Clinical UM Guideline

 

Subject: Eribulin mesylate (Halaven®)
Guideline #: CG-DRUG-70 Publish Date:    12/12/2018
Status: Reviewed Last Review Date:    11/08/2018

Description

This document addresses the indications and criteria for the use of eribulin mesylate in the treatment of oncologic conditions.

Eribulin mesylate (Halaven) (Eisai Incorporated, Woodcliff Lake, NJ) is a non-taxane, microtubule dynamics inhibitor with a distinct mechanism of action from other classes of tubulin-targeted agents such as the taxanes, vinca alkaloids, and epothilones. It is a synthetic analogue of halichondrin B, a product isolated from the rare marine sponge Halichondria okadai.

Clinical Indications

Medically Necessary:

  1. Eribulin mesylate is considered medically necessary in the treatment of an individual with locally recurrent or metastatic breast cancer when all of the following criteria are met:
    1. Used as a single agent; and
    2. Used in a single line of therapy; and
    3. Individual has previously received at least two chemotherapeutic regimens for locally recurrent or metastatic disease.
  2. Eribulin mesylate is considered medically necessary in combination with trastuzumab in the treatment of an individual with locally recurrent or metastatic HER2+ breast cancer with:
    1. Symptomatic visceral disease; or
    2. Either hormone receptor-negative disease or hormone receptor-positive and endocrine refractory disease.
  3. Eribulin mesylate is considered medically necessary in the treatment of an individual with locally recurrent or metastatic soft tissue sarcoma when all of the following criteria are met:
    1. Used as a single agent; and
    2. Used in a single line of therapy; and
    3. Individual has previously received at least two chemotherapeutic regimens for locally recurrent or metastatic disease.

Not Medically Necessary:

Eribulin mesylate is considered not medically necessary when criteria are not met and for all other indications, including but not limited to:

  1. Head and neck cancer; or
  2. Non-small cell lung cancer.
Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS

 

J9179

Injection, eribulin mesylate, 0.1 mg

 

 

ICD-10 Diagnosis

 

 

C48.0-C48.8

Malignant neoplasm of retroperitoneum and peritoneum

 

C49.0-C49.9

Malignant neoplasm of other connective and soft tissue

 

C50.011-C50.929

Malignant neoplasm of breast

 

C79.81

Secondary malignant neoplasm of breast

 

Discussion/General Information

Eribulin Mesylate for Metastatic Breast Cancer

According to the National Cancer Institute (NCI) Breast Cancer Treatment PDQ® (2018), “treatment for systemic disease (that is, stage IV metastatic disease) is palliative in intent. Goals of treatment include improving quality of life and prolongation of life.”

Single agents that have shown activity in metastatic breast cancer include alkylating agents, anthracyclines, antimetabolites, fluoropyrimidines, platinum, taxanes, vinca alkaloids, and other agents such as eribulin mesylate, gemcitabine, and mitomycin C.

Single Agent Use of Eribulin Mesylate

Eribulin mesylate (Halaven) received U.S. Food and Drug Administration (FDA) approval in November 2010 for the treatment of individuals with metastatic breast cancer who have previously received at least 2 chemotherapeutic regimens for the treatment of metastatic breast cancer disease. Prior therapy should have included an anthracycline (for example, doxorubicin, epirubicin, or mitoxantrone) and a taxane (for example, docetaxel or paclitaxel) in either the adjuvant or metastatic setting. Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that is a synthetic analogue of halichondrin B, a product isolated from the marine sponge Halichondria okadai. Although the exact mechanism is unknown, it is believed to work through inhibition of the growth phase of microtubule dynamics, without affecting the shortening phase, sequestering tubulin into nonproductive aggregates.

The efficacy of eribulin mesylate was evaluated in several open-label, single-arm, phase II clinical trials showing antitumor activity in individuals who were heavily pretreated for locally advanced or metastatic breast cancer. The first trial evaluated the efficacy of eribulin mesylate in individuals with prior exposure to an anthracycline and a taxane (Vahdat, 2009) and the second trial included prior therapy with an anthracycline, a taxane, and capecitabine (Cortes, 2010). Participants received a median number of four chemotherapeutic regimens at baseline. Both trials reported a significant improvement in the overall response rate, including median duration of response ranging from 4 to 5 months and progression-free survival (PFS) of 2.6 months.

