Original Study

An Open-Label, Multicenter, Randomized Phase Ib/II Study of Eribulin Mesylate Administered in Combination With Pemetrexed Versus Pemetrexed Alone as Second-Line Therapy in Patients With Advanced Nonsquamous NoneSmall-Cell Lung Cancer Cornelius F. Waller,1 Ihor Vynnychenko,2 Igor Bondarenko,3 Yaroslav Shparyk,4 Jeffrey P. Hodge,5 Anne Freeman,5 Brian Huber,5 Ronald Lieberman,5 Mark J. Shelton,5 Harish Dave5 Abstract Progression-free survival (PFS), overall survival (OS), and time to disease progression were similar between eribulin with pemetrexed and pemetrexed monotherapy (P) in second-line treatment of nonsquamous, nonesmall-cell lung cancer (NSCLC). At the eribulin dose administered for this phase II study, the combination of eribulin and pemetrexed was well tolerated; there was no therapeutic advantage with the combination of eribulin at this dose. Introduction: New treatment options are needed for second-line therapy in patients with NSCLC. Patients and Methods: This was a phase Ib/II study in patients with nonsquamous NSCLC in whom 1 previous platinum-based chemotherapy regimen had failed. Fifteen patients were enrolled in a dose escalation of eribulin mesylate in combination with pemetrexed (EþP). In phase II (n ¼ 80), EþP at the maximum tolerated dose was compared with P. Results: In phase Ib, the maximum tolerated dose of EþP was defined as eribulin 0.9 mg/m2 with pemetrexed (500 mg/m2) each on day 1 of a 21-day cycle. In phase II, adverse events were comparable between groups. PFS and OS were similar between treatment groups. Median PFS was 21.4 weeks for EþP (n ¼ 26; 95% confidence interval [CI], 12.7-39.6) and 23.4 weeks for P (n ¼ 29; 95% CI, 17.1-29.9), with a hazard ratio of 1.0 (95% CI, 0.6-1.7). Conclusion: During phase Ib, EþP was tolerated only at a markedly lower dosing intensity relative to the eribulin monotherapy regimen approved for breast cancer and used in phase II studies of NSCLC. At the selected phase II dosing regimen, EþP was generally safe and well tolerated but provided no therapeutic advantage for the second-line treatment of locally advanced or metastatic nonsquamous NSCLC. Clinical Lung Cancer, Vol. 16, No. 2, 92-9 ª 2015 Elsevier Inc. All rights reserved. Keywords: Eribulin mesylate, Overall survival, Phase II clinical trial, Progression-free survival, Time to progression

Phase 1 data for this study were presented at the 14th World Conference on Lung Cancer, July 3-7, 2011, Amsterdam, The Netherlands (abstract 488). 1 Universitätsklinikum Freiburg, Department of Internal Medicine, Oncology, Hematology, and Stem Cell Transplantation, Freiburg, Germany 2 Sumy State University, Sumy Regional Clinical Oncological Dispensary Thoracic Department, Sumy, Ukraine 3 Municipal Multifield Clinical Hospital #4, Department of Chemotherapy, Donetsk State Medical University, Donetsk, Ukraine 4 Department of Chemotherapy, Lviv State Oncology Regional Treatment and Diagnostic Center, Lviv, Ukraine

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Quintiles, Durham, NC

Submitted: Jul 18, 2014; Revised: Sep 30, 2014; Accepted: Oct 7, 2014; Epub: Oct 15, 2014 Address for correspondence: Cornelius F. Waller, MD, Department of Internal Medicine, Oncology, Hematology, and Stem Cell Transplantation, Universitätsklinikum Freiburg, Hugstetter Str 55, D-79106, Freiburg, Germany Fax: þ49-761-27034180; e-mail contact: [email protected]

