Fulvestrant (Faslodex®) in advanced breast cancer:

What the treatment guidelines say…

679113.011 Date of preparation: March 2015

Content

Fulvestrant indication Slide 3

Introduction: Treatment guidelines for ER+ BC Slide 4

International guidelines

ESO–ESMO recommendations: Endocrine therapy of ER+ advanced BC Slide 7

NCCN recommendations: Endocrine therapy for ER+ mBC Slide 9

National guidelines

NICE recommendations: Endocrine therapy of ER+ advanced BC Slide 12

Regional guidelines

East Midlands Cancer Network recommendations:Endocrine therapy for ER+ mBC

Slide 18

London Cancer Alliance recommendations:Endocrine therapy for ER+ mBC

Slide 22

SummaryEndocrine therapy for ER+ mBC

Slide 24

BC, breast cancer; ER, oestrogen receptor; ESMO, European Society for Medical Oncology; ESO, European School of Oncology; mBC, metastatic breast cancer; NCCN, National Comprehensive Cancer Network

Fulvestrant indication

• The recommended dose of fulvestrant is 500 mg at intervals of one month

- An additional 500 mg dose is given 2 weeks after the initial dose

• Each 500 mg pack contains two prefilled syringes

- Each prefilled syringe contains fulvestrant 250 mg

Fulvestrant is indicated for the treatment of post-menopausal women with ER+, locally advanced or

metastatic breast cancer (mBC) for disease relapse on or after adjuvant anti-oestrogen therapy or disease progression on

therapy with an anti-oestrogen1

ER, oestrogen receptor1. Faslodex SPC 17 Feb 2012. https://www.medicines.org.uk/emc/medicine/14381 Accessed Feb 2015

Introduction:Treatment guidelines for ER+ mBC

The views expressed in these guidelines are not those of AstraZeneca

Fulvestrant in clinical treatment guidelines

• Treatment of ER+ advanced breast cancer should be decided on a case-by-case basis, according to the clinical scenario and individual circumstances of each patient

• A range of guidelines are currently available to assist clinicians in selecting the most appropriate treatment for individual patients:

- International guidelines (e.g. Europe: ESO–ESMO, US: NCCN)

- National guidelines (e.g. NICE)

- UK regional guidelines (e.g. East Midlands Cancer Network, London Cancer Alliance)

• These guidelines indicate that fulvestrant should be considered as a second-line treatment for postmenopausal women with ER+ metastatic breast cancer

• However, recent changes to funding have resulted in disparities in access to fulvestrant across the UK. Consequently, some patients who could potentially benefit from this agent are currently denied unable to obtain this treatment

BC breast cancer; ER, oestrogen receptor; ESMO, European Society for Medical Oncology; ESO, European School of Oncology; NCCN, National Comprehensive Cancer Network

NHS England: Cancer Drug Fund decision on fulvestrant

• The Cancer Drugs Fund (CDF) is money set aside by the Government to pay for

cancer drugs that are not approved by NICE or available within the NHS in England

• Until recently, funding for fulvestrant was via the regional CDF, but this was removed

in 2013

Payment by Results Guidance 2013/14

- Paragraph 754

“If a hormone treatment is not used as an intrinsic part of a regimen, or as a supportive drug

to a regimen, it is only excluded from PbR when the drug is explicitly listed on the exclusion

list, or if it is included in a British national Formulary section or sub-section that is wholly

excluded from PbR”

• Fulvestrant was not considered to meet the definition of a supportive drug or an

intrinsic part of a chemotherapy regimen

• This implies that fulvestrant should be included in baseline commissioning

http://www.blueteq.com/cdf/forms/CDF_letter_to_AT_re_4_drugs_15.4.13.pdf

ESO–ESMO recommendations:Endocrine therapy for ER+ mBC

The views expressed in these guidelines are not those of AstraZeneca

ESO–ESMO:Second international consensus guidelines1

• Fulvestrant is considered a suitable treatment option for postmenopausal women with ER+ advanced BC

- Preferred first-line endocrine therapy is AI or tamoxifen, depending on the type and duration of adjuvant endocrine therapy Evidence IA

- Fulvestrant 500 mg is also an option Evidence IB

- Addition of everolimus to an AI is a valid option for some patients with disease progression after non-steroidal AI Evidence IB • The decision to treat must be made on a case-by-case basis and take into account the toxicities

associated with this combination

AI, aromatase inhibitor; ER, oestrogen receptor; ESMO, European Society for Medical Oncology ESO, European School of OncologyEvidence IA, strong recommendation, high-quality evidence Evidence IB, strong recommendation, moderate-quality evidence1. Cardoso F, et al. Annals Oncol 2014;25:1871–88

