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Eribulin mesylate (halichondrin B analog E7389) in platinum-resistant and platinum-sensitive ovarian cancer†
A 2-cohort, phase 2 study
Article first published online: 20 SEP 2011
Copyright © 2011 American Cancer Society
Volume 118, Issue 9, pages 2403–2410, 1 May 2012
How to Cite
Hensley, M. L., Kravetz, S., Jia, X., Iasonos, A., Tew, W., Pereira, L., Sabbatini, P., Whalen, C., Aghajanian, C. A., Zarwan, C. and Berlin, S. (2012), Eribulin mesylate (halichondrin B analog E7389) in platinum-resistant and platinum-sensitive ovarian cancer. Cancer, 118: 2403–2410. doi: 10.1002/cncr.26569
Presented in part at the 2011 Annual Meeting of the American Society of Clinical Oncology; June 3-7, 2011; Chicago, Ill.
- Issue published online: 20 APR 2012
- Article first published online: 20 SEP 2011
- Manuscript Revised: 25 AUG 2011
- Manuscript Accepted: 25 AUG 2011
- Manuscript Received: 17 JUN 2011
- ovarian cancer;
- phase 2;
Eribulin mesylate is a tubulin inhibitor with activity superior to paclitaxel in NIH:OVCAR-3 human epithelial ovarian cancer xenograft models. In this study, the authors assessed the efficacy of eribulin in platinum-resistant and platinum-sensitive recurrent ovarian cancer.
Patients with recurrent, measurable epithelial ovarian cancer who had received ≤2 prior cytotoxic regimens and who had adequate organ function were enrolled into 2 separate cohorts: 1) platinum-resistant patients (who had a progression-free interval <6 months after their last platinum-based therapy) and 2) platinum-sensitive patients (who had a progression-free interval ≥6 months after their last platinum-based therapy). Eribulin 1.4 mg/m2 was administered over 15 minutes intravenously on days 1 and 8 every 21 days. Efficacy was determined by objective response on computed tomography studies.
In the platinum-resistant cohort, 37 patients enrolled, and 36 patients were evaluable for response and toxicity. Two patients achieved a partial response (5.5%), and 16 patients (44%) had stable disease as their best response. The median progression-free survival was 1.8 months (95% confidence interval, 1.4-2.8 months). In the platinum-sensitive cohort, 37 patients enrolled, and all were evaluable for response. Seven patients achieved a partial response (19%). The median progression-free survival was 4.1 months (95% confidence interval, 2.8-5.8 months). The major toxicity was grade 3 or 4 neutropenia (42% of platinum-resistant patients; 54% of platinum-sensitive patients).
Eribulin produced an objective response in 5.5% of women with platinum-resistant, recurrent ovarian cancer and in 19% of women with platinum-sensitive disease. The median progression-free survival was 1.8 months in the platinum-resistant group and 4.1 months in the platinum-sensitive group. Cancer 2012. © 2011 American Cancer Society.
In 2010, epithelial ovarian cancer was diagnosed in approximately 21,880 women in the United States, and approximately 13,850 American women died from this disease.1 Nearly 75% of women with epithelial ovarian cancer have stage III or IV disease at the time of diagnosis. Although >80% of patients with advanced-stage ovarian cancer will demonstrate a clinical response to first-line platinum-based chemotherapy, the majority ultimately will die of their disease, and the 5-year overall survival rate ranges from 5% to 30%.2, 3
For patients who have disease progression on first-line therapy (primary refractory disease) and patients whose disease progresses within the first 6 to 12 months after completing first-line platinum-based chemotherapy, the efficacy of further chemotherapy is poor. Although several agents with some evidence of activity have been identified in phase 2 trials, responses (generally partial responses at best) are observed in approximately 15% to 30% of women (depending on the platinum sensitivity of the population). Responses in platinum-resistant patients are observed in only approximately 15% of patients, and the duration of response is only approximately 4 months.
