PALOMA-3
MONARCH-2

PALOMA-3: the first phase 3 trial to study FASLODEX (500 mg) in combination with palbociclib (125 mg)1,2

TRIAL SETUP

PALOMA-3

FASLODEX 500 mg was studied in combination with palbociclib 125 mg vs FASLODEX plus placebo,* the control arm, in PALOMA-3, a phase 3, international, randomized, double-blind, parallel-group, multicenter study in women (N=521) with HR-positive, HER2-negative ABC or mBC, regardless of their menopausal status, whose disease progressed on or after prior endocrine therapy.1,2

Patients were randomized 2:1 to FASLODEX plus palbociclib or the control arm, and stratified by documented sensitivity to prior hormonal therapy, menopausal status at study entry (pre-/peri- vs postmenopausal), and presence of visceral metastases.1

The primary endpoint was investigator-assessed PFS, evaluated according to RECIST v.1.1.1

Prior therapy in PALOMA-3

  • All patients received prior systemic therapy1
  • 75% of patients received a previous chemotherapy regimen, 34% of which was in the metastatic setting.1,2 Patients were permitted to have 1 prior line of chemotherapy for advanced disease and/or multiple lines of prior endocrine therapy2

ABC=advanced breast cancer; HER2=human epidermal growth factor receptor 2; HR=hormone receptor; mBC=metastatic breast cancer; PFS=progression-free survival; RECIST=Response Evaluation Criteria in Solid Tumors.

*Patients in both arms received FASLODEX 500 mg by intramuscular injection on Days 1, 15, and 29 of the first month, and every 28 (± 3) days thereafter, and either oral palbociclib 125 mg or placebo for 21 consecutive days followed by 7 days off treatment.1

Women who were either premenopausal (meaning that they had not reached menopause) or perimenopausal (meaning that their bodies were approaching menopause) were therapeutically induced to become postmenopausal and represented 20.7% of the study population.1-4

Indication for FASLODEX

Combination Therapy

  • FASLODEX in combination with palbociclib or abemaciclib is indicated for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in women with disease progression after endocrine therapy

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National Comprehensive Cancer Network® (NCCN®) recommends fulvestrant (FASLODEX) in combination with palbociclib

X

NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) recommend the use of fulvestrant (FASLODEX) in combination with palbociclib as a Category 1 option for postmenopausal women with HR-positive, HER2-negative mBC that progressed on endocrine therapy.5,‡

LHRH=luteinizing hormone-releasing hormone; NCCN=National Comprehensive Cancer Network® (NCCN®).

NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

For postmenopausal women or for premenopausal women receiving ovarian suppression with an LHRH agonist.5

EFFICACY

FASLODEX in combination with palbociclib significantly increased PFS vs the control arm: median 9.5 months vs 4.6, respectively1

FASLODEX® (fulvestrant) Injection Increase in PFS

Confirmed overall response rate in patients with measurable disease: 24.6% for the FASLODEX plus palbociclib arm (n=347) and 10.9% for the control arm (n=174)1

  • Duration of response was 9.3 months in the FASLODEX plus palbociclib arm and 7.6 months in the FASLODEX plus placebo arm1

FASLODEX in combination with palbociclib showed consistent results across select subgroups1,2

PALOMA-3 Trial Patient Population
  • This representation was not designed to assess efficacy in individual subgroups

National Comprehensive Cancer Network® (NCCN®) recommends fulvestrant (FASLODEX) in combination with palbociclib

    The NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) recommend the use of fulvestrant (FASLODEX) in combination with palbociclib as a Category 1 option for women with HR-positive, HER2-negative mBC that progressed on endocrine therapy.6

NCCN=National Comprehensive Cancer Network® (NCCN®).

NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

PALOMA-3 PATIENT POPULATION

Multiple types of patients with HR-positive, HER2-negative ABC were studied in PALOMA-31,6

In the PALOMA-3 Trial:

Number of prior treatments for metastatic disease
  • Approximately 25% of patients in the FASLODEX plus palbociclib arm (n=347) received this regimen as their first therapy for metastatic disease6
  • Approximately 75% of patients in the FASLODEX plus palbociclib arm received this regimen as their second or later therapy for metastatic disease6

A majority (66.6%) had more than 1 metastatic site, with levels of disease from bone-only to visceral involvement1,2

PALOMA-3 Trial Metastatic Breast Cancer Disease Sites
PALOMA-3 Trial Metastatic Breast Cancer Disease Sites

||Per protocol, visceral refers to lung, liver, brain, pleural, and peritoneal involvement, and was a study stratification factor.2

Eastern Cooperative Oncology Group (ECOG) performance status requirement: 0 or 11,2

Eastern Cooperative Oncology Group (ECOG) Performance Status

A majority were under 65 years of age1,6

PALOMA-3 Trial Median Age Range

SAFETY

Safety profile in PALOMA-31

FASLODEX® (fulvestrant) Injection Combo Therapy Side Effects

Grading according to Common Terminology Criteria for Adverse Events 4.0.

