VERZENIOS 100mg film-coated tablets medication leaflet

Verzenios 50 mg film-coated tablets

Verzenios 100 mg film-coated tablets

Verzenios 150 mg film-coated tablets

Verzenios 50 mg film-coated tablets

Each film-coated tablet contains 50 mg abemaciclib.

Each film-coated tablet contains 14 mg of lactose monohydrate.

Verzenios 100 mg film-coated tablets

Each film-coated tablet contains 100 mg abemaciclib.

Each film-coated tablet contains 28 mg of lactose monohydrate.

Verzenios 150 mg film-coated tablets

Each film-coated tablet contains 150 mg abemaciclib.

Each film-coated tablet contains 42 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Verzenios 50 mg film-coated tablets

Beige, oval tablet of 5.2 x 9.5 mm, debossed with “Lilly” on one side and “50” on the other.

Verzenios 100 mg film-coated tablets

White, oval tablet of 6.6 x 12.0 mm, debossed with “Lilly” on one side and “100” on the other.

Verzenios 150 mg film-coated tablets

Yellow, oval tablet of 7.5 x 13.7 mm, debossed with “Lilly” on one side and “150” on the other.

Early breast cancer

Verzenios in combination with endocrine therapy is indicated for the adjuvant treatment of adultpatients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2(HER2)-negative, node-positive early breast cancer at high risk of recurrence (see section 5.1).

In pre- or perimenopausal women, aromatase inhibitor endocrine therapy should be combined with aluteinising hormone-releasing hormone (LHRH) agonist.

Advanced or metastatic breast cancer

Verzenios is indicated for the treatment of women with hormone receptor (HR)-positive, humanepidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer incombination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy, or in womenwho have received prior endocrine therapy.

In pre- or perimenopausal women, the endocrine therapy should be combined with a LHRH agonist.

Verzenios therapy should be initiated and supervised by physicians experienced in the use ofanti-cancer therapies.

The recommended dose of abemaciclib is 150 mg twice daily when used in combination withendocrine therapy. Please refer to the summary of product characteristics of the endocrine therapycombination partner for the recommended posology.

Early breast cancer

Verzenios should be taken continuously for two years, or until disease recurrence or unacceptabletoxicity occurs.

Advanced or metastatic breast cancer

Verzenios should be taken continuously as long as the patient is deriving clinical benefit from therapyor until unacceptable toxicity occurs.

If a patient vomits or misses a dose of Verzenios, the patient should be instructed to take the next doseat its scheduled time; an additional dose should not be taken.

Management of some adverse reactions may require dose interruption and/or dose reduction as shownin Tables 1-7.

Table 1. Dose adjustment recommendations for adverse reactions

Verzenios dosecombination therapy

Recommended dose 150 mg twice daily

First dose adjustment 100 mg twice daily

Second dose adjustment 50 mg twice daily

Table 2. Management recommendations for haematologic toxicities

Complete blood counts should be monitored prior to the start of Verzenios therapy, every two weeksfor the first two months, monthly for the next two months, and as clinically indicated. Beforetreatment initiation, absolute neutrophil counts (ANC) ≥ 1 500/mm3, platelets ≥ 1 00 000/mm3, andhaemoglobin ≥ 8 g/dL are recommended.

Toxicitya, b Management recommendations

Grade 1 or 2 No dose adjustment required.

Grade 3 Suspend dose until toxicity resolves to Grade 2 or less.

Dose reduction is not required.

Grade 3, recurrent; or Grade 4 Suspend dose until toxicity resolves to Grade 2 or less.

Resume at next lower dose.

Patient requires administration of Suspend abemaciclib dose for at least 48 hours after the lastblood cell growth factors dose of blood cell growth factors was administered and untiltoxicity resolves to Grade 2 or less.

Resume at next lower dose unless the dose was already reducedfor the toxicity that led to the use of the growth factor.a NCI Common Terminology Criteria for Adverse Events (CTCAE)b ANC: Grade 1: ANC < LLN - 1 500/mm3; Grade 2: ANC 1 000 - < 1 500/mm3;

Grade 3: ANC 500 - < 1 000/mm3; Grade 4: ANC < 500/mm3

LLN = lower limit of normal

Table 3. Management recommendations for diarrhoea

Treatment with antidiarrhoeal agents, such as loperamide, should be started at the first sign of loosestools.

Toxicity a Management recommendations

Grade 1 No dose adjustment required.

Grade 2 If toxicity does not resolve within 24 hours to Grade 1 or less,suspend dose until resolution.

Dose reduction is not required.

Grade 2 that persists or recursafter resuming the same dosedespite maximal supportive Suspend dose until toxicity resolves to Grade 1 or less.measures Resume at next lower dose.

Grade 3 or 4 or requireshospitalisationa NCI CTCAE

Table 4. Management recommendations for increased aminotransferases

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be monitored prior tothe start of Verzenios therapy, every two weeks for the first two months, monthly for the next twomonths, and as clinically indicated.

Toxicitya Management recommendations

Grade 1 (> ULN - 3.0 x ULN)

Grade 2 (> 3.0 - 5.0 x ULN) No dose adjustment required.

Persistent or Recurrent Grade 2, Suspend dose until toxicity resolves to baseline or Grade 1.or Grade 3 (> 5.0 - 20.0 x ULN) Resume at next lower dose.

Elevation in AST and/or ALT Discontinue abemaciclib.> 3 x ULN WITH total bilirubin> 2 x ULN, in the absence ofcholestasis

Grade 4 (> 20.0 x ULN) Discontinue abemaciclib.a NCI CTCAE

ULN = upper limit of normal

Table 5. Management recommendations for interstitial lung disease (ILD)/pneumonitis

Toxicitya Management recommendations

Grade 1 or 2 No dose adjustment required.

Persistent or recurrent Grade 2 Suspend dose until toxicity resolves to baseline or Grade 1.toxicity that does not resolve Resume at next lower dose.with maximal supportivemeasures within 7 days tobaseline or Grade 1

Grade 3 or 4 Discontinue abemaciclib.

a NCI CTCAE

Table 6. Management recommendations for venous thromboembolic events (VTEs)

Toxicitya Management recommendations

Early breast cancer

All Grades (1, 2, 3, or 4) Suspend dose and treat as clinically indicated. Abemaciclib maybe resumed when the patient is clinically stable.

