Gilteritinib versus chemotherapy in Japanese patients with FLT3-mutated relapsed/refractory acute myeloid leukemia.

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 < 0.001). 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.

Health-related quality of life in patients receiving first-line eribulin mesylate with or without trastuzumab for locally recurrent or metastatic breast cancer.

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).

Phase 2 study of eribulin mesylate as first-line therapy for locally recurrent or metastatic human epidermal growth factor receptor 2-negative breast cancer.

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.

Multivariate and subgroup analyses of a randomized, multinational, phase 3 trial of decitabine vs treatment choice of supportive care or cytarabine in older patients with newly diagnosed acute myeloid leukemia and poor- or intermediate-risk cytogenetics.

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 <70 years; p = 0.0010), poorer performance status at baseline (HR 0.771 for 0 or 1 vs 2; p = 0.0321), poor cytogenetics (HR 0.699 for intermediate vs poor; p = 0.0010), higher bone marrow blast counts (HR 1.355 for >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.

Clinical effects of prior trastuzumab on combination eribulin mesylate plus trastuzumab as first-line treatment for human epidermal growth factor receptor 2 positive locally recurrent or metastatic breast cancer: results from a Phase II, single-arm, multicenter study.

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 9.5 months, 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% vs 25.8%), 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.

Phase II, Multicenter, Single-Arm, Feasibility Study of Eribulin Combined With Capecitabine for Adjuvant Treatment in Estrogen Receptor-Positive, Early-Stage Breast Cancer.

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.

Safety and tolerability of eribulin mesylate in patients with pretreated metastatic breast cancer.

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/m(2) 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.

Impact of prior anthracycline or taxane use on eribulin effectiveness as first-line treatment for metastatic breast cancer: results from two phase 2, multicenter, single-arm studies.

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/m(2) 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.

Post hoc analysis of the relationship between baseline white blood cell count and survival outcome in a randomized Phase III trial of decitabine in older patients with newly diagnosed acute myeloid leukemia.

BACKGROUND: In a Phase III trial, 485 patients (≥65 years) with newly diagnosed acute myeloid leukemia received decitabine 20 mg/m(2) intravenously for 5 days every 4 weeks or a treatment choice (supportive care or cytarabine 20 mg/m(2) 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: <1, 1-5, >5×10(9)/L; ≤10 or >10×10(9)/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 1-5×10(9)/L (P=0.005, HR =0.67), greater than 5×10(9)/L (P=0.027, HR =0.71), and up to 10×10(9)/L (P=0.003, HR =0.72). CONCLUSION: There was a trend toward improved outcome with decitabine, regardless of baseline white blood cell count.

Relationship between baseline white blood cell count and renal and hepatic function in older patients with acute myeloid leukemia.

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.

A post hoc sensitivity analysis of survival probabilities in a multinational phase III trial of decitabine in older patients with newly diagnosed acute myeloid leukemia.

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.

Phase 2, multicenter, single-arm study of eribulin mesylate with trastuzumab as first-line therapy for locally recurrent or metastatic HER2-positive breast cancer.

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 HER2+ breast cancer. PATIENTS AND METHODS: In this multicenter, phase II, single-arm study, patients with recurrent or metastatic HER2+ 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 = 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 HER2+ breast cancer.