N/A=not applicable.

*Most common infections (>1%) include: nasopharyngitis, upper respiratory infection, urinary tract infection, influenza, bronchitis, rhinitis, conjunctivitis, pneumonia, sinusitis, cystitis, oral herpes, and respiratory tract infection.1

Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, and stomatitis.1

Grade 1 events—17%; Grade 2 events—1%.1

§Grade 1 events—6%.1

||Rash includes: rash, rash maculopapular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, toxic skin eruption.1

  • Permanent discontinuation associated with an adverse reaction occurred in 19 of 345 (6%) patients receiving FASLODEX plus palbociclib and in 6 of 172 (3%) patients within the control arm1
  • Adverse reactions leading to discontinuation for those patients receiving FASLODEX plus palbociclib included fatigue (0.6%), infections (0.6%), and thrombocytopenia (0.6%)1

References: 1. Prescribing Information for FASLODEX. AstraZeneca Pharmaceuticals LP, Wilmington, DE. 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. NCI Dictionary of Cancer Terms: premenopausal. National Cancer Institute website. https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45268. Accessed July 6, 2017. 4. NCI Dictionary of Cancer Terms: perimenopausal. National Cancer Institute website. https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45826. Accessed July 7, 2017. 5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.1.2018. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed April 23, 2018. To view the most recent and complete version of the guideline, go online to NCCN.org. 6. Turner NC, Ro J, André F, et al. Palbociclib in hormone-receptor–positive advanced breast cancer. N Engl J Med. 2015;373(3):209-219.

MONARCH 2: FASLODEX 500 mg in combination with abemaciclib 150 mg in patients with disease progression in the neoadjuvant, adjuvant, or early-line metastatic setting1,2,*

TRIAL SETUP

MONARCH 2

FASLODEX 500 mg was studied in combination with abemaciclib 150 mg vs FASLODEX plus placebo,* the control arm, in MONARCH 2, a phase 3, randomized, double-blind, placebo-controlled, multicenter, international study in 669 women of any menopausal status with HR-positive, HER2-negative advanced breast cancer (ABC) or mBC that progressed while receiving prior endocrine therapy in the neoadjuvant, adjuvant, or early-line metastatic setting.1,2,‡

Patients were randomized 2:1 to FASLODEX plus abemaciclib or the control arm, and stratified according to 2 factors1,2:

MONARCH 2 Trial Metastatic Breast Cancer Disease Sites

The primary endpoint was investigator-assessed PFS.2

Eastern Cooperative Oncology Group (ECOG) status for patients

FASLODEX with or without abemaciclib was the first endocrine therapy received by a majority of patients (59.2%) for ABC2

PALOMA-3 Trial Metastatic Breast Cancer Disease Sites

CDK4/6i=cyclin-dependent kinase 4/6 inhibitor; ECOG=Eastern Cooperative Oncology Group; HER2=human epidermal growth factor receptor 2; HR=hormone receptor; mBC=metastatic breast cancer; PFS=progression-free survival; RECIST=Response Evaluation Criteria in Solid Tumors.

*Patients in both arms received FASLODEX 500 mg by intramuscular injection on Days 1 and 15 of the first cycle, and on Day 1 of subsequent cycles (every 28 days), and either oral abemaciclib 150 mg or placebo twice daily during each 28-day cycle.1,2

Pre- or perimenopausal women received a gonadotropin-releasing hormone agonist prior to treatment.2

Patients were permitted to have had only 1 prior endocrine therapy for ABC and no prior chemotherapy.2

§Primary endocrine resistance includes patients whose disease relapsed while receiving the first 2 years of neoadjuvant or adjuvant endocrine therapy or progressed while receiving the first 6 months of endocrine therapy for ABC.2

||Secondary endocrine resistance includes patients who were not considered to have primary endocrine therapy resistance.2

Indication for FASLODEX

Combination Therapy

  • FASLODEX in combination with palbociclib or abemaciclib is indicated for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in women with disease progression after endocrine therapy

Up

EXPANDED NATIONAL COMPREHENSIVE CANCER NETWORK® (NCCN®) RECOMMENDATIONS

X

NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) recommend the use of fulvestrant (FASLODEX) in combination with abemaciclib as a Category 1 option for postmenopausal women with HR-positive, HER2-negative mBC that progressed on endocrine therapy.3,¶

LHRH=luteinizing hormone-releasing hormone; NCCN=National Comprehensive Cancer Network® (NCCN®).

NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

For postmenopausal women or for premenopausal women receiving ovarian suppression with an LHRH agonist.3

EFFICACY

FASLODEX in combination with abemaciclib improved median PFS by 76%: 16.4 months vs 9.3 in the control arm1

FASLODEX® (fulvestrant) Injection Increase in PFS

Early separation between the curves was observed within 2 months of treatment initiation and continued throughout study assessment.1

  • Investigator-assessed PFS was the primary endpoint of the MONARCH 2 Trial2
  • Objective response rate* in patients with measurable disease more than doubled in the FASLODEX plus abemaciclib arm (n=318): 48.1% (95% CI: 42.6%-53.6%) and 21.3% (95% CI: 15.1%-27.6%) in the control arm (n=164)1
    • In the FASLODEX plus abemaciclib arm, complete response was observed in 14 patients (3.1%) and partial response in 143 patients (32.1%). For the control arm, complete and partial responses were observed in 1 patient (0.4%) and 35 patients (15.7%), respectively2

*Objective response rate: Complete response + partial response.

FASLODEX in combination with abemaciclib demonstrated consistent superiority compared with the control arm across patient subgroups2

MONARCH 2 Trial Patient Population
  • This representation was not designed to assess efficacy in individual subgroups

PgR=progesterone receptor.

MONARCH 2 PATIENT POPULATION

Nearly all patients in MONARCH 2 had disease progression on neoadjuvant endocrine therapy, shortly after adjuvant endocrine therapy, or while receiving endocrine therapy for ABC2

Patients developed primary or secondary endocrine therapy resistance during or after previous endocrine therapy.
  • 25.2% displayed primary endocrine therapy resistance
  • 73.1% displayed secondary endocrine therapy resistance

All patients had an ECOG performance status of 0 or 12

Eastern Cooperative Oncology Group (ECOG) status for patients

The majority of patients were white (56%) and 31.9% were Asian1,2

The majority of patients (72%) had measurable disease2

The median age of patients was 601,2

Median age for patients was 60 in MONARCH 2 Trial.

Patients with visceral metastases and patients with bone-only metastases were represented1

In MONARCH 2 Trial patients with visceral metastases and patients with bone-only metastases were represented.

A majority of patients in both arms had disease progression in the neoadjuvant or adjuvant setting on or after prior aromatase inhibition or chemotherapy2

Prior Aromatase Inhibition and Prior Chemotherapy

Nearly all patients in MONARCH 2 had disease progression on neoadjuvant endocrine therapy, shortly after adjuvant endocrine therapy, or while receiving endocrine therapy for ABC2

Patients developed primary or secondary endocrine therapy resistance during or after previous endocrine therapy.
  • 25.2% displayed primary endocrine therapy resistance
  • 73.1% displayed secondary endocrine therapy resistance

Patients with visceral metastases and patients with bone-only metastases were represented1

In MONARCH 2 Trial patients with visceral metastases and patients with bone-only metastases were represented.

All patients had an ECOG performance status of 0 or 12

Eastern Cooperative Oncology Group (ECOG) status for patients

A majority of patients in both arms had disease progression in the neoadjuvant or adjuvant setting on or after prior aromatase inhibition or chemotherapy2

Prior Aromatase Inhibition and Prior Chemotherapy

The majority of patients were white (56%) and 31.9% were Asian1,2

The majority of patients (72%) had measurable disease2

The median age of patients was 601,2

Median age for patients was 60 in MONARCH 2 Trial.

SAFETY

Safety profile in MONARCH 21

FASLODEX® (fulvestrant) Injection with abemaciclib Combo Therapy Side Effects
  • The most frequent adverse reactions of any grade in the safety population (FASLODEX plus abemaciclib [n=441]; control arm [n=223]) were diarrhea, neutropenia, nausea, fatigue, and abdominal pain. These predominantly occurred at Grades 1 or 22
  • Grade 1 or 2 diarrhea occurred in 322 patients (73.0%) in the FASLODEX plus abemaciclib arm vs 54 patients (24.2%) in the control arm. Grade 3 diarrhea occurred in 59 patients (13.4%) in the FASLODEX plus abemaciclib arm vs 1 patient (0.4%) in the control arm2
  • Serious adverse reactions were reported in 22.4% of patients in the FASLODEX plus abemaciclib arm and 10.8% of patients in the control arm2
  • Venous thromboembolic events (deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, subclavian vein thrombosis, and deep vein thrombosis inferior vena cava) were reported in 5% of patients treated with FASLODEX plus abemaciclib as compared to 0.9% of patients in the control arm.1 Of the patients in the former arm, 4 experienced pulmonary embolism, none of which resulted in death2

References: 1. Prescribing Information for FASLODEX. AstraZeneca Pharmaceuticals LP, Wilmington, DE. 2. Sledge GW Jr, 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):2875-2884. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.1.2018. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed April 23, 2018. To view the most recent and complete version of the guideline, go online to NCCN.org.