Advanced or metastatic breastcancer

Grade 1 or 2 No dose modification is required.

Grade 3 or 4 Suspend dose and treat as clinically indicated. Abemaciclib maybe resumed when the patient is clinically stable.a NCI CTCAE

Table 7. Management recommendations for non-haematologic toxicities (excluding diarrhoea,increased aminotransferases, and ILD/pneumonitis and VTEs)

Toxicity a Management recommendations

Grade 1 or 2 No dose adjustment required.

Persistent or recurrent Grade 2toxicity that does not resolvewith maximal supportive Suspend dose until toxicity resolves to Grade 1 or less.

measures to baseline or Grade 1 Resume at next lower dose.within 7 days

Grade 3 or 4a NCI CTCAE

Concomitant use of strong CYP3A4 inhibitors should be avoided. If strong CYP3A4 inhibitors cannotbe avoided, the abemaciclib dose should be reduced to 100 mg twice daily.

In patients who have had their dose reduced to 100 mg abemaciclib twice daily and in whomco-administration of a strong CYP3A4 inhibitor cannot be avoided, the abemaciclib dose should befurther reduced to 50 mg twice daily.

In patients who have had their dose reduced to 50 mg abemaciclib twice daily and in whomco-administration of a strong CYP3A4 inhibitor cannot be avoided, the abemaciclib dose may becontinued with close monitoring of signs of toxicity. Alternatively, the abemaciclib dose may bereduced to 50 mg once daily or discontinued.

If the CYP3A4 inhibitor is discontinued, the abemaciclib dose should be increased to the dose usedprior to the initiation of the CYP3A4 inhibitor (after 3 to 5 half-lives of the CYP3A4 inhibitor).

No dose adjustment is required based on age (see section 5.2).

No dose adjustments are necessary in patients with mild or moderate renal impairment. There are nodata regarding abemaciclib administration in patients with severe renal impairment, end stage renaldisease, or in patients on dialysis (see section 5.2). Abemaciclib should be administered with cautionin patients with severe renal impairment, with close monitoring for signs of toxicity.

No dose adjustments are necessary in patients with mild (Child Pugh A) or moderate (Child Pugh B)hepatic impairment. In patients with severe (Child Pugh C) hepatic impairment, a decrease in dosingfrequency to once daily is recommended (see section 5.2).

The safety and efficacy of abemaciclib in children and adolescents aged less than 18 years has notbeen established. No data are available.

Verzenios is for oral use.

The dose can be taken with or without food. It should not be taken with grapefruit or grapefruit juice(see section 4.5).

Patients should take the doses at approximately the same times every day.

The tablet should be swallowed whole (patients should not chew, crush, or split tablets beforeswallowing).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Neutropenia was reported in patients receiving abemaciclib. Dose modification is recommended forpatients who develop Grade 3 or 4 neutropenia (see section 4.2). Fatal events of neutropenic sepsisoccurred in < 1 % of patients with metastatic breast cancer. Patients should be instructed to report anyepisode of fever to their healthcare provider.

Infections/infestations

Infections were reported in patients receiving abemaciclib plus endocrine therapy at a higher rate thanin patients treated with endocrine therapy. Lung infection was reported in patients receivingabemaciclib without concurrent neutropenia. Fatal events occurred in < 1 % of patients with metastaticbreast cancer. Patients should be monitored for signs and symptoms of infection and treated asmedically appropriate.

Venous thromboembolic events were reported in patients treated with abemaciclib plus endocrinetherapy. Patients should be monitored for signs and symptoms of deep vein thrombosis and pulmonaryembolism and treated as medically appropriate. Based on the grade of VTE, abemaciclib may requiredose modification (see section 4.2).

Arterial Thromboembolic Events

A potential increased risk for serious arterial thromboembolic events (ATEs), including ischemicstroke and myocardial infarction, has been observed in metastatic breast cancer studies whenabemaciclib was administered in combination with endocrine therapies. The benefits and risks ofcontinuing abemaciclib in patients who experience a serious ATE should be considered.

Increased aminotransferases

Increases in ALT and AST were reported in patients receiving abemaciclib. Based on the level of ALTor AST elevation, abemaciclib may require dose modification (see section 4.2).

Diarrhoea is the most common adverse reaction. Across clinical studies, median time to onset of thefirst diarrhoea event was approximately 6 to 8 days, and median duration of diarrhoea was 7 to12 days (Grade 2) and 5 to 8 days (Grade 3). Diarrhoea can be associated with dehydration. Patientsshould start treatment with antidiarrhoeal agents such as loperamide at the first sign of loose stools,increase oral fluids and notify their healthcare provider. Dose modification is recommended forpatients who develop ≥ Grade 2 diarrhoea (see section 4.2).

ILD/Pneumonitis

ILD/pneumonitis was reported in patients receiving abemaciclib. Patients should be monitored forpulmonary symptoms indicative of ILD/pneumonitis and treated as medically appropriate. Based onthe grade of ILD/pneumonitis, abemaciclib may require dose modification (see section 4.2).

Permanently discontinue abemaciclib in patients with Grade 3 or 4 ILD/pneumonitis.

Concomitant use of inducers of CYP3A4

Concomitant use of CYP3A4 inducers should be avoided due to the risk of decreased efficacy ofabemaciclib (see section 4.5).

Visceral crisis

There are no data on the efficacy and safety of abemaciclib in patients with visceral crisis.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency orglucose-galactose malabsorption should not take this medicine.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially“sodium-free”.

Effects of other medicinal products on the pharmacokinetics of abemaciclib

Abemaciclib is primarily metabolised by CYP3A4.

Co-administration of abemaciclib with CYP3A4 inhibitors can increase plasma concentrations ofabemaciclib. In patients with advanced and/or metastatic cancer, co-administration of the CYP3A4inhibitor clarithromycin resulted in a 3.4-fold increase in the plasma exposure of abemaciclib and a2.5-fold increase in the combined unbound potency adjusted plasma exposure of abemaciclib and itsactive metabolites.

