Combination Of Eribulin Research Articles

Phase 2 study of eribulin mesylate in combination with carboplatin in patients with advanced triple-negative breast cancer.

e12551Background: Treatment of triple negative breast cancer (TNBC) remains one of the most challenging subtypes to treat because of the lack of specific therapies. In addition to the evaluation of platinum in the preoperative setting, studies in the metastatic setting further support that platinum may be active in metastatic TNBC. Another novel mitotic inhibitor currently being studied in this setting is eribulin.The aim of this Phase 2 study was to assess efficacy and safety of eribulin in combination with carboplatin as first-line therapy for locally recurrent or metastatic TNBC. Methods: Eligible patients were females with TNBC who had received one previous chemotherapy regimen in adjuvant setting (including an anthracycline and a taxane, but excluding platinum agents), an ECOG (PS) ≤ 1, and adequate hematological, renal and hepatic function. Patients received eribulin at 1.4 mg/m2 (IV over 2-5 minutes) on days 1 and 8 followed by carboplatin AUC5 (IV over 30 minutes) on day 1 every 21 days until dise...

Results of the Belgian expanded access program of eribulin in the treatment of metastatic breast cancer closely mirror those of the pivotal phase III trial

BackgroundEribulin is a non-taxane microtubule dynamics inhibitor that showed a survival benefit versus treatment of physician's choice in a phase III trial enrolling patients with metastatic breast cancer (MBC). MethodsThe E7389-G000-398 trial was designed to provide eribulin to MBC patients pre-treated with anthracylines, taxanes and capecitabine. Patient characteristics, efficacy and safety data were collected prospectively. Efficacy and survival analyses were performed using retrospectively collected data of patients treated at a single institution. ResultsOne hundred fifty-four patients were enrolled and the median number of previous lines of chemotherapy was 4. The most frequent adverse events were fatigue/asthenia (74%), alopecia (55%), peripheral neuropathy (46%) and neutropenia (43%). Objective response rate (ORR) was 24% in the evaluable population and 14% in patients pre-treated with both taxanes and vinorelbine. In patients with oestrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)– MBC, response rate was 29% and 21% with triple-negative disease. Activity was minimal in HER2+ MBC treated with eribulin monotherapy (14% ORR). Median progression-free survival was 3.2 months. Median overall survival was 11.3 months; 77% of patients were alive at 6 months and 43% at 12 months. ConclusionEribulin was active in MBC patients with a high tumour burden and predominant visceral disease. Safety profile was similar to what was reported in the phase III trials. Prophylactic granulocyte colony-stimulating factor administration allowed optimal dose intensity and could have contributed to the recorded response rate. Activity is sustained after treatment with taxanes and vinorelbine. The recently investigated combination of eribulin and trastuzumab should lead to higher activity in HER2-positive MBC.

Abstract P6-13-17: The combination of eribulin and everolimus results in enhanced suppression of tumors in mouse models of triple negative breast cancer

Abstract INTRODUCTION. Triple negative breast cancer (TNBC) is an aggressive form of breast cancer with poor overall and relapse free survival. TNBC does not have targeted or matched therapies. Patients have worse outcomes after chemotherapy than with other subtypes of breast cancer. TNBC accounts for 12-17% of all breast cancers, leaving an unmet need for targeted therapy. Efforts to profile these tumors have revealed several potential targets. The PI3K/AKT/mTOR pathway is a signal transduction pathway that links growth related hormone receptor interaction to downstream targets such as AKT and mammalian target of rapamycin (mTOR). This pathway targets affect cell proliferation, survival, and apoptosis. Patients with TNBC have high levels of AKT expression and activation of this pathway. Microtubule-targeting agents have been used in TNBC. Eribulin mesylate is a microtubule-targeting agent with benefits in treating taxane and anthracycline refractory breast cancer via a microtubule targeting anti-mitotic mechanism. It has been approved for the treatment of TNBC in heavily pretreated patients. Despite targeted therapy, breast cancer cells can grow resistant. Targeting multiple cancer growth pathways has been used in patients that progress on therapy or fail to respond. We hypothesized that targeting both mitotic blockade and PI3K/AKT/mTOR pathway may provide enhanced suppression of TNBC growth in both syngeneic and xenogeneic mouse models. MATERIALS AND METHODS. MDA-MB-468 is a human TNBC cell line. 4T1 is a highly metastatic mouse TNBC cell line derived from a spontaneously arising Balb/c mammary tumor. 4T1 and MDA-MB-468 tumor cells were injected into the mammary fat pad of female Balb/c and NOD/SCID/IL2Rgamma null (NSG) mice (with matrigel) respectively. After tumors were formed Balb/c mice were treated three times per week with vehicle, eribulin (0.75 mg/kg i.v.), RAD001 (5 mg/kg via oral gavage) or a combination of both. NSG mice were treated three times per week with vehicle, eribulin (0.5 mg/kg i.v.), RAD001 (5 mg/kg by oral gavage), or a combination of both. Tumor volumes and body weights were measured. Student t-test was used to compare the means of two groups and determine the p value (p<0.05 is significant). N=3-8 per group. Table I. 4T1 mouse breast cancer modelTreatmentTumor Volume (mm3)+/-SEMVehicle511.6+/-56.82Eribulin445.6+/-92.17Everolimus324.9+/-24.55Combination171.4+/-16.07 p valueCombination vs. Vehicle0.0001Combination vs. Eribulin0.01Combination vs. Everolimus0.001 Table II. MDA-MB-468 human breast cancer cells in immune deficient mice.TreatmentTumor Volume (mm3)+/-SEMVehicle966.8+/-69.2Eribulin67.81+/-11.79Everolimus830.6+/-156.3Combination31.37+/-3.37 p valueCombination vs. Eribulin0.041Combination vs. Everolimus0.0076 RESULTS. In the 4T1 syngeneic breast cancer mouse model, the combination of Eribulin and Everolimus resulted in marked suppression of tumor growth which was statistically significant versus vehicle treatment alone, or Eribulin or Everolimus alone (Table I). In the MDA-MB-468 model, the combination of Eribulin and Everolimus demonstrated marked suppression of tumor growth which was statistically significant compared to either agent alone (Table II). Citation Format: Marcinkowski E, Luu T, Yuan Y, Mortimer J, Leong L, Portnow J, Xing Q, Wen W, Yim J. The combination of eribulin and everolimus results in enhanced suppression of tumors in mouse models of triple negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-17.

