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For women with HR+, HER2− MBC who have concerning clinical characteristics, and for whom fulvestrant is the next step1-5

Patient: PamPatient: Pam

Pam*

Married, mother of 3,
accountant

Age: 58

Metastatic sites: Lung & bone

Treatment history: Recurred after 22 months of initiating adjuvant endocrine therapy

Patient: BarbaraPatient: Barbara

Barbara*

Married, mother of 2,
grandmother of 6,
retired school teacher

Age: 64

Metastatic site: Liver

Treatment history: Progressed after 5 months of initiating first-line metastatic therapy with a single-agent AI

*Hypothetical patient profile.

AI=aromatase inhibitor.

MONARCH 2: A study of Verzenio + fulvestrant vs placebo + fulvestrant in HR+, HER2− MBC1

Patients recurred or progressed while on endocrine therapy in the adjuvant or metastatic setting6

A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL1,6,7
MONARCH 2 Trial DesignMONARCH 2 Trial Design

Before a study amendment changed the starting dose to 150 mg, 121 of the 446 ITT patients (27%) initially received a 200-mg starting dose. Median duration for 200-mg dosing was 34 days.6

In MONARCH 2, the median patient age was 60 years (range, 32 to 91 years). Twenty percent of patients had de novo metastatic disease, 27% had bone-only disease, and 56% had visceral disease. Twenty-five percent of patients had primary endocrine therapy resistance.

*Pre/perimenopausal women were enrolled in the study and received the gonadotropin-releasing hormone agonist goserelin for at least 4 weeks prior to and for the duration of MONARCH 2.1

Each cycle was 28 days.6

§Primary resistance is defined as relapse while on the first 2 years of adjuvant endocrine therapy, or progressive disease within the first 6 months of first-line endocrine therapy for metastatic breast cancer.1

BID=twice a day; CDK4 & 6=cyclin-dependent kinases 4 and 6; ECOG PS=Eastern Cooperative Oncology Group Performance Status; IM=intramuscular; ITT=intent-to-treat; PO=orally.

For patients with HR+, HER2− MBC

>16-month PFS in patients who recurred or progressed on endocrine therapy1

The percentage of events at the time of analysis was 49.8% (n=222) and 70.4% (n=157) in the Verzenio + fulvestrant and placebo + fulvestrant arms, respectively.1

MEDIAN PFS1,6
Consistent PFS in MONARCH 2Consistent PFS in MONARCH 2

CI=confidence interval; HR=hazard ratio.

For patients with HR+, HER2− MBC

PFS with Verzenio + fulvestrant was consistent across subgroups, including those with concerning clinical characteristics1-4,6,8

PFS: PRIMARY AND SUBGROUP ANALYSIS1,6*
Consistent PFS Across Subgroups in MONARCH 2Consistent PFS Across Subgroups in MONARCH 2
  • Primary resistance is defined as relapse while on the first 2 years of adjuvant endocrine therapy, or progressive disease within the first 6 months of first-line endocrine therapy for MBC1

*Preplanned subgroup analyses of PFS were performed for stratification factors of disease site, endocrine resistance, and other potential prognostic factors that included measurable disease at baseline, number of organs involved, age, region, race, PgR status, and baseline ECOG PS. Estimated hazard ratios and CIs for the within subgroup preplanned analyses and for menopausal status are represented as a forest plot. The analyses were not adjusted for multiplicity and the study was not powered to test effect of Verzenio + fulvestrant among subgroups.6

Includes breast, lymph nodes, skin, soft tissue, and CNS (not including brain metastases).9

CNS=central nervous system; ET=endocrine therapy; PgR=progesterone receptor.

For patients with HR+, HER2− MBC

48.1% ORR in patients who recurred or progressed on endocrine therapy1

ORR IN PATIENTS WITH MEASURABLE DISEASE1,6
MONARCH 2 ORR: 48.1%MONARCH 2 ORR: 48.1%
  • ORR was defined as the proportion of patients with CR + PR and does not include stable disease1,10
  • Verzenio + fulvestrant arm: PR* (n=142), CR (n=11)6
  • Placebo + fulvestrant arm: all responses were PR6

Median duration of response not yet reached at the time of analysis with Verzenio + fulvestrant (95% CI: 18.1-NR) vs 25.6 months with placebo + fulvestrant (95% CI: 11.9-25.6)6,11§

PR defined as ≥30% reduction in target lesion size per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).10

§Of 157 patients with an objective response in the Verzenio + fulvestrant arm, 57.3% (n=90) were still on treatment at the time of the analysis.6,11

CR=complete response; NR=not reached; PR=partial response.

