IBRANCE 125 MG FILM-COATED TABLETS - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

IBRANCE 125 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 125 mg of palbociclib.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Oval, 16.2 × 8.6 mm, light purple, film-coated tablets debossed with “Pfizer” on one side and “PBC 125” on the other side.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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

– in combination with an aromatase inhibitor;

– in combination with fulvestrant in women who have received prior endocrine therapy (see section 5.1).

In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinizing hormone-releasing hormone (LHRH) agonist.

4.2 Posology and method of administration

Treatment with IBRANCE should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Posology

The recommended dose is 125 mg of palbociclib once daily for 21 consecutive days followed by 7 days off treatment (Schedule 3/1) to comprise a complete cycle of 28 days. The treatment with IBRANCE should be continued as long as the patient is deriving clinical benefit from therapy or until unacceptable toxicity occurs.

When coadministered with palbociclib, the aromatase inhibitor should be administered according to the dose schedule reported in the Summary of Product Characteristics. Treatment of pre/perimenopausal women with the combination of palbociclib plus an aromatase inhibitor should always be combined with an LHRH agonist (see section 4.4).

When coadministered with palbociclib, the recommended dose of fulvestrant is 500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter. Please refer to the Summary of Product Characteristics of fulvestrant. Prior to the start of treatment with the combination of palbociclib plus fulvestrant, and throughout its duration, pre/perimenopausal women should be treated with LHRH agonists according to local clinical practice.

Patients should be encouraged to take their dose at approximately the same time each day. If the patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time.

Dose adjustments

Dose modification of IBRANCE is recommended based on individual safety and tolerability.

Management of some adverse reactions may require temporary dose interruptions/de­lays, and/or dose reductions, or permanent discontinuation as per dose reduction schedules provided in Tables 1, 2, and 3 (see sections 4.4 and 4.8).

Table 1. IBRANCE recommended dose modifications for adverse reactions

If further dose reduction below 75 mg/day is required, discontinue the treatment.

Complete blood count should be monitored prior to the start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated.

For patients who experience a maximum of Grade 1 or 2 neutropenia in the first 6 cycles, complete blood counts for subsequent cycles should be monitored every 3 months, prior to the beginning of a cycle and as clinically indicated.

Absolute neutrophil counts (ANC) of > 1,000/mm3 and platelet counts of > 50,000/mm3 are recommended to receive IBRANCE.

Table 2. IBRANCE dose modification and management – Haematological toxicities

Grading according to CTCAE 4.0.

ANC=absolute neutrophil counts; CTCAE=Common Terminology Criteria for Adverse Events;

LLN=lower limit of normal.

a Table applies to all haematological adverse reactions except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).

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.

Table 3. IBRANCE dose modification and management – Non-haematological

toxicities

Grading according to CTCAE 4.0.

CTCAE=Common Terminology Criteria for Adverse Events.

IBRANCE should be permanently discontinued in patients with severe interstitial lung disease (ILD)/pneumonitis (see section 4.4).

Special populations

Elderly

No dose adjustment of IBRANCE is necessary in patients > 65 years of age (see section 5.2).

Hepatic impairment

No dose adjustment of IBRANCE is required for patients with mild or moderate hepatic impairment (Child-Pugh classes A and B). For patients with severe hepatic impairment (Child-Pugh class C), the recommended dose of IBRANCE is 75 mg once daily on Schedule 3/1 (see sections 4.4 and 5.2).

Renal impairment

No dose adjustment of IBRANCE is required for patients with mild, moderate or severe renal impairment (creatinine clearance [CrCl] > 15 mL/min). Insufficient data are available in patients requiring haemodialysis to provide any dose adjustment recommendation in this patient population (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of IBRANCE in children and adolescents < 18 years of age have not been established. No data are available.

Method of administration

IBRANCE is for oral use. The tablets may be taken with or without food (see section 5.2). Palbociclib should not be taken with grapefruit or grapefruit juice (see section 4.5).

IBRANCE tablets should be swallowed whole (should not be chewed, crushed, or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact.

4.3 Contraindications

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

Use of preparations containing St. John’s Wort (see section 4.5).

4.4 Special warnings and precautions for use

Pre/perimenopausal women

Ovarian ablation or suppression with an LHRH agonist is mandatory when pre/perimenopausal women are administered IBRANCE in combination with an aromatase inhibitor, due to the mechanism of action of aromatase inhibitors.