In response to the positive phase II results, the phase III international, multicenter, open-label randomized trial that accompanied the FDA approval (Study E7389-G000-305), the Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus Eribulin study (EMBRACE), enrolled 762 individuals with metastatic breast cancer previously treated with an average of four chemotherapeutic regimens. Study participants with a median age of 55 years (range, 27-85 years) received either eribulin mesylate (n=508) or single-agent therapy selected by their physician, known as the “treatment of physicians choice,” or TPC (control arm, n=254). Randomization was stratified by geographic region and baseline characteristics were comparable between the treatment groups. Tumor prognostic characteristics included estrogen receptor (ER) status (positive: 67%, negative: 28%), progesterone receptor (PR) status (positive: 49%, negative: 39%), HER2/neu receptor status (positive: 16%, negative: 74%), triple-negative status (ER, PR, HER2/neu: 19%), presence of visceral disease and bone disease (82% and 61%, respectively), and number of sites of metastases (> 2 or 50%). Participants were also required to have experienced disease progression within 6 months of their last chemotherapeutic regimen, including prior exposure to capecitabine, and had a prior anthracycline- and taxane-based chemotherapy regimen in either the adjuvant or metastatic setting. The eribulin mesylate treatment group received an intravenous (IV) dose of 1.4 mg/m2 on days 1 and 8 of a 21-day cycle, with dose delays and reductions for pre-specified toxicities. Most participants in the TPC arm received single-agent chemotherapy consisting of vinorelbine (26%), gemcitabine (18%), capecitabine (18%), taxane (16 %), anthracycline (9%), other chemotherapy (10%), or hormonal therapy (3%). The primary endpoint was overall survival (OS) in the intention-to-treat population.

The phase III results reported a statistically significant prolongation in OS in participants treated with eribulin mesylate: median OS was 13.1 months (95% confidence interval [CI], 11.8-14.3) for participants treated with eribulin mesylate compared to 10.6 months (95% CI, 9.3-12.5) for participants in the TPC group (Hazard ratio [HR] 0.81, 95% CI, 0.660-0.991; p=0.041), and increased median survival of 2.5 months in the eribulin mesylate group compared to the TPC arm. No difference in time to progression was observed (HR 0.087; 95% CI, 0.71-1.05; p=0.14). In participants treated with eribulin mesylate, the objective response rate (ORR) as measured by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria was 11% (95% CI, 8.6%-14.3%) and the median response duration was 4.2 months (95 % CI, 3.8-5.0 months) (Cortes, 2011).

Adverse events (AEs) associated with eribulin mesylate use were experienced in at least 25% of users during the clinical trial. Grade 3 or 4 AEs that occurred more often with eribulin mesylate than with TPC were neutropenia (grade 3, 21% [106 of 503]; grade 4, 24% [121 of 503] participants), leucopenia, and peripheral neuropathy. Severe neutropenia occurred in 57% of eribulin mesylate recipients and lasted more than 1 week in approximately 12% of recipients. Peripheral neuropathy was the most common AE leading to discontinuation from eribulin mesylate (5% [24 of 503] participants). Severe neuropathy occurred in 8% of clinical trial participants receiving eribulin mesylate, with 22% of users developing new or worsening neuropathy that had not recovered after almost 9 months. Other eribulin mesylate-associated AEs included alopecia, anemia, constipation, and nausea (Cortes, 2011) (Halaven Product Information [PI] label, 2016).

Kaufman and colleagues (2015) compared the clinical efficacy of eribulin mesylate to capecitabine in a phase III open-label, parallel, two-arm, multicenter randomized study of individuals with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. Although a possible benefit according to HER2 status was suggested for OS, an interaction test showed no benefit for eribulin mesylate when comparing participants with HER2-negative disease and all other participants (HER2+ and unknown HER2 status). Eribulin mesylate was not superior to capecitabine with regard to the coprimary outcome endpoint of OS or PFS. The median OS times for eribulin mesylate (n=554) and capecitabine (n=548) were 15.9 and 14.5 months, respectively (HR 0.88; 95% CI, 0.77-1.00; p=0.056); and, the median PFS times for eribulin mesylate and capecitabine were 4.1 and 4.2 months, respectively (HR 1.08; 95% CI, 0.93-1.25; p=0.30). ORRs were 11.0% for eribulin mesylate and 11.5% for capecitabine. Global health status and overall quality-of-life scores over time were similar in the treatment arms. The most common AEs in the eribulin mesylate group were grade 1 or 2, reported as neutropenia, alopecia, leukopenia, global peripheral neuropathy and nausea. Grade 3 or 4 global peripheral neuropathy occurred in 7.0% of participants receiving eribulin mesylate versus 0.9% receiving capecitabine.