1525-7304/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2014.10.001

Introduction Nonesmall-cell lung cancer (NSCLC) accounts for approximately 85% of all cases of lung cancer.1-3 In NSCLC, results of standard therapy are poor except for the most localized cancers in which surgery and/or combined modality therapy can provide a cure in a small number of patients. In advanced-stage disease, chemotherapy offers modest benefit, although overall survival is poor.4,5 Globally, there are 4 agents currently approved for the treatment of advanced NSCLC in the second- and third-line setting: docetaxel, pemetrexed, erlotinib, and gefitinib.6-15 Because of the low overall response rates of these agents (< 10%), the need for new treatment options—especially for second-line therapy for this patient population—is apparent. Eribulin mesylate (hereafter referred to as “eribulin”) is a novel tubulin-targeted agent being developed as an anticancer agent in a number of different solid tumors.16 Eribulin exerts its antiproliferative effects via a novel tubulin-based antimitotic mechanism. Through a unique binding site on tubulin, eribulin suppresses microtubule polymerization, has no effect on microtubule depolymerization, and segregates tubulin into nonfunctional aggregates. It has been approved by the Food and Drug Administration and the European Medicines Agency for the treatment of locally advanced and/or metastatic breast cancer as a third-line chemotherapy regimen at a dose of 1.4 mg/m2 infused intravenously over 2 to 5 minutes on days 1 and 8 of a 21-day cycle.16 Eribulin is also being developed as a chemotherapeutic agent for NSCLC. Eribulin—as a single agent—exhibited an overall response rate of 9.7%, median progression-free survival (PFS) of 3.4 months, and median overall survival of 9.4 months in a phase II study of previously treated patients with recurrent, advanced NSCLC.17 The overall response rate was not diminished with previous taxane therapy or increased number of previous chemotherapy regimens. Common drug-related adverse events were neutropenia, fatigue, nausea, alopecia, and anemia. In another phase II study in NSCLC patients previously treated with platinum and taxane-based therapies, eribulin monotherapy exhibited an objective response rate of 5%, median PFS of 2.7 months, and median overall survival of 11.6 months. Greater benefit was observed in the taxane-sensitive cohort (defined as sustained response or stable disease lasting at least 3 months).18 The activity of eribulin as a single agent in recurrent advanced NSCLC, its activity after taxane therapy, and its ease of administration as a 2- to 5-minute intravenous infusion without a requirement for premedication make it a good candidate to be evaluated in combination with pemetrexed for second- (or later) line nonsquamous NSCLC. In the current phase Ib/II study, we evaluated the safety and tolerability of eribulin (Halaven, Eisai Inc, Woodcliff Lake, NJ) in combination with pemetrexed, a current standard second-line therapy approved in the United States and the European Union as a single agent for nonsquamous NSCLC after failure of previous chemotherapy. The efficacy of eribulin in combination with pemetrexed compared with pemetrexed alone was also explored.

Patients and Methods The study was conducted in compliance with Good Clinical Practice and the Declaration of Helsinki (2008) and was approved

by all relevant institutional review boards. All participants signed a written informed consent document before enrolling in the study.

Study Design Phase Ib. This was an open-label, multicenter study consisting of 2 parallel treatment groups evaluating 3 ascending doses of eribulin in each treatment group: (1) treatment group 1: eribulin 0.9, 1.4, or 2.0 mg/m2 administered on day 1 of a 21-day cycle; and (2) treatment group 2: eribulin 0.7, 1.1, or 1.4 mg/m2 administered on days 1 and 8 of a 21-day cycle. Patients who had received a maximum of 3 previous chemotherapy regimens were recruited into cohorts, with a minimum of 3 and a maximum of 6 patients per cohort. All patients received the same dose of pemetrexed (500 mg/m2) on day 1 in combination with eribulin. All patients within a cohort received the same dose level of eribulin. The dose level of eribulin was escalated for additional cohorts unless 2 or more dose-limiting toxicities (DLTs) were reported at the lower dose level(s) before enrollment of the next dose level. DLTs were defined as clinically significant adverse events occurring  21 days after commencing study treatment and considered by the investigator to be possibly or probably related to study treatment. If 1 DLT occurred at any dose level, the cohort was expanded to include up to a maximum of 6 patients. If 2 DLTs occurred at any dose level, that dose was defined as not tolerated and the maximum tolerated dose (MTD) recommended for phase II was either to be defined as the preceding dose or an intermediate dose. Phase II. The Phase II portion of the study was a 2-arm design in which patients were randomized in a 1:1 ratio to receive either one of the following: (1) eribulin, at the dose of 0.9 mg/m2 as previously defined in the phase Ib part of the study, in combination with pemetrexed (500 mg/m2); or (2) pemetrexed (500 mg/m2) alone. All drugs were administered on day 1 of every 21-day cycle. Radiologic examinations, including a computerized tomography scan of the chest and abdomen, as appropriate (or magnetic resonance imaging as appropriate), were performed during screening and every 6 weeks after starting therapy. Radiographic assessments were to be repeated at withdrawal if the last assessment was obtained 3 or more weeks from withdrawal of therapy. Patients were followed for up to 1 year after completion of therapy. Scans were required every 8 weeks ( 1 week) until documentation of progressive disease or the start of a next line of therapy, whichever occurred first. In patients experiencing progressive disease, follow-up was for survival for up to 1 year after the last treatment or another anticancer therapy was started, whichever occurred first.

