by an enhanced mitotic arrest and apoptosis in sensitive PDX models. In addition, the combination was synergistic in reducing mammosphere formation, and markers for epithelial-mesenchymal transition (EMT). In conclusion, PI3K inhibition induces synergistic anti-tumor effect when combined with eribulin, by enhancing mitotic arrest and apoptosis, as well as, reducing the cancer stem cell population. This study provides a preclinical rationale to investigate the therapeutic potential for the combination of PI3K inhibition and eribulin in the difficult to treat TNBC. Further studies are needed to identify the biomarkers of response for target patient selection.

Eribulin ORA: A novel oral formulation of eribulin based on combination with the P-gp inhibitor HM30181A.

e12577 Background: Eribulin is a potent synthetic derivative of the marine sponge natural product Halichondrin B that uniquely targets microtubule growth to induce apoptotic cell death. Eribulin is currently administered intravenously (IV) to treat patients with breast cancer and liposarcoma refractory to taxane therapy due to its superior efficacy in taxane resistant tumor types. Methods: Utilizing a proprietary Orascovery platform, Eribulin ORA, a novel orally-administered eribulin formulation has been developed, which combines the P-glycoprotein (P-gp) inhibitor, HM30181A, with oral eribulin. Results: HM30181A significantly improves the systemic exposure of oral eribulin in rodents, which enables remarkable tumor regression in murine xenografts. HM30181A improves eribulin plasma exposure &gt; 5-fold in mouse model (AUC0-24hr = 8224 ng*hr/mL with HM30181A vs. 1516 ng*hr/mL without HM30181A) and also improves eribulin oral bioavailability in the rat (%F = 35.0 with HM30181A vs. 16.1 without HM30181A). In vitro cell viability assays of MCF-7 and MDA-MB-231 breast cancer cell lines show eribulin is synergistic with other microtubule disrupting agents, including common first-line breast cancer therapy paclitaxel. In mice bearing orthotopic MDA-MB-231 breast tumor xenografts, oral eribulin with HM30181A was administered at eribulin doses of 0.5, 1.0, and 1.5 mg/kg Q2Dx3 (M,W,F)/week for four weeks. Only mice treated with 1.5 mg/kg (highest dose) eribulin had weight loss during treatment, with the observed weight loss was &lt; 10%, (except for one mouse). All eribulin doses tested induced tumor regression, with 7/9 tumors in the 1.5 mg/kg eribulin group experiencing durable complete regression until study end, two-weeks post administration. Of the tumors in the Eribulin ORA-treated groups that resumed growth after treatment, the degree of tumor growth was minimal. Overall, Eribulin ORA was well tolerated and showed potent efficacy against breast cancer tumors, exhibiting nearly 100% growth inhibition at all dose levels tested. Conclusions: Eribulin ORA showed good oral absorption, efficacious systemic exposure, and importantly, excellent anti-cancer activity in a breast cancer model. In vitro studies demonstrated the synergistic potential of eribulin in combination with paclitaxel. Accordingly, the combination of Eribulin ORA with Oraxol (oral paclitaxel that has shown promising clinical data) may represent an excellent metronomic oral combination chemotherapy that warrants further investigation for patients with advanced breast cancer.

The safety of eribulin for the treatment of metastatic breast cancer

ABSTRACTIntroduction: Eribulin mesylate is a highly potent anticancer agent approved for use in pretreated metastatic breast cancer (MBC). Clinical trials of eribulin in MBC have demonstrated activity against this tumor type, and a phase 3 study in patients with MBC previously treated with an anthracycline and a taxane showed a significant increase in overall survival (OS) with eribulin versus control regimens.Areas covered: This review presents overviews of the development of eribulin, its pharmacology, and its efficacy in MBC. A detailed review of its safety profile is presented, and the safety of eribulin is compared with other agents commonly used to treat MBC.Expert opinion: As eribulin is the only drug shown to improve OS in patients with pretreated MBC, it is an important treatment option for many patients. Eribulin is currently considered a second-line (Europe) or third-line (United States) therapy, and studies have been examining use in the first-line setting. The use of eribulin in combination with other therapies is beginning to be explored because its manageable safety profile makes it an ideal combination-treatment partner. Emerging eribulin combination-treatment data suggest a manageable toxicity profile, and eribulin is set to be a key drug for the treatment of MBC in the future.