NCCN recommendations:Endocrine therapy for ER+ mBC

The views expressed in these guidelines are not those of AstraZeneca

NCCN Guidelines: Treatment of advanced, ER+ BC in postmenopausal women

BC, breast cancer; ER, oestrogen receptor; NCCN, National Comprehensive Cancer Network, PR, progesterone receptorAdapted from NCCN Guidelines Breast Cancer version 3.2014 Available from http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf Accessed Feb 2015

Recommended subsequent endocrine therapies:• Anastrozole, letrozole• Exemestane ± everolimus• Fulvestrant• Tamoxifen or toremifene• Megestrol acetate• Fluoxymesterone• Ethinyl estradiol

Women with ER+ and/or PR +; HER2 – or +advanced breast cancer

Continue endocrine therapy until progression or unacceptable toxicity

Clinical benefit after 3 sequential endocrine therapy regimens or symptomatic visceral disease?

Prior endocrine therapy within 1 year

No prior endocrine therapy within 1 year

Aromatase inhibitor, orSelective ER modulator, or

Selective ER-down-regulator

Chemotherapy Trial of new endocrine agent

NCCN Guidelines: Treatment of advanced, ER+ BC in postmenopausal women

• Fulvestrant is listed among the recommended subsequent endocrine therapies for postmenopausal women with ER+ advanced BC1

• NCCN Guidelines state that fulvestrant is at least as effective as anastrozole in patients with disease progression following tamoxifen therapy1

- Fulvestrant 500 mg (the recommended dose) demonstrated an increase in overall survival (4.1 months) and reduced risk of death (19%), compared with the 250 mg initially investigated in clinical trials1,2

BC, breast cancer; ER, oestrogen receptor; NCCN, National Comprehensive Cancer Network, PR, progesterone receptor1. NCCN Guidelines Breast Cancer version 3.2014 Available from http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf Accessed Feb 20152. Di Leo A et al. J Natl Cancer Inst 2014;106:1–7

NICE recommendations:Endocrine therapy for ER+ mBC

The views expressed in these guidelines are not those of AstraZeneca

NICE recommendations for endocrine therapy of ER+ mBC

• NICE guidelines1

- “Fulvestrant is not recommended, within its licensed indication, as an alternative to

aromatase inhibitors for the treatment of ER+, locally advanced or metastatic breast

cancer in postmenopausal women whose cancer has relapsed on or after adjuvant

anti-oestrogen therapy, or who have disease progression on anti-oestrogen therapy”

• NICE treatment pathway2

- Fulvestrant is included in the NICE treatment pathway patient flow- “Postmenopausal women currently receiving fulvestrant within its licensed indication

should have the option to continue treatment until they and their clinicians consider it

appropriate to stop”

NICE treatment pathway differs from the official NICE guidance

ER, oestrogen receptor; NICE, National Institute of Clinical Excellence1. http://www.nice.org.uk/guidance/ta239/resources/guidance-fulvestrant-for-the-treatment-of-locally-advanced-or-metastatic-breast-cancer-pdf (Dec 2011). Accessed Feb 20152. http://pathways.nice.org.uk/pathways/advanced-breast-cancer (June 2014). Accessed Feb 2015

NICE endocrine treatment pathway for advanced breast cancer

ER, oestrogen receptorAdapted from http://pathways.nice.org.uk/pathways/advanced-breast-cancer (June 2014). Accessed Feb 2015

Patient with ER+ advanced breast cancer

Man or womanEndocrine therapy – men

Rapid tumour response needed?Offer chemotherapy followed by

endocrine therapy

Menopausal status?

Patients received adjuvant endocrine therapy?

Patient previously treated with tamoxifen?

Offer tamoxifen and ovarian suppression

Offer ovarian suppressionPreviously treated with tamoxifen

Previously treated with aromatase inhibitor

Aromatase inhibitors and fulvestrant

Everolimus plus exemestane is not recommended

Consider offering chemotherapy or biological therapy

Woman

No

No

Pre/peri-menopausalPost-menopausal

YesYesYes

No

• Fulvestrant is included as a second-line treatment option

• Postmenopausal women currently receiving fulvestrant within its licensed indication should have the option to continue treatment

NICE endocrine treatment pathway for advanced breast cancer

ER, oestrogen receptorAdapted from http://pathways.nice.org.uk/pathways/advanced-breast-cancer (June 2014). Accessed Feb 2015

Patient with ER+ advanced breast cancer

Man or womanEndocrine therapy – men

Rapid tumour response needed?Offer chemotherapy followed by

endocrine therapy

Menopausal status?

Patients received adjuvant endocrine therapy?

Patient previously treated with tamoxifen?