Twelves and colleagues (2015) pooled data from two phase III studies of eribulin mesylate to assess whether specific individuals, previously treated with an anthracycline and a taxane, benefited from eribulin mesylate. In the pooled population, OS, PFS and response rates were analyzed in the intent-to-treat population and select subgroups. Overall, 1062 study participants were randomized to receive eribulin mesylate and 802 participants to control. The median OS was 15.2 months with eribulin mesylate versus 12.8 months with control (HR 0.85; 95% CI, 0.77-0.95; p=0.003). In all subgroups assessed, OS data favored eribulin mesylate with significant improvements reported in some subgroups, notably in women with HER2-negative disease (HR 0.82; p=0.002); although, the effect in those with HER2-negative but hormone-receptor-positive disease did not reach statistical significance. A treatment benefit was also seen among those participants with estrogen-receptor-negative and triple-negative disease. The authors stated that eribulin mesylate appeared to improve OS in various subgroups of individuals with advanced, metastatic breast cancer who had previously received an anthracycline and a taxane.

The NCI Breast Cancer Treatment PDQ (2018) states:

Patients on hormone therapy whose tumors have progressed are candidates for cytotoxic chemotherapy. There are no data suggesting that combination therapy results in an OS benefit over single-agent therapy. Patients with HR-negative tumors and those with visceral metastases or symptomatic disease are also candidates for cytotoxic agents (Wilcken, 2008).

The current National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines (CPGs) for breast cancer (V1.2018) state sequential single agents are preferred, but chemotherapy combinations may be used in select patients with high tumor burden, rapidly progressing disease, and visceral crisis. The NCCN CPGs recommend use of eribulin mesylate as a preferred single agent in the treatment of recurrent or metastatic breast cancer in individuals who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease; prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Combination Chemotherapy with Eribulin Mesylate

A multicenter, phase II, single-arm study evaluated the efficacy and safety of eribulin mesylate as first-line therapy with trastuzumab in 52 individuals with locally recurrent or metastatic HER2-positive (+) breast cancer (Wilks, 2014). The study had three phases: screening and baseline, six (21-day) cycles of eribulin mesylate with trastuzumab, and an extension phase in which participants who completed the initial six cycles continued to receive study treatment until the development of progressive disease or until another withdrawal criterion was met. Individuals were excluded from participation if they had received previous chemotherapy, biologic therapy, or investigational therapy for locally recurrent or metastatic HER2+ breast cancer, had previous exposure to specific doxorubicin or epirubicin doses, and preexisting neuropathy or clinically significant cardiovascular impairment. Eribulin mesylate at 1.4 mg/m2 was administered on days 1 and 8 of each 21-day cycle with an initial trastuzumab dose on day 1 of 8 mg/kg followed by 6 mg/kg of trastuzumab on day 1 of each subsequent cycle. Dose reductions were allowed for eribulin mesylate but not for trastuzumab. A total of 45 participants completed the treatment phase (first six cycles of treatment) and 9 participants discontinued because of AEs or other reasons. Eight participants remained in the extension phase of the treatment at the time of clinical data cut. No participant received palliative radiotherapy during the study. Overall, 52 participants in the full analysis set were evaluable for the primary endpoint measurement of the ORR. The ORR was 71% (n=37) with a median time to first response of 1.3 months. Complete response was reported in 3 (5.8%) participants and partial response in 34 (65.4%) participants. The duration of response and PFS was 11.1 and 11.6 months, respectively. The most common grade 3/4 treatment-emergent AEs were neutropenia (20 participants, 38.5%) and peripheral neuropathy (14 participants; 26.9%, all grade 3). The investigators suggested that the combination of eribulin mesylate with trastuzumab has considerable activity with an acceptable toxicity profile as first-line therapy for HER2+ locally advanced or metastatic breast cancer.