Abstract OT3-02-05: 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 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 characterized by high cell proliferation, aggressive tumor behavior, and chemo-resistance. Trial design: This is an open-label, national multicenter phase 2 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 triple negative breast cancer (TNBC). A prospective, molecular correlative study is being carried out on germinal DNA of study population. Eligibility criteria: Patients must have locally advanced or metastatic breast cancer with estrogen receptor-negative (ER < 1%), progesterone receptor-negative (PR < 1%), and human epidermal growth factor receptor 2-negative (Her2-) (0, 1+) or, e.g. in HER2 2+ cases, fluorescent in situ hybridization (FISH) < ratio of 1.8, status. Previous chemotherapy including an anthracycline and a taxane (unless one or both were clinically contraindicated) is mandatory. Up to one prior chemotherapy regimen for metastatic disease is permitted, with the exception of treatment with eribulin and gemcitabine. Patients must have: Measurable disease; Eastern Cooperative Oncology Group (ECOG) performance status 0-2; adequate bone marrow reserve, liver and renal function. Specific aims: The main objective of this trial is to evaluate the activity of eribulin plus gemcitabine in terms of overall response rate (ORR; RECIST 1.1). Secondary end-points are: Feasibiliy, safety (CTC-AE V4.0), progression-free and overall survival. The molecular correlative study aim is to assess the role of germinal DNA polymorphisms and BRCA mutations in predicting efficacy and toxicity with the combination regimen. Statistical methods: The primary endpoint is the ORR. The study is being carried out according to Optimal Simon's two stage design. We chose the lower activity (p0) of 0.20 and target activity level (p1) of 0.35. A total of 83 (37 in the first stage, 46 in the second one) assessable patients will be needed to guarantee 90% power under a α-level of 5%. Genotypic correlations with clinical responses and toxicities will be performed using a two-tailed Fisher's exact test. A logistic regression analysis including patients' genotypes will be used to identify independent prognostic variables influencing both clinical responses and toxicities. Present accrual and target accrual: A total of 83 eligible patients will be enrolled from multiple institutions. To date (June 09, 2015), the first stage has been closed with 37 patients enrolled. The second stage is now recruiting 46 additional patients. Citation Format: Musolino A, Caldara A, Montemurro F, Frassoldati A, Cavazzini G, Cavanna L, Todeschini R, Camisa R, Tognetto M, Pinto C. 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 on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-02-05.

Abstract OT1-03-19: Design of a phase 1b/2 study to evaluate the efficacy and safety of eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer

Abstract Eribulin mesylate, a microtubule inhibitor, is indicated for treatment of patients (pts) with metastatic breast cancer (MBC) with ≥2 prior chemotherapies for metastatic disease, including an anthracycline or taxane. Pembrolizumab is a human programmed death receptor-1 (PD-1)-blocking antibody indicated for treatment of pts with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAFV600-mutation positive, a BRAF inhibitor. Pembrolizumab is also being evaluated for treatment of metastatic triple-negative breast cancer (mTNBC) and multiple tumor types. We report the design of an open-label, single-arm, multicenter, phase 1b/2 study to evaluate safety and efficacy of the eribulin and pembrolizumab combination in pts with mTNBC previously treated with 0 to 2 lines of therapy in the metastatic setting. From August 2015 to February 2017, approximately 95 pts (aged ≥18 yrs) will be enrolled (n=12 phase 1b; n=83 phase 2) to reach 80 evaluable pts. Accrual has not yet commenced. Pts with measurable disease of ≥1 lesion >10 mm in long-axis diameter (nonlymph nodes) or >15 mm in short-axis diameter (lymph nodes) and an ECOG status of 0 or 1 will be included. Exclusion criteria include pts who received adjuvant chemotherapy within the past 6 months, chemotherapy/biological therapy within the past 3 wks, or radiation or small molecule targeted therapy within the past 2 wks. Pts will also be excluded if they have an autoimmune disease requiring immunosuppression or were previously treated with eribulin or any anti-PD-1, PD-ligand (L) 1, or PD-L2 agent. Phase 1b includes a safety run-in cohort in which ≥6 pts will receive intravenous (IV) eribulin 1.4 mg/m2 (equivalent to 1.23 mg/m2 eribulin [expressed as free base]) on day (d) 1 and d8 and IV pembrolizumab 200 mg on d1 of a 21d cycle. Dose-limiting toxicity (DLT) will be assessed in the first cycle. This dose will be selected as the recommended phase 2 dose (RP2D) if ≤1 pt has a DLT or, if necessary, alternative doses may be explored. Pts will be stratified by prior chemotherapy for MBC (0, ∼70%; 1–2, ∼30%) and will receive RP2D combination treatment. Pts can remain on 1 or both study drugs with clinical benefit until intercurrent illness, unacceptable toxicity, or disease progression. Bayesian predictive probability of response rate, based on the goal of claiming combination superiority at study end, will be used to monitor response rate after postbaseline tumor assessments for ≥38 pts. The study can be stopped early for efficacy or futility. Primary objectives include determination of safety and tolerability (phase 1b) and evaluation of objective response rate of the drug combination; secondary endpoints include evaluation of progression-free survival (PFS), overall survival (OS), and duration of response (DOR). PFS, OS, and DOR will be analyzed using Kaplan–Meier product-limit estimates. Median PFS, OS, and cumulative probability of PFS, OS, and DOR at 6 and 12 months will be presented with 2-sided 95% confidence intervals. Relationship between PD-L1 tumor status and efficacy endpoints will also be evaluated. For further information please contact Erhan Berrak (erhan_berrak@eisai.com). Citation Format: Berrak E, Atkan G, Song J, Almonte A, Karantza V, Yuan R. Design of a phase 1b/2 study to evaluate the efficacy and safety of eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-19.