Palbociclib in combination with fulvestrant in pre/perimenopausal women has only been studied in combination with an LHRH agonist.

Critical visceral disease

The efficacy and safety of palbociclib have not been studied in patients with critical visceral disease (see section 5.1).

Haematological disorders

Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia. Appropriate monitoring should be performed (see sections 4.2 and 4.8).

Interstitial lung disease/pneumonitis

Severe, life-threatening, or fatal ILD and/or pneumonitis can occur in patients treated with IBRANCE when taken in combination with endocrine therapy.

Across clinical studies (PALOMA-1, PALOMA-2, PALOMA-3), 1.4% of

IBRANCE-treated patients had ILD/pneumonitis of any grade, 0.1% had Grade 3, and no Grade 4 or fatal cases were reported. Additional cases of ILD/pneumonitis have been observed in the post-marketing setting, with fatalities reported (see section 4.8).

Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis (e.g. hypoxia, cough, dyspnoea). In patients who have new or worsening respiratory symptoms and are suspected to have developed ILD/pneumonitis, IBRANCE should be immediately interrupted and the patient should be evaluated. IBRANCE should be permanently discontinued in patients with severe ILD or pneumonitis (see section 4.2).

Infections

Since IBRANCE has myelosuppressive properties, it may predispose patients to infections.

Infections have been reported at a higher rate in patients treated with IBRANCE in randomised clinical studies compared to patients treated in the respective comparator arm. Grade 3 and Grade 4 infections occurred respectively in 5.6% and 0.9% of patients treated with IBRANCE in any combination (see section 4.8).

Patients should be monitored for signs and symptoms of infection and treated as medically appropriate (see section 4.2).

Physicians should inform patients to promptly report any episodes of fever.

Hepatic impairment

IBRANCE should be administered with caution to patients with moderate or severe hepatic impairment, with close monitoring of signs of toxicity (see sections 4.2 and 5.2).

Renal impairment

IBRANCE should be administered with caution to patients with moderate or severe renal impairment, with close monitoring of signs of toxicity (see sections 4.2 and 5.2).

Concomitant treatment with inhibitors or inducers of CYP3A4

Strong inhibitors of CYP3A4 may lead to increased toxicity (see section 4.5).

Concomitant use of strong CYP3A inhibitors during treatment with palbociclib should be avoided. Coadministration should only be considered after careful evaluation of the potential benefits and risks. If coadministration with a strong CYP3A inhibitor is unavoidable, reduce the IBRANCE dose to 75 mg once daily. When the strong inhibitor is discontinued, the dose of IBRANCE should be increased (after 3–5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor (see section 4.5).

Coadministration of CYP3A inducers may lead to decreased palbociclib exposure and consequently a risk for lack of efficacy. Therefore, concomitant use of palbociclib with strong CYP3A4 inducers should be avoided. No dose adjustments are required for coadministration of palbociclib with moderate CYP3A inducers (see section 4.5).

Women of childbearing potential or their partners

Women of childbearing potential or their male partners must use a highly effective method of contraception while taking IBRANCE (see section 4.6).

4.5 Interaction with other medicinal products and other forms of interaction

Palbociclib is primarily metabolised by CYP3A and sulphotransferase (SULT) enzyme SULT2A1. In vivo, palbociclib is a weak, time-dependent inhibitor of CYP3A.

Effects of other medicinal products on the pharmacokinetics of palbociclib

Effect of CYP3A inhibitors

Coadministration of multiple 200 mg doses of itraconazole with a single 125 mg palbociclib dose increased palbociclib total exposure (AUCinf) and the peak concentration (Cmax) by approximately 87% and 34%, respectively, relative to a single 125 mg palbociclib dose given alone.

The concomitant use of strong CYP3A inhibitors including, but not limited to: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/rito­navir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice, should be avoided (see sections 4.2 and 4.4).

No dose adjustments are needed for mild and moderate CYP3A inhibitors.

Effect of CYP3A inducers

Coadministration of multiple 600 mg doses of rifampin with a single 125 mg palbociclib dose decreased palbociclib AUCinf and Cmax by 85% and 70%, respectively, relative to a single 125 mg palbociclib dose given alone.

The concomitant use of strong CYP3A inducers including, but not limited to: carbamazepine, enzalutamide, phenytoin, rifampin, and St. John’s Wort should be avoided (see sections 4.3 and 4.4).