For heavily pretreated patients with HR+, HER2– MBC

MONARCH 1: The first and only CDK4 & 6 inhibitor approved as a single agent1

A separate, phase II, single-arm trial

MONARCH 1 Trial DesignMONARCH 1 Trial Design

Patients were heavily pretreated with a high disease burden1*

MONARCH 1 Disease BurdenMONARCH 1 Disease Burden

*Per RECIST 1.1, target lesion(s) are defined by 1 to 5 measurable lesions (a maximum of 2 lesions per organ) present at baseline that are representative of all involved organs.10

Objective response (CR + PR) must have been confirmed no less than 28 days from first evidence of response; PR defined as ≥30% reduction in target lesion size per RECIST 1.1.10,12

In a study protocol deviation, 1 patient received 3 chemotherapy regimens in the metastatic setting, first receiving capecitabine, followed by 2 regimens of docetaxel separated by a treatment-free interval of >1 year.12,13

19.7% of patients achieved an objective response1*†‡

MONARCH 1 ORR: 19.7%

(95% Cl: 13.3-27.5) per investigator assessment1

ORR was defined as the proportion of patients with CR or PR, and does not include stable disease10,12§

8.6-month median DoR (mDoR)1

dor-chart
dor-chart-m

*Per RECIST 1.1, target lesion(s) are defined by 1 to 5 measurable lesions (a maximum of 2 lesions per organ) present at baseline that are representative of all involved organs.10

Additional criteria apply, including absence of progression of nontarget lesions and no new lesions.10

Assessments by independent review yielded comparable rates and estimates.12

§Objective response (CR + PR) must have been confirmed no less than 28 days from first evidence of response; PR defined as ≥30% reduction in target lesion size per RECIST 1.1.10,12

References: 1. Verzenio [package insert]. Indianapolis, IN: Eli Lilly and Company; 2017. 2. Imkampe A, Bendall S, Bates T. The significance of the site of recurrence to subsequent breast cancer survival. Eur J Surg Oncol. 2007;33:420-423. 3. Largillier R, Ferrero JM, Doyen J, et al. Prognostic factors in 1038 women with metastatic breast cancer. Ann Oncol. 2008;19:2012-2019. 4. Cardoso F, Costa A, Senkus E, et al. 3rd ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 3). Breast. 2017;31:244-259. 5. Data on file. Lilly USA, LLC. ONC20170823a. 6. Sledge GW Jr, Masakazu T, 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;35:2875-2884. 7. ClinicalTrials.gov. A study of abemaciclib (LY2835219) combined with fulvestrant in women with hormone receptor positive HER2 negative breast cancer (MONARCH 2). https://clinicaltrials.gov/ct2/show/NCT02107703. Updated June 14, 2017. Accessed June 19, 2017. 8. Dunnwald LK, Rossing MA, Li CI. Hormone receptor status, tumor characteristics, and prognosis: a prospective cohort of breast cancer patients. Breast Cancer Res. 2007;9:R6. 9. Data on file. Lilly USA, LLC. ONC20170608a. 10. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247. 11. Data on file. Lilly USA, LLC. ONC20170608b. 12. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1, a phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2− metastatic breast cancer. Clin Cancer Res. 2017;23:5218-5224. 13. Data on file. Lilly USA, LLC. ONC20170111b.

Indication

Verzenio is indicated for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2−negative (HER2−) advanced or metastatic breast cancer (MBC):

  • In combination with fulvestrant for women with disease progression following endocrine therapy
  • In combination with an aromatase inhibitor (AI) for postmenopausal women as initial endocrine−based therapy
  • As a single agent for adult patients with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting

Important Safety Information

Diarrhea occurred in 81% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 86% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and 90% of patients receiving Verzenio alone in MONARCH 1. Grade 3 diarrhea occurred in 9% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 13% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and in 20% of patients receiving Verzenio alone in MONARCH 1. Episodes of diarrhea have been associated with dehydration and infection.

Diarrhea incidence was greatest during the first month of Verzenio dosing. In MONARCH 3, the median time to onset of the first diarrhea event was 8 days, and the median duration of diarrhea for Grades 2 and 3 were 11 and 8 days, respectively. In MONARCH 2, the median time to onset of the first diarrhea event was 6 days, and the median duration of diarrhea for Grades 2 and 3 were 9 days and 6 days, respectively. In MONARCH 3, 19% of patients with diarrhea required a dose omission and 13% required a dose reduction. In MONARCH 2, 22% of patients with diarrhea required a dose omission and 22% required a dose reduction. The time to onset and resolution for diarrhea were similar across MONARCH 3, MONARCH 2, and MONARCH 1.

Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy such as loperamide, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow-up. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue Verzenio until toxicity resolves to ≤Grade 1, and then resume Verzenio at the next lower dose.

Neutropenia occurred in 41% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 46% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and 37% of patients receiving Verzenio alone in MONARCH 1. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 22% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 32% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and in 27% of patients receiving Verzenio alone in MONARCH 1. In MONARCH 3, the median time to first episode of Grade ≥3 neutropenia was 33 days, and in MONARCH 2 and MONARCH 1, was 29 days. In MONARCH 3, median duration of Grade ≥3 neutropenia was 11 days, and for MONARCH 2 and MONARCH 1 was 15 days.

Monitor complete blood counts prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Febrile neutropenia has been reported in <1% of patients exposed to Verzenio in the MONARCH studies. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider.

Grade ≥3 increases in alanine aminotransferase (ALT) (6% versus 2%) and aspartate aminotransferase (AST) (3% versus 1%) were reported in the Verzenio and placebo arms, respectively, in MONARCH 3. Grade ≥3 increases in ALT (4% versus 2%) and AST (2% versus 3%) were reported in the Verzenio and placebo arms respectively, in MONARCH 2.

In MONARCH 3, for patients receiving Verzenio plus an aromatase inhibitor with Grade ≥3 increases in ALT or AST, median time to onset was 61 and 71 days, respectively, and median time to resolution to Grade <3 was 14 and 15 days, respectively. In MONARCH 2, for patients receiving Verzenio plus fulvestrant with Grade ≥3 increases in ALT or AST, median time to onset was 57 and 185 days, respectively, and median time to resolution to Grade <3 was 14 and 13 days, respectively.

For assessment of potential hepatotoxicity, monitor liver function tests (LFTs) prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or Grade 3 or 4, hepatic transaminase elevation.

Venous thromboembolic events were reported in 5% of patients treated with Verzenio plus an aromatase inhibitor as compared to 0.6% of patients treated with an aromatase inhibitor plus placebo in MONARCH 3. Venous thromboembolic events were reported in 5% of patients treated with Verzenio plus fulvestrant in MONARCH 2 as compared to 0.9% of patients treated with fulvestrant plus placebo. Venous thromboembolic events included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis. Across the clinical development program, deaths due to venous thromboembolism have been reported. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate.

Verzenio can cause fetal harm when administered to a pregnant woman based on findings from animal studies and the mechanism of action. In animal reproduction studies, administration of abemaciclib to pregnant rats during the period of organogenesis caused teratogenicity and decreased fetal weight at maternal exposures that were similar to the human clinical exposure based on area under the curve (AUC) at the maximum recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Verzenio and for at least 3 weeks after the last dose. There are no data on the presence of Verzenio in human milk or its effects on the breastfed child or on milk production. Advise lactating women not to breastfeed during Verzenio treatment and for at least 3 weeks after the last dose because of the potential for serious adverse reactions in breastfed infants. Based on findings in animals, Verzenio may impair fertility in males of reproductive potential.

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 3 for Verzenio plus anastrozole or letrozole and ≥2% higher than placebo plus anastrozole or letrozole vs placebo plus anastrozole or letrozole were diarrhea (81% vs 30%), neutropenia (41% vs 2%), fatigue (40% vs 32%), infections (39% vs 29%), nausea (39% vs 20%), abdominal pain (29% vs 12%), vomiting (28% vs 12%), anemia (28% vs 5%), alopecia (27% vs 11%), decreased appetite (24% vs 9%), leukopenia (21% vs 2%), creatinine increased (19% vs 4%), constipation (16% vs 12%), ALT increased (16% vs 7%), AST increased (15% vs 7%), rash (14% vs 5%), pruritus (13% vs 9%), cough (13% vs 9%), dyspnea (12% vs 6%), dizziness (11% vs 9%), weight decreased (10% vs 3%), influenza-like illness (10% vs 8%), and thrombocytopenia (10% vs 2%).