Abstract P5-03-09: Eribulin affects E-cadherin localization consistent with a reversal of the epithelial-to-mesenchymal transition

Abstract Microtubule targeting agents (MTAs) are some of the most important compounds used to treat breast cancer. While both microtubule stabilizers and destabilizers have utility against breast cancers, not all patients respond and there are differences among the agents. Eribulin is a microtubule depolymerizer used to treat patients with locally advanced or metastatic breast cancerwho have previously received at least two chemotherapeutic regimens, including an anthracycline and a taxane. Our goal was to compare the effects of eribulin to four other clinically relevant MTAs on signaling processes important for cancer cell metastasis that are known to be regulated by the cytoskeleton. One process is the appropriate localization of E-cadherin, which plays a critical role in maintaining an epithelial phenotype by facilitating the ability of cells to form cell-cell contacts. These contacts help prevent cell motility and epithelial to mesenchymal transition (EMT) by sequestering several proteins involved in EMT at the plasma membrane, including β-catenin. E-cadherin is absent from the cell membrane in cells with a mesenchymal phenotype. We hypothesized that eribulin could affect the internalization of E-cadherin and promote its retention at the cell periphery and that it might do so differently than other MTAs because eribulin has been shown to reverse EMT in breast cancer cells and in xenograft models. Mesenchymal breast cancer HCC1937 cells were treated for 2 hr with MTAs using a concentration that caused a similar degree of microtubule disruption and localization of E-cadherin was evaluated. The microtubule destabilizers eribulin and vinorelbine promoted a localization of E-cadherin to the plasma membrane. In contrast, the microtubule stabilizers paclitaxel, docetaxel and ixabepilone caused E-cadherin to localize to internal structures. β-catenin, a protein bound by E-cadherin, also became enriched at the cell periphery after microtubule destabilizer treatment. In the more epithelial MCF-7 cell line, E-cadherin was constitutively localized at the cell periphery and the MTAs had no effect on this localization, consistent with the epithelial phenotype. Src family kinases (SFKs) are known to promote the internalization and degradation of E-cadherin and to promote EMT. Accordingly, the SFK inhibitor dasatinib caused effects similar to eribulin and vinorelbine by promoting the localization of E-cadherin to the plasma membrane in the mesenchymal HCC1937 cell line. Subsequent studies supported this result and demonstrated the increased activity of the combination of eribulin and dasatinib in HCC1937 cells. The ability of eribulin to rapidly induce changes in E-cadherin localization is consistent with its ability to reverse EMT. Studies are ongoing to evaluate whether eribulin's effects are mediated through the ability of SFKs to regulate E-cadherin. Our results show differences between microtubule stabilizers and destabilizers and are consistent with the previously shown ability of eribulin to reverse EMT. Funding for this work provided by Eisai Inc. Citation Format: Dybdal-Hargreaves NF, Rohena CC, Risinger AL, Mooberry SL. Eribulin affects E-cadherin localization consistent with a reversal of the epithelial-to-mesenchymal transition. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-03-09.

Результаты первого ретроспективного анализа данных по применению эрибулина у пациенток с метастатическим раком молочной железы в условиях реальной клинической практики в России

The article shows the experience of eribulin application in actual clinical practice in Oncology institutions of the Russian Federation concerning metastatic breast cancer. We have analyzed the efficacy of the drug in case of different subtypes of the tumor and have chosen patients, depending on the location of metastases and with proven maximum efficacy of eribulin. We have shown the side reactions and the possibility of application of eribulin in combination with other antineoplastic agents.

Effects of Paclitaxel and Eribulin in Mouse Sciatic Nerve: A Microtubule-Based Rationale for the Differential Induction of Chemotherapy-Induced Peripheral Neuropathy

Microtubule targeting agents (MTAs) often lead to treatment limiting and life threatening side effects, including chemotherapy-induced peripheral neuropathy (CIPN). The frequency of severe CIPN varies among different MTAs. Since the microtubule binding interactions and mechanisms of action also vary among MTAs, we hypothesized that these distinct mechanisms may underlie the variability in frequency of severe CIPN. Using a two-week, maximum tolerated dose model, we morphologically and biochemically analyzed sciatic nerves from mice treated with either paclitaxel or eribulin. These drugs differ in their manner of microtubule binding and mechanisms of action and reports indicate paclitaxel also induces a higher frequency of severe CIPN than does eribulin. Morphologically, paclitaxel increased the frequency of observed signs of axon degeneration more significantly than did eribulin. Alternatively, eribulin but not paclitaxel induced occasional myelin "halo" structures. Biochemically, paclitaxel, and eribulin both induced α-tubulin expression (~1.9- and ~2.5-fold, respectively) and tubulin acetylation, a marker for microtubule stability, (~5- and ~11.7-fold, respectively). Eribulin but not paclitaxel-induced EB1 expression ~2.2-fold while paclitaxel but not eribulin mildly suppressed EB3 expression. Both EB proteins are associated with microtubule growth. Eribulin's combination of relatively mild deleterious morphological effects coupled with more potent biochemical changes promoting microtubule stability and growth in mice correlate with lower frequencies of severe CIPN in humans. We suggest that these eribulin-induced effects create a relatively stable microtubule network that compensates, in part, for the toxic anti-cancer effects of the drug, leading to fewer reported incidences of CIPN than for paclitaxel.

Combination of eribulin (E) and capecitabine (C) in elderly metastatic breast cancer (MBC): Update of a new option suitable in older elderly.

9540 Background: E mesylate, a nontaxane microtubule dynamics inhibitor is widely prescribed for MBC pts pretreated with at least 1-2 lines of chemotherapy, including anthracyclines and taxanes (A&...