Coadministration of multiple 400 mg daily doses of modafinil, a moderate

CYP3A inducer, with a single 125 mg IBRANCE dose decreased palbociclib AUCinf and Cmax by 32% and 11%, respectively, relative to a single 125 mg IBRANCE dose given alone. No dose adjustments are required for moderate CYP3A inducers (see section 4.4).

Effect of acid reducing agents

Coadministration of multiple doses of the PPI rabeprazole with a single 125 mg IBRANCE tablet under fasted conditions had no effect on the rate and extent of absorption of palbociclib when compared to a single 125 mg IBRANCE tablet administered alone.

Given the reduced effect on gastric pH of H2-receptor antagonists and local antacids compared to PPIs, no clinically relevant effect of H2-receptor antagonists or local antacids on palbociclib exposure is expected.

Effects of palbociclib on the pharmacokinetics of other medicinal products

Palbociclib is a weak, time-dependent inhibitor of CYP3A following daily 125 mg dosing at steady state. Coadministration of multiple doses of palbociclib with midazolam increased the midazolam AUCinf and Cmax values by 61% and 37%, respectively, as compared with administration of midazolam alone.

The dose of sensitive CYP3A substrates with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) may need to be reduced when coadministered with IBRANCE as IBRANCE may increase their exposure.

Drug-drug interaction between palbociclib and letrozole

Data from the drug-drug interaction (DDI) evaluation portion of a clinical study in patients with breast cancer showed that there was no drug interaction between palbociclib and letrozole when the 2 medicinal products were coadministered.

Effect of tamoxifen on palbociclib exposure

Data from a DDI study in healthy male subjects indicated that palbociclib exposures were comparable when a single dose of palbociclib was coadministered with multiple doses of tamoxifen and when palbociclib was given alone.

Drug-drug interaction between palbociclib and fulvestrant

Data from a clinical study in patients with breast cancer showed that there was no clinically relevant drug interaction between palbociclib and fulvestrant when the two medicinal products were coadministered.

Drug-drug interaction between palbociclib and oral contraceptives

DDI studies of palbociclib with oral contraceptives have not been conducted (see section 4.6).

In vitro studies with transporters

Based on in vitro data, palbociclib is predicted to inhibit intestinal P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) mediated transport. Therefore, administration of palbociclib with medicinal products that are substrates of P-gp (e.g., digoxin, dabigatran, colchicine) or BCRP (e.g., pravastatin, rosuvastatin, sulfasalazine) may increase their therapeutic effect and adverse reactions.

Based on in vitro data, palbociclib may inhibit the uptake transporter organic cationic transporter OCT1 and then may increase the exposure of medical product substrates of this transporter (e.g., metformin).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/Con­traception in males and females

Females of childbearing potential who are receiving this medicinal product, or their male partners should use adequate contraceptive methods (e.g., double-barrier contraception) during therapy and for at least 3 weeks or 14 weeks after completing therapy for females and males, respectively (see section 4.5).

Pregnancy

There are no or limited amount of data from the use of palbociclib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). IBRANCE is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

No studies have been conducted in humans or animals to assess the effect of palbociclib on milk production, its presence in breast milk, or its effects on the breastfed child. It is unknown whether palbociclib is excreted in human milk. Patients receiving palbociclib should not breast-feed.

Fertility

There were no effects on oestrous cycle (female rats) or mating and fertility in rats (male or female) in non-clinical reproductive studies. However, no clinical data have been obtained on fertility in humans. Based on male reproductive organ findings (seminiferous tubule degeneration in testis, epididymal hypospermia, lower sperm motility and density, and decreased prostate secretion) in non-clinical safety studies, male fertility may be compromised by treatment with palbociclib (see section 5.3). Thus, men may consider sperm preservation prior to beginning therapy with IBRANCE.

4.7 Effects on ability to drive and use machines

IBRANCE has minor influence on the ability to drive and use machines. However, IBRANCE may cause fatigue and patients should exercise caution when driving or using machines.

4.8 Undesirable effects

Summary of the safety profile

The overall safety profile of IBRANCE is based on pooled data from 872 patients who received palbociclib in combination with endocrine therapy (N=527 in combination with letrozole and N=345 in combination with fulvestrant) in randomised clinical studies in HR-positive, HER2-negative advanced or metastatic breast cancer.