The NCCN Drugs and Biologics Compendium (2018) includes a category 2A recommendation for use of eribulin mesylate in combination therapy “...with trastuzumab for human epidermal growth factor receptor 2-positive (HER2+) recurrent or metastatic trastuzumab-exposed disease” in individuals:

For chemotherapy for stage IV or recurrent metastatic disease, the NCCN CPG for breast cancer (V1.2018) states:

Women with hormone receptor-negative tumors not localized to the bone or soft tissue only, that are associated with symptomatic visceral metastasis, or that have hormone receptor-positive tumors that are refractory to endocrine therapy should receive chemotherapy...Combination chemotherapy generally provides higher rates of objective response and longer time to progression, in comparison to single-agent chemotherapy. Combination chemotherapy is, however, associated with an increase in toxicity and is of little survival benefit. Furthermore, administering single agents sequentially decreases the likelihood that dose reductions will be needed. Thus, the panel finds little compelling evidence that combination chemotherapy is superior to sequential single agents. Standard clinical practice is to continue first-line chemotherapy until progression.

A search of the ClinicalTrials.gov database has identified ongoing phase I/II trials evaluating the use of eribulin mesylate as a single agent or in combination chemotherapy for the treatment of triple-negative metastatic breast cancer.

Eribulin Mesylate for Soft Tissue Sarcoma

Soft tissue sarcomas are a heterogeneous group of rare solid tumors of mesenchymal cell origin with distinct clinical and pathologic features usually divided into two broad categories (NCCN, 2018):

More than 50 different histologic subtypes of soft tissue sarcoma have been identified; the most common are undifferentiated pleomorphic sarcoma, gastrointestinal stromal tumors (GISTs), liposarcoma, leiomyosarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumors (MPNSTs). Metastasis most commonly occurs in the lungs; liver and peritoneum metastasis is more common from tumors arising in the abdominal peritoneum. Rhabdomyosarcoma is the most common soft tissue sarcoma of children and adolescents (NCCN, 2018).

For individuals with advanced, unresectable, or metastatic disease, chemotherapy with single agents (such as dacarbazine, doxorubicin, epirubicin, or ifosfamide) or anthracycline-based combination regimens have been used. Eribulin mesylate has been used as single-agent therapy for individuals with soft tissue subtypes with non-specific histologies.

Schoffski and colleagues (2011) reported results from a non-randomized, multicenter, phase II clinical study that evaluated the efficacy and safety of eribulin mesylate in four groups of individuals with progressive or high-grade soft tissue sarcoma who received no more than one prior combination chemotherapy regimen or up to two single drugs for treatment-refractory, advanced disease. A total of 128 study participants included those with adipocytic sarcoma (n=37), leiomyosarcoma (n=40), synovial sarcoma (n=19), and 32 participants with other sarcomas. Tumor assessments evaluated by computed tomography or magnetic resonance imaging and based on RECIST criteria (v1.0) were performed at baseline and every 3 weeks during treatment to assess the primary outcome of PFS at 12 weeks. Safety analyses were completed in all participants who started treatment. Of the participants evaluable for the primary endpoint, 12 of 38 (31.6 %) with leiomyosarcoma, 15 of 32 (46.9 %) with adipocytic sarcoma, 4 of 19 (21.1 %) with synovial sarcoma, and 5 of 26 (19.2 %) participants with other sarcomas experienced PFS at 12 weeks. Participants with synovial sarcoma and other types of soft tissue sarcoma did not meet the prespecified primary efficacy criteria for activity; however, in the leiomyosarcoma group, approximately one-third of participants had non-progressive disease at week 12, and 86.8% were alive at 6 months. The most common grade 3 to 4 AEs were neutropenia (66 of 127 participants [52 %] evaluable for safety), leucopenia (44 participants, 35 %), and anemia, fatigue, febrile neutropenia, abnormal alanine aminotransferase concentrations, mucositis, and sensory neuropathy.