Abstract OT3-1-04: A phase 2 study of eribulin in combination with pertuzumab and trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 (HER2)-positive breast cancer (SONG-02)

Abstract Background: Pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization, has a mechanism of action that is complementary to that of trastuzumab, and the combination of pertuzumab plus trastuzumab plus taxanes, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival (PFS). However, in the second and later line treatment of HER2-positive advanced or recurrent breast cancer, it has not settled whether it should be treated with pertuzumab plus trastuzumab plus chemotherapy or with trastuzumab plus chemotherapy. Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that has been proved to prolong the overall survival of advanced or recurrent breast cancer patients compared with the treatment of physician's choice. The benefit of eribulin in combination with trastuzumab for patients with locally recurrent or metastatic HER2-positive breast cancer has been reported. However, the efficacy and safety of eribulin in combination with pertuzumab and trastuzumab for advanced or recurrent HER2-positive breast cancer patients has not been reported. The purpose of this study is to evaluate the efficacy and safety of eribulin in combination with pertuzumab and trastuzumab as second and later line therapy for patients with advanced or recurrent HER2-positive breast cancer. Trial Design: This is a multicenter single arm phase 2 study for advanced or recurrent HER2-positive breast cancer patients who have experienced progression with anti-HER2 therapy. Patients received eribulin mesylate 1.4mg/m2 administered via intravenous (IV) infusion over 2 to 5 minutes on Days 1 and 8 each 21-day cycle and pertuzumab 840mg/kg IV and trastuzumab 8mg/kg IV over 90 minutes on Day 1 of Cycle 1. Thereafter eribulin mesylate 1.4mg/m2 and pertuzumab 420mg/kg and trastuzumab 6mg/kg was infused each 21-day cycle until disease progression or the appearance of toxic effects that could not be effectively managed. The primary endpoint is PFS of the combination therapy, based on local assessment of response using RECIST 1.1 criteria. Secondary endpoints are overall response rate (ORR), safety and tolerability. In addition, we examine PFS and safety according to the most recent treatment regimen. The study was conducted in accordance with the Declaration of Helsinki (2008), and the protocol and informed consent forms were submitted for approval to institutional review boards by the primary investigators. All patients provided written informed consent before undergoing any study-related procedures Statistical Method: All efficacy analyses were based primarily on the full analysis set (FAS), which included all patients who received over 1 dose(s) of study treatment. The PFS and ORR were calculated 95% confidence intervals (CIs). Treatment of 39 evaluable patients with the identified phase 2 doses will detect this difference with a power of 80% and alpha=5% (one-sided test). Accounting for a 10% invaluable rate and lead-in patients, a total of 43 patients will be enrolled on the study. Clinical trial information UMIN000014107. Citation Format: Hajime Abe, Shunji Kamigaki, Yoshifumi Komoike, Nobuki Matsunami, Yoshiaki Nakano, Kenji Tezuka, Junji Tsurutani, Jun Yamamura, Keiichi Yamazaki. A phase 2 study of eribulin in combination with pertuzumab and trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 (HER2)-positive breast cancer (SONG-02) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-1-04.

Abstract P3-13-04: Efficacy and safety of eribulin in combination with capecitabine in patients with metastatic breast cancer: an open-label, phase II dose-confirmation study

Abstract Background: Two phase III trials have demonstrated the efficacy of eribulin monotherapy in patients with metastatic breast cancer (MBC) who have progressed after previous anthracycline and taxane chemotherapy. Capecitabine is also an effective agent in patients with MBC. A phase Ib dose-escalation study has investigated two dosing schedules of eribulin in combination with capecitabine to determine the recommended phase II dose. The aims of this open-label, non-randomized, phase II, dose-confirmation study were to determine efficacy and safety of this combination in patients with MBC. Interim data to April 2014 are provided here; final results will be presented at the meeting. Methods: Eligible patients were females with MBC who had received up to 3 previous chemotherapy regimens in any setting (including an anthracycline and a taxane, but excluding capecitabine), an ECOG performance status (PS) ≤1, and adequate hematological, renal and hepatic function (at study entry, 20 [47.6%] patients had liver metastases; 24 [57.1%] had lung metastases). Patients received 1.4 mg/m2 eribulin mesylate (equivalent to 1.23 mg/m2 eribulin [expressed as free base]) i.v. on days 1 and 8 plus oral capecitabine 1000 mg/m2 b.i.d. on days 1–14 (21-day cycles) until disease progression, unacceptable toxicity or death. Disease assessments (CT scans) were performed every 6 weeks. The primary outcome was the objective response rate (ORR); secondary outcomes included clinical benefit rate (CBR), progression-free survival (PFS), and safety and tolerability. Results: 42 females (median age: 52.5 years [range: 32–74]; ECOG-PS of 0: n = 18 [42.9%]) were enrolled; patients received study drug as a 1st-line (23.8% [n = 10]), 2nd-line (45.2% [n = 19]) or ≥3rd-line (31.0% [n = 13]) chemotherapy. A median of 8 (range: 1–30) treatment cycles were administered (59.5% of patients received ≥6 cycles), with 94.4% of eribulin doses and 94.5% of capecitabine doses given as planned. The ORR was 42.9% and the CBR was 57.1% (Table), with a median PFS of 7.1 months (95% CI: 4.4, 9.8). The most common grade 3/4 adverse events (AEs) were neutropenia (66.7%), leukopenia (14.3%), febrile neutropenia (7.1%) and anemia, fatigue, nausea and peripheral sensory neuropathy (each 4.8%). AEs of special interest (any grade) included: hand–foot syndrome (26.2%), peripheral neuropathy (23.8%), and diarrhea (21.4%). The incidences of AEs leading to study drug dose adjustment were: 47.6% of patients (dose interruption), 42.9% (dose reduction), and 2.4% (drug withdrawal). Table: Tumor response (investigator assessment)PatientsN = 42n (%)n (%)Complete response (CR)2 (4.8)Partial response (PR)16 (38.1)Stable disease (SD)16 (38.1)Progressive disease (PD)3 (7.1)Not evaluable5 (11.9)Objective response rate (CR + PR)18 (42.9)95% CI27.7, 59.0Clinical benefit rate (CR + PR + SD ≥ 6 months)24 (57.1)95% CI41.0, 72.3 Conclusions: This phase II study suggests that eribulin in combination with capecitabine is efficacious in patients with MBC, with a safety and tolerability profile consistent with previous data. Phase III studies of this combination in patients with MBC are warranted. Citation Format: Chris Twelves, Muhammad Y Nasim, Alan Anthoney, Claudio I Savulsky, Shuxin Yin, TR Jeffry Evans. Efficacy and safety of eribulin in combination with capecitabine in patients with metastatic breast cancer: an open-label, phase II dose-confirmation study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-13-04.