Offer tamoxifen and ovarian suppression

Offer ovarian suppressionPreviously treated with tamoxifen

Previously treated with aromatase inhibitor

Aromatase inhibitors and fulvestrant

Everolimus plus exemestane is not recommended

Consider offering chemotherapy or biological therapy

Woman

No

No

Pre/peri-menopausalPost-menopausal

YesYesYes

No

• Fulvestrant is included as a second-line treatment option

• Postmenopausal women currently receiving fulvestrant within its licensed indication should have the option to continue treatment

The NICE treatment pathway indicates fulvestrant should be continued in postmenopausal

patients with mBC who are currently receiving this therapy in accordance

with its indication

Why was fulvestrant not recommended second line by NICE guidelines1?

• From the CONFIRM study2

- No active comparator from aromatase inhibitor class

- Mixed trial population – previous anti-oestrogen and aromatase inhibitor treatment

• The submitted meta-analysis3

- Heterogeneity of included trials

- No difference in overall survival vs aromatase inhibitors

- Uncertainty about validity of methodology using parallel comparison of fulvestrant 500 mg vs 250 mg vs comparators

• Issues with health economic claims1

- Linked to meta-analysis – concerns about validity contaminated economic analysis

1. Advanced breast cancer: diagnosis and treatment, Full guideline 2009 http://www.nice.org.uk/guidance/cg81/evidence/cg81-advanced-breast-cancer-full-guideline3f. Accessed Feb 2015 2. Di Leo A et al. J Clin Oncol 2010; 28: 4594-46003. Cope S et al. Value in Health 2013; 16:403-417

Summary: NICE guidelines for endocrine therapy in postmenopausal women

• NICE Guidelines recommend offering an aromatase inhibitor (either non-steroidal or steroidal) to postmenopausal women with1:

- ER+ breast cancer and no prior history of endocrine therapy

- ER+ breast cancer previously treated with tamoxifen

• However, NICE treatment pathway also supports the continued use of fulvestrant within its indication for women who are currently receiving this treatment2

• NICE guidelines are considered limited by a lack of data regarding the sequencing of endocrine treatments, and may have failed to appreciate the complexity of patient management3

- Fulvestrant should be considered for postmenopausal women with indolent disease and continued endocrine sensitivity3

ER, oestrogen receptor1. Advanced breast cancer (update): Diagnosis and Treatment http://www.nice.org.uk/guidance/cg81 (July 2014). Accessed Feb 20152. http://pathways.nice.org.uk/pathways/advanced-breast-cancer (June 2014). Accessed Feb 20153. Coleman RE, et al. Clinical Oncol 2012;24:169–76

East Midlands Cancer Network recommendations:Endocrine therapy for ER+ mBC

The views expressed in these guidelines are not those of AstraZeneca

East Midland Cancer Network

• The East Midland Cancer Network ceased in March 2013 when Cancer Networks were amalgamated into a Strategic Clinical Network as part of the NHS re-organisation

• The chemotherapy section is maintained to reflect the changes in the CDF and other amendments to treatment pathways until national algorithms become available

CDF, Cancer Drugs Fundhttp://www.eastmidlandscancernetwork.nhs.uk/Default.aspx Accessed Feb 2014

East Midlands Cancer Network: Treatment of hormone-receptor positive advanced BC

AI, aromatase inhibitorEast Midlands Cancer Network Hormone algorithm advanced breast cancer. http://www.eastmidlandscancernetwork.nhs.uk/Library/AdvancedBreastHormone.pdf Accessed Feb 2015

According to the East Midlands Cancer Network, fulvestrant may

be a suitable treatment for postmenopausal women following prior endocrine

therapy with tamoxifen and AI

East Midlands Cancer Network: Treatment of hormone-receptor positive advanced BC

• The East Midlands Cancer Network recommends fulvestrant as a treatment option following disease progression with prior tamoxifen and AI therapy

AI, aromatase inhibitorEast Midlands Cancer Network Hormone algorithm advanced breast cancer, February 2015. http://www.eastmidlandscancernetwork.nhs.uk/Library/AdvancedBreastHormone.pdf Accessed Feb 2015

London Cancer Alliance recommendations:Endocrine therapy for ER+ mBC

The views expressed in these guidelines are not those of AstraZeneca

London Cancer Alliance: Endocrine therapy for ER-positive advanced BC

aConsider for patients with a long natural history and/or slow, indolent diseaseAdapted from London Cancer Alliance Breast Cancer Clinical Guidelines. October 2013http://www.londoncanceralliance.nhs.uk/media/59178/FINAL%20LCA_BreastGuidelines_231013%20revised%20(3).pdfAccessed Feb 2015

Postmenopausal women with ER+ breast cancer

No prior aromatase inhibitor

First line: letrozole or anastrozole

Second line: tamoxifen or exemestane

Third line: fulvestrant

Fourth line: megastrola

London Cancer Alliance Guidelines for West and South London indicate fulvestrant may be a suitable subsequent endocrine treatment for

postmenopausal women following prior aromatase inhibitor treatment

Summary of treatment guidelines:Endocrine therapy for ER+ mBC

Summary: Fulvestrant and the treatment guidelines for postmenopausal women with ER+ advanced BC

