Clinical UM Guideline

 

Subject: Fulvestrant (FASLODEX®)
Guideline #:  CG-DRUG-62 Publish Date:    06/06/2018
Status: Revised Last Review Date:    05/03/2018

Description

This document addresses clinical uses of fulvestrant (FASLODEX, AstraZeneca Pharmaceuticals LP; Wilmington, DE), an estrogen receptor (ER) antagonist used in the treatment of oncologic conditions.

Clinical Indications

Medically Necessary:

Fulvestrant is considered medically necessary in the treatment of recurrent or metastatic breast cancer when all the following criteria are met:

  1. Breast cancer, hormone receptor (HR)-positive; and
  2. Used as a single agent (along with ovarian suppression if indicated) or in combination with palbociclib or abemaciclib.

Not Medically Necessary:

Fulvestrant is considered not medically necessary when the above criteria are not met and for all other indications.

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

 

J9395

Injection, fulvestrant, 25 mg [Faslodex]

 

 

ICD-10 Diagnosis

 

C50.011-C50.929

Malignant neoplasm of breast

C79.81

Secondary malignant neoplasm of breast

Z17.0

Estrogen receptor positive status [ER+]

Z85.3

Personal history of malignant neoplasm of breast

Discussion/General Information

The U.S. Food and Drug Administration (FDA) Product Information (PI) Label for fulvestrant (FASLODEX PI Label, 2017) describes the mechanism of action as “an estrogen receptor antagonist that binds to the estrogen receptor in a competitive manner with affinity comparable to that of estradiol and downregulates the ER protein in human breast cancer cells.”

Fulvestrant has received FDA approval for the following uses (FASLODEX PI Label, 2017):

Breast cancer is a type of tumor comprised of malignant (cancerous) cells that start to grow in the breast and may spread (metastasize) to surrounding tissues and other areas of the body. Breast cancer is managed by various treatment modalities including combinations of surgery, radiation therapy, chemotherapy and hormone therapy (National Cancer Institute, 2018). The prognosis and selection of therapies can be affected by clinical and pathologic features of the tumor, reoccurrence and metastatic status. In 2018, the American Cancer Society (ACS) estimates that there will be about 268,670 new cases of breast cancer diagnosed in the United States and approximately 41,400 deaths from the disease.

On April 25, 2002, fulvestrant was first approved by the FDA for intramuscular (IM) injection, as a single agent in the treatment of HR+ metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy. Fulvestrant functions to down-regulate estrogen receptors (ER) with a rapid loss of ER protein in the tumor. The FDA approval was based on two phase III studies with 851 postmenopausal women with advanced breast cancer, 400 in a North American double-blind study and 451 in a European open-label study that compared the efficacy and tolerability of fulvestrant and anastrozole in post-menopausal women with advanced breast cancer progressing after prior endocrine treatment. Participants were randomized to receive fulvestrant 250 mg monthly by IM injection (n=428) or anastrozole 1 mg orally every day (n=423). Anastrozole is an aromatase inhibitor which functions to lower estrogen levels. Participants were followed for a median of 14.4 and 16.8 months (Howell, 2002; Osborne, 2002; respectively). Enrollees were considered hormone sensitive either by receptor status or previous response to endocrine therapy. The primary study endpoints were response rate and time to progression (TTP). Response rates for participants treated with fulvestrant were 17% and 20.3% in the North American and European trials, respectively, compared with 17% and 14.9% in the anastrozole treatment arms. Median TTP was 5.5 months for fulvestrant and 5.1 months for anastrozole (Howell, 2002) and 5.4 months with fulvestrant and 3.4 months with anastrozole (Osborne, 2002). The most common adverse events attributed to the treatment (> 10%) were injection-site reactions and hot flashes. Common events (1%-10%) included asthenia, headache, and gastrointestinal disturbances (nausea, vomiting, and diarrhea), as well as rash and urinary tract infections. A small increase in joint disorders was reported in the anastrozole-treated patients. The authors in both studies concluded that fulvestrant was as effective as anastrozole (FASLODEX PI Label, 2017).

March 6, 2016, the FDA approved expanded use of fulvestrant to include treatment of HR+, HER2- advanced or metastatic breast cancer used in combination with palbociclib in women with disease progression after endocrine therapy. The FDA approval of this new indication is based on data from the PALOMA-3 (Palbociclib Combined With Fulvestrant in Hormone Receptor–Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial, a phase III, a randomized double-blind, placebo-control trial conducted in 521 pre and postmenopausal women with HR+, HER2- advanced or metastatic breast cancer (Cristofanilli, 2016). The primary endpoint was progression free survival (PFS). Participants were randomized (2:1) to receive palbociclib plus fulvestrant (n=347) or placebo plus fulvestrant (n=174). Median progression-free survival was 9.5 months (95% CI, 9.2-11.0) in the fulvestrant plus palbociclib group and 4.6 months (3.5-5.6) in the fulvestrant plus placebo group (hazard ration 0.46, 95% CI, 0.36-0.56; p<0.0001). The most common adverse reactions (> 20%) in participants treated with palbociclib were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea, and thrombocytopenia. In summary Cristofanilli and colleagues conclude that:

Fulvestrant plus palbociclib was associated with significant and consistent improvement in progression-free survival compared with fulvestrant plus placebo, irrespective of the degree of endocrine resistance, hormone-receptor expression level, and PIK3CA mutational status. The combination could be considered as a therapeutic option for patients with recurrent hormone-receptor-positive, HER2-negative metastatic breast cancer that has progressed on previous endocrine therapy.

The most common adverse reactions (≥ 5%) among participant who received fulvestrant (500mg) included: injection site pain, headache, nausea, vomiting, anorexia, constipation, cough, dyspnea, fatigue, bone pain, arthralgia, back pain, pain in extremity, and hot flash. Greater than 15% of participants receiving fulvestrant experienced an increase in hepatic enzymes (ALT, AST, ALP) (FASLODEX PI Label, 2017).

The National Comprehensive Cancer Network® NCCN Drugs & Biologic Compendium™ and NCCN clinical practice guideline (CPG) in Oncology® for breast cancer (2018) includes off-label recommendations for use of fulvestrant in the treatment of breast cancer. The NCCN panel suggests endocrine therapy for recurrent or metastatic disease for the treatment of pre/perimenopausal individuals (selective ER modulators or ovarian ablation/suppression plus endocrine therapy as for postmenopausal women) when used as a single agent (category 1 recommendation) or in combination with palbociclib (category 2A recommendation). In males with breast cancer, the NCCN Panel recommends they “be treated similarly to postmenopausal women, except that the use of aromatase inhibitors is ineffective without concomitant suppression or testicular steroidogenesis.” The NCCN CPG recommendations are based on general consensus and data from the peer reviewed literature including Phase II/III studies using fulvestrant in the treatment of recurrent or metastatic breast cancer for pre or postmenopausal women (De Leo, 2010; De Leo. 2014; Giordano, 2002; Robertson, 2009). The NCCN panel does not include recommendations for addition of fulvestrant to anastrozole for endocrine therapy for metastatic disease; results from the FACT and SOFEA trial “demonstrated no advantage in time to progression with the addition of fulvestrant to anastrozole” (Bergh, 2012; Johnston, 2013).

November 15, 2017, the FDA approved a new indication for fulvestrant, expanding the indication to include treatment of advanced breast cancer in combination with abemaciclib (oral), a CDK4/6 inhibitor, for HR+, HER2- in women (pre/perimenopausal) with disease progression after endocrine therapy. The FDA approval is based on data from the MONARCH 2 trial, a Phase III international, randomized, double-blind, placebo-controlled, multicenter study, sponsored by Eli Lilly and Company of fulvestrant with abemaciclib versus fulvestrant with placebo conducted in women with HR+, HER2- advanced or metastatic cancer, who had disease progression on or after neoadjuvant or adjuvant endocrine therapy (Sledge, 2017). Sledge and colleagues reported results of 669 women with HR+, HER2- advanced breast cancer, randomly assigned to receive abemaciclib in combination with fulvestrant (n=446) or placebo plus fulvestrant (n=223). The results showed a statistically significant increase in investigator-assessed median PFS of 7.1 months (16.4 months vs 9.3 months) in participants who received fulvestrant and abemaciclib over fulvestrant and placebo (HR: 0.553; 95% CI: 0.449-0.681; p<0.0001). The participants with measurable disease, fulvestrant and abemaciclib achieved an objective response rate (ORR) of 48.1% (95% CI, 42.6% to 53.6% compared with 21.3% (95% CI, 15% to 27.6%) in participants who received fulvestrant with placebo.

Other Uses

The updated 2018 NCCN CPG for breast cancer provides a Category 2A recommendation for use of fulvestrant with or without trastuzumab for systemic therapy for ER and/or PR- positive recurrent stage IV disease in postmenopausal women. The NCCN Drugs and Biologics Compendia and NCCN NCG for uterine cancer (2018) includes Category 2A recommendation for use of fulvestrant as a treatment option for systemic therapy for recurrent, metastatic or high-risk  disease (strongly encourage participation in clinical trials), However, at this time, there is no published evidence of safety and efficacy to support these off-label indications.

FDA PI Label Information for FASLODEX

The FDA PI label for FASLODEX (2017) includes the following contraindications, warning and precautions:

Contraindications:

Hypersensitivity

Warnings and Precautions:

Definitions

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.