Abstract P3-10-07: Phase I trial of eribulin in combination with S-1 for advanced and recurrent breast cancer patients

Abstract Introduction: Eribulin is a non-taxane microtubule dynamics inhibitor that has been proved to prolong overall survival in patients with advanced and recurrent breast cancer compared to treatment of physician’s choice. S-1 is an oral fluoropyrimidine anticancer agent that combines tegafur as the effector drug with two modulators, gimeracil, and oteracil potassium, and has shown promising antitumor activity as a single agent for the treatment of advanced breast cancer. In the basis of these results, we aimed to assess the efficacy of the combination of these two drugs in patients with advanced and recurrent breast cancer. In this trial, we determined maximum tolerated dose (MTD) and phase II recommended dose of Eribulin and S-1 combination therapy. Methods: A traditional 3+3 dose escalation design was implemented. 12 patients pre-treated with anthracycline and taxane were enrolled. As an initiation level, patients received s-1 50 mg/m2 from day1 to day14, and Eribulin 1.1mg/m2 on day1, and day8. In level 2, Eribulin dose was increased to 1.4mg/m2. In level 3, S-1 dose was increased to 80 mg/m2. Results: In level 1 or 2, no dose limiting toxicity (DLT) was observed. In level 3, grade 3 hypokalemia occurred in 1 case. The level 3 dose level was determined as phase II recommended dose. Neutropenia was observed in all cases, 3 of which was grade 3 febrile neutropenia. However, other non-hematological toxicity was mild, and the toxicity of the both drugs Safety (N=12)Adverse EventGrade 3/4Leukopenia3 (25%)Neutropenia10 (83%)Febrile Neutropenia3 (25%)Hypokalemia1 (8%) was not enhanced by the combination. Partial response Efficacy (N=12)CR0 (0%)PR5 (41%)SD≥24 weeks2 (17%)SD<24 weeks3 (25%)PD2 (17%)Clinical Benefit7 (58%)Disease Control Rate10 (83%) is confirmed in 5/11 patients with measurable lesions. Conclusion: We have shown that treatment with Eribulin and S-1 is active and well tolerated in patients with advanced and recurrent breast cancer, suggesting that this combination therapy may have potential as a new treatment option. A phase II study is being conducted to evaluate the efficacy and safety. Citation Format: Tsutomu Iwasa, Junji Tsurutani, Satomi Nishida, Yoshifumi Komoike, Kazuhiko Nakagawa. Phase I trial of eribulin in combination with S-1 for advanced and recurrent breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-10-07.

Abstract OT2-2-02: Phase I/II clinical trial on the combination of carboplatin, eribulin and E7449

Abstract The combination of carboplatin and eribulin has been found to be effective in triple negative breast cancer patients. A recently conducted neoadjuvant clinical trial showed a pathologic complete response (pCR) of 45% with four cycle of carboplatin and eribulin. Recent preclinical data from EISAI suggest that there is synergy between carboplatin, eribulin and E7449 (an oral PARP inhibitor) in BRCA deficient and PTEN mutated xenograft models. Loss of Heterozygosity (LOH) is DNA alterations which develop through double strand DNA breaks. The homologous recombination (HRD) Score is calculated by the number of LOH regions greater 15Mb in length and less than an entire chromosome present in the genome. A high HRD score is present in BRCA deficient tumors and predicts for sensitivity to platinum-based chemotherapy. We propose a phase I/II clinical trial on the combination of carboplatin, eribulin and E7449. As part of the phase I clinical trial HRD will be performed and correlated to response to therapy. In the phase II clinical trial women with BRCA related breast or ovarian cancer, triple negative breast or ovarian cancer with high HRD score or PTEN deficient will be enrolled at a dose level found during the phase I clinical trial. Tissue will be requested to test for PARP inhibition. The primary endpoint of the phase II clinical trial is response rate. A total of 30 patients will be enrolled to the phase II clinical trial. Citation Format: Virginia Kaklamani, Ruth o'Regan, Kari Wisinski, Kent Hoskins, James Wade, William Gradishar. Phase I/II clinical trial on the combination of carboplatin, eribulin and E7449 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-2-02.

Abstract P5-06-03: Combination of the PARP inhibitor E7449 with eribulin +/- carboplatin in preclinical models of triple negative breast cancer