Use of strong CYP3A4 inhibitors together with abemaciclib should be avoided. If strong CYP3A4inhibitors need to be co-administered, the dose of abemaciclib should be reduced (see section 4.2),followed by careful monitoring of toxicity. Examples of strong CYP3A4 inhibitors include, but notlimited to: clarithromycin, itraconazole, ketoconazole, lopinavir/ritonavir, posaconazole orvoriconazole. Avoid grapefruit or grapefruit juice.

No dose adjustment is necessary for patients treated with moderate or weak CYP3A4 inhibitors. Thereshould, however, be close monitoring for signs of toxicity.

Co-administration of abemaciclib with the strong CYP3A4 inducer rifampicin decreased the plasmaconcentration of abemaciclib by 95 % and unbound potency adjusted plasma concentration ofabemaciclib plus its active metabolites by 77 % based on AUC0-∞. Concomitant use of strong

CYP3A4 inducers (including, but not limited to: carbamazepine, phenytoin, rifampicin and St. John’swort) should be avoided due to the risk of decreased efficacy of abemaciclib.

Effects of abemaciclib on the pharmacokinetics of other medicinal products

Medicinal products that are substrates of transporters

Abemaciclib and its major active metabolites inhibit the renal transporters organic cation transporter 2(OCT2), multidrug and extrusion toxin protein (MATE1), and MATE2-K. In vivo interactions ofabemaciclib with clinically relevant substrates of these transporters, such as dofetilide or creatinine,may occur (see section 4.8). In a clinical drug interaction study with metformin (substrate of OCT2,

MATE1 and 2) co-administered with 400 mg abemaciclib, a small but not clinically relevant increase(37 %) in metformin plasma exposure was observed. This was found to be due to reduced renalsecretion with unaffected glomerular filtration.

In healthy subjects, co-administration of abemaciclib and the P-glycoprotein (P-gp) substrateloperamide resulted in an increase in loperamide plasma exposure of 9 % based on AUC0-∞ and 35 %based on Cmax. This was not considered to be clinically relevant. However, based on the in vitroinhibition of P-gp and breast cancer resistance protein (BCRP) observed with abemaciclib, in vivointeractions of abemaciclib with narrow therapeutic index substrates of these transporters, such asdigoxin or dabigatran etexilate, may occur.

In a clinical study in patients with breast cancer, there was no clinically-relevant pharmacokinetic druginteraction between abemaciclib and anastrozole, fulvestrant, exemestane, letrozole or tamoxifen.

It is currently unknown whether abemaciclib may reduce the effectiveness of systemically actinghormonal contraceptives.

Women of childbearing potential should use highly effective contraception methods (e.g.double-barrier contraception) during treatment and for at least 3 weeks after completing therapy (seesection 4.5).

There are no data from the use of abemaciclib in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3). Verzenios is not recommended during pregnancy and inwomen of child-bearing potential not using contraception.

It is unknown whether abemaciclib is excreted in human milk. A risk to breast-feeding children cannotbe excluded. Patients receiving abemaciclib should not breast-feed.

The effect of abemaciclib on fertility in humans is unknown. While in rats no effects on male fertilitywere noted, cytotoxic effects to the male reproductive tract in mice, rats, and dogs indicate thatabemaciclib may impair fertility in males. No adverse effects on female reproductive organs in mice,rats, or dogs, nor effects on female fertility and early embryonic development in rats were observed(see section 5.3).

Verzenios has minor influence on the ability to drive and use machines. Patients should be advised tobe cautious when driving or using machines in case they experience fatigue or dizziness duringtreatment with Verzenios (see section 4.8).

The most commonly occurring adverse reactions are diarrhoea, infections, neutropenia, leukopenia,anaemia, fatigue, nausea, vomiting, alopecia and decreased appetite.

Of the most common adverse reactions, Grade ≥ 3 events were less than 5 % with the exception ofneutropenia, leukopenia, and diarrhoea.

In the following table, adverse reactions are listed in order of MedDRA body system organ class andfrequency. Frequency gradings are: very common (≥1/10), common (≥1/100 to < 1/10),uncommon (≥1/1 000 to < 1/100), rare (≥1/10 000 to < 1/1 000), very rare (< 1/10 000), and notknown (cannot be estimated from the available data). Within each frequency grouping, adversereactions are presented in order of decreasing seriousness.

Table 8. Adverse reactions reported in the phase 3 studies of abemaciclib in combination withendocrine therapya (N = 3 559) and during post-marketing experience

System organ class Very common Common Uncommon Rare

Infections and Infections binfestations

Blood and lymphatic Neutropenia Febrilesystem disorders Leukopenia neutropenia e

Lymphopenia h

Metabolism and Decreased appetitenutrition disorders

Nervous system Headache fdisorders Dysgeusia g

Dizziness g

Eye disorders Lacrimation Photopsiaincreased Keratitis

Vascular disorders Venousthromboembolismc

Respiratory, thoracic ILD/pneumonitis dand mediastinaldisorders

Gastrointestinal Diarrhoea Dyspepsia fdisorders Vomiting

Nausea

Stomatitis f

Skin and subcutaneous Alopecia g Nail disorder f Erythematissue disorders Pruritus g Dry skin e multiforme

Rash g

Musculoskeletal and Muscularconnective tissue weakness edisorders

General disorders and Pyrexia eadministration site Fatigueconditions

Investigations Alanineaminotransferaseincreased g

Aspartateaminotransferaseincreased ga Abemaciclib in combination with anastrozole, letrozole, exemestane, tamoxifen, or fulvestrant.b Infections include all reported preferred terms that are part of the system organ class infections andinfestations.c Venous thromboembolic events include deep vein thrombosis (DVT), pulmonary embolism, cerebralvenous sinus thrombosis, subclavian, axillary vein thrombosis, DVT inferior vena cava and pelvicvenous thrombosis.

d ILD/pneumonitis for early breast cancer (EBC) include all reported preferred terms that are part ofthe MedDRA SMQ interstitial lung disease. For metastatic breast cancer (mBC) preferred termsinclude interstitial lung disease, pneumonitis, organising pneumonia, pulmonary fibrosis andbronchiolitis obliterans.

e Considered ADRs in the mBC setting only (MONARCH 2 and MONARCH 3).f Considered ADRs in the EBC setting only (monarchE).g Common frequency in the EBC setting (monarchE), very common in the mBC setting(MONARCH 2 and MONARCH 3).h Common frequency in mBC setting (MONARCH 2 and MONARCH 3), very common in the EBCsetting (monarchE).