Patients Patients 18 years of age and older were eligible for study entry if they had the following: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, adequate organ function, histologically or cytologically confirmed nonsquamous NSCLC with locally advanced or metastatic disease that was not amenable to curative therapy, 1 or more sites of measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria, and history of stage III disease that relapsed after chemotherapy and radiotherapy. Failure of 1 previous

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Eribulin Mesylate With Pemetrexed Versus Pemetrexed Alone platinum-based doublet chemotherapy regimen for stage IV nonsquamous NSCLC was also required. A maximum of 3 total previous chemotherapy regimens was permitted in phase Ib. In phase II, all patients received study treatment as second-line therapy, although 1 additional cytotoxic regimen was allowed for neoadjuvant, adjuvant, or neoadjuvant with adjuvant therapy. Exclusion criteria included the following: presence of brain metastases (unless stable and asymptomatic), previous treatment with pemetrexed, epothilone, ixabepilone, patupilone, halichondrin B, or halichondrin B-like compounds, previous chemotherapy, radiotherapy, or biological, hormonal, or targeted therapy within 30 days before commencing study treatment, or failure to recover from all treatment-related toxicities to Common Toxicity Criteria Grade  1. Colony stimulating factors were disallowed during phase Ib, but were allowed in phase II.

Procedure During phase Ib, eribulin was administered as a 2- to 5-minute intravenous bolus on day 1 of each 21-day cycle or days 1 and 8 of each 21-day cycle. For the phase Ib portion, the planned doses for treatment group 1 were 0.9 mg/m2, 1.4 mg/m2, or 2.0 mg/m2, and for treatment group 2 the doses were 0.7 mg/m2, 1.0 mg/m2, or 1.4 mg/m2. Pemetrexed was administered at a dose of 500 mg/m2 as an intravenous infusion on day 1 of each 21-day cycle. During phase II, patients randomized to receive eribulin were administered eribulin at 0.9 mg/m2 on day 1 of each 21-day cycle. Pemetrexed was administered at a dose of 500 mg/m2 as an intravenous infusion on day 1 of each 21-day cycle. Patients also received dexamethasone and vitamin supplements as recommended in the prescribing information for pemetrexed. Patients received study treatment (eribulin and pemetrexed in combination or pemetrexed alone) until the occurrence of progressive disease, unacceptable toxicity, withdrawal of consent, withdrawal by investigator, or loss to follow-up or death (whichever occurred first). For patients in the eribulin with pemetrexed arm, if 1 agent (ie, either eribulin or pemetrexed) needed to be discontinued for toxicity reasons following the specified dose modification guidelines, the companion agent could be continued to 1 year after completion of therapy.

Study End Points Safety. Safety parameters for phase Ib and II included: adverse events, vital signs, ECOG performance status, clinical laboratory evaluations, physical examinations, and 12-lead electrocardiograms. Phase II Efficacy. An exploratory efficacy end point was the median PFS within treatment group, defined as the time from the date of randomization of a patient until either: (1) the date of first documented progression of such patient’s disease based on investigator assessments according to RECIST; or (2) the date of such patient’s death due to any cause. Other exploratory efficacy end points included median time to progression, overall survival, and overall response rate.

Statistical Analyses

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The safety analysis set for phase II included all patients except for those who dropped out of the study before receiving any study drug

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or were without any safety assessment after the first dose of study drug. The phase II modified intent-to-treat (MITT) analysis set included all patients randomized in the applicable study arm, except a patient who dropped out of such arm before receiving any comparator or investigative drug. Safety end points were based on the safety analysis set and efficacy end points were based on the MITT analysis set. In general, descriptive summaries were presented for the safety and efficacy variables collected. Continuous variables were summarized using mean, standard deviation, minimum, median, and maximum. Categorical variables were summarized using frequency counts and percentages. For time to event variables, KaplaneMeier plots, median time to event, and other percentiles were presented. Adverse events were coded using the Medical Dictionary for Regulatory Activities and were summarized according to System Organ Class and Preferred Term. In addition, summaries of adverse events according to severity and relationship to study drug were presented. A planned analysis was to be carried out when 60 patients experienced progressive disease or death; however, because of the unanticipated high rate of censored PFS efficacy events (23 of the 78 patients in the MITT population), this analysis was conducted before 60 events.