Abstract Introduction: In a small neoadjuvant study in patients with triple negative breast cancer (TNBC) the combination of eribulin plus carboplatin was effective, with a pathologic complete response rate of 43% following 4 cycles of treatment. Significant numbers of sporadic TNBC tumors are deficient in DNA repair capacity and share clinical and pathological features with hereditary BRCA1 mutant disease. PARP inhibitors have demonstrated synthetic lethality in cancer cells with defective DNA repair and have therapeutic potential for TNBC. In this study we describe the combination of PARP inhibitor E7449 with eribulin +/- carboplatin in preclinical models of TNBC. Methods: E7449, an orally available PARP inhibitor, was administered in combination with eribulin +/- carboplatin to 4 s.c. xenograft models of TNBC: MDA-MB-436 (BRCA1 mutant, PTEN deficient), MDA-MB-468 (BRCA wild type, PTEN deficient), HCC1806 and MDA-MB-231 (BRCA and PTEN wild type). Results and Discussion: Addition of E7449 to eribulin significantly delayed tumor progression in PTEN deficient MDA-MB-468 xenografts. In the BRCA1 mutant and PTEN deficient MDA-MB-436 xenograft model, combination of E7449 with eribulin enhanced antitumor activity versus eribulin alone. Similar potentiation was observed for carboplatin upon combination with E7449. Treatment of MDA-MB-436 xenografts with the triple combination of E7449 + eribulin + carboplatin was more efficacious than any double combination and was well tolerated at the doses examined. In contrast, no significant combination activity was observed for E7449 plus eribulin in the BRCA and PTEN wild type xenografts HCC1806 and MDA-MB-231, and similarly no potentiation of carboplatin was observed in an MDA-MB-231 xenograft. Notably, combination activity was observed in the BRCA1 mutant (MDA-MB-436) and PTEN deficient (MDA-MB-436 and MDA-MB-468) xenografts and not in the BRCA and PTEN wild-type models (HCC1806 and MDA-MB-231). Data from ongoing studies to evaluate the combination activity of E7449 + eribulin in patient-derived xenograft (PDx) models of TNBC will be presented at the meeting. Potential biomarkers of sensitivity to the combination are under investigation in both cell line xenograft and PDx models and will be described. Conclusion: The addition of E7449 to eribulin +/- carboplatin increased antitumor activity in a subset of TNBC models. Biomarker studies aimed at a better understanding of the underlying cause of sensitivity are underway. The preclinical data support assessment of E7449 + eribulin + carboplatin combination therapy in the current phase I/II clinical trial. Citation Format: Sharon McGonigle, Jiayi Wu, Donna Kolber-Simonds, Natalie C Twine, Jue-lon Shie, Noel Taylor, Sergei Agoulnik, Zoltan Dezso, Shannon McGrath, Mark Matijevic, Shanqin Xu, Galina Kuznetsov, Mary Woodall-Jappe, Kenichi Nomoto. Combination of the PARP inhibitor E7449 with eribulin +/- carboplatin in preclinical models of triple negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-06-03.

Abstract P3-11-08: Eribulin/cyclophosphamide (ErC) versus docetaxel/cyclophosphamide (TC) as neoadjuvant therapy in locally advanced HER2-negative breast cancer: A randomized phase II trial of the Sarah Cannon Research Institute

Abstract Background: Pathologic complete response (pCR) following neoadjuvant chemotherapy for locally advanced breast cancer strongly correlates with improved disease-free survival, rates of breast-conserving surgery, and provides an early indicator of treatment efficacy. Standard taxane-containing neoadjuvant combinations result in pCR rates of 18% in unselected patient (pt) populations. Eribulin (Er) is a novel inhibitor of microtubule dynamics. In the EMBRACE trial, Er demonstrated a survival advantage in anthracycline and taxane pretreated breast cancer. This study evaluated non-anthracycline regimens of Er in combination with cyclophosphamide (ErC) and docetaxel/cyclophosphamide (TC) as neoadjuvant therapy in HER2-negative breast cancer. Methods: Adult women with histologically confirmed invasive HER2-negative (defined as IHC 0-1+ or FISH/SISH negative), clinical stage T1-3, N0-2, M0 (pN3a disease allowed) adenocarcinoma of the breast were eligible. Additional eligibility criteria included: ECOG PS 0,1 or 2; normal cardiac function, known hormone receptor status for stratification; adequate hematologic, liver, and renal function. Following a 10 pt lead-in to confirm the safety and feasibility of ErC, pts were randomized in a 2:1 ratio: Arm 1, Er 1.4 mg/m2 IV (Days 1 & 8) and C 600 mg/m2 IV (Day 1); Arm 2, T 75 mg/m2 IV and C 600 mg/m2 IV on Day 1, both regimens administered q 21 days x 6 cycles followed by surgery. Locoregional radiation and/or antiestrogen therapy were prescribed postoperatively according to standard guidelines. Tumor samples were collected at baseline and from residual disease noted at the time of surgery. A pCR rate ≥18% in pts treated with ErC warranted further evaluation. Results: Enrollment was completed April 2014 (76 pts); 66 pts were randomized (Arm 1, 44; Arm 2, 22). Median age was 52 years (range, 23-77); 88% ECOG 0; 79% invasive ductal adenocarcinoma; median baseline primary tumor size 3cm (range, 0.4-10cm; 30% were T3); axillary nodes clinically positive in 51%. Thirty-three percent were triple negative. 55 pts (72%) received neoadjuvant therapy and underwent surgery. 16 pts continue to receive study treatment. At this time, pts who underwent surgery have similar pCR rates with ErC and TC (14%, 5/37 vs. 11%, 2/18 respectively). 3 of 51 hormone receptor positive pts (6%) and 4 of 25 triple negative pts (16%) had pCR. Neutropenia (40%) was the most common grade 3/4 toxicity. Common treatment-related toxicities included: fatigue (66%), alopecia (57%), and nausea (54%). Peripheral neuropathy incidence is currently lower with ErC than with TC (30% vs 45%) with 3 grade 3 events on TC. Prophylactic growth factor use was higher in TC than with ErC (77% vs 24%). Conclusions: Eribulin in combination with cyclophosphamide was well tolerated with no unexpected toxicities. At present, pCR rates with both regimens are within the range previously reported with docetaxel/cyclophosphamide and other standard taxane-containing neoadjuvant regimens. Final efficacy and toxicity data will be presented. A planned exploratory correlative tissue analysis may identify tumors more likely to derive benefit from eribulin-based therapies. Citation Format: Denise Yardley, Karyn Dyehouse, Aruna Mani, Carmen Calfa, David Drosick, Kathleen Yost, Diana Shipley, Raven Quinn, Robyn Young, Lindsey Finney, Chris Earwood, Mythili Shastry, John Hainsworth. Eribulin/cyclophosphamide (ErC) versus docetaxel/cyclophosphamide (TC) as neoadjuvant therapy in locally advanced HER2-negative breast cancer: A randomized phase II trial of the Sarah Cannon Research Institute [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-11-08.