Neutropenia was reported frequently across studies. In the monarchE study, neutropenia was reportedin 45.8 % of patients. Grade 3 or 4 decrease in neutrophil counts (based on laboratory findings) wasreported in 19.1 % of patients receiving abemaciclib in combination with endocrine therapy with amedian time to onset of 30 days, and median time to resolution of 16 days. Febrile neutropenia wasreported in 0.3 % patients. In MONARCH 2 and MONARCH 3 studies, neutropenia was reported in45.1 % of patients. Grade 3 or 4 decrease in neutrophil counts (based on laboratory findings) wasreported in 28.2 % of patients receiving abemaciclib in combination with aromatase inhibitors orfulvestrant. The median time to onset of Grade 3 or 4 neutropenia was 29 to 33 days, and median timeto resolution was 11 to 15 days. Febrile neutropenia was reported in 0.9 % patients. Dose modificationis recommended for patients who develop Grade 3 or 4 neutropenia (see section 4.2).

Diarrhoea was the most commonly reported adverse reaction (see Table 8). Incidence was greatestduring the first month of abemaciclib treatment and was lower subsequently. In the monarchE study,the median time to onset of the first diarrhoea event of any grade was 8 days. The median duration ofdiarrhoea was 7 days for Grade 2 and 5 days for Grade 3. In MONARCH 2 and MONARCH 3 studies,the median time to onset of the first diarrhoea event of any grade was approximately 6 to 8 days. Themedian duration of diarrhoea was 9 to 12 days for Grade 2 and 6 to 8 days for Grade 3. Diarrhoeareturned to baseline or lesser grade with supportive treatment such as loperamide and/or doseadjustment (see section 4.2).

Increased aminotransferases

In the monarchE study, ALT and AST elevations were reported frequently (12.3 % and 11.8 %,respectively) in patients receiving abemaciclib in combination with endocrine therapy. Grade 3 or 4

ALT or AST elevations (based on laboratory findings) were reported in 2.6 % and 1.6 % patients. Themedian time to onset of Grade 3 or 4 ALT elevation was 118 days, and median time to resolution was14.5 days. The median time to onset of Grade 3 or 4 AST elevation was 90.5 days, and median time toresolution was 11 days. In MONARCH 2 and MONARCH 3 studies, ALT and AST elevations werereported frequently (15.1 % and 14.2 %, respectively) in patients receiving abemaciclib incombination with aromatase inhibitors or fulvestrant. Grade 3 or 4 ALT or AST elevations (based onlaboratory findings) were reported in 6.1 % and 4.2 % patients. The median time to onset of Grade 3or 4 ALT elevation was 57 to 61 days, and median time to resolution was 14 days. The median time toonset of Grade 3 or 4 AST elevation was 71 to 185 days, and median time to resolution was 13 to15 days. Dose modification is recommended for patients who develop Grade 3 or 4 ALT or ASTincrease (see section 4.2).

Creatinine

Although not an adverse reaction, abemaciclib has been shown to increase serum creatinine. In themonarchE study, 99.3 % of patients had serum creatinine elevations (based on laboratory findings),and of these, 0.5 % of patients had Grade 3 or 4 elevations. In patients receiving endocrine therapyalone, 91.0 % reported an increase in serum creatinine (all laboratory grades). In MONARCH 2 and

MONARCH 3 studies, 98.3 % of patients had serum creatinine elevations (based on laboratoryfindings), and of these, 1.9 % of patients had Grade 3 or 4 elevations. In patients receiving anaromatase inhibitor or fulvestrant alone, 78.4 % reported an increase in serum creatinine (alllaboratory grades). Abemaciclib has been shown to increase serum creatinine due to inhibition of renaltubular secretion transporters without affecting glomerular function (as measured by iohexolclearance) (see section 4.5). In clinical studies, increases in serum creatinine occurred within the firstmonth of abemaciclib dosing, remained elevated but stable through the treatment period, werereversible upon treatment discontinuation, and were not accompanied by changes in markers of renalfunction, such as blood urea nitrogen (BUN), cystatin C, or calculated glomerular filtration rate basedon cystatin C.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In the event of an abemaciclib overdose, fatigue and diarrhoea may occur. General supportive careshould be provided.

Pharmacotherapeutic group: Antineoplastic agents, protein kinases inhibitors, ATC code: L01EF03

Abemaciclib is a potent and selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and

CDK6), and most active against Cyclin D1/CDK4 in enzymatic assays. Abemaciclib preventsretinoblastoma protein (Rb) phosphorylation, blocking cell cycle progression from the G1 to the

S-phase of cell division, leading to suppression of tumour growth. In oestrogen receptor-positivebreast cancer cell lines, sustained target inhibition with abemaciclib prevented rebound of Rbphosphorylation resulting in cell senescence and apoptosis. In vitro, Rb-negative and Rb-depletedcancer cell lines are generally less sensitive to abemaciclib. In breast cancer xenograft models,abemaciclib dosed daily without interruption at clinically relevant concentrations alone or incombination with anti-oestrogens resulted in reduction of tumour size.

In cancer patients, abemaciclib inhibits CDK4 and CDK6 as indicated by inhibition ofphosphorylation of Rb and topoisomerase II alpha, which results in cell cycle inhibition upstream ofthe G1 restriction point.

The effect of abemaciclib on the QTcF interval was evaluated in 144 patients with advanced cancer.

No large change (that is, > 20 ms) in the QTcF interval was detected at the mean observed maximalsteady state abemaciclib concentration following a therapeutic dosing schedule.

In an exposure-response analysis in healthy subjects at exposures comparable to a 200 mg twice-dailydose, abemaciclib did not prolong the QTcF interval to any clinically relevant extent.

