Search

Background Until recently, no effective targeted therapies for FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML) were available in Japan. The FLT3 inhibitor, gilteritinib, was approved in Japan for patients with FLT3mut+ R/R AML based on the phase 3 ADMIRAL trial, which demonstrated the superiority of gilteritinib over salvage chemotherapy (SC) with respect to overall survival (OS; median OS, 9.3 vs 5.6 months, respectively; hazard ratio, 0.64 [95% confidence interval 0.49, 0.83]; P Methods We evaluated the Japanese subgroup (n = 48) of the ADMIRAL trial, which included 33 patients randomized to 120-mg/day gilteritinib and 15 randomized to SC. Results Median OS was 14.3 months in the gilteritinib arm and 9.6 months in the SC arm. The complete remission/complete remission with partial hematologic recovery rate was higher in the gilteritinib arm (48.5%) than in the SC arm (13.3%). After adjustment for drug exposure, fewer adverse events (AEs) occurred in the gilteritinib arm than in the SC arm. Common grade ≥ 3 AEs related to gilteritinib were febrile neutropenia (36%), decreased platelet count (27%), and anemia (24%). Conclusion Findings in Japanese patients are consistent with those of the overall ADMIRAL study population.

Background Eribulin mesylate is a nontaxane microtubule dynamics inhibitor approved for second-line (European Union) or third-line (United States) treatment of metastatic breast cancer. Two phase 2 single trials, evaluating first-line eribulin as monotherapy (Study 206; NCT01268150) or in combination with trastuzumab (Study 208; NCT01269346) in locally recurrent or metastatic breast cancer, demonstrated objective response rates of 28.6 and 71.2%, respectively. Median progression-free survival was 6.8 and 11.6 months, respectively. Tolerability profiles were similar to those from previous studies. This secondary analysis was conducted to assess health-related quality of life (HRQoL) in both phase 2 trials. Methods Patients received eribulin mesylate 1.4 mg/m2 intravenously on days 1 and 8 of each 21-day cycle. Patients in Study 208 also received intravenous trastuzumab on day 1 of each cycle (8 mg/kg in cycle 1, then 6 mg/kg). HRQoL was assessed by the European Organization for Research and Treatment of Cancer Quality-of-Life (QLQ-C30) assessment tool and the Quality-of-Life Questionnaire for Breast Cancer (QLQ-BR23) at baseline and cycles 2, 4, and 6. Results for clinically meaningful changes were based on previously published minimum important differences. Results Of the 108 patients (56 in Study 206 and 52 in Study 208) treated, 57 and 87%, respectively, completed 6 cycles. Completion rates for both questionnaires were 94 and 98%, respectively, at cycle 6. Most patients had stable/improved HRQoL scores with some exceptions; for example, more patients experienced a worsening in cognitive functioning and systemic therapy side effects than experienced improvement. Mean QLQ-C30 symptom scores correlated with corresponding adverse event rates for nausea/vomiting, dyspnea, appetite loss, constipation, and diarrhea in Study 206 and for fatigue, nausea/vomiting, pain, dyspnea, insomnia, constipation, and diarrhea in Study 208. Conclusions First-line eribulin ± trastuzumab therapy did not lead to deterioration of overall HRQoL in most patients, with more than 60% of patients having stable/improved global health status/quality-of-life scores. Eribulin has been demonstrated to be comparable with other chemotherapy agents with an acceptable safety profile. Therefore, further evaluation is warranted to determine whether eribulin ± trastuzumab therapy may be a potential option for first-line treatment in some patients with metastatic breast cancer who were recently treated in the neoadjuvant setting. Trial registration NCT01268150 (December 29, 2010), NCT01269346 (January 4, 2011) Electronic supplementary material The online version of this article (10.1186/s12885-019-5674-5) contains supplementary material, which is available to authorized users.