Abstract P3-09-09: Eribulin mesylate plus capecitabine for adjuvant treatment in post-menopausal ER+ early-stage breast cancer: A phase 2, multicenter, open-label study using 2 different dosage regimens

Abstract Introduction: Eribulin mesylate is a novel non-taxane microtubule inhibitor. The primary objective of this study was to explore feasibility of administering eribulin plus capecitabine as adjuvant therapy in subjects with early-stage, estrogen receptor-positive (ER+) breast cancer. Methods: In this phase 2, open-label, multicenter study, 67 postmenopausal women with early HER2-normal/HER2-negative, ER+ breast cancer received four 21-day cycles of treatment with eribulin mesylate (1.4 mg/m2 IV on day 1 and day 8 of each cycle) in combination with capecitabine (900 mg/m2 orally twice daily on days 1 through 14 of each cycle). A second dosage regimen for capecitabine was initiated after dose reductions and treatment discontinuations were noted and attributed to capecitabine-related toxicities, such as grade 3/4 GI events and hand-foot syndrome. As a consequence, capecitabine was administered to an additional cohort of 10 subjects at a fixed dose of 1500 mg given orally twice daily on a 7 days on/7 days off schedule for the 4 cycles; eribulin mesylate was administered on the same dosage schedule as the original regimen (1.4 mg/m2 IV on day 1 and day 8 of each cycle). The 7 days on/7 days off regimen for capecitabine was based on mathematical modeling and has been shown to have an acceptable toxicity profile, including minimal gastrointestinal toxicity, when given in combination with bevacizumab to patients with metastatic breast cancer. Feasibility was assessed based on relative dose intensity (RDI) of the combination using prespecified criteria of 80% of subjects achieving an RDI of at least 85% of the regimen with lower 95% confidence boundary >70%; safety and tolerability were also assessed. Results: Among subjects on the original eribulin plus capecitabine dosing schedule (n=64), the average (SD) RDI was 90.6% (11.94%) and the feasibility rate was 81.3% (95% lower CI: 71.4%), indicating that this dosage regimen is feasible. Dose reductions, missed doses, and withdrawals due to adverse events were ascribed more to capecitabine (36%, 85%, and 18%, respectively) than to eribulin (21%, 8%, and 12%, respectively), which led to higher RDI and feasibility rates for eribulin (93.5% and 82.8%, respectively) than for capecitabine (87.8% and 71.9%). Grade 3/4 hand-foot syndrome ascribed to capecitabine only, led to dose reductions in 11.9% of subjects under the original dosing schedule. The most common adverse events under the original dosing schedule were alopecia (77.6%), fatigue (58.2%), and nausea (52.2%). With the new dosing schedule (n=9), higher RDI and feasibility rates were achieved, the average RDI was 96% and the feasibility rate was 100%, indicating that this alternative regimen is also feasible, and probably better. (Detailed feasibility and safety data with new dosing regimen will be available at the time of the presentation.) Conclusions: Adjuvant use of the combination of eribulin plus capecitabine is feasible in patients with early, HER2-normal/HER2-negative, ER+ breast cancer. The combination had an acceptable safety profile under the original dosing schedule and has the potential to be improved by use of a 7 day on/7 day off regimen of capecitabine. Citation Format: John W Smith II, Svetislava Vukelja, Anthony Hoffman, Vicky Jones, Kristi McIntyre, Erhan Berrak, Angela Teng, David Cox, Joyce O'Shaughnessy. Eribulin mesylate plus capecitabine for adjuvant treatment in post-menopausal ER+ early-stage breast cancer: A phase 2, multicenter, open-label study using 2 different dosage regimens [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-09-09.

Clinical effects of prior trastuzumab on combination eribulin mesylate plus trastuzumab as first-line treatment for HER2+ locally recurrent or metastatic breast cancer (MBC): Results from a phase 2, single-arm, multicenter study.

139 Background: Eribulin mesylate, a novel nontaxane microtubule dynamics inhibitor in the halichondrin class of antineoplastic drugs, is indicated for women with MBC who previously received ≥ 2 chemotherapy regimens in the metastatic setting. Primary data from a phase 2 trial on first-line combination eribulin + trastuzumab (TRAS) in HER2+ patients (pts) showed a 71% objective response rate (ORR) and tolerability consistent with the known profile of these agents. Here we present prespecified endpoint data for this study by prior TRAS use. Methods: Pts with HER2+ MBC who had not received prior chemotherapy for MBC received eribulin mesylate 1.4 mg/m2 IV on days 1 and 8 of each 21-day cycle and initial TRAS (8 mg/kg IV/day 1), followed by 6 mg/kg/day 1 of each subsequent cycle. Response, progression-free survival (PFS), and tolerability were assessed in patients who had and had not received prior TRAS treatment. Results: The 52 pts (median age, 59.5 years) received combination eribulin + TRAS, for a median treatment duration of ~30 weeks; 40% (n=21) were previously treated with TRAS in the neo-adjuvant/adjuvant setting. There was median of 23 months since completion of adjuvant treatment prior to retreatment with eribulin + TRAS for first-line MBC.Efficacy, assessed by ORR, clinical benefit rate (CBR), PFS, and duration of response (DOR), was largely consistent in pts who received prior TRAS relative to pts who had not received prior TRAS (see table). Overall, grade (G) 3-5 adverse events (AEs), treatment-related AEs (TRAEs), and discontinuations (d/c) were similar between groups (Table). Conclusions: In this phase 2 single-arm trial in pts with HER2+ MBC, eribulin + TRAS demonstrated activity and was well tolerated as first-line treatment, irrespective of prior (neo) adjuvant TRAS treatment. Clinical trial information: NCT01269346. [Table: see text]

Clinical effects of prior anthracycline or taxane use on eribulin as first-line treatment for HER+/- locally recurrent or metastatic breast cancer (BC): Results from 2 phase 2, multicenter, single-arm studies.