Eribulin mesylate (E7389; halichondrin B) is a tubulin inhibitor whose mechanism of action differs from that of other antitubulin agents, effecting cell cycle block at G2/M, disruption of mitotic spindle formation, and initiation of apoptosis.4 Eribulin mesylate appears to have a tubulin interaction mechanism that differs from that of paclitaxel. In in vivo studies using NIH:OVCAR-3 human ovarian cancer xenograft models, treatment with eribulin mesylate increased survival and reduced the size and number of metastases, with activity superior to that of paclitaxel.4, 5
There is a clinical need for new, effective agents for the treatment of ovarian cancer, particularly for patients who have received prior taxane-platinum-based chemotherapy. Because the response rates to second-line treatment are generally higher among patients with platinum-sensitive disease, we designed this study to determine whether eribulin mesylate could achieve objective responses among patients with recurrent ovarian cancer who were studied in 2 separate cohorts: platinum-resistant patients and platinum-sensitive patients.
MATERIALS AND METHODS
Eligible patients were aged ≥18 years and had histologically or cytologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal cancer; measurable disease (defined according to Response Evaluation Criteria in Solid Tumors [RECIST], version 1.0); no more than 2 prior therapies for this cancer; and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Prior surgery, chemotherapy, and/or radiation must have been completed at least 4 weeks before enrollment (6 weeks for nitrosoureas or mitomycin C), and patients must have recovered from any prior treatment-related adverse events. Patients were required to have adequate bone marrow function (white blood cell count [WBC] ≥3000/μL, absolute neutrophil count [ANC] ≥1500/μL, and platelets ≥100,000/μL), renal function (creatinine within normal institutional limits), and hepatic function (total bilirubin within normal institutional limits, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤2.5 times the institutional upper limit of normal). Eligible patients had to have a life expectancy >2 months and the ability to understand and willingness to sign a written informed consent form. Patients were not permitted to take concomitant antitumor hormone therapy and/or investigational agents, and they must have discontinued any prior hormone therapy at least 14 days before starting study treatment. Patients who had had another invasive malignancy within the past 5 years were excluded, except for patients with a history of stage IA or IB endometrial cancer (who were considered disease free from endometrial cancer) and patients with a history of nonmelanoma skin cancer. Other exclusions included patients with known brain metastases; patients who were pregnant or breastfeeding; patients with known human immunodeficiency virus; and patients with uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Patients who previously received eribulin or patients who had a history of allergic reaction to compounds of similar chemical or biologic composition of eribulin were ineligible. An effort was made to switch patients who were taking enzyme-inducing anticonvulsant agents and any other medications/substances known to affect (or with the potential to affect) the pharmacokinetics of eribulin to other medications before starting study treatment. Patients were assigned to the platinum-resistant cohort if the progression-free interval from last platinum-based therapy was <6 months, and they were assigned to the platinum-sensitive cohort if the progression-free interval from last platinum-based therapy was ≥6 months. All patients signed written informed consent forms. The protocol was reviewed annually by the institutional review boards/privacy boards of the participating institutions.
Eribulin mesylate 1.4 mg/m2 was administered intravenously over 15 minutes on days 1 and 8 every 21 days (to accommodate scheduling difficulties, all day-1 treatments could be given 1 day early or up to 2 days late, provided all treatment parameters were met). On day 1 of each cycle, an ANC ≥1000/μL and platelets ≥100,000/μL were required. On day 8 of each cycle, eribulin was held if the ANC was <500/μL or if the platelets were <50,000/μL. If the day-8 eribulin was held for myelosuppression, then the dose was not “made up.” Day 1 treatment delays were permitted for up to 2 weeks for recovery of the ANC to ≥1000/μL and of platelets to ≥100,000/μL. The use of granulocyte-colony–stimulating factors (GCSFs) was not allowed during Cycle 1 of treatment, and prophylactic or routine use during subsequent cycles was not recommended. In the case of neutropenia without fever or febrile neutropenia, administration of GCSFs according to current American Society of Clinical Oncology guidelines, was allowed. If GCSFs were used in subsequent cycles, then a 24-hour window before and after treatment with eribulin was recommended. The use of GCSFs between days 1 and 8 of treatment was not recommended. Dose reduction of eribulin to 1 mg/m2 for all subsequent cycles was required in the event of febrile neutropenia; a platelet count <10,000/μL; grade 4 neutropenia that lasted ≥7 days; grade 3 or 4 elevations in ALT, AST, or alkaline phosphatase; grade 3 or 4 stomatitis; or grade 2 or worse renal toxicity. Eribulin-related toxicities had to resolve to within eligibility parameters (within 2 weeks) before the next cycle could be given. Treatment with eribulin was continued for as long as there was no evidence of disease progression, unacceptable toxicity, an intercurrent illness that prevented further treatment, patient withdrawal of consent from study, or any change in the patient's condition that, in the opinion of the investigator, rendered the patient unable to continue safely on study.