Early breast cancer

Randomised Phase 3 Study monarchE: Verzenios in combination with endocrine therapy

The efficacy and safety of Verzenios in combination with adjuvant endocrine therapy was evaluated inmonarchE, a randomised, open label, two cohort, phase 3 study, in women and men with HR-positive,

HER2-negative, node positive early breast cancer at high risk of recurrence. High risk of recurrence in

Cohort 1 was defined by clinical and pathological features: either ≥ 4 pALN (positive axillary lymphnodes), or 1-3 pALN and at least one of the following criteria: tumor size ≥ 5 cm or histologicalgrade 3.

A total of 5 637 patients were randomised in a 1:1 ratio to receive 2 years of Verzenios 150 mg twicedaily plus physician’s choice of standard endocrine therapy, or standard endocrine therapy alone.

Randomization was stratified by prior chemotherapy, menopausal status, and region. Men werestratified as postmenopausal. Patients had completed definitive locoregional therapy (with or withoutneoadjuvant or adjuvant chemotherapy). Patients must have recovered from the acute side effects ofany prior chemotherapy or radiotherapy. A washout period of 21 days after chemotherapy and 14 daysafter radiotherapy prior to randomization was required. Patients were allowed to receive up to12 weeks of adjuvant endocrine therapy prior to randomisation following the last non-endocrinetherapy (surgery, chemotherapy or radiation). Adjuvant treatment with fulvestrant was not allowed asstandard endocrine therapy. Patients with eastern cooperative oncology group (ECOG) Performance

Status 0 or 1 were eligible. Patients with history of VTEs were excluded from the study. After the endof the study treatment period, in both treatment arms patients continued to receive adjuvant endocrinetherapy for a cumulative duration of at least 5 years and up to 10 years, if medically appropriate.

LHRH agonists were given when clinically indicated to pre- and perimenopausal women, and men.

Among the 5 637 randomised patients, 5 120 were enrolled in Cohort 1, representing 91 % of the

ITT population. In Cohort 1, patient demographics and baseline tumour characteristics were balancedbetween treatment arms. The median age of patients enrolled was approximately 51 years (range,22-89 years), 15 % of patients were 65 or older, 99 % were women, 71 % were Caucasian, 24 % were

Asian, and 5 % Other. Forty three percent of patients were pre- or perimenopausal. Most patientsreceived prior chemotherapy (36 % neoadjuvant, 62 % adjuvant), and prior radiotherapy (96 %).

Initial endocrine therapy received by patients included letrozole (39 %), tamoxifen (31 %), anastrozole(22 %), or exemestane (8 %).

Sixty-five percent of the patients had 4 or more positive lymph nodes, 41 % had Grade 3 tumour, and24 % had pathological tumour size ≥ 5 cm at surgery.

The primary endpoint was invasive disease-free survival (IDFS) in ITT population defined as the timefrom randomization to the first occurrence of ipsilateral invasive breast tumour recurrence, regionalinvasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, secondprimary non-breast invasive cancer, or death attributable to any cause. Key secondary endpoint wasdistant relapse free survival (DRFS) in ITT population defined as time from randomization to the firstoccurrence of distant recurrence, or death attributable to any cause.

The primary objective of the study was met at the pre-planned interim analysis (16 Mar 2020 cut-off).

A statistically significant improvement in IDFS was observed in patients who received Verzenios plusendocrine therapy versus endocrine therapy alone in the ITT population. At the time of the subsequentfinal overall survival (OS) analysis (15 July 2025 cut-off) a statistically significant improvement in OSwas also observed in patients who received Verzenios plus endocrine therapy versus endocrine therapyalone in the ITT population. The approval was granted for the large subpopulation, Cohort 1.

At the final OS analysis all patients in Cohort 1 were off the 2-year study treatment period and themedian duration of follow-up was 76 months (6.3 years).

Efficacy results in Cohort 1 are summarised in Table 9, Figure 1 and Figure 2.

Table 9. monarchE: Summary of efficacy data (Cohort 1 population)

Verzenios plus Endocrine therapyendocrine therapy alone

N = 2 555 N = 2 565

Invasive disease-free survival (IDFS)

Number of patients with event (n, %) 512 (20.0) 678 (26.4)

Hazard ratio (95 % CI) 0.726 (0.648, 0.815)

IDFS at 84 months (%, 95 % CI) 77.0 (75.0, 78.8) 70.1 (68.0, 72.1)

Distant relapse free survival (DRFS)

Number of patients with an event (n, %) 448 (17.5) 589 (23.0)

Hazard ratio (95 % CI) 0.736 (0.651, 0.832)

DRFS at 84 months (%, 95 % CI) 79.5 (77.6, 81.2) 74.0 (72.0, 75.9

Overall Survival (OS)

Number of events, n (%) 286 (11.2) 344 (13.4)

Hazard Ratio (95% CI) 0.835 (0.713, 0.977)

Abbreviation: CI = confidence interval.

Data cut-off date 15 July 2025

Figure 1. monarchE: Kaplan-Meier plot of IDFS (Investigator assessment, Cohort 1 population)

Abbreviations: IDFS = invasive disease-free survival; N = number of patients in the population.

Data cut-off date 15 July 2025

Figure 2. monarchE: Kaplan-Meier plot of OS (Cohort 1 population)

Patients at risk

Abemaciclib plus Endocrine Therapy2555 2381 2290 2186 2123 2030 1798 423 0

Endocrine Therapy2565 2416 2305 2211 2117 2005 1753 431 0

Abbreviations: ET = endocrine therapy; OS = overall survival; N = number of patients in thepopulation.

Data cut-off date 15 Jul 2025

Benefit was observed across patient subgroups defined by geographic region, menopausal status andprior chemotherapy within Cohort 1.

Advanced or metastatic breast cancer

Randomised Phase 3 Study MONARCH 3: Verzenios in combination with aromatase inhibitors

The efficacy and safety of Verzenios in combination with an aromatase inhibitor (anastrozole orletrozole) was evaluated in MONARCH 3, a randomised, double-blind, placebo-controlled phase 3study in women with HR positive, HER2 negative locally advanced or metastatic breast cancer whohad not received prior systemic therapy in this disease setting. Patients were randomised in a 2:1 ratioto receive Verzenios 150 mg twice daily plus a non-steroidal aromatase inhibitor given daily at therecommended dose versus placebo plus a non-steroidal aromatase inhibitor according to the sameschedule. The primary endpoint was investigator-assessed progression-free survival (PFS) evaluatedaccording to RECIST 1.1; key secondary efficacy endpoints included objective response rate (ORR),clinical benefit rate (CBR) and overall survival (OS).

