Medical Policy



Subject: Ixabepilone (Ixempra®)
Document #: DRUG.00085 Current Effective Date:    06/28/2017
Status: Revised Last Review Date:    05/04/2017

Description/Scope

This document addresses ixabepilone (Ixempra), a non-taxane chemotherapy agent which blocks cells in the mitotic phase of the cell division cycle, leading to cell death. Ixabepilone is used alone or in combination with oral capecitabine to treat breast cancer which has been previously treated with other therapies.

Position Statement

Medically Necessary:

Use of ixabepilone is considered medically necessary for the treatment of metastatic or locally advanced breast cancer for any of the following indications:

Investigational and Not Medically Necessary:

Use of ixabepilone is considered investigational and not medically necessary when the criteria above are not met and for all other indications.

Rationale

Ixabepilone is an antimicrotubule agent classified as an epothilone. Similar to taxanes, epothilones bind to β-tubulin sites which polymerize and stabilize microtubules, thus preventing mitosis and causing apoptosis. While this mechanism of action is similar to taxanes, epothilones appear to bind to different sites than taxanes and remain active in cases of taxane resistance. Ixabepilone is currently the only U.S. Food and Drug Administration (FDA) approved epothilone analog. Ixabepilone (Ixempra) was FDA approved in 2007 for the following indications:

The safety and effectiveness of ixabepilone used in combination with capecitabine was established in an open-label, multicenter, randomized trial which included individuals with metastatic or locally advanced breast cancer (Corey-Lisle, 2012). Participants were randomized to receive a combination of ixabepilone and capecitabine (n=375) or capecitabine (n=377). In order to evaluate the trade-off between quality and quantity of life, the area under the survival curve was divided into three states: toxicity, time without symptoms of disease progression or toxicity, and recurrence. The mean time in each state was weighted and used to estimate quality-adjusted survival (QAS). Self-reported outcomes assessing quality of life (QOL) were reported using the Functional Assessment of Cancer Therapy (FACT)-Breast Symptom Index (FBSI). The researchers performed a quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis, which compares disease and treatment related outcomes but also incorporates a QOL component into the evaluation. The mean duration in the toxicity state, before disease progression in the combination therapy versus capecitabine was significant (4.3 weeks versus 1.9 weeks; p<0.0001). The QAS for combination therapy versus capecitabine was 42.2 weeks versus 38.4 weeks (p=0.0227). In a comparison between QOL outcomes, the authors noted there was statistically significant difference favoring the capecitabine group. However, the changes in QOL scores from baseline in the combination therapy group were not clinically significant. The authors noted that due to greater disease progression in the capecitabine group, there were fewer individuals with missing data in the combination therapy group. Statistical analysis that did not take into account that disease progression rates may result in an overestimation of the QOL benefits of capecitabine monotherapy. There were no significant differences in FBSI scores between the groups after adjusting for deaths.

In a multinational, open-label, phase III study, 1221 individuals with metastatic or locally advanced breast cancer were randomized to receive ixabepilone plus capecitabine or capecitabine alone. Individuals were eligible if they had previously been treated with two or fewer regimens of chemotherapy with both an anthracycline-containing (doxorubicin or epirubicin) and a taxane-containing (paclitaxel or docetaxel) agent. At the time of analysis, there was no significant difference in overall survival between the combination group and the capecitabine group median (16.4 and 15.6 months; hazard ratio [HR]: 0.9; 95% confidence interval [CI], 078 to 1.03; p=0.1162). In those individuals with measurable disease, the median progression-free survival was significantly improved in the combination therapy group versus the capecitabine only group (6.24 months [95% CI, 5.59 to 6.97] versus 4.4 months [95% CI, 4.14 to 5.42] [HR=0.79; 95% CI, 0.69 to 0.90; p=0.0005]). There were four deaths (0.7%) attributed to study drug toxicity in the combination group compared to two deaths (0.3%) in the capecitabine group. The authors noted that the results supported evidence from previous trials showing prolonged PFS when ixabepilone is combined with capecitabine over capecitabine alone, although overall survival is not affected (Sparano, 2010).