Monitoring for Toxicity and Assessment of Response
All patients had the following evaluations: physical examination, vital signs, assessment of performance status, weekly complete blood counts and serum chemistries, serum CA 125 on day 1 of each cycle, and ongoing assessment of adverse events and concurrent medications. For evaluation of response, all patients had computed tomography scans of chest/abdomen/pelvis every other cycle. Radiographic response was determined according to RECIST (version 1.0),6 with the following definitions: a complete response (CR) was defined as the disappearance of all target lesions; a partial response (PR) was defined as a decrease ≥30% in the sum of the greatest dimension of target lesions, taking as reference the baseline sum of the greatest dimension; progressive disease (PD) was defined as an increase ≥20% in the sum of the greatest dimension of target lesions, taking as reference the smallest sum of the greatest dimension recorded since treatment started or the appearance of 1 or more new lesions; and stable disease (SD) was defined as neither sufficient shrinkage to qualify for a PR nor a sufficient increase to qualify as PD, taking as reference the smallest sum of the greatest dimension since treatment started. Patients were considered to be evaluable by CA 125 if the CA 125 level was >35 U/mL before the start of study treatment. Patients were considered to have had a CA 125 response if there had been a serial decrease in CA 125 of at least 50% over 4 samples or a serial decrease of at least 75% over 3 samples.7, 8
The primary endpoint of the study was to determine the frequency of objective response to treatment with eribulin in patients with recurrent ovarian, fallopian tube, or peritoneal cancer. The study was designed to assess the objective response rate (CR + PR) separately for the following 2 cohorts: 1) patients with platinum-resistant disease (progression-free interval from last platinum-based therapy <6 months) and 2) patients with potentially platinum-sensitive disease (progression-free interval from last platinum-based therapy ≥6 months). The 2 cohorts were accrued and analyzed separately. Within each cohort, an optimal 2-stage Simon design was used in which a 20% response rate was considered promising, and a 5% response rate was considered unacceptable.9 With both type I error and type II error set at 10%, 12 patients were to be enrolled initially and treated with eribulin, and enrollment was to be expanded to 37 patients if at least 1 patient had an objective response (CR or PR) in each cohort.
The treatment regimen was considered to have demonstrated a promising level of single-agent activity in the respective cohort if at least 4 of 37 patients had objective responses. Within each cohort, this design yields at least a 90% probability of a positive result if the true response rate is ≥20%, and it yields a 90% probability of a negative result if the true response rate is 5%. Platinum-sensitive patients and platinum-resistant patients were analyzed separately. Descriptive statistics were provided on patient characteristics, toxicities, and responses. Objective response rates were calculated for each cohort. In addition, the response rate and its 1-sided 90% confidence interval (CI) were estimated using an exact inference method that appropriately accounted for the 2-stage design feature.10 The Kaplan-Meier method11 was used to estimate the progression-free survival. Analyses were performed using the R statistical software package “Clinfun” (R Project for Statistical Computing, Vienna, Austria) and SAS software (version 9.2; SAS Institute Inc., Cary, NC).12 Although it was not designated as a study endpoint, in response to reviewers, the “disease control rate,” defined as the percentage of patients achieving CR, or PR, or SD, and its 90% CI were calculated for each cohort.