The most common (> 20%) adverse reactions of any grade reported in patients receiving palbociclib in randomised clinical studies were neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anaemia, diarrhoea, alopecia and thrombocytopenia. The most common (> 2%) Grade > 3 adverse reactions of palbociclib were neutropenia, leukopenia, infections, anaemia, aspartate aminotransferase (AST) increased, fatigue, and alanine aminotransferase (ALT) increased.

Dose reductions or dose modifications due to any adverse reaction occurred in 38.4% of patients receiving IBRANCE in randomised clinical studies regardless of the combination.

Permanent discontinuation due to an adverse reaction occurred in 5.2% of patients receiving IBRANCE in randomised clinical studies regardless of the combination.

Tabulated list of adverse reactions

Table 4 reports the adverse reactions from the pooled dataset of 3 randomised studies. The median duration of palbociclib treatment across the pooled dataset at the time of the final OS analysis was 14.8 months.

Table 5 reports the laboratory abnormalities observed in pooled datasets from 3 randomised studies.

The adverse reactions are listed by system organ class and frequency category. Frequency categories are defined as: very common (> 1/10), common (> 1/100 to

< 1/10), and uncommon (> 1/1,000 to < 1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

ALT=alanine aminotransferase; AST=aspartate aminotransferase; ILD=interstitial lung disease;

N/n=number of patients; N/A=not applicable.

Adverse drug reaction identified post-marketing.

a PTs are listed according to MedDRA 17.1.

b Infections includes all PTs that are part of the System Organ Class Infections and infestations.

c Neutropenia includes the following PTs: Neutropenia, Neutrophil count decreased.

d Leukopenia includes the following PTs: Leukopenia, White blood cell count decreased.

e Anaemia includes the following PTs: Anaemia, Haemoglobin decreased, Haematocrit decreased.

f Thrombocytopenia includes the following PTs: Thrombocytopenia, Platelet count decreased.

g Stomatitis includes the following PTs: Aphthous stomatitis, Cheilitis, Glossitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral pain, Oropharyngeal discomfort, Oropharyngeal pain, Stomatitis.

h Rash includes the following PTs: Rash, Rash maculo-papular, Rash pruritic, Rash erythematous, Rash papular, Dermatitis, Dermatitis acneiform, Toxic skin eruption.

i ILD/pneumonitis includes any reported PTs that are part of the Standardised MedDRA Query Interstitial Lung Disease (narrow).

Table 5. Laboratory abnormalities observed in pooled dataset from 3

WBC=white blood cells; AST=aspartate aminotransferase; ALT=alanine aminotransferase; N=number of patients; N/A=not applicable.

Note: Laboratory results are graded according to the NCI CTCAE version 4.0 severity grade.

* letrozole or fulvestrant

Description of selected adverse reactions

Overall, neutropenia of any grade was reported in 716 (82.1%) patients receiving

IBRANCE regardless of the combination, with Grade 3 neutropenia being reported in 500 (57.3%) patients, and Grade 4 neutropenia being reported in 97 (11.1 %) patients (see Table 4).

The median time to first episode of any grade neutropenia was 15 days (12–700 days) and the median duration of Grade > 3 neutropenia was 7 days across 3 randomised clinical studies.

Febrile neutropenia has been reported in 0.9% of patients receiving IBRANCE in combination with fulvestrant and in 1.7% of patients receiving palbociclib in combination with letrozole.

Febrile neutropenia has been reported in about 2% of patients exposed to IBRANCE across the overall clinical programme.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

In the event of a palbociclib overdose, both gastrointestinal (e.g., nausea, vomiting) and haematological (e.g., neutropenia) toxicity may occur and general supportive care should be provided.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE33.

Mechanism of action

Palbociclib is a highly selective, reversible inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream of multiple signalling pathways which lead to cellular proliferation.

Pharmacodynamic effects

Through inhibition of CDK4/6, palbociclib reduced cellular proliferation by blocking progression of the cell from G1 into S phase of the cell cycle. Testing of palbociclib in a panel of molecularly profiled breast cancer cell lines revealed high activity against luminal breast cancers, particularly ER-positive breast cancers. In the cell lines tested, the loss of retinoblastoma (Rb) was associated with loss of palbociclib activity. However, in a follow-up study with fresh tumour samples, no relation between RB1 expression and tumour response was observed. Similarly, no relation was observed when studying the response to palbociclib in in vivo models with patient-derived xenografts (PDX models). Available clinical data are reported in the clinical efficacy and safety section (see section 5.1).