Background: Gilteritinib is approved for patients (pts) with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML), based on findings from the phase 3 ADMIRAL trial (Perl AE, et al. N Engl J Med. 2019). A phase 3 trial, QuANTUM-R, demonstrated the benefit of quizartinib in pts with R/R AML with FLT3 internal tandem duplication (FLT3-ITD) mutations (Cortes JE, et al. Lancet Oncol. 2019). Although eligibility criteria across both studies were similar, QuANTUM-R was more stringent as to prior therapy intensity and remission duration, which potentially enriched for higher-risk pts. We sought to describe outcomes from ADMIRAL among pts who otherwise met eligibility for QuANTUM-R. Methods: In this post-hoc analysis, a subset of pts from ADMIRAL were matched with R/R FLT3-ITD+ AML pts from QuANTUM-R on the basis of baseline characteristics and prior treatment criteria. Matched pts were either refractory to initial anthracycline-based chemotherapy or had relapsed ≤6 mos after achieving composite complete remission (CRc) with an anthracycline-based regimen. Results: Overall, 218 pts with R/R FLT3-ITD+ AML in the ADMIRAL trial (gilteritinib, n=140; salvage chemotherapy [SC], n=78) were matched with the QuANTUM-R intention-to treat (ITT) population (N=367; quizartinib, n=245; SC, n=122). Proportions of pts preselected for high-intensity SC were 66% (n=143/218) in the matched ADMIRAL ITT population and 77% (n=281/367) in the QuANTUM-R ITT populations. Demographic and baseline characteristics of the matched ADMIRAL ITT population and QuANTUM-R ITT population were similar. Median durations of exposure to gilteritinib and quizartinib were 3.8 mos and 3.2 mos, respectively, and median number of treatment cycles received were five and four, respectively. Rates of hematopoietic stem cell transplantation (HSCT) were similar in pts treated with gilteritinib (35%; n=49/140) or quizartinib (32%; n=78/245), as were the proportions of pts who resumed gilteritinib (23%; n=32/140) or quizartinib (20%; n=48/245) therapy post-HSCT. Median overall survival (OS) in pts treated with gilteritinib or quizartinib was longer than that observed with SC. After a median follow-up of 17.4 mos, median OS was 10.2 mos with gilteritinib versus 5.6 mos with SC (hazard ratio [HR]=0.573 [95% CI: 0.403, 0.814]; one-sided nominal P=0.0008). After a median follow-up of 23.5 mos, median OS with quizartinib was 6.2 mos versus 4.7 mos with SC (HR=0.76 [95% CI: 0.58-0.98]; one-sided P=0.02). After censoring for HSCT, median OS was 9.3 mos with gilteritinib versus 5.5 mos with SC (HR=0.525 [95% CI: 0.356-0.775]; nominal one-sided P=0.0005), and 5.7 mos versus 4.6 mos with quizartinib versus SC, respectively (HR=0.79 [95% CI: 0.59, 1.05]; one-sided P=0.05). In both QuANTUM-R and matched ADMIRAL populations, the survival benefits of quizartinib and gilteritinib compared with SC were maintained across multiple subgroups, including high FLT3-ITD allelic ratio subsets. Compared with SC, high CRc rates were observed in pts treated with either gilteritinib (57%; n=80/140) or quizartinib (48%; n=118/245). The complete remission (CR) rate with gilteritinib was 23% (n=32/140), whereas the CR rate with quizartinib was 4% (n=10/245) (Table). Median time to achieve CRc was 1.8 mos with gilteritinib and 1.1 mos with quizartinib, median duration of CRc was 5.5 mos with gilteritinib and 2.8 mos with quizartinib. The safety profiles of gilteritinib and quizartinib were generally similar, though aspartate or alanine aminotransferase elevations (any grade) were more frequent with gilteritinib (41-44%) than quizartinib (≤13%), whereas neutropenia (14% vs 34%, respectively), fatigue (24% vs 39%, respectively), and prolonged QT intervals (9% vs 27%, respectively) were more frequent with quizartinib. Conclusions: In pts with R/R FLT3-ITD+ AML and similar baseline characteristics, both gilteritinib and quizartinib were generally well tolerated and associated with improved survival and treatment response compared with SC. Responses to gilteritinib and quizartinib, as measured by CRc, were similar; blood count recovery varied between the two FLT3 inhibitors. Although cross-study comparisons have substantial limitations, the findings suggest that while remission is achieved faster with quizartinib, response may be more durable and survival potentially longer with gilteritinib. Disclosures Perl: Syndax: Consultancy, Honoraria; Leukemia & Lymphoma Society, Beat AML: Consultancy; Novartis: Honoraria, Other, Research Funding; Agios: Consultancy, Honoraria, Other; Jazz: Honoraria, Other; FORMA Therapeutics: Consultancy, Honoraria, Other; Daiichi Sankyo: Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding; FUJIFILM Pharmaceuticals USA, Inc: Research Funding; New Link Genetics: Honoraria, Other; Arog Pharmaceuticals Inc: Other: uncompensated consulting, travel costs for meetings; Actinium Pharmaceuticals Inc: Consultancy, Honoraria, Research Funding; Biomed Valley Discoveries: Research Funding; Astellas: Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding; Bayer HealthCare Pharmaceuticals: Research Funding; AbbVie Inc: Consultancy, Honoraria, Other, Research Funding; Takeda: Honoraria, Other: Travel costs for meeting; Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Consultancy, Honoraria, Other. Lu:Astellas: Current Employment. Fan:Astellas Pharma: Current Employment. Hasabou:Astellas Pharma: Current Employment. Berrak:Astellas: Current Employment. Tiu:Eli Lilly & Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Astellas Pharma Global Development: Current Employment.

Background: Eribulin has demonstrated antitumor activity and significantly improved overall survival (OS) in patients (pts) with heavily pretreated locally advanced/metastatic breast cancer (BC). This trial assessed the feasibility of eribulin as adjuvant therapy following dose-dense doxorubicin and cyclophosphamide (AC) for pts with human epidermal growth factor receptor 2 (HER2)-negative early-stage BC. Methods: Pts with HER2(-), stage I–III, invasive BC were enrolled. Pts received dose-dense AC (doxorubicin 60 mg/m2 IV and cyclophosphamide 600 mg/m2 IV) on D1 of each 14-day cycle for 4 cycles with pegfilgrastim, followed by 4 cycles of eribulin (1.4 mg/m2 IV) on D1 and D8 every 21 days. Pts were divided into 2 cohorts: Cohort 1 did not receive any prophylactic growth factor (GF); Cohort 2 received a short course of prophylactic GF (filgrastim) on days 3, 4, 10, and 11 of each eribulin cycle. Primary endpoint of feasibility was determined as %pts who completed eribulin portion of the regimen without a dose delay (>2 days) or reduction due to eribulin-related adverse event (AE). Based on similar previous studies, the target for feasibility was 80%. Relative dose intensity of eribulin and toxicities were also summarized by cohort. Exploratory objectives include efficacy endpoints of 3-yr disease-free survival and OS. Results: We report data from 81 pts (55 Cohort 1; 26 Cohort 2) enrolled in the study, of whom 88% completed study treatment. Pt characteristics include median age 49 yrs (range 26–69), ECOG status 0 (85%), BC stages 1/2/3 (21%/57%/22%). Of 90% (73/81) pts evaluable for feasibility, 27% and 40% of pts in Cohorts 1 and 2, respectively, had dose delay or reduction during eribulin treatment, indicating the primary endpoint was not met. Overall, results were similar between the 2 cohorts (Table). Median duration of treatment with eribulin was 10.14 weeks in both cohorts (vs 10 weeks planned). Most eribulin-related dose delays were due to grade 3 (n=18) or grade 4 (n=7) neutropenia. Non-fatal serious AEs were observed in 11% of pts in Cohort 1 and 15% in Cohort 2. Discontinuations due to AEs occurred in 6% of pts in Cohort 1 and 0 in Cohort 2. Neutropenia (all grades) was reported in 36% of pts in Cohort 1 and 42% in Cohort 2. Most common AEs (all grades) were fatigue (96%), nausea (75%), alopecia (73%), hot flush (63%), and constipation (57%). ACEribulin Cohort 1*Cohort 2*Cohort 1 (without GCSF)Cohort 2 (with GCSF)Relative dose intensity, mean99.5%99.0%92.0%90.9%Completed all planned doses98.2%96.2%87.0%84.0%Dose modification†12.7%15.4%35.2%40.0%GCSF, granulocyte-colony simulating factor. *With pegfilgrastim 6 mg given subcutaneously on D2 of each AC cyle; † including dose delays (>2 days)/reduction/interruptions, missing, and permanent discontinuation due to AE. Conclusions: The primary study endpoint of >80% feasibility of planned dose delivery without any dose delays or reduction was not met. However, adjuvant treatment with dose-dense AC-eribulin was given safely, with two-thirds (67%) of pts achieving full dosing with no dose delay or reduction. Investigation into alternative dosing schedules or GF support is recommended. Citation Format: Cadoo K, Kaufman PA, Hudis C, Chang C, Berrak E, Song J, Seidman AD, Traina TA. Phase 2 study of dose-dense doxorubicin and cyclophosphamide followed by eribulin mesylate with or without prophylactic growth factor for adjuvant treatment of early-stage 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 P1-12-05.