Patient demographics and response rates for both cohorts are summarized in Table 1. Toxicity results are summarized in Table 2. Responses, toxicities, and survival outcomes are detailed below for each cohort.
|Variable||Platinum-Resistant Cohort||Platinum-Sensitive Cohort|
|No. of patients enrolled/no. evaluable||37/36||37/37|
|Age: Median [range], y||61 [38-80]||60 [45-77]|
|Platinum-free interval: Median [range], mo||3 [0.1-5.9]||10 [6.5-45]|
|No. of previous prior regimens: Median [range]||2 [1-2]||1.5 [1-2]|
|ECOG PS: Median [range]||0 [0-1]||0 [0-1]|
|No. of cycles delivered: Median [range]||2 [1-10]||6 [1-51]|
|Response: No. of patients/total (%)|
|Partial response||2/36 (5.5)||7/37 (19)|
|Stable disease||16/36 (44)||21/37 (57)|
|CA 125 response||3/31 (9.6)||11/31 (35)|
|No. of Patients (%)|
|Toxicity||Platinum-Resistant, n = 36||Platinum-Sensitive, n = 37|
|Neutropenia||15 (42)||20 (54)|
|Febrile neutropenia||1 (2.7)||0 (0)|
|Leucopenia||12 (33)||11 (30)|
|Thrombocytopenia||0 (0)||0 (0)|
|Anemia, grade 3||1 (2.7)||0 (0)|
|Lymphopenia||1 (2.7)||2 (5.4)|
|Thrombosis||2 (5.5)||1 (2.7)|
|Infection: Pneumonia, urinary tract infection||2 (5.5)||0 (0)|
|Pain, grade 3||0 (0)||3 (8)|
|Hyperglycemia, grade 3||1 (2.7)||1 (2.7)|
|Hypokalemia, grade 3||2 (5.5)||0 (0)|
|Hyponatremia, grade 3||0 (0)||1 (2.7)|
|Hypophosphatemia, grade 3||0 (0)||1 (2.7)|
|Hypomagnesemia, grade 3||0 (0)||1 (2.7)|
|Generalized muscle weakness, grade 3||1 (2.7)||2 (5.4)|
|Elevated ALT/AST, grade 3||0 (0)||2 (5.4)|
|Diarrhea, grade 3||0 (0)||1 (2.7)|
|Ataxia, grade 3||0 (0)||1 (2.7)|
Thirty-seven patients were accrued to the platinum-resistant cohort, and 36 were evaluable for response and toxicity (1 patient was removed from study before initiating study treatment because of declining performance status). All patients had received platinum-taxane first-line treatment (carboplatin or cisplatin plus paclitaxel in 34 patients, docetaxel in 2 patients) and had a median platinum-free interval of 3 months (range, 0.1-5.9 months). Thirty patients had received second-line treatment: 5 were retreated with paclitaxel plus carboplatin, 10 received gemcitabine plus carboplatin, 10 received liposomal doxorubicin, 2 received carboplatin plus pemetrexed, 1 received carboplatin plus liposomal doxorubicin, 1 received single-agent carboplatin, and 1 received topotecan. In addition, 2 patients had received maintenance paclitaxel after achieving complete clinical remission with first-line treatment. The median age was 61 years (range, 38-80 years), and the median ECOG performance status was 0. Among the 36 evaluable patients, the median number of cycles delivered per patient was 2 (range, 1-10 cycles). Two patients achieved a PR (5.5%). Calculating the response rate using a bias-correcting estimate yields an objective response rate of 9.9%, and the lower bound of the 1-sided 90% CI was 2%. The response durations of these 2 PRs were 84 days and 128 days. The time to achieve an objective PR was 2.8 months in both patients. Sixteen patients had SD as their best response (44%). Thirty-one patients had serum CA 125 values that were evaluable for response. Only 3 of those 31 patients (9.6%) had a CA 125 response. According to a definition of the “disease control rate” as CR + PR + SD, 18 of 36 patients achieved disease control (50%; 90% CI, 38%-100%). However, the median progression-free survival was only 1.8 months (95% CI, 1.4-2.8 months). The median overall survival among platinum-resistant patients was 18 months (95% CI, 11-25 months) (Fig. 1). On a per-patient basis, grade 3 or 4 adverse events that were at least possibly treatment-related included neutropenia in 42% of patients, leucopenia in 33% of patients, anemia in 2.7% of patients, lymphopenia in 2.7% of patients, febrile neutropenia in 2.7% of patients, infection in 5.5% of patients, thrombosis in 5.5% of patients, hypokalemia in 5.5% of patients, hyperglycemia in 2.7% of patients, and generalized muscle weakness in 2.7% of patients.