140 Background: Eribulin mesylate, a nontaxane microtubule dynamics inhibitor, has demonstrated an overall survival benefit relative to other commonly used agents in patients (pts) with at least 2 prior MBC cytotoxic therapies. Primary data presented from 2 phase 2 trials, Study 206 (eribulin in HER2- BC pts) and Study 208 (combination eribulin + trastuzumab [TRAS] in HER2+ BC pts), showed clinical activity and acceptable tolerability profiles as first-line cytotoxic therapy (tx). Here we present prespecified efficacy data for both trials based on prior anthracycline (A) and taxane (T) use. Methods: In both studies, pts received eribulin mesylate 1.4 mg/m2 IV on days 1 and 8 of each 21-day cycle. Pts in Study 208 (HER2+) also received initial TRAS (8 mg/kg IV/Day 1), followed by 6 mg/kg/day 1 of each subsequent cycle. Objective response rate (ORR), progression-free survival (PFS), and tolerability were assessed. Results: In Study 206 (N=56), 48% and 46% received prior A and T, and in Study 208 (N=52), 21% and 44% received prior A and T, respectively. ORR, the primary endpoint, was similar in pts, regardless of prior A or T, except in pts w/o prior T in Study 208 whose ORR trended higher (table). Clinical benefit rate (CBR), PFS, and duration of response (DOR) were either similar or trended higher in pts w/o prior A or T. PFS was higher in HER2+ BC patients receiving eribulin + TRAS who had not received prior A or T compared with those who had. Grade (G) 3-5 adverse event rates were similar or lower in pts who had not received prior A or T. Conclusions: As first-line therapy, eribulin in HER2- BC pts and eribulin + TRAS in HER2+ BC pts were effective and well tolerated, regardless of prior A or T tx. However, in HER2+ BC pts receiving eribulin + TRAS, the lack of prior A or T tx may be a lead to longer median PFS. Clinical trial information: NCT01268150/NCT01269346. [Table: see text]

470P - A Phase I Study of Eribulin and Gemcitabine in Patients with Avanced Solid Tumours. a Study of the Princess Margaret Phase Ii Consortium

ABSTRACT Aim: Gemcitabine, a nucleoside analogue, and eribulin (E7389), an investigational tubulin-based anti-mitotic drug exhibited synergistic cytotoxic effects pre-clinically and were combined in a Phase I dose finding clinical trial. Methods: A phase I clinical dose-escalation study of these 2 drugs in combination was initiated in patients with advanced solid tumours who had received up to two prior chemotherapy regimens for metastatic disease (CP cohort). Dose escalation was performed in a 3 + 3 design to identify the recommended phase II dose (RPTD). Two additional expansion cohorts consisting of women with gynecologic cancers at the recommended phase II dose (G cohort), and further dose-escalation of chemotherapy-naive patients (CN cohort), were evaluated. Results: Forty five patients were treated in 3 cohorts - 21 (CP), 10 (G), and 14 (CN). The initial combination of eribulin and gemcitabine was administered on days 1, 8, 15 of a 28 day cycle (CP) but due to 2/6 DLTs, a less dose-intense schedule with the 2 drugs given days 1 and 8 on a q21day cycle was assessed. Dose Dose Level N Schedule E7389 (mg/m2) Gemcitbaine (mg/m2) DLT Toxicity 1 (q28) 6 D1,8,15 q28d 0.7 800 2 Thrombocytopenia 1 (q21) 3 D1,8 q21d 0.7 800 2 3 D1,8 q21d 0.7 1000 3-CP 6 D1,8 q21d 1.0 1000 1 Neutropenia 3-G 10 D1,8 q21d 1.0 1000 4-CP 3 D1.8 q21d 1.4 1000 2 Diarrhea; fatigue 4-CN 7 D1,8 q21d 1.4 1000 1 Elevated transaminases 5-CN 5 D1,8 21d 1.6 1000 6-CN 2 D1,8q21d 1.8 1000 1 Neutropenia The RPTD was at dose level 3. No other significant hematologic or non-hematologic toxicities were observed with the CP patients. For the CN cohort, additional escalation at dose levels 4, 5, and 6 was attempted, but due to dose limiting neutropenia seen after Cycle 1, DL3 remained RPTD. Objective responses were seen in all three cohorts – 2/21 (CP), 1/10 (G) and 2/14 (CN). Conclusions: The combination of eribulin and gemcitabine was well tolerated with preliminary evidence of activity being seen. Phase II investigation of this regimen should be considered at a dose of 1.0mg/m2 eribulin and 1000 mg/m2 gemcitabine day 1 and 8 q3 weeks. Support by contract HHSN261201100032C/NO1-CM-2011-00032. Disclosure: All authors have declared no conflicts of interest.

Randomized phase II study of two intercalated combinations of eribulin mesylate and erlotinib in patients with previously treated advanced non-small-cell lung cancer

This phase II, open-label study investigated intercalated combinations of eribulin and erlotinib in unselected patients with advanced non-small-cell lung cancer previously treated with platinum-based chemotherapies. Eligible patients were randomized to eribulin mesylate 2.0 mg/m(2) on day 1 with erlotinib 150 mg on days 2-16 (21-day regimen) or eribulin mesylate 1.4 mg/m(2) on days 1 and 8 with erlotinib 150 mg on days 15-28 (28-day regimen). The primary end point was objective response rate (ORR). One hundred and twenty-three patients received ≥ 1 cycle of therapy (63, 21-day regimen; 60, 28-day regimen). ORRs were 13% [95% confidence interval (CI) 6%-24%] and 17% (95% CI 8%-29%), and disease control rates were 48% (95% CI 35%-61%) and 63% (95% CI 50%-75%) for the 21- and 28-day regimens, respectively. The median progression-free survival and overall survival were similar with both regimens. Both regimens were well tolerated with common grade ≥ 3 toxicities being neutropenia, asthenia/fatigue, and dyspnoea. Sequential administration of erlotinib did not interfere with the pharmacokinetic profile of eribulin. Intercalated combination of eribulin and erlotinib demonstrated modest activity and the addition of erlotinib did not appear to improve treatment outcome in an unselected population. The 28-day regimen is suitable for further investigation. Clinicaltrials.gov identifier: NCT01104155.