Purpose The safety and tolerability of eribulin mesylate for the treatment of metastatic breast cancer (MBC) are examined. Methods This retrospective analysis used pooled safety and tolerability data from three Phase II trials and one Phase III trial of eribulin in patients with MBC. In these studies, patients with pretreated MBC received eribulin mesylate 1.4 mg/m2 as a two- to five-minute i.v. infusion on days 1 and 8 of a 21-day cycle. Adverse events were assessed according to the Common Terminology Criteria for Adverse Events, version 3.0. Results Across the four trials, 908 patients received eribulin and were assessed for safety. Aside from anthracyclines and taxanes, the most common prior chemotherapy agents were capecitabine, vinorelbine, and gemcitabine. Patients had received a mean of 3.7 (range, 1–11) prior chemotherapeutic regimens. Dose delays, reductions, and interruptions due to treatment-emergent adverse events occurred in 35.0%, 17.3%, and 2.9% of patients, respectively. Treatment was discontinued in 12.3% of patients due to adverse events, regardless of whether the adverse event was considered treatment related. The most common grade 3 or 4 treatment-related adverse events were neutropenia (52.4%) and leukopenia (19.3%). Serious adverse events occurred in 26.1% of patients, with the most common being febrile neutropenia (3.6%) and pyrexia (2.3%). Peripheral neuropathy was seen in 30.6% of patients, with 6.6% experiencing grade 3 or 4 reactions. Conclusion Despite heavy pretreatment with anthracyclines, taxanes, and capecitabine, eribulin was well tolerated in this pooled analysis of patients with MBC.

Introduction: Eribulin mesylate is a nontaxane microtubule dynamics inhibitor that has showed an overall survival benefit relative to other commonly used agents in patients with ≥2 prior MBC therapies. Primary data from a phase 2 trial for first-line eribulin + trastuzumab [TRAS] in HER2+ patients with MBC showed an objective response rate of 71%, clinical benefit rate of 84.6%, disease control rate of 96.2%, PFS of 11.6 months, and tolerability similar to known profiles for these agents. Here, we present prespecified QoL, efficacy, and safety/tolerability results. Methods: Patients 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 on day 1 of each subsequent cycle. Response, PFS, QoL as measured by EORTC QoL assessment tool (QLQ-C30) and QLQ-BR23, and tolerability were assessed. Percentage of patients with at least ±10-point change from baseline was calculated at each visit. Time to deterioration was defined as time from first dose to worsening in QoL score that reached minimally clinically important difference (MID) (ie, 10 points in global health status [GHS] in QLQ-C30) without further improvement of at least MID; this was estimated overall and by response status. Results: At cycle 6 (n=44; completion rate=84.6% of 52 patients enrolled), more patients fell in the stable category (within +/-10 points change from baseline), except for pain (47.7% with improvement), cognitive functioning (45.5% worsening), fatigue and systemic therapy side effects (50% worsening for each), and arm symptoms (47.7% improvement) (Table). Median times to deterioration for GHS/QoL were 7.6 months overall (n=51), and 7.6 and 7.0 months for responders (n=36) and nonresponders (n=15), respectively (HR 0.73; 95% CI 0.32, 1.68; P=0.446). Mean symptom scores in EORTC QLQ-C30 were significantly correlated with corresponding AE rates for fatigue (r=0.31), nausea/vomiting (r=0.50), pain (r=0.41), dyspnea (r=0.49), insomnia (r=0.35), constipation (r=0.30), and diarrhea (0.40; P≤0.03 for all comparisons). The most common treatment-related AEs (all grade incidence ≥25%) were alopecia (88.5%), fatigue (69.2%), peripheral neuropathy (69.2%), neutropenia (59.6%), nausea (46.2%), diarrhea (32.7%), anemia (25%), constipation (25%), and decreased appetite (25%). Table. Qol EORTC QLQ-C30 Scores: Change from Baseline to Cycle 6 (n=44)Functional orCategory, n (%)Symptom ScaleImprovedStableWorsenedGHS/Qol13 (29.5)23 (52.3)8 (18.2)Physical10 (22.7)26 (59.1)8 (18.2)Role13 (29.5)20 (45.5)11 (25.0)Emotional17 (38.6)18 (40.9)9 (20.5)Cognitive6 (13.6)18 (40.9020 (45.5)Social12 (27.3)18 (40.9)14 (31.8)Fatigue14 (31.8)8 (18.2)22 (50.0)Nausea/vomiting9 (20.5)24 (54.5)11 (25.0)Pain21 (47.7)14 (31.8)9 (20.5)Dyspnea12 (27.3)19 (43.2)13 (29.5) Conclusions: Given the improvements in pain and in arm and breast symptoms, long median time to deterioration in functioning/symptom scales in this analysis, and the tumor response rates and safety profile in the primary analysis, combination eribulin/TRAS may be an acceptable treatment option for locally recurrent or HER2+ MBC and merits further study in larger clinical trials. Citation Format: Lee Schwartzberg, Sharon Wilks, Shannon Puhalla, Joyce O'Shaughnessy, Erhan Berrak, James Song, David Cox, Linda Vahdat. Quality of life results from a phase 2, multicenter, single-arm study of eribulin mesylate plus trastuzumab as first-line therapy for locally recurrent or metastatic HER2+ 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 P5-17-03.