Thirty-seven patients were accrued to the platinum-sensitive cohort, and all were evaluable for response. The median platinum-free interval was 10 months (range, 6.5-45 months). All patients had received platinum (carboplatin or cisplatin) plus taxane-based first-line treatment (36 received paclitaxel, and 1 received docetaxel). Sixteen patients had received second-line therapy: 6 patients were retreated with paclitaxel plus carboplatin, 6 patients received gemcitabine plus carboplatin, 1 received oxaliplatin plus gemcitabine, 1 received carboplatin plus pemetrexed, 1 received liposomal doxorubicin, and 1 received bevacizumab. In addition, 2 patients in the platinum-sensitive cohort had received maintenance paclitaxel after achieving first complete clinical remission. The median age of the patients in the platinum-sensitive cohort was 60 years (range, 45-77 years), and the median ECOG performance status was 0. The median number of cycles delivered was 6 per patient (range, 1-51 cycles per patient). Seven of 37 evaluable patients achieved an objective response (PR; 19%), and no patients achieved a CR. Calculating the response rate using a bias-correcting estimate yielded an objective response rate of 19.8%, and the lower bound of the 1-sided 90% CI was 11%. Twenty-one patients had SD as their best response (57%). Thirty-one patients had serum CA 125 values that were evaluable, and 11 patients (35%) had CA 125 responses. The “disease control rate” (CR + PR + SD) was 28 of 37 patients (76%; 90% CI, 61%-100%). Response durations for the 7 patients who achieved objective responses are listed in Table 3. The median progression-free survival was 4.1 months (95% CI, 2.8-5.8 months), and the median overall survival among platinum-sensitive patients was 26 months (95% CI, 21-38 months) (Fig. 2). On a per-patient basis, grade 3 or 4 adverse events that were at least possibly treatment-related included neutropenia in 54% of patients, leucopenia in 30% of patients, lymphopenia in 5.4% of patients, pain in 8% of patients, generalized muscle weakness in 5.4% of patients, elevated liver enzymes in 5.4% of patients, thrombosis in 2.7% of patients, hyperglycemia in 2.7% of patients, hyponatremia in 2.7% of patients, hypophosphatemia in 2.7% of patients, hypomagnesemia in 2.7% of patients, diarrhea in 2.7% of patients, and ataxia in 2.7% of patients.