Results Phase Ib A total of 15 patients were enrolled in the phase Ib portion of the study. Four patients were enrolled in treatment group 1-cohort 1 and received eribulin 0.9 mg/m2 in combination with pemetrexed at a dose of 500 mg/m2 as an intravenous infusion on day 1 of each 21-day cycle. After enrollment, 1 patient was considered ineligible for the study because of failure to meet entry criterion (inadequate washout from previous therapy) and was replaced. There were no DLTs in this cohort and the eribulin dose was escalated to 1.4 mg/m2 in the next cohort of treatment group 1. In treatment group 1-cohort 2, 3 patients were initially enrolled and received eribulin 1.4 mg/m2 with pemetrexed on day 1. Because of the occurrence of a DLT of febrile neutropenia in the first patient, the cohort was expanded to 6 patients. Because of the occurrence of 5 DLTs in 3 of 6 patients in treatment group 1-cohort 2 (Grade 3 aspartate aminotransferase [AST] and Grade 3 alanine aminotransferase [ALT] in 1 patient, Grade 4 neutropenia and Grade 4 thrombocytopenia in 1 patient, and Grade 4 febrile neutropenia in 1 patient), there were no additional dose escalations in treatment group 1. Eribulin 0.9 mg/m2 in combination with pemetrexed on day 1 was defined as the MTD for treatment group 1. In treatment group 2-cohort 1, 5 patients were enrolled and received eribulin 0.7 mg/m2 in combination with pemetrexed on days 1 and 8. After the first 3 patients were enrolled, 1 patient who received filgrastim could not be evaluated for DLTs and was replaced. After the replacement patient experienced a DLT of Grade 4 transaminitis, the cohort was to be expanded to 6 patients. When the fifth patient developed a DLT of Grade 4 pneumonia, enrollment was capped at 5 patients in treatment group 2-cohort 1. There were no additional dose escalations in treatment group 2. The MTD could not be defined for treatment group 2. Therefore, the phase II portion of the study proceeded with the dose from treatment group 1-cohort 1 (ie, eribulin 0.9 mg/m2 on day 1).

Cornelius F. Waller et al Phase II Subject Disposition. Eighty-three patients were enrolled; 42 patients in the eribulin with pemetrexed group and 41 patients in the pemetrexed group. Eighty patients received study treatment and were included in the safety population (41 patients from the eribulin with pemetrexed group and 39 patients from the pemetrexed group; Table 1). Seventy-eight patients were included in the MITT population (39 patients from each group). Twelve patients (28.6%) in the eribulin with pemetrexed group and 15 patients (37%) in the pemetrexed group received 6 cycles of treatment. Overall, the most frequent reason for treatment discontinuation was progressive disease, reported for 23 patients (55%) in the eribulin with pemetrexed group and 18 patients (44%) in the pemetrexed group. The most frequent reason for discontinuation from the study was death, reported for 16 patients (38%) in the eribulin with pemetrexed group and 17 patients (42%) in the pemetrexed group. Patient disposition throughout the study is described in Figure 1. All patients had received a least 1 previous therapy for NSCLC including: 38 patients (93%) in the eribulin with pemetrexed group and 38 patients (97%) in the pemetrexed monotherapy group who had received previous chemotherapy; 5 patients (12.2%) in the eribulin with pemetrexed group and 6 patients (15%) in the

Table 1 Baseline Patient and Disease Characteristics Eribulin With Pemetrexed (n [ 41)

Pemetrexed (n [ 39)

Sex Male

25 (61%)

26 (67%)

Female

16 (39%)

13 (33%)

Age Median

59

60

Range

38-80

46-77

White Race

41 (100%)

39 (100%)

Ethnicity Hispanic or Latino Not Hispanic or Latino

3 (7%)

1 (3%)

38 (93%)

38 (97%)

ECOG Performance Status 0

10 (24%)

3 (8%)

1

31 (76%)

36 (92%)