On January 28, 2016, the FDA approved eribulin mesylate for the treatment of individuals with unresectable or metastatic liposarcoma (a specific type of soft tissue sarcoma) who have received a prior anthracycline-containing regimen. The FDA’s approval did not include use of eribulin mesylate for the treatment of other types of soft tissue sarcomas (such as, leiomyosarcoma). The FDA priority review and orphan drug designation was based on results of an open-label, phase II, randomized, multicenter, active-controlled trial in 446 individuals with unresectable, locally advanced or metastatic liposarcoma (n=143, 32%) or leiomyosarcoma (n=303, 68%) who received at least two prior systemic chemotherapies (one prior systemic chemotherapy must have included an anthracycline) and experienced disease progression within 6 months of the most recent chemotherapy cycle (Halaven PI Label, 2016). Study participants included those with a median age of 56 years (range, 24-83); 33% were male; 44% and 53% had Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 and ECOG PS 1, respectively; 47% of participants received more than two prior systemic chemotherapies. A total of 446 participants were randomized 1:1 to eribulin mesylate 1.4 mg/m2 on days 1 and 8 of a 21-day cycle (n=225) or dacarbazine at a dose of 850 mg/m2, 1000 mg/m2, or 1200 mg/m2 (n=221) (chosen by the investigator prior to randomization) administered intravenously on day 1 of a 21-day cycle. Treatment continued until disease progression or unacceptable toxicity. Eribulin mesylate was not offered at the time of progression to participants in the dacarbazine arm. The trial met its primary endpoint of a statistically significant improvement in OS in the eribulin mesylate arm compared to the dacarbazine arm (HR 0.75; 95% CI, 0.61-0.94; p=0.011). The median OS was 13.5 months in the eribulin mesylate arm and 11.3 months in the dacarbazine arm; however, there was no improvement in PFS or confirmed ORR in the overall study population (Halaven PI label, 2016).

Treatment effects of eribulin mesylate were limited to a stratified subgroup of participants with liposarcoma, as observed in pre-planned, exploratory subgroup analyses of OS and PFS. The median OS was 15.6 versus 8.4 months (HR 0.51; 95% CI, 0.35-0.75; p<0.001) and the median PFS was 2.9 versus 1.7 months (HR 0.52; 95% CI, 0.35-0.78; p=0.0015) in participants with liposarcoma treated with eribulin mesylate compared to dacarbazine, respectively (Demetri, 2017). The trial outcomes data reported no evidence of efficacy for eribulin mesylate in participants with leiomyosarcoma. The median OS was 12.8 versus 12.3 months (HR 0.90; 95% CI, 0.69-1.18) and median PFS of 2.2 versus 2.6 months (HR 1.05; 95% CI, 0.81-1.35) in participants in the eribulin mesylate-treated arm compared to the dacarbazine-treated arm, respectively (Halaven PI label, 2016).

The most common AEs (≥ 25%) reported in eribulin mesylate-treated participants (n=223) were abdominal pain, alopecia, constipation, fatigue, fever, nausea, and peripheral neuropathy. Grade 3 or 4 laboratory abnormalities (≥ 5%) included neutropenia, hypocalcemia, and hypokalemia. Febrile neutropenia occurred in 0.9% of eribulin mesylate-treated participants and fatal neutropenic sepsis in 0.9%. Grade 3 peripheral neuropathy occurred in 3.1% (7 of 223) of eribulin mesylate-treated participants. Peripheral neuropathy led to discontinuation of eribulin mesylate in 0.9% of participants. Neuropathy lasting more than 60 days occurred in 58% (38 of 65) of participants. A total of 63% (41 of 65) of participants had not recovered within a median follow-up duration of 6.4 months (range: 27 days to 29 months) (Halaven PI Label, 2016).

The current NCCN CPG for soft tissue sarcoma (V2.2018) includes a category 1 recommendation for use of eribulin mesylate as single-agent palliative therapy for unresectable or progressive retroperitoneal/intra-abdominal liposarcoma; and, as a category 1 recommendation for use as single-agent palliative therapy for synchronous stage IV or recurrent liposarcoma in individuals with disseminated, metastatic pleomorphic rhabdomyosarcoma of the extremity/superficial trunk, head/neck.