Combination of eribulin plus AKT inhibitor evokes synergistic cytotoxicity in soft tissue sarcoma cells

An activated AKT pathway underlies the pathogenesis of soft tissue sarcoma (STS), with over-expressed phosphorylated AKT (p-AKT) correlating with a poor prognosis in a subset of STS cases. Recently, eribulin, a microtubule dynamics inhibitor, has demonstrated efficacy and is approved in patients with advanced/metastatic liposarcoma and breast cancer. However, mechanisms of eribulin resistance and/or insensitivity remain largely unknown. In this study, we demonstrated that an increased p-AKT level was associated with eribulin resistance in STS cells. We found a combination of eribulin with the AKT inhibitor, MK-2206, synergistically inhibited STS cell growth in vivo as well as in vitro. Mechanistically, eribulin plus MK-2206 induced G1 or G2/M arrest by down-regulating cyclin-dependent kinases, cyclins and cdc2, followed by caspase-dependent apoptosis in STS cells. Our findings demonstrate the significance of p-AKT signaling for eribulin-resistance in STS cells and provide a rationale for the development of an AKT inhibitor in combination with eribulin to treat patients with STS.

Perspectives on the mechanism of action and clinical application of eribulin for metastatic breast cancer.

Eribulin is a novel microtubule inhibitor with mitotic and nonmitotic mechanisms of action. Both pooled and subgroup analyses from large-scale Phase III clinical trials demonstrated that eribulin has substantial activity in patients with pretreated (anthracycline and a taxane) advanced or metastatic breast cancer. We review recent pharmacological and clinical findings pertaining to eribulin use in metastatic breast cancer - particularly highlighting eribulin in difficult-to-treat and aggressive disease, and safety data in specific patient populations.Additionally, recent advancements in our understanding of the mechanism of action of eribulin and potential future directions for its clinical development are discussed. Ongoing studies of eribulin in combination with immunotherapies and established cytotoxic agents may help shape the future landscape of breast cancer treatment.

A phase 1b/2, open-label, dose-escalation, and dose-confirmation study of eribulin mesilate in combination with capecitabine

BackgroundCapecitabine and eribulin are widely used as single agents in metastatic breast cancer (MBC) and have nonoverlapping toxicities.MethodsIn phase 1b (dose escalation), patients with advanced, treatment-refractory, solid tumours received eribulin mesilate intravenously in 21-day cycles according to schedule 1 (day 1) or schedule 2 (days 1, 8) with twice-daily oral capecitabine (1000 mg/m2 days 1–14). In phase 2 (dose confirmation), women with advanced/MBC and ≤3 prior chemotherapies received eribulin mesilate at the maximum tolerated dose (MTD) per the preferred schedule plus capecitabine. Primary objectives were MTD and dose-limiting toxicities (DLTs; phase 1b) and objective response rate (ORR; phase 2). Secondary objectives included progression-free survival (PFS), safety, and pharmacokinetics.ResultsDLTs occurred in 4/19 patients (schedule 1) and 2/15 patients (schedule 2). Eribulin pharmacokinetics were dose proportional, irrespective of schedule or capecitabine coadministration. The MTD of eribulin was 1.6 mg/m2 day 1 for schedule 1 and 1.4 mg/m2 days 1 and 8 for schedule 2. ORR in phase 2 (eribulin 1.4 mg/m2 days 1, 8 plus capecitabine) was 43% and median PFS 7.2 months. The most common treatment-related adverse events were neutropenia, leukopenia, alopecia, nausea, and lethargy.ConclusionsThe combination of capecitabine and eribulin showed promising efficacy with manageable tolerability in patients with MBC.

Abstract P1-14-05: Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer (ERIGE Trial). Clinical and pharmacogenetic results on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC)