The median age of patients enrolled was 63 years (range 32 - 88). Approximately 39 % of patients hadreceived chemotherapy and 44 % had received antihormonal therapy in the (neo)adjuvant setting.

Patients with prior (neo)adjuvant endocrine therapy must have completed this therapy at least12 months before study randomisation. The majority of patients (96 %) had metastatic disease atbaseline. Approximately 22 % of patients had bone-only disease, and 53 % patients had visceralmetastases.

The study met its primary endpoint of improving PFS. Primary efficacy results are summarised in

Table 10 and Figure 3.

Table 10. MONARCH 3: Summary of efficacy data (Investigator assessment, intent-to-treatpopulation)

Verzenios plus Placebo plus aromatasearomatase inhibitor inhibitor

Progression-free survival N = 328 N = 165

Investigator assessment, number of events 138 (42.1) 108 (65.5)(%)

Median [months] (95 % CI) 28.18 (23.51, NR) 14.76 (11.24, 19.20)

Hazard ratio (95 % CI) and p-value 0.540 (0.418, 0.698), p = 0.000002

Independent radiographic review, 91 (27.7) 73 (44.2)number of events (%)

Median [months] (95 % CI) NR (NR, NR) 19.36 (16.37, 27.91)

Hazard ratio (95 % CI) and p-value 0.465 (0.339, 0.636); p < 0.000001

Objective response rateb [%] (95 % CI) 49.7 (44.3, 55.1) 37.0 (29.6, 44.3)

Duration of response [months] (95 % CI) 27.39 (25.74, NR) 17.46 (11.21, 22.19)

Objective response for patients withmeasurable diseasea N = 267 N = 132

Objective response rateb [%] (95 % CI) 61.0 (55.2, 66.9) 45.5 (37.0, 53.9)

Complete response, (%) 3.4 0

Partial response, (%) 57.7 45.5

Clinical benefit ratec (measurable disease) 79.0 (74.1, 83.9) 69.7 (61.9, 77.5)[%] (95 % CI)a Measurable disease defined per RECIST version 1.1b Complete response + partial responsec Complete response + partial response + stable disease for ≥ 6 months

N = number of patients; CI = confidence interval; NR = not reached.

Figure 3. MONARCH 3: Kaplan-Meier plot of progression-free survival (Investigatorassessment, intent-to-treat population)

These results correspond to a clinically meaningful reduction in the risk of disease progression ordeath of 46 % for patients treated with abemaciclib plus an aromatase inhibitor.

OS was not mature at the final PFS analysis (93 events observed across the two arms). The HR was1.057 (95 % CI: 0.683, 1.633), p = 0.8017.

A series of prespecified subgroup PFS analyses showed consistent results across patient subgroupsincluding age (< 65 or ≥ 65 years), disease site, disease setting (de novo metastatic vs recurrentmetastatic vs locally advanced recurrent), presence of measurable disease, progesterone receptorstatus, and baseline ECOG performance status. A reduction in the risk of disease progression or deathwas observed in patients with visceral disease, (HR of 0.567 [95 % CI: 0.407, 0.789]), median PFS21.6 months versus 14.0 months; in patients with bone-only disease (HR of 0.565 [95 % CI: 0.306,1.044]); and in patients with measurable disease (HR of 0.517 [95 % CI: 0.392, 0.681]).

At the first OS interim analysis, 197 events were observed across the two arms and the HR was0.786 (95 % CI: 0.589, 1.049).

At the second OS interim analysis, 255 events were observed across the two arms and the HR was0.754 (95 % CI: 0.584, 0.974).

The results from the Final OS analysis were not statistically significant (summarised in Table 11 and

Figure 4).

Table 11.: MONARCH 3: Summary of Overall Survival data (Intent-to-Treat Population)

Verzenios plus Placebo plus

Anastrozole or Anastrozole or

Letrozole Letrozole

Overall survival N = 328 N = 165

Number of events (n, %) 198 (60.4) 116 (70.3)

Median OS [months] (95% CI) 66.81 (59.21, 74.83) 53.72 (44.75, 59.34)

Hazard ratio (95% CI) 0.804 (0.637, 1.015)

Abbreviations: N = number of patients; CI = confidence interval; ITT = intent-to-treat; OS = overall survival.

Analyses for OS in patients with visceral disease showed an OS HR of 0.758 (95% CI: 0.558, 1.030).

Median OS was 63.72 months in the abemaciclib plus AI arm and 48.82 months in the placebo plus AIarm. Similar to the ITT population, the results were not statistically significant.

Figure 4. MONARCH 3: Kaplan-Meier plot of overall survival (Intent-to-treat population)

Randomised Phase 3 Study MONARCH 2: Verzenios in combination with fulvestrant

The efficacy and safety of Verzenios in combination with fulvestrant was evaluated in MONARCH 2,a randomised, double-blind, placebo-controlled phase 3 study in women with HR positive, HER2negative locally advanced or metastatic breast cancer. Patients were randomised in a 2:1 ratio toreceive Verzenios 150 mg twice daily plus fulvestrant 500 mg at intervals of one month, with anadditional 500 mg dose given two weeks after the initial dose, versus placebo plus fulvestrantaccording to the same schedule. The primary endpoint was investigator-assessed PFS evaluatedaccording to RECIST 1.1; key secondary efficacy endpoints included ORR, CBR and OS.

The median age of patients enrolled was 60 years (range, 32 - 91 years). In each treatment arm themajority of patients were white, and had not received chemotherapy for metastatic disease. 17 % ofpatients were pre/perimenopausal on ovarian suppression with a GnRH agonist. Approximately 56 %patients had visceral metastases. Approximately 25 % of patients had primary endocrine resistance(progression on endocrine therapy within the first 2 years of adjuvant endocrine therapy or within thefirst 6 months of first line endocrine therapy for metastatic breast cancer) and for the majority,endocrine resistance developed later. 59 % of patients had most recent endocrine therapy in the(neo)adjuvant setting, and 38 % in metastatic setting.

The study met its primary endpoint of improving PFS. Primary efficacy results are summarised in

Table 12 and Figure 5.