Laboratory abnormalities in MONARCH 21

FASLODEX® (fulvestrant) Injection with abemaciclib Combo Therapy Side Effects

*Includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness.1

Includes upper respiratory tract infection, urinary tract infection, lung infection, pharyngitis, conjunctivitis, sinusitis, vaginal infection, sepsis.1

Includes neutropenia, neutrophil count decreased.1

§Includes anemia, hematocrit decreased, hemoglobin decreased, red blood cell count decreased.1

||Includes leukopenia, white blood cell count decreased.1

Includes platelet count decreased, thrombocytopenia.1

#Includes asthenia, fatigue.1

References: 1. Prescribing Information for FASLODEX. AstraZeneca Pharmaceuticals LP, Wilmington, DE. 2. Sledge GW Jr, 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):2875-2884. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.1.2018. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed April 23, 2018. To view the most recent and complete version of the guideline, go online to NCCN.org.

Important Safety Information About FASLODEX

Contraindications

  • FASLODEX is contraindicated in patients with known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema, have been reported in association with FASLODEX

Risk of Bleeding

  • Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use

Hepatic Impairment

  • FASLODEX is metabolized primarily in the liver. A 250 mg dose is recommended in patients with moderate hepatic impairment (Child-Pugh class B). FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C)

Injection Site Reaction

  • Use caution while administering FASLODEX at the dorsogluteal injection site due to the proximity of the underlying sciatic nerve. Injection site–related events, including sciatica, neuralgia, neuropathic pain, and peripheral neuropathy, have been reported with FASLODEX injection

Embryo-Fetal Toxicity and Lactation

  • Advise pregnant women of the potential risk to a fetus. Advise women of reproductive potential to use effective contraception during FASLODEX treatment and for 1 year after the final dose. Advise lactating women not to breastfeed during treatment with FASLODEX and for 1 year after the final dose because of the potential risk to the infant

Immunoassay Measurement of Serum Estradiol

  • Due to structural similarity of fulvestrant and estradiol, FASLODEX can interfere with estradiol measurement by immunoassay, resulting in falsely elevated estradiol levels

Adverse Reactions

Monotherapy

  • The most common adverse reactions occurring in ≥5% of patients receiving FASLODEX 500 mg were injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot flash, myalgia, vomiting, anorexia, diarrhea, asthenia, musculoskeletal pain, cough, dyspnea, and constipation
  • Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of FASLODEX patients and were not dose-dependent

Combination Therapy—FASLODEX plus palbociclib

  • The most frequently reported serious adverse reactions in patients receiving FASLODEX plus palbociclib were infections (3%), pyrexia (1%), neutropenia (1%), and pulmonary embolism (1%)
  • The most common adverse reactions (≥10%) of any grade reported in patients receiving FASLODEX 500 mg plus palbociclib 125 mg/day were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea, thrombocytopenia, constipation, vomiting, alopecia, rash, decreased appetite, and pyrexia

Combination Therapy—FASLODEX plus abemaciclib

  • The most frequently reported (≥5%) Grade 3 or 4 adverse reactions in patients receiving FASLODEX plus abemaciclib were neutropenia, diarrhea, leukopenia, anemia, and infections
  • The most common adverse reactions (≥20%) of any grade reported in patients receiving FASLODEX 500 mg plus abemaciclib 150 mg twice daily were diarrhea, fatigue, neutropenia, nausea, infections, abdominal pain, anemia, leukopenia, decreased appetite, vomiting, and headache

Indications for FASLODEX

Monotherapy

FASLODEX is an estrogen receptor antagonist indicated for the:

  • Treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in postmenopausal women not previously treated with endocrine therapy
  • Treatment of HR-positive advanced breast cancer in postmenopausal women with disease progression following endocrine therapy

Combination Therapy

  • FASLODEX in combination with palbociclib or abemaciclib is indicated for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in women with disease progression after endocrine therapy

Please see full Prescribing Information for FASLODEX with Patient Information.

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