Abstract Background: There are no well-established chemotherapy regimens for metastatic triple negative breast cancer. The combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, especially in tumors like triple negative breast cancers (TNBC) characterized by high cell proliferation, aggressive tumor behavior, and chemo-resistance. Materials and Methods:This is an open-label, national multicenter phase II study evaluating the combination of eribulin (0.88 mg/m2) plus gemcitabine (1000 mg/m2) on day 1 and 8, q21 as either first- or second-line treatment of locally advanced or metastatic TNBC.The primary endpoint was the objective response rate (ORR) for evaluable patients (pts). The study was designed according to the Simon's two stage optimal design. We chose the lower activity (p0) of 0.20 and target activity level (p1) of 0.35. A prospective, molecular correlative study has been being carried out on germinal DNA of study population to assess the role of BRCA mutations and single nucleotide polymorphisms (SNPs) in predicting efficacy and toxicity of the combination regimen. Results: From July 2013 to September 2016, 83 evaluable pts (37 in the first stage, 46 in the second one) were enrolled. They received a median number of 6 cycles of treatment (range 1-24). The ORR (CR+PR) was 37.35% (90% CI: 28.47-46.93) and the clinical benefit rate (CR+PR+SD ≥ 24wks) was 48.78% (90% CI: 39.24%-58.39%). The most common grade 3-4 adverse events (&amp;gt; 10% of patients) were neutropenia and liver toxicity. With a median follow-up of 28.8 months, the median progression-free survival (PFS) and overall survival (OS) were 5.1 months (95% CI: 4.2-7.0) and 14.7 months (95% CI: 10.2-20.0), respectively. BRCA1/2 deleterious mutations were observed in 15 (22%) out of 68 genotyped pts. Women with BRCA1/2 mutations were associated with worse ORR, PFS and OS than those with BRCA1/2 wild-type. A panel of SNPs in genes of study drug metabolism pathways was evaluated. Among these, CYP3A4 392A &amp;gt;G and FGD4 2044236G&amp;gt;A SNPs were associated with greater liver toxicity by logistic regression analysis. Furthermore, CDA*2 79A&amp;gt;C, RRM1 2455 A&amp;gt;G, and CYP2C8 416G&amp;gt;A SNPs were associated with poorer overall survival by Cox proportional hazards model. Conclusions:The combination of eribulin and gemcitabine shows promising activity and a moderate toxicity profile in metastatic TNBC. BRCA status and pharmacogenetics tests may help identify pts with high probability of response with negligible toxicity. Citation Format: Musolino A, Cavanna L, Boggiani D, Zamagni C, Frassoldati A, Caldara A, Rocca A, Gori S, Piacentini F, Berardi R, Brandes AA, Foglietta J, Villa F, Pellegrino B, Todeschini R, Tognetto M, Naldi N, Bortesi B, Boni L, Montemurro F, Ardizzoni A. Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer (ERIGE Trial). Clinical and pharmacogenetic results on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC) [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 P1-14-05.

Abstract P6-21-13: A phase II single arm trial evaluating the efficacy and safety of eribulin in combination with bevacizumab for second-line treatment of human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer (MBC) progressing after first-line therapy with bevacizumab and paclitaxel

Abstract Background: At present, there is no standard second-line chemotherapy-based treatment in patients with HER2-negative MBC. Continued VEGF inhibition with bevacizumab is a new potential option in patients progressing to first line bevacizumab and chemotherapy. Eribulin is a non-taxane microtubule dynamics inhibitor, with a unique mechanism of action and suggested beneficial effects on tumor microenvironment and neoangiogenesis. This study evaluated efficacy and safety of eribulin plus bevacizumab as a novel second-line chemotherapy scheme, in patients progressing after first line paclitaxel and bevacizumab. Methods: This is a multicenter, single-arm, Simon's two-stage, Phase II study. Patients with HER2-negative MBC progressing to paclitaxel and bevacizumab received eribulin (1.23 mg/m2 intravenously on Days 1 and 8 of every 21-day cycle) plus bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks intravenously), as second-line chemotherapy. The primary endpoint was the overall response rate (ORR), considered as sum of partial (PR) and complete response (CR), basing on the best overall response. The present safety and efficacy analyses, as planned per study design, refer to six cycles of treatment (18 weeks). Results: Among the 61 patients enrolled in the study, 55 (90,2% ) were evaluable for efficacy. ORR (PR/CR) was 9.1% [95% confidence intervals (C.I.) 3.0 to 19.9]; stable disease (SD) rate was 63.6% [95% C.I. 49.6 to 76.2]; clinical benefit rate (CR/PR/SD) at 24 weeks was 35% [95% C.I. 22.0 to 49.1]. The median progression free survival was 6.3 months [95% C.I. 4.1 to 7.8 months]. Drugs-related adverse events (AEs) were: 49.5% related to eribulin, 7.7% related to bevacizumab, and 11.8% related to both the study drugs. The most common AEs were fatigue (9.9% of all AEs), paresthesia (6.5% of all AEs) and neutropenia (6.2% of all AEs). Quality of life was well preserved among the majority of patients. Conclusions: The results of our trial suggest that continuing bevacizumab in combination with eribulin, beyond first line treatment with bevacizumab and paclitaxel, offers a reasonable therapeutic option for patients with HER2-negative MBC, without detrimentally affecting quality of life. Citation Format: De Placido S, De Laurentiis M, Bruzzese D, Bernardo A, Baldini EE, Montesarchio V, Fabi A, Gamucci T, De Placido P, Russo S, Lauria R, De Santo I, De Angelis C, Del Mastro L, Giuliano M, Arpino G. A phase II single arm trial evaluating the efficacy and safety of eribulin in combination with bevacizumab for second-line treatment of human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer (MBC) progressing after first-line therapy with bevacizumab and paclitaxel [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 P6-21-13.