Cardiac electrophysiology

The effect of palbociclib on the QT interval corrected for heart rate (QTc) interval was evaluated using time matched electrocardiogram (ECG) evaluating the change from baseline and corresponding pharmacokinetic data in 77 patients with advanced breast cancer. Palbociclib did not prolong the QTc to any clinically relevant extent at the recommended dose of 125 mg daily (Schedule 3/1).

Clinical efficacy and safety

Randomised Phase 3 Study PALOMA-2: IBRANCE in combination with letrozole

The efficacy of palbociclib in combination with letrozole versus letrozole plus placebo was evaluated in an international, randomised, double-blind, placebo-controlled, parallel-group, multicentre study conducted in women with ER-positive, HER2-negative locally advanced breast cancer not amenable to resection or radiation therapy with curative intent or metastatic breast cancer who had not received prior systemic treatment for their advanced disease.

A total of 666 postmenopausal women were randomised 2:1 to the palbociclib plus letrozole arm or placebo plus letrozole arm and were stratified by site of disease (visceral versus nonvisceral), disease-free interval from the end of (neo)adjuvant treatment to disease recurrence (de novo metastatic versus < 12 months versus > 12 months), and by the type of prior (neo)adjuvant anticancer therapies (prior hormonal therapy versus no prior hormonal therapy). Patients with advanced symptomatic, visceral spread, that were at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver involvement), were not eligible for enrolment into the study.

Patients continued to receive assigned treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first. Crossover between treatment arms was not allowed.

Patients were well matched for baseline demographics and prognostic characteristics between the palbociclib plus letrozole arm and the placebo plus letrozole arm. The median age of patients enrolled in this study was 62 years (range 28–89), 48.3% of patients had received chemotherapy and 56.3% had received antihormonal therapy in the (neo)adjuvant setting prior to their diagnosis of advanced breast cancer while 37.2% of patients had received no prior systemic therapy in the (neo)adjuvant setting. The majority of patients (97.4%) had metastatic disease at baseline, 23.6% of patients had bone-only disease, and 49.2% of patients had visceral disease.

The primary endpoint of the study was progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, as assessed by investigator. Secondary efficacy endpoints included objective response (OR), clinical benefit response (CBR), safety, and change in quality of life (QoL).

At the data cutoff date of 26-February-2016, the study met its primary objective of improving PFS. The observed hazard ratio (HR) was 0.576 (95% confidence interval [CI]: 0.46, 0.72) in favour of palbociclib plus letrozole, with a stratified log-rank test 1-sided p-value of < 0.000001. An updated analysis of the primary and secondary endpoints was performed after an additional 15 months of follow up (data cutoff date: 31-May-2017). A total of 405 PFS events were observed; 245 events (55.2%) in the palbociclib plus letrozole arm and 160 (72.1%) in the comparator arm respectively.

Table 6 shows the efficacy results based on the primary and the updated analyses from the PALOMA-2 study, as assessed by the investigator and by the independent review.

Table 6. PALOMA-2 (intent-to-treat population) – Efficacy results based on primary

and updated cutoff dates

N=number of patients; CI=confidence interval; NE=not estimable; OR=objective response; CBR=clinical benefit response; PFS=progression-free survival.

* Secondary endpoints results are based on confirmed and unconfirmed responses according to RECIST 1.1.

The Kaplan-Meier curves for PFS based on the updated cutoff date of 31 May 2017 are displayed in Figure 1 below.

Figure 1. Kaplan-Meier plot of progression-free survival (investigator

assessment, intent-to-treat population) – PALOMA-2 study (31-May-

A series of prespecified subgroup PFS analyses was performed based on prognostic factors and baseline characteristics to investigate the internal consistency of treatment effect. A reduction in the risk of disease progression or death in favour of the palbociclib plus letrozole arm was observed in all individual patient subgroups defined by stratification factors and baseline characteristics in the primary and in the updated analysis.