In a multicenter, phase II, single arm study (n=126), the safety and efficacy of ixabepilone as a monotherapy was evaluated in individuals with metastatic or locally advanced breast cancer resistant to anthracycline, taxane, and capecitabine (Perez, 2007). Approximately 88% of those within the study group had previously been treated with at least two lines of chemotherapy in the metastatic setting. Within the study group, 13 individuals were categorized as inassessable, 11 did not have independent radiology facility (IRF) measurable disease and 2 individuals did not have taxane-resistant disease. Participants were infused with ixabepilone every 21 days for less than or equal to 18 cycles or until disease progression or unacceptable toxicity. The primary study endpoint was objective response rate (ORR). A total of 13 of the 113 (11.5%) individuals considered response assessable reported a partial response (PR). An additional 15 individuals were classified as having stable disease (SD) for greater than or equal to 6 months. Within the treatment group, 23/126 (18.3%) participants reported a PR. The median tumor duration response was 5.7 months (95% CI, 4.4 to 7.3 months). In those individuals with response-assessable disease, 50% had SD as their best response and 13% of those individuals achieved a durable SD of 6 months or greater. At least one treatment-related adverse event (AE) was reported by 118 individuals, with 55% of the AEs graded as an intensity of 1/2. A treatment-related death was reported in an individual with baseline grade 4 cardiac failure. The authors noted that ixabepilone had a manageable safety profile and showed activity in this group of individuals who were resistant to multiple prior therapies.

Tolaney and colleagues (2013) conducted a non-randomized, multicenter phase II study to evaluate the safety and efficacy of combination therapy with ixabepilone and trastuzumab in individuals with metastatic HER2-positive breast cancer. Participants included 2 cohorts: cohort 1 contained those with no history of chemotherapy or trastuzumab (n=15) for metastatic disease and cohort 2 contained those who had received one to two trastuzumab containing regimens (n=24). All individuals received treatment with both ixabepilone and trastuzumab until disease progression or unacceptable toxicity. Across both groups, the ORR, which included both complete responses (CR) and PR, was 44% in the intent-to-treat population. The response rate in cohort 1 (73%; 95% CI, 45%-92%) was higher than cohort 2 (25%; 95% CI, 10%-47%). In addition, the clinical benefit rate, defined as the combination of complete response, partial response and stable disease cases greater than 24 weeks, was reported as 80% in cohort 1 and 42% in cohort 2. The most common AE was sensory neuropathy with 82% of individuals reporting grade 1 or higher neuropathy. Approximately half of the individuals reported grade 2 or higher toxicity. Other significant grade 2 or higher AEs included leukopenia (21%), neutropenia (21%), myalgia (21%) and febrile neutropenia (5%). There were no reported AEs of any cardiac toxicity. The authors noted this study demonstrates the safety and efficacy of combination ixabepilone and trastuzumab therapy.

The National Comprehensive Cancer Network® Clinical Practice Guidelines in Oncology (NCCN Guidelines® , 2017) for breast cancer recommends ixabepilone as a 2A recommendation for the treatment of recurrent or metastatic breast cancer. NCCN recommends ixabepilone as a monotherapy in human epidermal growth factor receptor 2 (HER2)-negative disease or in combination therapy with trastuzumab in HER2-positive disease previously exposed to trastuzumab. The 2A recommendation was based upon three phase II studies which did not focus on this specific population of individuals.

Ixabepilone has been evaluated as a potential treatment in a number of oncologic conditions with little conclusive success. Trials evaluating the use of ixabepilone as a neoadjuvant treatment in those with other forms of breast cancer or in those with platinum- and taxane-resistant endometrial or ovarian cancers have been inconsistent. Some trials have reported promising results, but further studies are needed (Yardley, 2015; Zagouri, 2015). However, a 2015 multicenter, open-label, randomized phase III trial evaluating ixabepilone as a single agent therapy in women with locally advanced, recurrent, or metastatic endometrial cancer who had failed prior platinum-based chemotherapy did not support the use of ixabepilone in this population. At interim analysis, the study was discontinued due to not meeting the interim overall survival (OS) results (McMeekin, 2015). Ixabepilone has also been studied in a phase II clinical trial as a potential treatment of metastatic cervical carcinoma. The authors noted that treatment did not result in sufficient activity to recommend as a therapy (Burotto, 2015). Another trial evaluating the use in squamous cell cancer of the head and neck did not support the use of ixabepilone for this condition (Burtness, 2008).