The current NCCN CPG for soft tissue sarcoma (V2.2018) includes a category 2A recommendation for use of eribulin mesylate as single-agent palliative therapy in individuals with soft tissue sarcoma subtypes with non-specific, non L-type histologies. “Anthracycline-based regimens are preferred in the neoadjuvant and adjuvant setting” (Schoffski, 2011). The NCCN Drugs and Biologics Compendium (2018) includes 2A recommendations for use of eribulin mesylate as single-agent palliative therapy for soft tissue sarcoma subtypes including angiosarcoma, unresectable or progressive retroperitoneal/intra-abdominal sarcoma, pleomorphic rhabdomyosarcoma, and soft tissue sarcoma of the extremity/superficial trunk, head/neck (synchronous stage IV or recurrent disease with disseminated metastases). These category 2A off-label recommendations are based on uniform consensus and the results of the phase II trial that evaluated eribulin mesylate as single-agent therapy for soft tissue sarcoma subtypes (Schoffski, 2011).

Proposed Uses of Eribulin Mesylate

Uterine Sarcoma

In 2017, the NCCN CPG for uterine neoplasms (V2.2018) revised their recommendation from a category 2A to a category 2B (with a strong recommendation for clinical trial participation) for use of eribulin mesylate as single-agent therapy for high-grade endometrial stromal sarcoma, uterine leiomyosarcoma, and undifferentiated uterine sarcoma. The revised recommendation is based on NCCN panel review of “mature trial data” from the phase III clinical trial (NCT01327885) that compared the OS benefit of eribulin mesylate to dacarbazine in 452 individuals aged 18 years or older with advanced leiomyosarcoma or adipocytic sarcoma incurable by surgery and/or radiation therapy (Schoffski, 2016). Participants with ECOG PS 2 who received two standard systemic treatment regimens including an anthracycline were randomized 1:1 to eribulin mesylate 1.4 mg/m2 on days 1 and 8 (n=228) or dacarbazine 850 to 1200 mg/m2 on day 1 of a 21-day cycle (n=224) until disease progression. The primary endpoint was OS; secondary endpoints included PFS, PFS rate at week 12 and safety. The median OS for eribulin mesylate and dacarbazine was 13.5 and 11.5 months, respectively (HR 0.77; 95% CI, 0.62-0.95; p=0.017); PFS was 2.6 months in both arms (HR 0.877; 95% CI, 0.710-1.085; p=0.229) and PFS rate at week 12 was 33% and 29% for eribulin mesylate and dacarbazine, respectively. Dose reductions or treatment discontinuation occurred due to treatment-emergent AEs in both eribulin mesylate-treated (26% and 8%, respectively) and dacarbazine-treated participants (14% and 5%, respectively). Treatment-emergent AEs (grade 3, 39% vs. 36%; grade 4, 24% vs. 19%) were more frequent in the eribulin mesylate arm than in the dacarbazine arm and included neutropenia, pyrexia, peripheral sensory neuropathy, and alopecia. Thrombocytopenia was less frequent in the eribulin mesylate arm than in the dacarbazine arm.

Other Proposed Uses

Eribulin mesylate has been studied in phase I/II clinical trials in individuals with advanced solid malignancies (Goel, 2009; Koczywas, 2014; Tan, 2009) and in phase I/II clinical trials for other malignancies, including urothelial bladder cancer, head and neck cancer (Arnold, 2011), non-small cell lung cancer (NSCLC) (Gitlitz, 2012; Mok, 2014; Spira, 2012; Waller, 2015), platinum-susceptible ovarian epithelial, fallopian tube or peritoneal cancers (Hensley, 2012), pancreatic cancer (Renouf, 2012), and metastatic castration-resistant prostate cancer (de Bono, 2012). Eribulin mesylate did not demonstrate efficacy in the studies of treatment for head and neck or pancreatic cancer (Scarpace, 2012). In the open-label, multicenter, randomized phase Ib/II study of eribulin mesylate administered in combination with pemetrexed versus pemetrexed alone as second-line therapy in individuals with advanced nonsquamous NSCLC, eribulin mesylate and pemetrexed at the selected phase II dosing regimen was generally safe and well tolerated but provided no therapeutic advantage for the second-line treatment of locally advanced or metastatic nonsquamous NSCLC. The FDA has not approved the use of eribulin mesylate for the treatment of any of these conditions.