Based on the 31-May-2017 data cutoff date, this reduction in risk continued to be observed in the following subgroups: (1) patients with either visceral metastases (HR of 0.62 [95% CI: 0.47, 0.81], median progression-free survival [mPFS] 19.3 months versus 12.3 months) or without visceral metastases (HR of 0.50 [95% CI: 0.37, 0.67], mPFS 35.9 months versus 17.0 months) and (2) patients with either bone only disease (HR of 0.41 [95% CI: 0.26, 0.63], mPFS 36.2 months versus 11.2 months) or without bone-only disease (HR of 0.62 [95% CI: 0.50, 0.78], mPFS 24.2 months versus 14.5 months). Similarly, a reduction in the risk of disease progression or death in the palbociclib plus letrozole arm was observed in 512 patients whose tumour tested positive for Rb protein expression by immunohistoche­mistry (IHC) (HR of 0.543 [95% CI: 0.433, 0.681], mPFS 27.4 months versus 13.7 months). For the 51 patients IHC negative for Rb expression, the difference between treatment arms was not statistically significant (HR of 0.868 [95% CI: 0.424, 1.777], mPFS 23.2 versus 18.5 months) for the palbociclib plus letrozole arm versus the placebo plus letrozole arm, respectively.

Additional efficacy measures (OR and time to response [TTR]) assessed in the subgroups of patients with or without visceral disease based on the 31-May-2017 updated cutoff date are displayed in Table 7.

Table 7. Efficacy results in patients with visceral or non-visceral disease from

N=number of patients; CI=confidence interval; OR=objective response based on confirmed and unconfirmed responses according to RECIST 1.1; TTR=time to first tumour response.

At the time of the updated analyses, the median time from randomisation to second subsequent therapy was 38.8 months in the palbociclib + letrozole arm and 28.8 months in the placebo + letrozole arm, HR 0.73 (95% CI: 0.58, 0.91).

Randomised Phase 3 Study PALOMA-3: IBRANCE in combination with fulvestrant

The efficacy of palbociclib in combination with fulvestrant versus fulvestrant plus placebo was evaluated in an international, randomised, double-blind, parallel-group, multicentre study conducted in women with HR-positive, HER2-negative locally advanced breast cancer not amenable to resection or radiation therapy with curative intent or metastatic breast cancer, regardless of their menopausal status, whose disease progressed after prior endocrine therapy in the (neo)adjuvant or metastatic setting.

A total of 521 pre/peri- and postmenopausal women who had progressed on or within 12 months from completion of adjuvant endocrine therapy or on or within 1 month from prior endocrine therapy for advanced disease, were randomised 2:1 to palbociclib plus fulvestrant or placebo plus fulvestrant and stratified by documented sensitivity to prior hormonal therapy, menopausal status at study entry (pre/peri-versus postmenopausal), and presence of visceral metastases. Pre/perimenopausal women received the LHRH agonist goserelin. Patients with advanced/metas­tatic, symptomatic, visceral spread, that were at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver involvement), were not eligible for enrolment into the study.

Patients continued to receive assigned treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first. Crossover between treatment arms was not allowed.

Patients were well matched for baseline demographics and prognostic characteristics between the palbociclib plus fulvestrant arm and the placebo plus fulvestrant arm. The median age of patients enrolled in this study was 57 years (range 29, 88). In each treatment arm the majority of patients were White, had documented sensitivity to prior hormonal therapy, and were postmenopausal. Approximately 20% of patients were pre/perimenopausal. All patients had received prior systemic therapy and most patients in each treatment arm had received a previous chemotherapy regimen for their primary diagnosis. More than half (62%) had an ECOG PS of 0, 60% had visceral metastases, and 60% had received more than 1 prior hormonal regimen for their primary diagnosis.

The primary endpoint of the study was investigator-assessed PFS evaluated according to RECIST 1.1. Supportive PFS analyses were based on an Independent Central Radiology Review. Secondary endpoints included OR, CBR, OS, safety, and time-to-deterioration (TTD) in pain endpoint.

The study met its primary endpoint of prolonging investigator-assessed PFS at the interim analysis conducted on 82% of the planned PFS events; the results crossed the prespecified Haybittle-Peto efficacy boundary (a=0.00135), demonstrating a statistically significant prolongation in PFS and a clinically meaningful treatment effect.

A more mature update of efficacy data is reported in Table 8.