Previous Taxane

19

13

Taxane-sensitive

10

9

Not taxane-sensitive

9

4

13

12

Best Response to Previous Chemotherapy CR/PR SD

18

13

PD/unknown

10

14

Histology Adenocarcinoma

34 (83%)

36 (92%)

Large cell carcinoma

2 (5%)

1 (3%)

Other

5 (12%)

2 (5%)

Patients were considered to be taxane-sensitive if they achieved a complete or partial response as best response to a previous taxane-based regimen or stable disease as best response with a treatment duration of at least 90 days. Abbreviation: ECOG ¼ Eastern Cooperative Oncology Group.

pemetrexed monotherapy group who had received a previous targeted agent; and 3 patients (7%) in the eribulin with pemetrexed group and 1 patient (3%) in the pemetrexed monotherapy group who had received chemotherapy and a targeted agent. Nineteen patients in the eribulin with pemetrexed group had received previous therapy with a taxane compared with 13 patients in the pemetrexed monotherapy group. Fifteen patients (37%) in the eribulin with pemetrexed group and 13 patients (33%) in the pemetrexed monotherapy group had received previous radiotherapy. Safety. Thirty-nine patients (95%) treated with eribulin with pemetrexed and 37 patients treated with pemetrexed alone (95%) experienced adverse events; 25 patients (61%) in the eribulin with pemetrexed group and 27 patients in the pemetrexed monotherapy group (69.2%) had an adverse event of Grade  3. Adverse events considered to be (possibly, probably, or definitely) related to eribulin (“drug-related”) occurred in 24 (59%) of patients treated with eribulin with pemetrexed. Adverse events related to pemetrexed occurred in 31 (76%) of patients treated with eribulin with pemetrexed and 28 (72%) of patients treated with pemetrexed alone. All adverse events occurring in 6 or more patients (including those considered to be related to study drug) are listed in Table 2, whereas drug-related adverse events are summarized herein. The most frequently occurring adverse event related to eribulin in the combination treatment group was neutropenia (7 patients, 17%) followed by anemia (6 patients, 15%), and increased ALT and AST (5 patients, 12% each). The most frequently occurring adverse event related to pemetrexed in the combination treatment group was neutropenia (11 patients, 27%) followed by increased ALT and AST (9 patients, 22% each), and anemia (6 patients, 15%). The most frequently occurring adverse event related to pemetrexed in the pemetrexed treatment group was increased ALT and AST (15 patients, 39% each), followed by anemia (14 patients, 36%), and neutropenia (11 patients, 28%). In the eribulin with pemetrexed treatment group, anemia was the adverse event that led to an eribulin dose reduction, interruption, or withdrawal in most patients (2 patients, 4.9%). Anemia and increased ALT were the adverse events that led to a pemetrexed dose reduction, interruption, or withdrawal in most patients (2 patients, 4.9% each). In the eribulin with pemetrexed treatment group, 13 patients (32%) experienced 1 or more serious adverse events, 3 patients (7%) discontinued from the study because of an adverse event, and 2 patients (5%) died because of an adverse event. In the pemetrexed treatment group, 7 patients (18%) experienced 1 or more serious adverse events, 4 patients (10%) were withdrawn from the study because of an adverse event, and 4 patients (10%) died because of an adverse event. Dyspnea was the adverse event reported as serious in most patients (3 patients, 7.3%) in the eribulin with pemetrexed treatment group, followed by anemia (2 patients, 4.9%). No adverse event was reported as serious in more than 1 patient in the pemetrexed treatment group. The eribulin dose was reduced in the eribulin with pemetrexed treatment group in 6 patients (15%) and eribulin dosing was interrupted in 3 patients (7%). Eribulin was withdrawn in 8 patients (20%). Pemetrexed dose modifications were similar

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Eribulin Mesylate With Pemetrexed Versus Pemetrexed Alone Figure 1 Disposition of Patients for PFS Efficacy Analysis in Phase II

Patients randomized (n = 83)

Eribulin and pemetrexed (n = 42)

Not in MITT population (n = 3)

Not in MITT population (n = 2)

MITT population (n = 39)

Censored from PFS evaluation without event (n = 13)

Pemetrexed (n = 41)

Evaluated for PFS (n = 26)

Continued taking active study treatment (n = 2)

MITT population (n = 39)

Censored from PFS evaluation without event (n = 10)

Evaluated for PFS (n = 29)

Continued taking active study treatment (n = 3)

Discontinued study treatment continued follow-up (n = 3)