Introduction: Eribulin mesylate is a nontaxane microtubule inhibitor approved to treat MBC in patients (pts) who previously received ≥2 chemotherapeutic regimens for MBC. A phase 2 study of first-line eribulin for HER2-negative (HER2-) MBC showed an overall response rate of 29%, median 6.8 m progression-free survival, and tolerability consistent with earlier studies. We present prespecified quality of life (QoL) results for this trial. Methods: Pts (N=56) received eribulin mesylate 1.4 mg/m2 IV on days 1 and 8 of each 3-wk cycle (median: 7 cycles). QoL was assessed using the EORTC QoL assessment (QLQ-C30) and a breast-cancer specific questionnaire (QLQ-BR23) pretreatment (baseline) and on day 1 of every other cycle during treatment. Percentage of pts with at least ±10-point change from baseline was summarized descriptively. Linear mixed-effects models were used to evaluate changes over time and compare responders vs nonresponders controlling for baseline score and time effect. Time-to-event analysis was performed on time to deterioration, defined as time from 1st dose to 1st occurrence of worsening in QoL score that reached minimally clinically important difference (MID; eg, 10 points in global health status in QLQ-C30) from baseline without further improvement of at least MID. Results: For QLQ-C30 at cycle 6 (n=29), more pts had at least a 10-point improvement from baseline in role, emotional, and social functioning; fatigue, nausea/vomiting, pain, dyspnea, and insomnia item scores, than had worsening. More pts had worsening in global health status/QoL, cognitive functioning, and diarrhea (Table). Category, n (%) ImprovedStableWorsenedGlobal health status/QoL2 (7)16 (55)11 (38)Physical functioning9 (31)13 (45)7 (24)Role functioning14 (48)10 (35)5 (17)Emotional functioning9 (31)14 (48)6 (21)Cognitive functioning2 (7)13 (45)14 (48)Social functioning10 (35)13 (45)6 (21)Fatigue16 (55)5 (17)8 (28)Nausea and vomiting8 (28)16 (55)5 (17)Pain15 (52)8 (28)6 (21)Dyspnea9 (31)18 (62)2 (7)Insomnia12 (41)15 (52)2 (7)Appetite loss7 (24)16 (55)6 (21)Constipation5 (17)18 (62)6 (21)Diarrhea2 (7)21 (72)6 (21) Median time to deterioration in global health status/QoL was 5.06 m (responders, 8.54 m; nonresponders, 3.71 m; hazard ratio=0.60, P=0.22). In linear mixed models, responders (n=16) performed better than nonresponders (n=40) in role functioning (P=0.011), emotional functioning (P=0.031), fatigue (P=0.007), pain (P=0.047), insomnia (P=0.018), and appetite loss (P=0.032). Mean symptom scores were significantly correlated with corresponding adverse event rates for nausea and vomiting, dyspnea, appetite loss, constipation, and diarrhea; Spearman rank correlation coefficients ranged from 0.31 to 0.54. For QLQ-BR23 at cycle 6, symptom scores were mostly stable; more pts had worsening in body image and systemic therapy side effects than had improvement and more pts had improvement in breast and arm symptoms than had worsening. Responders also had longer time to symptom deterioration. Conclusions: In this study of first-line eribulin treatment for HER2- MBC, a majority of pts had stable or improvement in QoL scales. Responders to eribulin were more likely than nonresponders to have stable or improved QoL. Citation Format: Lee Schwartzberg, Kristi McIntyre, Joyce O'Shaughnessy, Stefan Glück, Erhan Berrak, James Song, David Cox, Linda Vahdat. Quality of life in patients receiving first-line eribulin mesylate for HER2- locally recurrent or MBC [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 P5-17-02.

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.

Background: In a phase III trial, older patients with acute myeloid leukemia (N=485) received decitabine or treatment choice (supportive care or cytarabine). This post hoc analysis examined whether baseline renal and hepatic function and white blood cell (WBC) counts predicted response. Methods: Baseline WBCs and renal and liver function markers were tabulated for responders/nonresponders. Results: Nonresponders had higher mean baseline creatinine (P=0.005). Creatinine data showed no significant between-group differences by treatment within responder category. Conclusions: No relationship was found between baseline WBCs or hepatic function and response. Higher baseline creatinine in nonresponders may not be clinically relevant.