National Comprehensive Cancer Network® NCCN Clinical Practice Guidelines in Oncology™ (NCCN) Categories of Evidence and Consensus:

Category 1: The recommendation is based on high level evidence, and there is uniform NCCN consensus.

** Category 2A: The recommendation is based on lower level evidence, including clinical experience and there is uniform NCCN consensus.

* Category 2B: The recommendation is based on lower level evidence, including clinical experience and there is non-uniform NCCN consensus (but no major disagreement).

Category 3: Based on any level of evidence but reflects major disagreement.

All recommendations of the NCCN are Category 2A unless otherwise noted.

Off-Label: Utilization of an 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.

References

Peer Reviewed Publications:

  1. Bergh J, Jonsson PE, Lidbrink EK, et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol. 2012; 30:1919-1925.
  2. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016; 17(4):425-439.
  3. Di Leo A, Jerusalem G, Petruzelka L, et al. Final overall survival: fulvestrant 500 mg vs 200 mg in the randomized CONFIRM trial. J Natl Cancer Inst. 2014; 106(1):djt337.
  4. Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM Phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2010; 28(30):4594-4600.
  5. Giordano SH, Buzdar AU, Hortobagyi GN. Breast cancer in men. Ann Intern Med. 2002; 137(8):678-687.
  6. Howell A, Robertson JF, Quaresma Albano J, et al. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002; 20(16):3396-3403.
  7. Johnston SR, Kilburn LS, Ellis P, et al. Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicenter, phase 3 randomised trial. Lancet Oncol. 2013; 14:989-998.
  8. Loibl S, Turner NC, Ro J, et al. Palbociclib combined with fulvestrant in prermenopausal women with advanced breast cancer and prior progression on endocrine therapy: PALOMA-3 results. Oncologist. 2017; 9:1028-1038.
  9. Mehta RS, Barlow WE, Albain KS, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012; 367:435-444.
  10. Osborne CK, Pippen J, Jones SE, et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol. 2002; 20(16):3386-3395.
  11. Robertson JF, Llombart-Cussac A, Rolski J, et al. Activity of fulvestrant 500 mg versus anastrozole 1 mg first-line treatment for advanced breast cancer: results from the FIRST study. J Clin Oncol. 2009; 27(27):4530-4535.
  12. Sledge GW, Toi M, Neven P, et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017; 35(25):2875-2886.
  13. Verma S Bartlett CH, Schnell P, et al. Palbociclib in combination with fulvestrant in women with hormone receptor-positive/HER2-negative advanced metastatic breast cancer: detailed safety analysis from a multicenter, randomized, placebo-controlled, phase III study (PALMOA-3). Oncologist. 2016; 21(10):1165-1175.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Cancer Society. Cancer facts & figures 2018. Atlanta: American Cancer Society; 2018. Available at: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2018.html. Accessed on March 27, 2018.
  2. FASLODEX [Product Information], Wilmington, DE. AstraZeneca Pharmaceuticals LP; November 16, 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021344s035lbl.pdf. Accessed on March 27, 2018.
  3. Fulvestrant Monograph. Lexicomp® Online, American Hospital Formulary Services® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised August 10, 2017. Accessed on March 27, 2018.
  4. Fulvestrant (systemic). In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated February 07, 2018. Available at: http://www.micromedexsolutions.com. Accessed on March 27, 2018.
  5. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium™ (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on March 26, 2018.
  6. National Comprehensive Cancer Network® NCCN Clinical Practice Guidelines in Oncology™. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on March 26, 2018.
    • Breast cancer (V.1.2018). Revised March 20, 2018.
  7. Pfizer. Palbociclib (PD-0332991) combined with fulvestrant in hormone receptor+ HER2-negative metastatic breast cancer after endocrine failure (PALOMA-3). NLM Identifier: NCT01942135. Last updated: March 9, 2018. Available at: https://clinicaltrials.gov/show/NCT01942135. Accessed on March 27, 2018.
Websites for Additional Information
  1. American Cancer Society. What is breast cancer? Revised September 21, 2017. Available at: http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-what-is-breast-cancer. Accessed on March 27, 2018.
  2. National Cancer Institute. Breast cancer (PDQ®) – Health Professional Version. Last modified February 4, 2018. Available at: https://www.cancer.gov/types/breast/hp/breast-treatment-pdq. Accessed on March 27, 2018.
Index

FASLODEX
Fulvestrant

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

Revised

05/03/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.

Revised

05/02/2018

Hematology/Oncology Subcommittee review. The document header wording updated from “Current Effective Date” to “Publish Date.” Revised MN Criteria to include coverage in combination with abemaciclib. Updated Discussion, References and Websites sections.

Reviewed

05/04/2017

MPTAC review.

Reviewed

05/03/2017

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

New

11/03/2016

MPTAC review.

New

11/02/2016

Hematology/Oncology Subcommittee review. Initial document development. Initial document development.