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 2 for Verzenio plus fulvestrant and ≥2% higher than placebo plus fulvestrant vs placebo plus fulvestrant were diarrhea (86% vs 25%), neutropenia (46% vs 4%), fatigue (46% vs 32%), nausea (45% vs 23%), infections (43% vs 25%), abdominal pain (35% vs 16%), anemia (29% vs 4%), leukopenia (28% vs 2%), decreased appetite (27% vs 12%), vomiting (26% vs 10%), headache (20% vs 15%), dysgeusia (18% vs 3%), thrombocytopenia (16% vs 3%), alopecia (16% vs 2%), stomatitis (15% vs 10%), ALT increased (13% vs 5%), pruritus (13% vs 6%), cough (13% vs 11%), dizziness (12% vs 6%), AST increased (12% vs 7%), peripheral edema (12% vs 7%), creatinine increased (12% vs <1%), rash (11% vs 4%), pyrexia (11% vs 6%), and weight decreased (10% vs 2%).

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 1 with Verzenio were diarrhea (90%), fatigue (65%), nausea (64%), decreased appetite (45%), abdominal pain (39%), neutropenia (37%), vomiting (35%), infections (31%), anemia (25%), thrombocytopenia (20%), headache (20%), cough (19%), leukopenia (17%), constipation (17%), arthralgia (15%), dry mouth (14%), weight decreased (14%), stomatitis (14%), creatinine increased (13%), alopecia (12%), dysgeusia (12%), pyrexia (11%), dizziness (11%), and dehydration (10%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 3 were neutropenia (22% vs 2%), diarrhea (9% vs 1%), leukopenia (8% vs <1%), ALT increased (7% vs 2%), and anemia (6% vs 1%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 2 were neutropenia (27% vs 2%), diarrhea (13% vs <1%), leukopenia (9% vs 0%), anemia (7% vs 1%), and infections (6% vs 3%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions from MONARCH 1 with Verzenio were neutropenia (24%), diarrhea (20%), fatigue (13%), infections (7%), leukopenia (6%), anemia (5%), and nausea (5%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 3 in ≥10% for Verzenio plus anastrozole or letrozole and ≥2% higher than placebo plus anastrozole or letrozole vs placebo plus anastrozole or letrozole were increased serum creatinine (98% vs 84%; 2% vs 0%), decreased white blood cells (82% vs 27%; 13% vs <1%), anemia (82% vs 28%; 2% vs 0%), decreased neutrophil count (80% vs 21%; 22% vs 3%), decreased lymphocyte count (53% vs 26%; 8% vs 2%), decreased platelet count (36% vs 12%; 2% vs <1%), increased ALT (48% vs 25%; 7% vs 2%), and increased AST (37% vs 23%; 4% vs <1%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 2 in ≥10% for Verzenio plus fulvestrant and ≥2% higher than placebo plus fulvestrant vs placebo plus fulvestrant were increased serum creatinine (98% vs 74%; 1% vs 0%), decreased white blood cells (90% vs 33%; 23% vs 1%), decreased neutrophil count (87% vs 30%; 33% vs 4%), anemia (84% vs 33%; 3% vs <1%), decreased lymphocyte count (63% vs 32%; 12% vs 2%), decreased platelet count (53% vs 15%; 2% vs 0%), increased ALT (41% vs 32%; 5% vs 1%), and increased AST (37% vs 25%; 4% vs 4%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 1 with Verzenio were increased serum creatinine (98%; <1%), decreased white blood cells (91%; 28%), decreased neutrophil count (88%; 27%), anemia (68%; 0%), decreased lymphocyte count (42%; 14%), decreased platelet count (41%; 2%), increased ALT (31%; 3%), and increased AST (30%; 4%).

Strong CYP3A inhibitors increased the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity. Avoid concomitant use of ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold. In patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the Verzenio dose to 100 mg twice daily with concomitant use of other strong CYP3A inhibitors. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the Verzenio dose to 50 mg twice daily with concomitant use of other strong CYP3A inhibitors. If a patient taking Verzenio discontinues a strong CYP3A inhibitor, increase the Verzenio dose (after 3 to 5 half-lives of the inhibitor) to the dose that was used before starting the strong inhibitor. Patients should avoid grapefruit products.

Avoid concomitant use of strong CYP3A inducers and consider alternative agents. Coadministration of Verzenio with rifampin, a strong CYP3A inducer, decreased the plasma concentrations of abemaciclib plus its active metabolites and may lead to reduced activity.

With severe hepatic impairment (Child-Pugh Class C), reduce the Verzenio dosing frequency to once daily. The pharmacokinetics of Verzenio in patients with severe renal impairment (CLcr <30 mL/min), end stage renal disease, or in patients on dialysis is unknown. No dosage adjustments are necessary in patients with mild or moderate hepatic (Child-Pugh A or B) and/or renal impairment (CLcr ≥30-89 mL/min).

Please see full Prescribing.Information for Verzenio.

AL HCP ISI 26FEB2018