Background: Eribulin mesylate, a non-taxane microtubule dynamics inhibitor, has been approved for patients with metastatic breast cancer (MBC) who have previously received ≥2 chemotherapeutic regimens for MBC. We present final data from a phase 2 study that evaluated efficacy and safety of eribulin + trastuzumab as first-line therapy for locally recurrent or metastatic human epidermal growth factor receptor 2 positive (HER2+) BC. Methods: Patients received eribulin mesylate at 1.4 mg/m2 IV on days 1 and 8 of each 21-day cycle and an initial trastuzumab dose of 8 mg/kg IV on day 1, followed by 6 mg/kg on day 1 of each subsequent cycle. Endpoints include objective response rate (ORR), safety, progression-free survival (PFS), time to response (TTR), and duration of response (DOR). Tumor assessments were conducted every 6 weeks for the first 6 cycles and every 6-12 weeks thereafter per RECIST 1.1. Results: Fifty-two patients with a median age of 60 years (range 31- 81) were treated; 96% had stage IV disease, 73% had visceral disease, and 48% had liver metastases. Thirty one patients had prior neo/adjuvant chemotherapy (11 had prior anthracycline, and 22 had prior taxane). Patients received a median of 10(0, 33) cycles of eribulin and 11(1, 31) cycles of trastuzumab. ORR was 67% with median TTR of 1.3 months and PFS of 11.5 months (Table). The most common (>5%) Grade 3/4 treatment related treatment emergent (TRTE) AEs were neutropenia (n = 20; 38.5%), peripheral neuropathy (n = 14; 26.9%) and febrile neutropenia (n = 4; 7.7%). Serious TRTE AEs occurred in 14 patients and included neutropenia (n = 9; 17.3%), febrile neutropenia (n = 4; 7.7%), and peripheral neuropathy (n = 3; 5.8%). Reasons for discontinuation were AEs (n = 7) and PD (n = 22). Table. Summary of Efficacy EndpointsEfficacy EndpointsEribulin/Trastuzumab N = 52Objective Response Rate, n (%)35 (67)- Complete Response (CR)2 (4)- Partial Response (PR)33 (64)Stable Disease (SD)15 (29)Progressive Disease (PD)1 (2)Not Evaluable1 (2)Overall Clinical Benefit Rate, n (%)42 (81)Time to First Objective Response, median months (95% CI)1.3 (1.2, 1.4)Duration of Objective Response, median months (95% CI)a11.1 (6.5, 17.8)Progression-Free Survival, median months (95% CI)11.5 (7.3, 13.5)Duration of Stable Disease, median months (95% CI)7.1 (5.2, 13.5)Clinical Benefit Rate = ORR+ ≥6 mo SD; an = 35 Conclusions: This study suggests that the combination of eribulin + trastuzumab first-line therapy for locally recurrent or metastatic HER2+ BC has an acceptable safety profile and results in considerable tumor response with a long DOR. Additional larger studies with this combination are warranted. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-12.

Background: Eribulin mesylate is a novel nontaxane microtubule dynamics inhibitor that is approved for treatment of metastatic breast cancer (MBC) in patients who have previously received at least two chemotherapeutic regimens for MBC. We present final data from a phase 2 study that evaluated the efficacy and safety of eribulin as first-line therapy for HER2-negative (HER2-) MBC. Methods: Patients with measureable HER2- locally recurrent or MBC with ≥12 months since prior neoadjuvant or adjuvant chemotherapy received eribulin mesylate 1.4 mg/m2 IV on days 1 and 8 of each 3-week cycle. Endpoints included objective response rate (ORR) (primary), safety, progression-free survival (PFS), time to response (TTR), and duration of response (DOR). Tumor assessments were conducted every 6 weeks for the first 6 cycles and every 6-12 weeks thereafter per RECIST 1.1. Results: Fifty-six patients enrolled and received eribulin. Patients had a median age of 56 years (range 31-85); 32 (57%) had an ECOG status of 0; 17 (30%) had de novo stage IV; 33 (59%) had prior (neo)adjuvant therapy, including anthracycline and/or taxane (A/T) chemotherapy. Thirty-nine patients (70%) had visceral disease (45% liver, 32% lung); 41(73%) had estrogen receptor-positive (ER+) disease and 12 (21%) had triple negative (TN) disease. Thirty-two patients (57%) completed at least 6 cycles of treatment; among the 24 patients who completed fewer than 6 cycles, reasons for not completing were progressive disease (PD; n = 18), adverse events (AEs; n = 3) and patient choice (n = 3). The median number of cycles delivered was 7 (range 1-39); 6 patients (11%) received treatment for ≥12 months. Overall ORR was 27%, with median TTR of 1.4 months and median DOR of 7.4 months; stable disease (SD) rate was 48% (Table 1). Median PFS was 6.8 months. Thirty-five patients (63%) had grade 3/4 treatment-related AEs (Table 2). Treatment-related serious AEs occurred in 5 (9%) patients: neutropenia (5%), febrile neutropenia (5%), and leukopenia (2%). Conclusions: The results of this study suggest that first-line eribulin has antitumor activity in ER+/HER2- and TN MBC with safety consistent with the known profile. Further exploration of this treatment as part of earlier lines of breast cancer therapy, including neo/adjuvant, is warranted. Table 1. Summary of EfficacyEfficacyEribulin-treated patients N = 56ORR, n (%)15 (27)CR0PR15 (27)SD27 (48)PD12 (21)Clinical benefit rate (ORR + ≥6 mo SD)27 (48)Median months (95% CI) TTR1.4 (1.2, 2.7)DOR7.4 (4.7, NE)PFS6.8 (4.4, 7.4)NE, not estimable Table 2. Treatment-Related AEsAE (N = 56)All events (%)Grade 3/4 (%)Leading to study drug withdrawal1111Leading to dose reduction3427Common AEs (≥25%) Alopecia820Neutropenia7050Fatigue572Peripheral neuropathy5420Nausea460Anemia364Leukopenia3018Constipation270 Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-13-05.