|Patient No.||Duration of Objective Response, Days|
This study was designed for 2 separate cohorts of patients with recurrent ovarian cancer to determine the activity of eribulin in platinum-resistant and platinum-sensitive patients. Objective responses were observed in only 5.5% of platinum-resistant patients; in contrast, 19% of platinum-sensitive patients achieved objective responses. A similar contrast in sensitivity to nonplatinum chemotherapy agents has been reported with most other agents tested in ovarian cancer. In a large phase 3 trial, liposomal doxorubicin was compared with topotecan among patients who were stratified as platinum resistant or platinum sensitive before randomization. Objective response rates did not differ substantially between the 2 drugs, but they were higher in the platinum-sensitive patients (liposomal doxorubicin, 28%; topotecan, 28%) than in the platinum-resistant patients (liposomal doxorubicin, 12.3%; topotecan, 6.5%).13 In a phase 3 trial comparing gemcitabine with liposomal doxorubicin in patients with platinum-resistant ovarian cancer, objective responses were observed in 9.2% of patients assigned to gemcitabine and in 11.7% of patients assigned to liposomal doxorubicin.14 In a single-arm phase 2 trial of liposomal doxorubicin in platinum-resistant patients, 9.9% of patients had objective responses15; however, an earlier trial reported an 18% response rate in a platinum-resistant and taxane-resistant population.16 Although the observed response rate of 19% among patients with platinum-sensitive ovarian cancer makes eribulin a promising new agent for this population, effective treatment for platinum-resistant ovarian cancer remains a significant therapeutic challenge.
The treatment schedule of eribulin is convenient, with a short infusion time and no required steroid premedications. Neutropenia was the most common toxicity, although neutropenic fever events were rare (2.7% of patients in the platinum-resistant cohort and no events in the platinum-sensitive cohort). Patients in this study had received only 1 or 2 prior regimens. Subsequent to the design and conduct of this study for patients with ovarian cancer, eribulin was approved by the US Food and Drug Administration for the treatment of metastatic breast cancer based on results from a randomized phase 3 trial.17 Prolonged neutropenia and neuropathy both were more common in the breast cancer studies18 than they were in this ovarian cancer study, perhaps because patients in the breast cancer studies were much more heavily pretreated.
It is noteworthy that, in the breast cancer studies, eribulin achieved high objective response rates although most patients had received prior taxane therapy. We observed a similar result in our study: All patients enrolled had received prior platinum, and all had received prior taxane, yet objective responses were observed despite prior taxane therapy.
There has been increasing focus on progression-free survival, rather than the objective response rate, as a measure of drug efficacy, particularly for clinical trials involving targeted therapeutic agents.19 In this 2-cohort phase 2 study, progression-free survival was a secondary objective. Among patients in the platinum-resistant cohort, progression-free survival did not appear to be prolonged by treatment with eribulin (median progression-free survival, 1.8 months). In the platinum-sensitive cohort, progression-free survival was 4.1 months, which is similar to what has been observed with other agents with activity in platinum-sensitive ovarian cancer. Some studies have used the “disease control rate” as a measure of treatment efficacy. Although the current study was not designed with the disease control rate as an endpoint, in response to article reviewers, we have reported these results. The disease control rate in the platinum-sensitive cohort is high (76%), which mirrors the relatively high objective response rate. Although the observed disease control rate in the platinum-resistant cohort appears favorable (50%), the wide CI and the very short progression-free survival of 1.8 months support the conclusion that eribulin is not active in the platinum-resistant population.
To our knowledge, this study is the first to demonstrate the efficacy of eribulin in recurrent ovarian cancer. We demonstrate that eribulin is a novel and active agent for patients with platinum-sensitive, recurrent disease and that eribulin is inactive in platinum-resistant disease.
Funding for this study was provided by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute NO1-CM62206 (Clinicaltrials.gov registration no. NCT00334893).
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
- 4Cancer Therapy Evaluation Program (CTEP). Rapid Communication: Solicitation for Letters of Intent: E7389, Halichondrin B Analog (NSC 707389). Bethesda, MD: CTEP, National Cancer Institute; 2005.
- 6New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000; 92: 205-216., , , et al.
- 7Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125. J Clin Oncol. 1996; 5: 1545-1551., , , et al.
- 11Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958; 53: 457-481., .
- 122010. Available at: http://CRAN.R-project.org/package=clinfun. Accessed August 2011.. Clinfun: Clinical Trial Design and Data Analysis Functions. R package version 0.9.6.
- 17on behalf of the Study 305 investigators. A phase III study (EMBRACE) of eribulin mesylate versus treatment of physician's choice in patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline and a taxane [abstract]. J Clin Oncol. 2010; 28: 18S. Abstract CRA1004., , , et al;