• It is widely accepted that postmenopausal women with ER+ advanced breast cancer should be considered for systemic endocrine therapy

• International guidelines from both Europe (ESO–ESMO) and the US (NCCN) support the use of fulvestrant according to its licensed indication:

- Fulvestrant is recommended as a treatment option for postmenopausal women with ER+ advanced BC and disease progression following first-line endocrine therapy1,2

• While NICE Guidelines do not include fulvestrant, NICE treatment pathway supports the continued use of fulvestrant for women already receiving this treatment3,4

• UK regional treatment guidelines also widely support the use of fulvestrant as a therapeutic option for postmenopausal women with ER+ advanced BC6,7

Consequently, there is an urgent need to address the current disparity in access to fulvestrant across the UK and ensure it is available to all patients who may potentially benefit from this treatment

BC, breast cancer; ER, oestrogen receptor; ESMO, European Society for Medical Oncology; ESO, European School of Oncology; NCCN, National Comprehensive Cancer Network,1. NCCN Guidelines Breast Cancer version 3.2014 Available from http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf 2. Cardoso F, et al. Annals Oncol 2014;25:1871–88; 3. Advanced breast cancer (update): Diagnosis and Treatment http://www.nice.org.uk/guidance/cg81 (July 2014). 4. http://pathways.nice.org.uk/pathways/advanced-breast-cancer (June 2014). 5. Coleman RE, et al. Clinical Oncol 2012;24:169–76; 6. East Midlands Cancer Network Hormone algorithm advanced breast cancer. Available from http://www.eastmidlandscancernetwork.nhs.uk/Library/AdvancedBreastHormone.pdf Accessed Feb 2015; 7. London Cancer Alliance Breast Cancer Clinical Guidelines. October 2013 http://www.londoncanceralliance.nhs.uk/media/59178/FINAL%20LCA_BreastGuidelines_231013%20revised%20(3).pdf.

Faslodex prescribing informationFaslodex® 250 mg solution for injectionfulvestrantConsult the Summary of Product Characteristics before prescribing.Use Faslodex is indicated for the treatment of postmenopausal women with oestrogen receptor positive, locally advanced or metastatic breast cancer for disease relapse on or after adjuvant antioestrogen therapy or disease progression on therapy with an antioestrogen.Presentation A pre-filled syringe contains 250 mg fulvestrant in 5 ml solution. Safety needles (SafetyGlide™) are also provided.Dosage and administration Adult females (including the elderly): 500 mg at monthly intervals, with an additional 500 mg dose given two weeks after initial dose. Administered intramuscularly as two consecutive injections, one in each buttock. Faslodex is not recommended for use in children or adolescents, as safety and efficacy have not been established in this age group. No dose adjustments are needed for patients with mild to moderate hepatic or renal impairment (creatinine clearance 30 ml/min). However, safety and efficacy have not been evaluated in patients with severe hepatic or renal impairment. Dosage adjustment is not necessary for patients co-prescribed Faslodex and CYP3A4 inhibitors or inducers.Contraindications Hypersensitivity to the active substance or to any of the excipients, pregnancy, in breast-feeding and in patients with severe hepatic impairment.Precautions Caution in patients with mild to moderate, hepatic impairment and severe renal impairment. Caution if treating patients with bleeding diatheses, thrombocytopenia or those taking anticoagulant treatment. Thromboembolic events are commonly observed in women with advanced breast cancer in clinical trials. There are no long-term data on the effect of fulvestrant on bone. There is a potential risk of osteoporosis with Faslodex. Patients of childbearing potential should be advised to use effective contraception during treatment. Breast-feeding must be stopped during treatment. Asthenia (a loss of strength) has been reported during treatment with Faslodex, therefore caution if experiencing this symptom when driving or operating machinery.Undesirable events Very common: Nausea, asthenia, injection site reactions, increased liver enzymes. Common: GI disturbances including vomiting, diarrhoea and anorexia; rash; urinary tract infections; hot flushes; venous thromboembolism; headache; back pain; hypersensitivity reactions; elevated bilirubin. Consult SmPC for a full list of side-effects. Legal category POM.Marketing Authorisation number EU/1/03/269/002Basic NHS cost 2 x 5 ml pre-filled syringes: £522.41Further information is available from AstraZeneca UK Limited, 600 Capability Green, Luton, LU1 3LU, UK.Faslodex® is a trade mark of the AstraZeneca group of companies.SafetyGlideTM is a trade mark of Becton Dickinson and CompanyAstraZeneca Medical Information Freephone 0800 783 003304/2012

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to AstraZeneca on

0800 783 0033