Shannon Puhalla,1 Sharon Wilks,2 Adam M Brufsky,1 Joyce O’Shaughnessy,3 Lee S Schwartzberg,4 Erhan Berrak,5 James Song,5 Linda Vahdat6 1Department of Hematology and Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA, 2Department of Hematology Oncology, US Oncology-Cancer Care Centers of South Texas, San Antonio, TX, 3Department of Medical Oncology, Texas Oncology-Baylor Charles A. Sammons Cancer Center US Oncology, Dallas, TX, 4Department of Hematology/Oncology, West Cancer Center, University of Tennessee Health Science Center, Memphis, TN, 5Department of Medical Affairs, Formerly of Eisai Inc., Woodcliff Lake, NJ, 6Department of Medicine, Weill Cornell Medical College, New York, NY, USA Abstract: Eribulin mesylate, a novel nontaxane microtubule dynamics inhibitor in the halichondrin class of antineoplastic drugs, is indicated for the treatment of patients with metastatic breast cancer who previously received ≥2 chemotherapy regimens in the metastatic setting. Primary data from a Phase II trial for the first-line combination of ­eribulin plus trastuzumab in human epidermal growth factor receptor 2 positive patients showed a 71% objective response rate and tolerability consistent with the known profile of these agents. Here, we present prespecified analyses of efficacy of this combination based on prior trastuzumab use. Patients received eribulin mesylate 1.4 mg/m2 (equivalent to 1.23 mg/m2 eribulin [expressed as free base]) intravenously on days 1 and 8 plus trastuzumab (8 mg/kg intravenously/cycle 1, then 6 mg/kg) on day 1 of each 21-day cycle. Objective response rates, progression-free survival, and tolerability were assessed in patients who had and had not received prior adjuvant or neoadjuvant (neo/adjuvant) trastuzumab treatment. Fifty-two patients (median age: 59.5 years) received eribulin/trastuzumab for a median treatment duration of ~31 weeks; 40.4% (n=21) had been previously treated with neo/adjuvant trastuzumab prior to treatment with eribulin plus trastuzumab for metastatic disease (median time between neo/adjuvant and study treatment: 23 months). In trastuzumab-naïve patients (n=31) compared with those who had received prior trastuzumab, objective response rate was 77.4% versus 61.9%, respectively; duration of response was 11.8 versus 9.5months, respectively; clinical benefit rate was 87.1% versus 81.0%, respectively; and median progression-free survival was 12.2 versus 11.5 months, respectively. The most common grade 3/4 treatment-emergent adverse events (occuring in ≥5% of patients) in patients who received prior trastuzumab versus trastuzumab naïve patients, respectively, were neutropenia (47.6% vs 32.3%), peripheral neuropathy (14.3%vs25.8%), febrile neutropenia (14.3% vs 3.2%), fatigue (9.5% vs 6.5%), nausea (9.5% vs 0%), vomiting (9.5% vs 3.2%), and leukopenia (9.5% vs 3.2%). In patients with human epidermal growth factor receptor 2 positive metastatic breast cancer, first-line eribulin/trastuzumab treatment demonstrated substantial antitumor activity and was well tolerated, regardless of prior neo/adjuvant trastuzumab treatment. Keywords: oncology, breast neoplasms, advanced breast cancer, chemotherapy, eribulin mesylate, trastuzumab, HER2

Eribulin is indicated in the EU for advanced/metastatic breast cancer patients following ≥1 prior chemotherapy for advanced disease, and anthracycline and taxane in adjuvant/metastatic setting. We pooled 1644 patients from two phase III trials and found that eribulin significantly increased survival versus control, particularly in some subgroups of interest like HER2- and triple-negative disease., Background Based on data from two multicenter, phase III clinical trials (Studies 301 and 305), eribulin (a microtubule dynamics inhibitor) is indicated in the European Union (EU) for patients with locally advanced or metastatic breast cancer (MBC) after ≥1 prior chemotherapy for advanced disease, including an anthracycline and a taxane in either the adjuvant or metastatic setting. Data from Studies 305 and 301 were pooled to investigate the efficacy of eribulin in various subgroups of patients who matched the EU label, including those with human epidermal growth factor receptor 2 (HER2)-negative and triple-negative disease. Patients and methods In Study 305 (NCT00388726), patients were randomized 2:1 to eribulin mesylate 1.4 mg/m2 (equivalent to eribulin 1.23 mg/m2 [expressed as free base]) intravenously on days 1 and 8 every 21 days] or treatment of physician's choice after 2–5 prior chemotherapies (≥2 for advanced disease), including an anthracycline and a taxane (in early/advanced setting). In Study 301 (NCT00337103), patients were randomized 1:1 to eribulin (as above) or capecitabine (1.25 g/m2 orally twice daily on days 1–14 every 21 days) following ≤3 prior chemotherapies (≤2 for advanced disease), including an anthracycline and a taxane. Efficacy end points were investigated in the intent-to-treat population and subgroups, pooled as discussed above. Results Overall, 1644 patients were included (eribulin: 946; control: 698); baseline characteristics were well matched. Overall survival was significantly longer with eribulin versus control (P < 0.01), as were progression-free survival and clinical benefit rate (both P < 0.05). Significant survival benefits with eribulin versus control were observed in a wide range of patient subgroups, including HER2-negative or triple-negative disease (all P < 0.05). Conclusion Our findings underline the survival benefit achieved by eribulin used according to EU label in the overall MBC population and in various subgroups of interest, including patients with HER2-negative and triple-negative disease.

Background The present phase II, open-label, multicenter study explored the feasibility, safety, and tolerability of eribulin, a novel non-taxane microtubule inhibitor, plus capecitabine as adjuvant therapy. Patients and Methods Postmenopausal women with early-stage, human epidermal growth factor receptor 2 (HER2)-negative, estrogen-receptor (ER)-positive breast cancer received four 21-day cycles of treatment with eribulin mesylate (1.4 mg/m 2 intravenously on days 1 and 8 of each cycle) combined with capecitabine (900 mg/m 2 orally twice daily on days 1-14 of each cycle [standard schedule] or 1500 mg orally twice daily using a 7-days on/7-days off schedule [weekly schedule]). Feasibility was determined by the relative dose intensity (RDI) of the combination using prespecified criteria for 80% of patients achieving an RDI of ≥ 85%, with a lower 95% confidence boundary > 70%. Results The mean RDI was 90.6%, and the feasibility rate was 81.3% among women (n = 67, mean age, 61.3 years) receiving the standard schedule and 95.6% and 100% among women (n = 10, mean age 62.3 years) receiving the weekly schedule. Dose reductions, missed doses, and withdrawals due to adverse events (most commonly hand-foot syndrome) ascribed to capecitabine led to a higher RDI (93.5% vs. 87.8%) and feasibility rate (82.8% vs. 71.9%) for eribulin than for capecitabine using the standard dosing schedule. The most common adverse events were alopecia and fatigue. Conclusion Eribulin plus capecitabine with standard or weekly dosing schedules is feasible in patients with early-stage, HER2-negative, ER-positive breast cancer. Full-dose eribulin (1.4 mg/m 2 on days 1 and 8) with capecitabine (1500 mg orally twice daily, 7 days on/7 days off) is recommended as a regimen for further evaluation.