Abstract P6-17-28: Outcomes of real-world use of eribulin plus trastuzumab for HER2-positive metastatic breast cancer

Abstract Background Eribulin mesylate is approved for the treatment of metastatic breast cancer (mBC) after two prior chemotherapy regimens including an anthracycline or a taxane in either the metastatic or adjuvant setting. Eribulin in combination with trastuzumab (E+T) has demonstrated tolerability and anti-tumor activity in phase I and II trials but is not FDA-approved for the treatment of HER2-positive mBC. Case series and retrospective research have noted the use of E+T in clinical practice. We sought to describe patient characteristics and long-term outcomes of treatment with E+T for HER2-positive mBC patients treated outside of clinical trials in the US. Methods US-based community oncologists from an open network of over 7,000 oncologists, hematologists, and urologists were invited to participate in identifying HER2-positive mBC patients treated with E+T between 01/01/11 and 12/31/13 outside of clinical trials. Data were collected from 03/18/2016 until 09/01/2016. Providers completed an electronic case report form (CRF) by abstracting data on disease characteristics, treatment patterns, disease response (per provider assessment), adverse events (Aes), and date of death. Duration of treatment and overall survival (OS) were calculated from the initiation of the E+T regimen. The target sample size was 60 patients and patients were selected according to resource available for chart data abstraction. Results Twenty-three providers submitted CRFs for 62 total patients. After data collection, 59 of 62 submitted records were validated for analysis. At mBC diagnosis, 69.4% of patients were ER/PR negative and 42.4% of patient had de novo stage IV disease. At initiation of E+T, the median age was 57 years and 81.4% were ECOG-OS 0/1. Mean length of follow-up from the initiation of any therapy was 33.6 months. Twenty-two (37.3%) patients initiated E+T as their first- or second-line of treatment; those remaining were in third-line or greater. At initiation of E+T, 72.8% of patients had prior treatment with trastuzumab in combination with chemotherapy, 25.4% had prior trastuzumab in combination with pertuzumab and chemotherapy, and 16.9% had received TDM-1. Mean duration of E+T treatment was 5.2 months (SD=2.4). A response (complete [CR] or partial [PR]) was recorded by the providers for 64.4% of patients (not independently verified). The most common Aes reported were fatigue (67.8%), weakness (50.8%), decreased appetite (28.8%), decreased hemoglobin (27.1%), peripheral neuropathy (25.4%), and neutropenia (18.6%). At the end of the study period, 34 patients (57.6%) were deceased; the median OS from the initiation of E+T was 23.9 months (95% CI: 17.8-30.4). Conclusions In a small cohort of patients treated with E+T in the community setting, the observed response rate of 64.4% (CR+PR) was comparable to that of a prior phase II trial of E+T which reported an ORR with first-line E+T of 71.2% overall, 77.4% among T-naïve and 61.9% in T-pretreated patients. Further research is warranted to examine the tolerability and efficacy of E+T for metastatic HER2-positive breast cancer patients in different treatment settings. Citation Format: Mougalian SS, Copher R, McAllister L, Radtchenko J, Wang EC, Broscious M, Yu H-T, Kish J. Outcomes of real-world use of eribulin plus trastuzumab for HER2-positive 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 P6-17-28.