Background/Overview

Breast cancer is the second most common type of cancer among women in the United States (U.S.). Breast cancer is also the second leading cause of cancer death in women as well, surpassed only by lung cancer. In 2016, approximately 246,660 new cases of invasive breast cancer will be diagnosed. In addition, an estimated 40,450 women will die from the disease. Approximately 6-10% of new breast cancer cases will initially be stage IV or metastatic. Approximately 20-30% of all breast cancer cases will become metastatic.

Breast cancer can be treated with a variety of regimens, with anthracyclines being one of the most active drug classes used, as the ORR is between 30%-50% (Zeichner, 2016). However, there are concerns about the risk of cardiotoxicity associated with exceeding cumulative dose levels from previous adjuvant chemotherapy treatments. These concerns have led to limited use of anthracyclines in the metastatic setting and it is typically reserved for the treatment of anthracycline-naive individuals (Zeichner, 2016). Gradishar (2009) noted:

Higher response rates were observed in taxane naïve and/or anthracycline pretreated patients receiving ixabepilone. Reduced response rates were observed in patients resistant to taxanes or anthracyclines, taxanes and capecitabine.

Ixabepilone is administered intravenously at a dose of 40 mg/m2 over 3 hours every 21 days. The drug is given until disease progression or the individual is unable to tolerate additional treatment.

Adverse Events and Warnings

Black box warning from the FDA PI Label (2016) includes the following information and recommendation:

Additional Warnings from the FDA PI Label (2016) include:

Definitions

Line of therapy:

Locally advanced cancer: Cancer that has spread only to nearby tissues or lymph nodes.

Metastatic: The spread of cancer from one part of the body to another. A metastatic tumor contains cells that are like those in the original (primary) tumor and have spread.

Taxane resistance: Progression during therapy or within 12 months in the adjuvant setting or 4 months in the metastatic setting.

Coding

The following codes for treatments and procedures applicable to this document 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.  

When services may be Medically Necessary when criteria are met:

HCPCS  
J9207 Injection, ixabepilone, 1 mg [Ixempra]
   
ICD-10 Diagnosis    
C50.011-C50.929 Malignant neoplasm of breast  
Z85.3 Personal history of malignant neoplasm of breast  