Christopher Arthur,1 Jaroslav Cermak,2 Jacques Delaunay,3 Jirí Mayer,4 Grzegorz Mazur,5 Xavier Thomas,6 Agnieszka Wierzbowska,7 Mark M Jones,8 Erhan Berrak,8 Hagop Kantarjian9 1Department of Haematology, Royal North Shore Hospital, Sydney, NSW, Australia; 2Institute of Hematology and Blood Transfusion, Prague, Czech Republic; 3Department of Clinical Hematology, University of Nantes, Nantes, France; 4Department of Internal Medicine, Masaryk University Hospital Brno, Central European Institute of Technology, Brno, Czech Republic; 5Department of Hematology, Wroclaw Medical University, Wroclaw, Poland; 6Department of Hematology, Edouard Herriot Hospital, Lyon, France; 7Copernicus Memorial Hospital, Lodz, Poland; 8Oncology Product Creation Unit, Eisai Inc., Woodcliff Lake, NJ, USA; 9Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA Background: In a Phase III trial, 485 patients (≥65 years) with newly diagnosed acute myeloid leukemia received decitabine 20 mg/m2 intravenously for 5 days every 4 weeks or a treatment choice (supportive care or cytarabine 20 mg/m2 subcutaneously for 10 days every 4 weeks). Materials and methods: We summarized overall and progression-free survival by baseline white blood cell count using two analyses: 5×109/L; ≤10 or .10×109/L. Results: There were 446 deaths (treatment choice, n=227; decitabine, n=219). Median overall survival was 5.0 (treatment choice) versus 7.7 months (decitabine; nominal P=0.037). Overall survival differences between white blood cell groups were not significant; hazard ratios (HRs) favored decitabine. Significant progression-free survival differences favored decitabine for groups 1–5×109/L (P=0.005, HR =0.67), greater than 5×109/L (P=0.027, HR =0.71), and up to 10×109/L (P=0.003, HR =0.72). Conclusion: There was a trend toward improved outcome with decitabine, regardless of baseline white blood cell count. Keywords: decitabine, acute myeloid leukemia, prognosis, leukemia, adult

Objective: In a phase III trial, 485 patients aged 65 years or older with newly diagnosed acute myeloid leukemia received decitabine (20 mg/m2 intravenously for 5 days) or treatment of choice (supportive care or cytarabine 20 mg/m2 subcutaneously for 10 days) every 4 weeks. This post hoc analysis investigated potential efficacy and safety indicators and treatment response. Methods: Transfusions, intravenous antibiotics, and dose modifications were tabulated for responders (morphologic complete remission, complete remission with incomplete blood count recovery, or partial response) and nonresponders. Results: Median overall survival was significantly greater for treatment responders than for nonresponders (17.4 months vs 4.3 months; P

In this multicenter, phase II, single-arm study, 52 patients with recurrent or metastatic HER2-positive (D) breast cancer received first-line eribulin with trastuzumab. The objective response rate (ORR) was 71.2% (n [ 37) with a median time to first response (TTR) of 1.3 months; duration of response (DOR) and progressionfree survival (PFS) were 11.1 and 11.6 months, respectively. Eribulin/trastuzumab combination resulted in a substantial tumor response with an acceptable safety profile. Background: The aim of this study was to assess efficacy and safety of eribulin with trastuzumab as first-line therapy for locally recurrent or metastatic HER2þ breast cancer. Patients and Methods: In this multicenter, phase II, singlearm study, patients with recurrent or metastatic HER2þ breast cancer received eribulin mesylate at 1.4 mg/m 2 intravenously (I.V.) on days 1 and 8 of each 21-day cycle with an initial trastuzumab dose of 8 mg/kg I.V. on day 1, followed by 6 mg/kg of trastuzumab on day 1 of each subsequent cycle. Tumor assessments were conducted every 6 weeks for the first 6 cycles and every 12 weeks thereafter. The primary end point was ORR, and secondary end points included PFS, TTR, DOR, and safety. Results: Fifty-two patients were enrolled. Fifty-one patients (98.1%) had metastatic disease, 25 (48.1%) with liver metastases, 24 (46.2%) with lung metastases, and 19 (36.5%) with bone metastases. Patients received a median of 10.0 cycles of eribulin and 11.0 cycles of trastuzumab. The ORR was 71.2% (n ¼ 37) with median TTR of 1.3 months, DOR of 11.1 months, and PFS of 11.6 months. The most common Grade 3/4 treatment-emergent adverse events were neutropenia in 20 (38.5%) patients, peripheral neuropathy in 14 (26.9%; all Grade 3) patients, fatigue in 4 (7.7%) patients, and febrile neutropenia in 4 (7.7%) patients. Conclusions: Because of the high ORR, prolonged median PFS, and acceptable safety profile, combination eribulin/trastuzumab is an acceptable treatment option for locally recurrent or metastatic HER2þ breast cancer.

Background In a multicenter, randomized, open-label phase III study, patients ≥ 65 years with newly diagnosed AML received decitabine 20 mg/m 2 once daily for 5 days every 4 weeks (n = 242) or treatment choice (supportive care or cytarabine 20 mg/m 2 once daily for 10 days every 4 weeks; n = 243). Decitabine use demonstrated greater response rates ( P = .001) and OS data favored decitabine. Patients and Methods In a post hoc sensitivity analysis of mature data of patients in the intent-to-treat population (N = 485), OS at 3, 6, 12, 18, and 24 months after randomization was estimated for each arm using Kaplan-Meier methods. Age, cytogenetic risk, and Eastern Cooperative Oncology Group performance status were used as stratification factors in the Cox regression model to estimate the hazard ratio. Results A survival advantage was seen with decitabine at each cutoff time point; hazard ratios for OS for decitabine vs. treatment choice were 0.83, 0.71, 0.83, 0.80, and 0.79 at 3, 6, 12, 18, and 24 months, respectively. A trend toward improved OS with decitabine was observed at fixed time points over 2 years. Conclusion Decitabine should be considered as a treatment option for older patients with AML and poor prognostic risk factors.