Abstract 1861: Combination of eribulin plus AKT inhibitor evokes synergistic cytotoxicity in soft tissue sarcoma cells

Abstract [Background] Prognosis of unresectable or metastatic (UM)-soft tissue sarcoma (STS) is poor, with overall survival (OS) less than 1.2 years after diagnosis. Recommended therapy for most UM-STS patients is doxorubicin (Dox) as first line palliative chemotherapy. Recently, three new drugs, pazopanib, trabectedin and eribulin, were introduced for treatment of UM-STS after Dox therapy. Only eribulin could significantly improve OS. However, outcomes with eribulin for UM-STS did not satisfy an unmet clinical need. Therefore, despite recent advances in its treatment, prognosis of UM-STS remains dismal, underscoring the need to develop novel strategies for UM-STS. Resistance to anti-cancer drugs frequently arise that would hamper results of cancer therapy. Mechanisms of eribulin resistance have been largely unknown. Overexpressed p-AKT underlies the pathogenesis of a broad range of human malignancies including STS. The high expression of p-AKT has been identified as a negative surrogate marker for survival of STS patients. Therefore, AKT is an attractive target for STS therapeutics. [Aims] Our study aimed to investigate the molecular mechanism of eribulin-resistance and to evaluate the effect of combination therapy with eribulin and AKT-inhibitor on STS cells. [Methods] Eribulin-resistant STS cell lines were established by culturing HT1080 and SK-LMS-1 cells with stepwise increases in the eribulin concentration for more than 3 months. Alterations in the phosphorylation status of kinases in eribulin-resistant cells compared to parental cells were screened using a Human Phospho-Kinase Array Kit. The effect of eribulin and AKT-inhibitor MK-2206 on STS cell lines was examined using an MTT assay. To elucidate the cytotoxic mechanism of eribulin and MK-2206, immunoblotting and flow cytometry analyses were performed. [Results] In established eribulin-resistant cell lines, those IC50s were 2.40- to 27.14-fold greater than in the parental cell lines. Phospho-Kinase Array revealed increased p-AKT (S473) levels in eribulin-resistant cells compared to the parental cells. Eribulin treatment increased p-AKT levels in STS cells in a dose-dependent fashion. Combination treatment of eribulin and AKT-inhibitor MK-2206 inhibited the proliferation of STS cells accompanied with G1 and/or G2/M arrest by down-regulating CDKs, cdc2 and cyclins. Furthermore, eribulin combined with MK-2206 synergistically induced apoptosis in STS cell lines. The apoptosis was via Caspase 8 and 9 pathways. [Conclusion] This study demonstrated that activated-AKT was associated with eribulin-resistance in STS cells and that eribulin combined with MK-2206 suppressed STS growth synergistically through G1 and G2/M arrest and caspase-dependent apoptosis. Our results uncover a potential clinical application of eribulin and MK-2206 combination therapy to improve clinical outcomes for UM-STS patients. Citation Format: Kohichi Takada, Naotaka Hayasaka, Yutaka Kawano, Hajime Nakamura, Yohei Arihara, Kazuyuki Murase, Shohei Kikuchi, Satoshi Iyama, Koji Miyanishi, Masayoshi Kobune, Junji Kato. Combination of eribulin plus AKT inhibitor evokes synergistic cytotoxicity in soft tissue sarcoma 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 1861.

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.

Abstract CT152: A phase II study of pembrolizumab and eribulin in patients with HR-positive/HER2-negative metastatic breast cancer previously treated with anthracyclines and taxanes (KELLY study)