When services are Investigational and Not Medically Necessary:
For the procedure code listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Baselga J, Zambetti M, Llombart-Cussac A, et al. Phase II genomics study of ixabepilone as neoadjuvant treatment for breast cancer. J Clin Oncol. 2009; 27(4):526-534.
  2. Burotto M, Edgerly M, Poruchynsky M, et al. Phase II Clinical Trial of Ixabepilone in Metastatic Cervical Carcinoma. Oncologist. 2015; 20(7):725-726.
  3. Burtness BA, Manola J, Axelrod R, et al; Eastern Cooperative Oncology Group. A randomized phase II study of ixabepilone (BMS-247550) given daily x 5 days every 3 weeks or weekly in patients with metastatic or recurrent squamous cell cancer of the head and neck: an Eastern Cooperative Oncology Group study. Ann Oncol. 2008; 19(5):977-983.
  4. Corey-Lisle PK, Peck R, Mukhopadhyay P, et al. Q-TWiST analysis of ixabepilone in combination with capecitabine on quality of life in patients with metastatic breast cancer. Cancer. 2012; 118(2):461-468.
  5. De Luca A, D'Alessio A, Maiello MR, et al. Evaluation of the pharmacokinetics of ixabepilone for the treatment of breast cancer. Expert Opin Drug Metab Toxicol. 2015; 11(7):1177-1185.
  6. Gradishar W. Management of advanced breast cancer with the epothilone B analog, ixabepilone. Drug Des Devel Ther. 2009; 3:163-171.
  7. Li J, Ren J, Sun W. Systematic review of ixabepilone for treating metastatic breast cancer. Breast Cancer. 2017; 24(2):171-179.
  8. McMeekin S, Dizon D, Barter J, et al. Phase III randomized trial of second-line ixabepilone versus paclitaxel or doxorubicin in women with advanced endometrial cancer. Gynecol Oncol. 2015; 138(1):18-23.
  9. Moulder S, Li H, Wang M, et al. A phase II trial of trastuzumab plus weekly ixabepilone and carboplatin in patients with HER2-positive metastatic breast cancer: an Eastern Cooperative Oncology Group Trial. Breast Cancer Res Treat. 2010; 119(3):663-671.
  10. Perez EA, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2007; 25(23):3407-3414.
  11. Puhalla S, Brufsky A. Ixabepilone: a new chemotherapeutic option for refractory metastatic breast cancer. Biologics. 2008; 2(3):505-515.
  12. Roché H, Yelle L, Cognetti F, et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, as first-line therapy  in patients with metastatic breast cancer previously treated with anthracycline chemotherapy. J Clin Oncol. 2007; 25(23):3415-3420.
  13. Roque DM, Ratner ES, Silasi DA, et al. Weekly ixabepilone with or without biweekly bevacizumab in the treatment of recurrent or persistent uterine and ovarian/primary peritoneal/fallopian tube cancers: a retrospective review. Gynecol Oncol. 2015; 137(3):392-400.
  14. Sparano JA, Vrdoljak E, Rixe O, et al. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010; 28(20):3256-3263.
  15. Thomas E, Tabernero J, Fornier M, et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. J Clin Oncol. 2007; 25(23):3399-3406.
  16. Tolaney SM, Najita J, Sperinde J, et al. A phase II study of ixabepilone and trastuzumab for metastatic HER2-positive breast cancer. Ann Oncol. 2013; 24(7):1841-1847.
  17. Yardley DA, Dickson N, Drosick D, et al. Sorafenib plus Ixabepilone as first-line treatment of metastatic HER2-negative breast cancer: a Sarah Cannon Research Institute phase I/II trial. Clin Breast Cancer. 2016; 16(3):180-187.
  18. Yardley DA, Zubkus JD, Eakle JF, et al. Neoadjuvant Ixabepilone/Carboplatin/Trastuzumab in HER2-positive operable breast cancer: a phase II trial of the Sarah Cannon Research Institute. Clin Breast Cancer. 2015; 15(4):251-258.
  19. Zagouri F, Sergentanis TN, Chrysikos D, et al. Epothilones in epithelial ovarian, fallopian tube, or primary peritoneal cancer: a systematic review. Onco Targets Ther. 2015; 8:2187-2198.
  20. Zeichner SB, Terawaki H, Gogineni K. A review of systemic treatment in metastatic triple-negative breast cancer. Breast Cancer (Auckl). 2016; 10:25-36.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Ixabepilone. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Last Update March 17, 2017. Available at: http://www.micromedexsolutions.com. Accessed on April 8, 2017.
  2. Ixabepilone Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised August 10, 2012. Accessed on April 8, 2017.
  3. Ixempra [Product Information]. Princeton, NJ. R-PHARM US; January, 2016. Available at: http://ixemprahcp.com/downloads/full_pi.pdf. Accessed on April 8, 2017.
  4. National Comprehensive Cancer Network® . NCCN Drugs & Biologic Compendium® (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on April 8, 2017.
  5. NCCN Clinical Practice Guidelines in Oncology® . © 2017 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on April 8, 2017.
    • Breast Cancer (V.2.2017). Revised April 6, 2017.
Websites for Additional Information
  1. American Cancer Society. Breast Cancer. Available at: http://www.cancer.org/cancer/breastcancer/index. Accessed on April 7, 2017.
  2. BreastCancer. Tumor Resistance. Revised on November 5, 2015. Available at: http://www.breastcancer.org/treatment/planning/types_treatment/tumor_resist. Accessed on April 7, 2017.
  3. Metastatic Breast Cancer Network. Available at: http://mbcn.org/. Accessed on April 7, 2017.
  4. U.S. National Library of Medicine. MedlinePlus. Ixabepilone Injection. Last reviewed September 1, 2010. Available at: https://medlineplus.gov/druginfo/meds/a608042.html . Accessed on April 7, 2017.
Index

Antimicrotubule agent
Epothilone B analog
Ixempra

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.

Document History
Status Date Action
Reviewed 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review.
Reviewed 05/03/2017 Hematology/Oncology Subcommittee review. Updated Rationale, References and Websites sections.
Revised 11/03/2016 MPTAC review.
Revised 11/02/2016 Hematology/Oncology Subcommittee review. Revised position statement to remove requirement that the individual be resistant or refractory to or been previously treated with anthracyclines, taxanes, and capecitabine. Updated Description, Rationale, Background, Definitions, References and Websites sections. Updated formatting in Position Statement section.
New 05/05/2016 MPTAC review.
New 05/04/2016 Hematology/Oncology Subcommittee review. Initial document development.