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]

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]

TPS670^ Background: In a previous phase 3 randomized, open-label trial, eribulin mesylate demonstrated antitumor activity and significantly improved overall survival (OS) in patients (pts) with hea...

Eribulin mesylate, a novel non-taxane microtubule dynamics inhibitor, is approved for treatment of metastatic breast cancer (MBC) in patients who have previously received at least 2 chemotherapeutic regimens for MBC that should have included an anthracycline and a taxane in the adjuvant or metastatic setting. This phase 2 study evaluated efficacy and safety of eribulin as first-line therapy for human epidermal growth factor receptor 2-negative (HER2-negative) MBC. Patients with measurable HER2-negative locally recurrent breast cancer or MBC with ≥12 months since prior neoadjuvant or adjuvant (neo/adjuvant) chemotherapy received eribulin mesylate 1.4 mg/m(2) IV on days 1 and 8 of each 3-week cycle. Endpoints included objective response rate (ORR) per RECIST v1.1 (primary), safety, progression-free survival (PFS), clinical benefit rate (ORR + stable disease ≥6 months; CBR), and duration of response (DOR). Fifty-six patients were enrolled and received eribulin; 38 (68 %) had prior neo/adjuvant therapy, including 33 who had anthracycline and/or taxane-containing chemotherapy; 41 (73 %) had estrogen receptor-positive disease, and 12 (21 %) had estrogen receptor-negative, progesterone receptor-negative, and HER2-negative (triple-negative) disease. Patients received a median of 7 cycles (range 1-43); 6 (11 %) received treatment for ≥12 months. ORR was 29 % (95 % CI 17.3-42.2), CBR was 52 %, and median DOR was 5.8 months. Median PFS was 6.8 months. Thirty-six patients (64 %) had grade 3/4 treatment-related adverse events; most common were neutropenia (50 %), leukopenia (21 %), and peripheral neuropathy (21 %). These results demonstrate that eribulin has substantial antitumor activity as first-line treatment for HER2-negative MBC with acceptable safety.

Eribulin mesylate has efficacy in patients who have received ≥2 prior chemotherapies for metastatic breast cancer (MBC) including an anthracycline and taxane. Phase 2 trials showed clinical activity and acceptable tolerability of first-line eribulin (HER2− MBC; Study 206) and eribulin plus trastuzumab (HER2+ MBC; Study 208). Prespecified analyses evaluated efficacy by prior anthracycline and/or taxane use. Patients received eribulin mesylate (1.4 mg/m2 IV; Days 1 and 8) and, in Study 208, trastuzumab (8 mg/kg IV/Cycle 1, then 6 mg/kg; Day 1) in 21-day cycles. Endpoints included objective response rate (ORR), progression-free survival (PFS), and tolerability. In Study 206 (N = 56), 48 % of patients had received prior anthracycline, 46 % prior taxane, 36 % prior anthracycline and taxane, and 41 % were chemotherapy-naïve. In Study 208 (N = 52), these percentages were 21, 44, 17, and 52 %, respectively. In Study 206, ORR and median PFS were similar for anthracycline-pretreated (25.9 %, 5.8 months), taxane-pretreated (26.9 %, 5.8 months), anthracycline- and taxane-pretreated (25.0 %, 6.7 months), and anthracycline/taxane-naïve patients (30.4 %, 7.6 months). In Study 208, ORR/median PFS were 63.6 %/6.7 months among anthracycline-pretreated patients, 56.5 %/6.8 months among taxane-pretreated patients, 55.6 %/5.9 months among anthracycline- and taxane-pretreated patients, and 81.5 %/13.1 months among anthracycline/taxane-naïve patients. Tolerability was generally similar among subgroups. In these studies, first-line eribulin in HER2− MBC and eribulin/trastuzumab in HER2+ MBC was effective with acceptable tolerability, regardless of prior anthracycline/taxane treatment. Prior chemotherapy was associated with lower ORR and shorter PFS with eribulin/trastuzumab in HER2+ MBC but not with eribulin in HER2− MBC. Electronic supplementary material The online version of this article (doi:10.1186/s40064-015-1322-y) contains supplementary material, which is available to authorized users.

Background Compared with younger patients, older adults with acute myeloid leukemia (AML) generally have poorer survival outcomes and less benefit from clinical trials. A recent phase 3 trial demonstrated a trend toward improved overall survival (OS) with decitabine, a hypomethylating agent, compared with treatment choice of either cytarabine or supportive care (7.7 months, 95% CI: 6.2–9.2 vs 5.0 months, 95% CI: 4.3–6.3, respectively) in older adults with newly diagnosed AML. The current analyses investigated prognostic factors for outcomes in this trial and examined OS and responses in prespecified subgroups. Methods A multivariate Cox proportional hazards model was used to investigate effects of demographic and baseline characteristics, including age, sex, cytogenetic risk, AML type, ECOG Performance Status, geographic region, bone marrow blasts, platelets, and white blood cells on OS, based on mature data. Similar analyses were conducted with a logistic regression model to predict response rates. Prespecified subgroup analyses were performed for OS and response rates, also using mature data. Results Patient characteristics that appeared to negatively influence OS included more advanced age (hazard ratio [HR] 1.560 for ≥75 vs 50% vs ≤50%; p = 0.0045), low baseline platelet counts (HR 0.775 for each additional 100 × 109/L; p = 0.0015), and high white blood cell counts (HR 1.256 for each additional 25 × 109/L; p = 0.0151). Regarding geographic regions, patients from Western Europe had the longest median OS. Response rates favored decitabine for all subgroups investigated, including patients ≥75 years (odds ratio 5.94, p = 0.0006). Conclusion Response to decitabine in AML is associated with known prognostic factors related to both patient demographics and disease characteristics. Trial registration ClinicalTrials.gov identifier NCT00260832