Abstract BACKGROUND: Preliminary results with MK3475 (pembrolizumab) in heavily pretreated Estrogen Receptor (ER)-positive/ Human Epidermal Growth Factor Receptor 2 (HER2)-negative metastatic breast cancer (MBC) patients have shown promising antitumor activity. However, no data are available with anti-Programmed Death-Ligand 1 (PD-L1) agents in combination with chemotherapy in this tumor subtype in the metastatic setting. The aim of this trial is to evaluate the efficacy of pembrolizumab in combination with eribulin in patients with Hormone Receptor (HR)-positive/HER2-negative MBC who have been previously treated with an anthracycline and a taxane. TRIAL DESIGN: This is an open-label, non-randomized, multicenter phase IIA clinical trial. Patients will receive intravenously pembrolizumab (200 mg) followed by eribulin (1.23 mg/m2) on day 1 of each cycle (every three weeks). Eribulin will also be administered alone on day 8 of each cycle until progression or unacceptable toxicity. The end of study will be 12 months after last study dose or progressive disease experienced in all patients. The principal selection criteria are: (1) HR-positive/HER2-negative inoperable locally recurrent or MBC; (2) prior therapy with an anthracycline and a taxane in the early or metastatic disease setting unless contraindicated; (3) at least one, but not more than two, previous chemotherapeutic regimens for locally recurrent and/or MBC; (4) measurable disease based on Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1; (5) available tumor tissue for PD-L1 biomarker analysis. The primary objective of the study is to assess the efficacy of this combination as determined by the clinical benefit rate (CBR) defined as the percentage of patients who achieve complete response, partial response, or stable disease ≥24 weeks based on RECIST v.1.1. Secondary objectives evaluate: (1) safety-related outcomes and (2) efficacy measures as progression-free survival (PFS), overall survival, overall response rate (ORR), and duration of response in the intention-to-treat population and in patients with PD-L1 positive tumors. Exploratory objectives include: (1) the analysis of PFS and ORR based on irRECIST; and (2) the identification of new predictive factors of response to the combination of pembrolizumab and eribulin based on gene signatures, mutational load, and circulating tumor cells. The trial uses an exact single-stage design. We hypothesized that excluding a CBR ≤30% while targeting an improvement of the CBR to ≥50% would be an optimal approach to evaluation of the study strategy. At least 17 patients with clinical benefit among 39 evaluable patients will be adequate to justify the investigation of this strategy in further clinical trials. Considering a drop-out rate of 10%, a sample size of 44 patients will be needed to attain 80% power at nominal level of one-sided alpha of 0.05. TRIAL REGISTRATION: NCT03222856. Date of registration: July 19th, 2017. First Patient First Visit: December 14th, 2017. Citation Format: José Manuel Pérez García, Antonio Llombart, José Luis Alonso, Begoña Bermejo, Lourdes Calvo, Vicente Carañana, Giuseppe Curigliano, Susana de la Cruz Sánchez, María Gión Cortés, Raúl Márquez Vázquez, Aleix Prat, Manuel Ruiz Borrego, Miguel Sampayo, Peter Schmid, Miguel Ángel Seguí, Javier Cortés, Esther Holgado. A phase II study of pembrolizumab and eribulin in patients with HR-positive/HER2-negative metastatic breast cancer previously treated with anthracyclines and taxanes (KELLY study) [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 CT152.

Concomitant administration of radiation with eribulin improves the survival of mice harboring intracerebral glioblastoma.

Glioblastoma is the most common and devastating type of malignant brain tumor. We recently found that eribulin suppresses glioma growth in vitro and in vivo and that eribulin is efficiently transferred into mouse brain tumors at a high concentration. Eribulin is a non‐taxane microtubule inhibitor approved for breast cancer and liposarcoma. Cells arrested in M‐phase by chemotherapeutic agents such as microtubule inhibitors are highly sensitive to radiation‐induced DNA damage. Several recent case reports have demonstrated the clinical benefits of eribulin combined with radiation therapy for metastatic brain tumors. In this study, we investigated the efficacy of a combined eribulin and radiation treatment on human glioblastoma cells. The glioblastoma cell lines U87MG, U251MG and U118MG, and SJ28 cells, a patient‐derived sphere culture cell line, were used to determine the radiosensitizing effect of eribulin using western blotting, flow cytometry and clonogenic assay. Subcutaneous and intracerebral glioma xenografts were generated in mice to assess the efficacy of the combined treatment. The combination of eribulin and radiation enhanced DNA damage in vitro. The clonogenic assay of U87MG demonstrated the radiosensitizing effect of eribulin. The concomitant eribulin and radiation treatment significantly prolonged the survival of mice harboring intracerebral glioma xenografts compared with eribulin or radiation alone (P < .0001). In addition, maintenance administration of eribulin after the concomitant treatment further controlled brain tumor growth. Aberrant microvasculature was decreased in these tumors. Concomitant treatment with eribulin and radiation followed by maintenance administration of eribulin may serve as a novel therapeutic strategy for glioblastomas.

Broad-spectrum Preclinical Antitumor Activity of Eribulin (Halaven®): Combination with Anticancer Agents of Differing Mechanisms.

Eribulin is used in many countries to treat patients with advanced breast cancer or liposarcoma and exerts in vivo anticancer activity under monotherapy conditions against various human tumor xenograft models. Here, eribulin in combination with mechanistically different anticancer agents was evaluated. Eribulin was combined with cytotoxic agents (capecitabine, carboplatin, cisplatin, doxorubicin, gemcitabine) or targeted agents (bevacizumab, BKM-120, E7449, erlotinib, everolimus, lenvatinib, palbociclib) in tumor xenograft models of breast cancer, melanoma, non-small cell lung cancer (NSCLC), and ovarian cancer. Across nearly all models, eribulin with either cytotoxic or targeted agents demonstrated combination activity, defined as the activity demonstrably greater than that of either agent alone. Combination activity was absent only with doxorubicin (MDA-MB-435 model) and with lenvatinib (NCI-H1975 model), both of which responded to the agents as monotherapy. Eribulin has combination activity with multiple agents from different mechanistic classes in several human cancer models, including breast, NSCLC, ovarian, and melanoma.