Discontinued study treatment continued follow-up (n = 1)

Discontinued study treatment – started new therapy (n = 7)

Discontinued study treatment – started new therapy (n = 4)

Completed follow-up (n = 1)

Completed follow- up (n = 1) Withdrew from study (n =1)

Abbreviations: MITT ¼ Modified Intent-to-Treat; PFS ¼ Progression-Free Survival.

between the eribulin with pemetrexed and pemetrexed treatment groups, although fewer patients were withdrawn from pemetrexed treatment in the combination group compared with the pemetrexed Table 2 All Adverse Events Reported by ‡6 Patients in Phase II (Including Those Considered to Be Related to Study Drug)

Adverse Event Increased ALT Increased AST Anemia Neutropenia Leukopenia Fatigue Nausea Dyspnea Decreased Appetite Asthenia

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Eribulin With Pemetrexed (n [ 41)

Pemetrexed (n [ 39)

All Grades

Grade ‡3

All Grades

Grade ‡3

11 (27%)

4 (10%)

16 (41%)

7 (18%)

10 (24%)

1 (2%)

15 (39%)

6 (15%)

8 12 3 6 10 6 7

4 7 1 1

15 11 7 12 6 7 5

4 7 2 5

(20%) (29%) (7%) (15%) (24%) (15%) (17%)

6 (15%)

(10%) (17%) (2%) (2%) 0 3 (7%) 0 1 (2%)

(39%) (28%) (18%) (31%) (15%) (18%) (13%)

1 (7%)

(10%) (18%) (5%) (13%) 0 5 (13%) 0 1 (3%)

Abbreviations: ALT ¼ alanine aminotransferase; AST ¼ aspartate aminotransferase.

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monotherapy group (8 patients [20%] vs. 12 patients [31%], respectively). Efficacy. Progression-free survival was similar between treatment groups, with an imputed median PFS of 21.4 weeks in the eribulin with pemetrexed group (n ¼ 26; 95% confidence interval [CI], 12.739.6) and 23.4 weeks in the pemetrexed group (n ¼ 29; 95% CI, 17.1-29.9), with a hazard ratio of 1.0 (95% CI, 0.6-1.7; Figure 2). The observed median PFS was 18.1 weeks in the eribulin with pemetrexed group (n ¼ 26; 95% CI, 8.4-34.1) and 22.0 weeks in the pemetrexed group (n ¼ 29; 95% CI, 12.1-29.0), with a hazard ratio of 1.1 (95% CI, 0.6-1.8) and was, therefore, consistent with the results. Time to progression was similar between treatment groups, with an imputed median time to progression in the eribulin with pemetrexed group of 21.4 weeks (n ¼ 24; 95% CI, 12.7-39.6) and 23.4 weeks in the pemetrexed group (n ¼ 27; 95% CI, 17.1-29.9), with a hazard ratio of 1.1 (95% CI, 0.6-1.9). Observed results were consistent with imputed results, with an observed median time to progression in the eribulin with pemetrexed group of 18.1 weeks (n ¼ 25; 95% CI, 8.4-34.1) and 23.4 weeks in the pemetrexed group (n ¼ 27; 95% CI, 13.4-29.0), with a hazard ratio of 1.1 (95% CI, 0.7-2.0). A post hoc analysis of the PFS and time to progression using an intent to treat population that did not exclude patients who failed to meet major protocol eligibility was consistent with the MITT analysis.

Cornelius F. Waller et al Figure 2 KaplaneMeier Curve of Progression-Free Survival (Phase 2 Modified Intent-to-Treat Population): (A) Imputed; (B) Observed

Overall survival was similar between treatment groups, with an observed median overall survival of 59.1 weeks in the eribulin with pemetrexed group (n ¼ 14; 95% CI, 27.7-not reached) and 57.1 weeks in the pemetrexed group (n ¼ 15; 95% CI, 29.4-not reached), with a hazard ratio of 1.0 (95% CI, 0.5-2.0). An overall response (confirmed complete or partial response) was reported for

8 patients in the eribulin with pemetrexed group (20.5%; 95% CI, 7.8%-33.2%) compared with 6 patients in the pemetrexed group (15.4%; 95% CI, 4.1%-26.7%). All confirmed responses were partial responses. The number of patients who experienced progressive disease or death at 12 weeks was 15 in the eribulin with pemetrexed group (38.5%; 95% CI, 23.2%-53.7%) and

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Eribulin Mesylate With Pemetrexed Versus Pemetrexed Alone 12 in the pemetrexed monotherapy group (30.8%; 95% CI, 16.3%-45.3%).