Table 12. MONARCH 2: Summary of efficacy data (Investigator assessment, intent-to-treatpopulation)

Verzenios plus Placebo plusfulvestrant fulvestrant

Progression-free survival N = 446 N = 223

Investigator assessment, number of events 222 (49.8) 157 (70.4)(%)

Median [months] (95 % CI) 16.4 (14.4, 19.3) 9.3 (7.4, 12.7)

Hazard ratio (95 % CI) and p-value 0.553 (0.449, 0.681), p = 0.0000001

Independent radiographic review, 164 (36.8) 124 (55.6)number of events (%)

Median [months] (95 % CI) 22.4 (18.3, NR ) 10.2 (5.8, 14.0)

Hazard ratio (95 % CI) and p-value 0.460 (0.363, 0.584); p < 0.000001

Objective response rateb [%] (95 % CI) 35.2 (30.8, 39.6) 16.1 (11.3, 21.0)

Duration of response [months] (95 % CI) NR (18.05, NR) 25.6 (11.9, 25.6)

Objective response for patients withmeasurable diseasea N = 318 N = 164

Objective response rateb [%] (95 % CI) 48.1 (42.6, 53.6) 21.3 (15.1, 27.6)

Complete response, (%) 3.5 0

Partial response, (%) 44.7 21.3

Clinical benefit ratec (measurable disease) 73.3 (68.4, 78.1) 51.8 (44.2, 59.5)[%] (95 % CI)a Measurable disease defined per RECIST version 1.1b Complete response + partial responsec Complete response + partial response + stable disease for ≥ 6 months

N = number of patients; CI = confidence interval; NR = not reached.

Figure 5. MONARCH 2: Kaplan-Meier plot of progression-free survival (Investigatorassessment, intent-to-treat population)

These results correspond to a clinically meaningful reduction in the risk of disease progression ordeath of 44.7 % for patients treated with Verzenios plus fulvestrant. Verzenios plus fulvestrantprolonged progression-free survival with neither a clinically meaningful, or significant detriment tohealth-related quality of life.

A series of prespecified subgroup PFS analyses showed consistent results across patient subgroupsincluding age (< 65 or ≥ 65 years), race, geographic region, disease site, endocrine therapy resistance,presence of measurable disease, progesterone receptor status, and menopausal status. A reduction inthe risk of disease progression or death was observed in patients with visceral disease, (HR of 0.481[95 %CI: 0.369, 0.627]), median PFS 14.7 months versus 6.5 months; in patients with bone-onlydisease (HR of 0.543 [95 % CI: 0.355, 0.833]); patients with measurable disease (HR of 0.523[95 % CI: 0.412, 0.644]). In patients who were pre/perimenopausal, the hazard ratio was0.415 (95 % CI: 0.246, 0.698); in patients who were progesterone receptor negative, the HR was0.509 (95 % CI: 0.325, 0.797).

In a sub-population with locally advanced or metastatic disease that had not received prior endocrinetherapy, the PFS was also consistent.

At the pre-specified interim OS analysis (20 June 2019 cut-off), the ITT population showed astatistically significant improvement in patients receiving Verzenios plus fulvestrant compared withthose receiving placebo plus fulvestrant. The OS results are summarized in Table 13.

Table 13. MONARCH 2: Summary of overall survival data (Intent-to-treat population)

Verzenios plus Placebo plusfulvestrant fulvestrant

Overall survival N = 446 N = 223

Number of events (n, %) 211 (47.3) 127 (57.0)

Median OS [months] (95 % CI) 46.7 (39.2, 52.2) 37.3 (34.4, 43.2)

Hazard ratio (95 % CI) 0.757 (0.606, 0.945)p-value 0.0137

N = number of patients; CI = confidence interval; OS = overall survival

Analyses for OS by stratification factors showed OS HR of 0.675 (95 % CI: 0.511, 0.891) in patientswith visceral disease, and 0.686 (95 % CI: 0.451, 1.043) in patients with primary endocrine resistance.

At the pre-specified final OS analysis (18 March 2022 cut-off), 440 events were observed across the2 arms. The improvement in OS previously observed at the interim OS analysis (20 June 2019 cut-off)was maintained in the abemaciclib plus fulvestrant arm compared to the placebo plus fulvestrant arm,with a HR of 0.784 (95 % CI: 0.644, 0.955). Median OS was 45.8 months in the abemaciclib plusfulvestrant arm and 37.25 months in the placebo plus fulvestrant arm. The OS results are presented in

Figure 6.

Figure 6. MONARCH 2: Kaplan-Meier plot of overall survival (Intent-to-treat population)

The European Medicines Agency has waived the obligation to submit the results of studies with

Verzenios in all subsets of the paediatric population in breast cancer (see section 4.2 for informationon paediatric use).

The efficacy and safety of Verzenios in combination with irinotecan and temozolomide was evaluatedin Study J1S-MC-JP04, a multicentre, randomised, open-label, phase 2 study in participants withrelapsed or refractory Ewing sarcoma. The primary endpoint was progression-free survival (PFS)assessed by a blinded independent review committee. 46 participants, 3 to 35 years of age, wererandomised to receive Verzenios plus irinotecan and temozolomide or irinotecan and temozolomide ina 2:1 ratio. 58.7 % of patients (27 patients) were < 18 years of age. 45 participants were treated in 21-day cycles until disease progression or having met other discontinuation criteria. No difference in PFSwas observed with the addition of Verzenios. The median PFS was 2.8 months in patients treated with

Verzenios in combination irinotecan and temozolomide and 2.9 months in patients treated withirinotecan and temozolomide (HR 0.64 [95% CI: 0.28, 1.45]).

Abemaciclib absorption is slow, with a Tmax of 8 hours and a mean absolute bioavailability ofapproximately 45 %. In the therapeutic dose range of 50 - 200 mg, the increase in plasma exposure(AUC) and Cmax is approximately dose proportional. Steady state was achieved within 5 daysfollowing repeated twice daily dosing, and abemaciclib accumulated with a geometric meanaccumulation ratio of 3.7 (58 % CV) and 5.8 (65 % CV) based on Cmax and AUC, respectively. Ahigh-fat meal increased combined AUC of abemaciclib and its active metabolites by 9 % andincreased Cmax by 26 %. These changes were not considered to be clinically relevant. Therefore,abemaciclib can be taken with or without food.