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.

Abstract P5-21-07: Phase II study of eribulin in combination with pertuzumab plus trastuzumab for human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer

Abstract Background: Pertuzumab provided overall and progression-free survival (PFS) benefits in HER2-positive metastatic breast cancer patients (pts) in the CLEOPATRA (Clinical evaluation of docetaxel, pertuzumab and trastuzumab) study. However, few studies have described the efficacy of other drugs in combination with pertuzumab plus trastuzumab. Here, we present a pre-specified analysis of eribulin in combination with pertuzumab plus trastuzumab as first- and second-line therapy for advanced or metastatic breast cancer (AMBC) in a multicenter, open-label phase II study (UMIN000012232, JBCRG-M03). Methods: HER2-positive AMBC with no or single prior chemotherapy for AMBC were enrolled. All pts were administered trastuzumab and taxane as adjuvant or first-line chemotherapy. Treatment consisted of eribulin 1.4 mg/m2 on days 1 and 8 of a 21-day cycle and trastuzumab (8 mg/kg loading dose, then 6 mg/kg) plus pertuzumab (840 mg/body loading dose, then 420 mg/ body) once every 3 weeks, all administered intravenously. The primary endpoint was PFS, and secondary endpoints included overall response rate (ORR) and safety. PFS was determined using Kaplan–Meier analysis. Tumor response was assessed according to RECIST ver. 1.1. Results: Fifty pts were enrolled from November 2013 to April 2016. Forty-nine pts were eligible for safety analysis and the full analysis set (FAS) included 46 pts. The median age was 56 years (23–70), and 8 (16%) and 41 (84%) pts were treated in first- and second-line settings, respectively. Eleven pts (23.9%) were de-novo Stage 4, and 35 pts (76.1%) had progressed in metastatic disease after completion of local therapy. Median PFS was 9.3 months (M) (95% confidence interval [CI]: 6.4–12.3). Table 1 shows the efficacy data for each treatment line and includes ORR, complete response rate (CR), partial response rate (PR), stable disease rate (SD), progressive disease rate (PD), not evaluable rate (NE) and PFS in the FAS. The median relative dose intensities of eribulin, trastuzumab, and pertuzumab were 93.3% (77.0%–100%), 100% (96.0%–100%), and 100% (89.7%–100%), respectively, in the FAS. The grade 3/4 adverse events (AE) were neutropenia in 5 pts (10.2%), including 2 pts (4.1%) with febrile neutropenia; hypertension in 3 pts (6.1%), and other AEs in only one patient. The average of the ejection fraction did not decrease significantly. Symptomatic left ventricular systolic dysfunction was not observed. Conclusion: In pts with HER2-positive AMBC, first- and second-line therapy of eribulin in combination with pertuzumab plus trastuzumab demonstrated substantial antitumor activity with an acceptable safety profile. We are planning a phase III study comparing eribulin with taxanes in combination with pertuzumab plus trastuzumab for the treatment of HER2-positive AMBC. Efficacy data for each treatment lineTreatment LineTotal (n=46)First line (n=8)Second line (n=38)PFS (95% CI), months9.3 (6.4-12.3)20.8 (2.8-38.7)8.7 (7.2-10.2)ORR (%)28 (60.9)7 (87.5)21 (55.3)CR (%)8 (17.4)3 (37.5)5 (13.2)PR (%)20 (43.5)4 (50.0)16 (42.1)SD (%)11 (23.9)1 (12.5)10 (26.3)PD (%)5 (10.9)05 (13.2)NE (%)2 (4.3)02 (5.3) Citation Format: Kawaguchi H, Yamashita T, Masuda N, Kitada M, Narui K, Hattori M, Yoshinami T, Matsunami N, Yanagihara K, Kawasoe T, Nagashima T, Bando H, Yano H, Hasegawa Y, Nakamura R, Kashiwaba M, Morita S, Ohno S, Toi M. Phase II study of eribulin in combination with pertuzumab plus trastuzumab for human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-07.