Discussion

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The phase I portion of this study was conducted as a typical 3þ3 dose escalation with 2 dosing arms—one in which eribulin was administered on days 1 and 8 of a 21-day cycle and another in which eribulin was administered on day 1 only. Because of the occurrence of DLTs using the initial eribulin dose on the days 1 and 8 regimen, dose escalation proceeded with the day 1 schedule only, because eribulin doses < 0.7 mg/m2 were considered below the range of doses expected to have a therapeutic effect. As previously noted, the MTD and the recommended phase 2 dose was determined to be the initial dose for the day 1 schedule (eribulin at 0.9 mg/m2 with pemetrexed 500 mg/m2 on day 1 of each 21-day treatment cycle). This dosing regimen of eribulin is approximately one-third the dosing intensity compared with the eribulin monotherapy regimen that has been evaluated in NSCLC and breast cancer (eribulin 1.4 mg/m2 on days 1 and 8 of a 21-day cycle).17-22 The recommended phase 2 dose was generally well tolerated and had an expected toxicity profile. Although the combination of eribulin and pemetrexed was generally safe and well tolerated at this dose, there was no therapeutic advantage with combination therapy over pemetrexed monotherapy at the dose selected for eribulin. The exploratory efficacy end points of PFS (imputed and observed), overall survival, and time to disease progression were similar between the 2 treatment groups. It should be highlighted that 19 patients in the eribulin with pemetrexed group had previous taxane treatment (10 patients met the criteria for taxane sensitivity) versus 13 patients in the pemetrexed monotherapy group with previous taxane treatment (9 patients met the criteria for taxane sensitivity). Thus, this apparent imbalance might have affected the efficacy results. However, there was a similar number of patients with taxane sensitivity in each arm. In a previous study of eribulin monotherapy in previous taxane-treated NSCLC patients, taxane-sensitive patients appeared to experience improved response and clinical benefit relative to taxane-resistant patients.18 The rates of neutropenia (17%) and anemia (15%) observed with eribulin with pemetrexed during the phase II portion of this study were less than expected based on the phase Ib results and previous experience with eribulin monotherapy using a regimen of eribulin 1.4 mg/m2 on days 1 and 8 of a 21-day cycle in NSCLC.17,18 Aside from anemia, which was more common in the pemetrexed treatment group, adverse event rates were similar between study groups in phase II. The rates of common adverse events with eribulin 0.9 mg/m2 on day 1 in combination with pemetrexed in this study were lower compared with other studies of eribulin monotherapy in which eribulin was dosed at 1.4 mg/m2 on days 1 and 8 each cycle in heavily pretreated breast cancer patients19-22 and in patients with advanced NSCLC previously treated with a taxane.17,18 Previous reports of eribulin monotherapy dosed at 1.4 mg/m2 on days 1 and 8 of a 21-day cycle in NSCLC patients reported the following rates of common adverse events (all Grades): neutropenia, 54% to 62%; anemia, 23% to 65%; peripheral neuropathy, 30% to 31%; and fatigue, 50% to 64%.17,18 Eribulin dose reductions and interruptions were relatively infrequent (15% and 7%, respectively)

Clinical Lung Cancer March 2015

in the current study. The rate of eribulin treatment discontinuation (20%) was similar to another study of eribulin monotherapy in heavily pretreated patients with breast cancer in which therapy discontinuation because of adverse events occurred at a rate of 13%.19 Several limitations in methodology might have affected the results of this study. First, the eribulin dose identified in the phase Ib portion of this study was approximately 30% of the dosing intensity compared with other phase II NSCLC studies in which eribulin (1.4 mg/m2) was beneficial as monotherapy.17,18 Second, there was a lack of follow-up after patients started a new line of anticancer therapy, which might have affected the robustness of overall survival data. Third, the dosing regimen selected from the 3þ3 dose escalation study design might have resulted in an overly-conservative eribulin dose selection for phase II. Alternative dose escalation study designs or administration schedules might have allowed for the selection of a more efficacious regimen or eribulin in combination with pemetrexed. For example, if colony stimulating factor support had been allowed in the phase Ib portion of the study, a more aggressive eribulin regimen might have been identified for the phase II portion of the study. Although eribulin in combination with pemetrexed does not appear to provide a clinical benefit with the eribulin dosing regimen used in this study, eribulin as a new cytostatic drug is being investigated as monotherapy in patients with nonsquamous NSCLC.23 A phase III study comparing eribulin monotherapy with treatment of physician’s choice in advanced NSCLC (third-line or greater) is currently being conducted (NCT01454934). This ongoing study is using the same eribulin regimen that is currently approved for the treatment of metastatic breast cancer for patients who have previously received at least 2 chemotherapeutic regimens for the treatment of metastatic disease. Eribulin is also being studied as combination therapy in advanced NSCLC with other chemotherapeutic agents such as gemcitabine or vinorelbine, and in taxane-naive patients.