Abemaciclib is highly bound to plasma proteins in humans (mean bound fraction approximately 96 %to 98 %). The geometric mean systemic volume of distribution is approximately 750 L (69 % CV),indicating distribution of abemaciclib into tissues.

Concentrations of abemaciclib and its active metabolites in cerebrospinal fluid are comparable tounbound plasma concentrations.

Hepatic metabolism is the main route of clearance for abemaciclib. Abemaciclib is metabolised toseveral metabolites primarily by cytochrome P450 (CYP) 3A4. The primary biotransformation ishydroxylation to a metabolite that circulates with an AUC that is 77 % of parent drug. In addition,

N-desethyl and N-desethylhydroxy metabolites circulate at AUCs that are 39 % and 15 % of parentdrug. These circulating metabolites are active with similar potency to abemaciclib.

The geometric mean hepatic clearance (CL) of abemaciclib was 21.8 L/h (39.8 % CV), and the meanplasma elimination half-life for abemaciclib in patients was 24.8 hours (52.1 % CV). After a singleoral dose of [14C] -abemaciclib, approximately 81 % of the dose was excreted in faeces and 3.4 %excreted in urine. The majority of the dose eliminated in faeces was metabolites.

Age, gender, and body weight

Age, gender, and body weight had no effect on the exposure of abemaciclib in a populationpharmacokinetic analysis in patients with cancer (135 males and 859 females; age range 24 - 91 years;and body weight range 36 - 175 kg).

Abemaciclib is metabolised in the liver. Mild (Child Pugh A) and moderate (Child Pugh B) hepaticimpairment had no effect on the exposure of abemaciclib. In subjects with severe hepatic impairment(Child Pugh C), the AUC0-∞ of abemaciclib and potency adjusted unbound abemaciclib plus its activemetabolites increased 2.1-fold and 2.4-fold, respectively. The half-life of abemaciclib increased from24 to 55 hours (see section 4.2).

Renal clearance of abemaciclib and its metabolites is minor. Mild and moderate renal impairment hadno effect on the exposure of abemaciclib. There are no data in patients with severe renal impairment,end stage renal disease or in patients on dialysis.

The primary target organ findings of potential relevance to humans occurred in the gastrointestinaltract, haematolymphopoietic organs, and male reproductive tract in mice, rats and dogs in studies up to13 weeks duration. Effects in eyes and heart valves occurred only in rodents at clinically relevantexposure levels. Effects in lung and skeletal muscle occurred only in rodents at exposure levels at least2-fold higher than human exposure levels. Effects in kidney occurred only in rodents at exposurelevels at least 6-fold higher than human exposure levels. Complete or partial recovery was observedfor all target organ findings at the end of the 28 - day recovery period, with the exception of malereproductive tract effects.

Abemaciclib was not mutagenic in a bacterial reverse mutation (Ames) assay, was not clastogenic inan in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and was notclastogenic in an in vivo rat bone marrow micronucleus assay.

Abemaciclib was assessed for carcinogenicity in 2-year studies in rats and mice. In male rats, dailyoral administration of abemaciclib resulted in benign testicular interstitial cell adenomas at exposuresapproximately 1.5 times human clinical exposure. In addition, interstitial cell hyperplasia wasobserved at exposures approximately 0.1 times human clinical exposure. It is unknown if these effectswill translate to humans. There were no neoplastic findings in mice or in female rats that were due toadministration of abemaciclib.

Abemaciclib may impair fertility in males of reproductive potential. In repeat-dose toxicity studies upto 3 months duration, abemaciclib-related findings in the testis, epididymis, prostate, and seminalvesicle included decreased organ weights, intratubular cellular debris, hypospermia, tubular dilatation,atrophy, and degeneration/necrosis. These effects occurred in rats and dogs at exposuresapproximately 2 and 0.02 times human clinical exposure, respectively. In a rat male fertility study,abemaciclib had no effects on reproductive performance.

In a rat female fertility and early embryonic development study and in repeat-dose toxicity studies,abemaciclib did not have any effect on reproductive performance or any important effects on thefemale reproductive tract indicative of a risk of impaired fertility in females.

Developmental toxicity

Abemaciclib was teratogenic and caused decreased foetal weight at maternal exposures similar to therecommended human dose.

Croscarmellose sodium

Lactose monohydrate

Microcrystalline cellulose

Colloidal hydrated silica

Sodium stearyl fumarate

Verzenios 50 mg film-coated tablets

Polyvinyl alcohol (E1203)

Titanium dioxide (E171)

Macrogol (E1521)

Talc (E553b)

Iron oxide yellow (E172)

Iron oxide red (E172)

Verzenios 100 mg film-coated tablets

Polyvinyl alcohol (E1203)

Titanium dioxide (E171)

Macrogol (E1521)

Talc (E553b)

Verzenios 150 mg film-coated tablets

Polyvinyl alcohol (E1203)

Titanium dioxide (E171)

Macrogol (E1521)

Talc (E553b)

Iron oxide yellow (E172)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

PCTFE/PE/PVC blisters sealed with an aluminium foil in packs of 14, 28, 42, 56, 70 or168 film-coated tablets.

Aluminium/aluminium perforated unit dose blisters of 28 x 1 film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Eli Lilly Nederland B.V., Orteliuslaan 1000, 3528 BD Utrecht, The Netherlands.

EU/1/18/1307/001

EU/1/18/1307/002

EU/1/18/1307/003

EU/1/18/1307/004

EU/1/18/1307/005

EU/1/18/1307/006

EU/1/18/1307/007

EU/1/18/1307/008

EU/1/18/1307/009

EU/1/18/1307/010

EU/1/18/1307/011

EU/1/18/1307/012

EU/1/18/1307/013

EU/1/18/1307/014

EU/1/18/1307/015

EU/1/18/1307/016

EU/1/18/1307/017

EU/1/18/1307/018

EU/1/18/1307/019

EU/1/18/1307/020

EU/1/18/1307/021

Date of first authorisation: 27 September 2018

Date of latest renewal: 23 June 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency: https://www.ema.europa.eu