After a median follow-up time of 45 months, the final OS analysis was performed based on 310 events (60% of randomised patients). A 6.9-month difference in median OS in the palbociclib plus fulvestrant arm compared with the placebo plus fulvestrant arm was observed; this result was not statistically significant at the prespecified significance level of 0.0235 (1-sided). In the placebo plus fulvestrant arm, 15.5% of randomised patients received palbociclib and other CDK inhibitors as post progression subsequent treatments.

The results from the investigator-assessed PFS and final OS data from PALOMA-3 study are presented in Table 8. The relevant Kaplan-Meier plots are shown in Figures 2 and 3, respectively.

Table 8. Efficacy results – PALOMA-3 study (investigator assessment, intent-

to-treat population)

CBR=clinical benefit response; CI=confidence interval; N=number of patients; OR=objective response. Secondary endpoint results are based on confirmed and unconfirmed responses according to RECIST 1.1. *

Not statistically significant. t. , ,     ,             ,       ..... ← ,,                      ■      ,    ..        ,     .......

1-sided p-value from the log-rank test stratified by the presence of visceral metastases and sensitivity to prior endocrine therapy per randomisation.

Figure 2. Kaplan-Meier plot of progression-free survival (investigator

assessment, intent-to-treat population) – PALOMA-3 study (23

FUL=fulvestrant; PAL=palbociclib; PCB=placebo.

A reduction in the risk of disease progression or death in the palbociclib plus fulvestrant arm was observed in all individual patient subgroups defined by stratification factors and baseline characteristics. This was evident for pre/perimenopausal women (HR of 0.46 [95% CI: 0.28, 0.75]) and postmenopausal women (HR of 0.52 [95% CI: 0.40, 0.66]) and patients with visceral site of metastatic disease (HR of 0.50 [95% CI: 0.38, 0.65]) and non-visceral site of metastatic disease (HR of 0.48 [95% CI: 0.33, 0.71]). Benefit was also observed regardless of lines of prior therapy in the metastatic setting, whether 0 (HR of 0.59 [95% CI: 0.37, 0.93]), 1 (HR of 0.46 [95% CI: 0.32, 0.64]), 2 (HR of 0.48 [95% CI: 0.30, 0.76]), or > 3 lines (HR of 0.59 [95% CI: 0.28, 1.22]).

PAL+FUL 347    321     286    247    209     165     148     126 17

PCB+FUL 174     155     135     115     86     68     57     43 7

FUL=fulvestrant; PAL=palbociclib; PCB=placebo.

Additional efficacy measures (OR and TTR) assessed in the sub-groups of patients with or without visceral disease are displayed in Table 9.

Table 9. Efficacy results in visceral and non-visceral disease from PALOMA-3 study

(intent-to-treat population)

N=number of patients; CI=confidence interval; OR=objective response based on confirmed and unconfirmed responses according to RECIST 1.1; TTR=time to first tumour response.

Patient-reported symptoms were assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and its Breast Cancer Module (EORTC QLQ-BR23). A total of 335 patients in the palbociclib plus fulvestrant arm and 166 patients in the fulvestrant only arm completed the questionnaire at baseline and at least 1 postbaseline vi­sit.

Time-to-Deterioration was prespecified as time between baseline and first occurrence of > 10 points increase from baseline in pain symptom scores. Addition of palbociclib to fulvestrant resulted in a symptom benefit by significantly delaying time-to-deterioration in pain symptom compared with placebo plus fulvestrant (median 8.0 months versus 2.8 months; HR of 0.64 [95% CI: 0.49, 0.85]; p< 0.001).

The European Medicines Agency has waived the obligation to submit the results of studies with IBRANCE in all subsets of the paediatric population in the treatment of breast carcinoma (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Microcrystalline cellulose

Colloidal silicon dioxide

Crospovidone

Magnesium stearate

Succinic acid

Film-coating

Hypromellose (E464)

Titanium dioxide (E171)

Triacetin

Indigo carmine aluminum lake (E132)

Iron oxide red (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions.

Store in the original blister package in order to protect from moisture.

6.5 Nature and contents of container

PVC/OPA/Al/PVC/Al blister card containing 7 film-coated tablets (1 film-coated tablet per cell). Each carton contains 21 film-coated tablets (3 blister cards per carton) or 63 film-coated tablets (9 blister cards per carton).

PVC/OPA/Al/PVC/Al blister card containing 7 film-coated tablets (1 film-coated tablet per cell) in a wallet card. Each carton contains 21 film-coated tablets (3 wallet cards per carton).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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