Conclusion Using the regimen selected for phase II, the combination of eribulin (0.9 mg/m2) with pemetrexed (500 mg/m2) on day 1 of each 21-day cycle was generally safe and well tolerated, but there was no evidence in the current study of a therapeutic advantage for patients receiving this combination over patients receiving pemetrexed monotherapy for the second-line treatment of locally advanced or metastatic nonsquamous cell NSCLC. The efficacy end points of PFS, overall survival, and time to disease progression were similar between treatment groups.

Clinical Practice Points  Eribulin mesylate is a novel nontaxane microtubule dynamics

inhibitor.  Eribulin mesylate is approved for treatment of metastatic

breast cancer in patients who have previously received at least 2 chemotherapeutic regimens for metastatic disease.  In other single-arm, phase II studies, eribulin mesylate monotherapy has demonstrated activity in previously treated NSCLC patients. 2 2  Eribulin mesylate (0.9 mg/m ) with pemetrexed (500 mg/m ) each on day 1 of a 21-day cycle was tolerated. Adverse events

Cornelius F. Waller et al were generally manageable, with neutropenia being the most common hematological adverse event.  Imputed median PFS was 21.4 weeks in the eribulin mesylate with pemetrexed group (n ¼ 26; 95% CI, 12.7-39.6) and 23.4 weeks in the pemetrexed group (n ¼ 29; 95% CI, 17.1-29.9), with a hazard ratio of 1.0 (95% CI, 0.6-1.7).  Using the regimen selected for phase 2, eribulin mesylate (0.9 mg/m2) with pemetrexed (500 mg/m2) each on day 1 of a 21-day cycle failed to demonstrate a therapeutic advantage over patients who received pemetrexed monotherapy for the secondline treatment of locally advanced or metastatic nonsquamous cell NSCLC.

Acknowledgments This study was funded by Eisai Inc, Woodcliff Lake, NJ; study protocol number E7389-701. The authors acknowledge the contribution of the investigators (funded by Eisai Inc) and their patients who participated in this study: Volodymyr Bondar (Donetsk, Ukraine), Davey Daniel (Chattanooga, TN), Filippo Tommaso De Marinis (Rome, Italy), Luca Gianni (Milan, Italy), Yuriy Golovko (Kyiv, Ukraine), Vanessa Gregorc (Milan, Italy), Robert Jotte (Denver, CO), Leona Koubkova (Praha, Czech Republic), James Lee (Mt Holly, NJ), Manuel Modiano (Tucson, AZ), Moacyr Oliviera (Tacoma, WA), Norbert Pauk (Praha, Czech Republic), Olga Ponomarova (Kyiv, Ukraine), David Spigel (Nashville, TN), Oksana Tarasova (Kharkiv, Ukraine), Michael Thomas (Heidelberg, Germany), and Robert Weaver (Fort Myers, FL). We also acknowledge Kim Poinsett-Holmes, PharmD (Poinsett Publications, Inc), for writing the first draft and revising subsequent drafts of the manuscript as a medical writer and editorial assistant (funded by Quintiles).

Disclosure J.P.H., A.F., B.H., R.L., M.J.S., and H.D. are employees of Quintiles, a company involved in the conduct of clinical trials for Eisai Inc. C.F.W., I.V., I.B., and Y.S. were provided grants from Eisai for conduct of the study.

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Clinical Lung Cancer March 2015

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II study of eribulin mesylate administered in combination with pemetrexed versus pemetrexed alone as second-line therapy in patients with advanced nonsquamous non-small-cell lung cancer.

New treatment options are needed for second-line therapy in patients with NSCLC...
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