FDA PI Label Information

Adverse Events and Warnings

Eribulin mesylate has the following Warnings and Precautions (Halaven PI Label, 2016):

The safety and effectiveness of eribulin mesylate therapy in pediatric individuals below the age of 18 years has not been established (Halaven PI Label, 2016).

Definitions

Adjuvant therapy: Treatment given after the primary treatment to increase the chances of a cure; may include chemotherapy, radiation, hormone, or biologic therapy.

Anthracycline: A type of antibiotic that comes from certain types of Streptomyces bacteria and are used to treat many types of cancer. Anthracyclines damage the DNA in cancer cells, causing the cells to die.

Cardiotoxicity: Having a toxic effect on the heart.

Human epidermal growth factor receptor 2 (ERBB2) status: A laboratory finding related to the presence or absence of cellular receptors for HER2/neu; also known as ErbB-2 protein family.

Line of therapy:

Metastasis: A cancer that has spread from one part of the body to another; a metastatic tumor contain cells that are like those in the original (primary) tumor that has spread beyond the local lymph nodes.

Microtubule inhibitors (MTI): A class of drugs including taxanes, vinca alkaloids, and epothilones that stabilize or destabilize microtubules, thereby suppressing microtubule dynamics required for proper mitotic function, effectively blocking cell cycle progression and resulting in cell death.

Off-label: Utilization of a United States Food and Drug Administration (FDA) approved drug for uses other than those listed in the FDA approved label.

Relapse or recurrence: After a period of improvement, during which time a disease (for example, cancer) could not be detected, the return of signs and symptoms of illness or disease. For cancer, it may come back to the same place as the original (primary) tumor or to another place in the body.

Taxane: A type of mitotic inhibitor and antimicrotubule drug used to treat cancer that blocks cell growth by stopping mitosis (cell division).

References

Peer Reviewed Publications:

  1. Arnold SM, Moon J, Williamson SK, et al. Phase II evaluation of eribulin mesylate (E7389, NSC 707389) in patients with metastatic or recurrent squamous cell carcinoma of the head and neck: Southwest Oncology Group trial S0618. Invest New Drugs. 2011; 29(2):352-359.
  2. Cortes J, O'Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomized study. Lancet. 2011; 377(9769):914-923.
  3. Cortes J, Vahdat L, Blum JL, et al. Phase II study of the halichondrin B analog eribulin mesylate in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2010; 28(25):3922-3928.
  4. de Bono JS, Molife LR, Sonpavde G, et al. Phase II study of eribulin mesylate (E7389) in patients with metastatic castration-resistant prostate cancer stratified by prior taxane therapy. Ann Oncol. 2012; 23(5):1241-1249.
  5. Demetri GD, Schoffski P, Grignani G, et al. Activity of eribulin in patients with advanced liposarcoma demonstrated in a subgroup analysis from a randomized phase III study of eribulin versus dacarbazine. J Clin Oncol. 2017; 35(30):3433-3439.
  6. Gitlitz BJ, Tsao-Wei DD, Groshen S, et al. A phase II study of halichondrin B analog eribulin mesylate (E7389) in patients with advanced non-small cell lung cancer previously treated with a taxane: a California cancer consortium trial. J Thorac Oncol. 2012; 7(3):574-578.
  7. Goel S, Mita AC, Mita M, et al. A phase I study of eribulin mesylate (E7389), a mechanistically novel inhibitor of microtubule dynamics, in patients with advanced solid malignancies. Clin Cancer Res. 2009; 15(12):4207-4212.
  8. Hensley ML, Kravetz S, Jia X, et al. Eribulin mesylate (halichondrin B analog E7389) in platinum-resistant and platinum-sensitive ovarian cancer: a 2-cohort, phase 2 study. Cancer. 2012; 118(9):2403-2410.
  9. Kaufman PA, Awada A, Twelves C, et al. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2015; 33(6):594-601.
  10. Koczywas M, Frankel PH, Synold TW, et al. Phase I study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors. Br J Cancer. 2014; 111(12):2268-2274.
  11. Mok TS, Geater SL, Iannotti N, et al. Randomized phase II study of two intercalated combinations of eribulin mesylate and erlotinib in patients with previously treated advanced non-small-cell lung cancer. Ann Oncol. 2014; 25(8):1578-1584.
  12. Renouf DJ, Tang PA, Major P, et al. A phase II study of the halichondrin B analog eribulin mesylate in gemcitabine refractory advanced pancreatic cancer. Invest New Drugs. 2012; 30(3):1203-1207.
  13. Scarpace SL. Eribulin mesylate (e7389): review of efficacy and tolerability in breast, pancreatic, head and neck, and non-small cell lung cancer. Clin Ther. 2012; 34(7):1467-1473.
  14. Schoffski P, Chawla S, Maki RG, et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet. 2016; 387(10028):1629-1637.
  15. Schoffski P, Ray-Coquard IL, Cioffi A, et al. Activity of eribulin mesylate in patients with soft-tissue sarcoma: a phase 2 study in four independent histological subtypes. Lancet Oncol. 2011; 12(11):1045-1052.
  16. Spira AI, Iannotti NO, Savin MA, et al. A Phase II study of eribulin mesylate (E7389) in patients with advanced, previously treated non-small-cell lung cancer. Clin Lung Cancer. 2012; 13(1):31-38.
  17. Tan AR, Rubin EH, Walton DC, et al. Phase I study of eribulin mesylate administered once every 21 days in patients with advanced solid tumors. Clin Cancer Res. 2009; 15(12):4213-4219.
  18. Twelves C, Cortes J, Vahdat L, et al. Efficacy of eribulin in women with metastatic breast cancer: a pooled analysis of two phase 3 studies. Breast Cancer Res Treat. 2014; 148(3):553-561. Erratum in: Breast Cancer Res Treat. 2015; 149(1):313.
  19. Twelves C, Cortes J, Vahdat LT, et al. Phase III trials of eribulin mesylate (E7389) in extensively pretreated patients with locally recurrent or metastatic breast cancer. Clin Breast Cancer. 2010; 10(2):160-163.
  20. Vahdat LT, Pruitt B, Fabian CJ, et al. Phase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2009; 27(18):2954-2961.
  21. Waller CF, Vynnychenko I, Bondarenko I, et al. 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 non-small-cell lung cancer. Clin Lung Cancer. 2015; 16(2):92-99.
  22. Wilcken N, Dear R. Chemotherapy in metastatic breast cancer: a summary of all randomised trials reported 2000-2007. Eur J Cancer. 2008: 44(15):2218-2225.
  23. Wilks S, Puhalla S, O'Shaughnessy J, et al. Phase 2, multicenter, single-arm study of eribulin mesylate with trastuzumab as first-line therapy for locally recurrent or metastatic HER2-positive breast cancer. Clin Breast Cancer. 2014; 14(6):405-412.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Eribulin mesylate. In: DrugPoints® System (electronic version. Truven Health Analytics, Greenwood Village, CO. Updated August 16, 2018. Available at: https://www.micromedexsolutions.com. Accessed on September 6, 2018.
  2. Eribulin mesylate Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised October 31, 2011. Accessed on September 6, 2018.
  3. Halaven® [Product Information]. Eisai Incorporated, Woodcliff Lake, NJ; October 2016. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/201532s016lbl.pdf. Accessed on September 6, 2018.
  4. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium® (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on September 6, 2018.
  5. NCCN Clinical Practice Guidelines in Oncology®. © 2018 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website at: http://www.nccn.org/index.asp. Accessed on September 6, 2018.
    • Breast Cancer (V1.2018). Revised March 20, 2018.
    • Soft Tissue Sarcoma (V2.2018). Revised March 27, 2018.
    • Uterine Neoplasms (V2.2018). Revised May 28, 2018.
Websites for Additional Information
  1. National Cancer Institute (NCI). Cancer Topics. Available at: http://www.cancer.gov/cancertopics. Accessed on September 6, 2018.
    • Breast Cancer Treatment (PDQ). Last updated May 31, 2018.
Index

Microtubule Dynamics Inhibitor

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

Reviewed

11/08/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.

Reviewed

10/31/2018

Hematology/Oncology Subcommittee review. Updated Discussion, References, and Websites for Additional Information sections.

New

11/02/2017

MPTAC review.

New

11/01/2017

Hematology/Oncology Subcommittee review. Initial document development. Moved content of DRUG.00048 Eribulin mesylate (Halaven®) to new clinical utilization management guideline document with the same title.