Comparative effectiveness of first line palbociclib plus letrozole vs. letrozole alone for hormone-receptor positive metastatic breast cancer in real world clinical practice

March 2022 Jolien Blokken
(sponsored)

Results of a comparative effectiveness analysis in a large, heterogenous real-world population of women with hormone-receptor positive (HR+), HER2-negative (HER2-) metastatic breast cancer demonstrate that first line treatment with a combination of palbociclib and letrozole significantly delays disease progression and pro longs survival compared to letrozole alone.1 As such, these real-world findings further solidify palbociclib + letrozole as a preferred first line treatment in this setting.1

Introduction

Backed by the results of multiple randomized phase III trials, combinations of a cyclin dependent kinase (CDK) 4/6 inhibitor and endocrine therapy (i.e. an aromatase inhibitor or fulvestrant) have become the standard of care in the first- and second-line treatment of women with HR+/HER2- metastatic breast cancer.2 Palbociclib was the first CDK4/6 inhibitor to enter the therapeutic armory for these patients.3 The registration of palbociclib by both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) was based on the convincing results of the pivotal PALOMA-1, PALOMA-2 and PALOMA-3 trials. In PALOMA-1 and -2, the addition of palbociclib to letrozole as initial treatment for postmenopausal women with advanced HR+/HER2- breast cancer resulted in a significant delay in the occurrence of disease progres sion.4-7 Similarly, the PALOMA-3 trial showed that the combination of palbociclib + fulvestrant was associated with a significantly better progression-free survival (PFS) compared to fulvestrant alone in the treatment of pre- and postmenopausal women who suffered disease progression after endocrine therapy.8,9 In both PALOMA-1 and PALOMA-3, this bene fit in PFS also translated into a clinically relevant, though statistically not significant, prolongation in median overall survival (OS).5,10 For PALOMA-2, data on OS are not yet available.

While the results obtained in the previously mentioned clinical trials strongly support the use of palbociclib in patients with HR+/HER2- metastatic breast cancer, it remains important to gain insights into how this treatment performs in daily clinical practice. In fact, real-world evidence is essential to evaluate the generalizability of clinical trial findings across a more heterogeneous patient population, including patients who would not have met the inclusion criteria of the registrational clinical trials.1 Previously reported real-world data on palbociclib indicated a consistent efficacy and safety to what was observed in clinical trials. Unfortunately, however, small sample sizes, a lack of a control group, and/or short patient follow-up limit the clinical persuasiveness of these findings.11-13 In order to generate more reliable real-life data, the effectiveness of palbociclib plus letrozole was compared to letrozole alone in a large cohort of HR+/HER2- breast cancer patients treated across the USA.1

An expert’s opinion

Prof. dr. Hannelore Denys; University Hospital Ghent

Randomized clinical trials typically use (very) restrictive inclusion criteria, resulting in a patient population that is not always very representa tive for the daily clinical practice. In fact, a large propor tion of patients that we are treating on a daily basis would not have been eligible for the pivotal clinical trials that form the basis for the registration of the drugs with which they are being treated. In this context it is no surprise to see that real-life data, generated in patient populations that better reflect our daily practice, are becoming increasingly important in the onco logical community. The analysis of the Flatiron data base discussed here is of particular interest given the fact that it contains a high number of patients (>1400) coming from a broad range of clinical centers.

The analysis at hand con vincingly demonstrates that first line treatment with a com-bination of palbociclib and letrozole significantly delays disease progression and prolongs survival compared to letrozole alone in patients with HR+, HER2- metastatic breast cancer. Interestingly, the over-all survival (OS) benefit obtained with palbociclib proved to be statistically significant, irrespective of the statistical analysis that was used which further underscores the robustness of these data. In expec tation of OS data from the phase III PALOMA-2 trial, this analysis provides physicians with the assurance that the delayed disease progression i nduced by palbociclib translates into a significant survival benefit for our patients. Combined with the significant OS advantage that was already reported with the other CDK4/6 inhibitors in this setting, these data further solidify the combination of a CDK4/6 inhibitor in combination with an aromatase inhibitor as the preferred first line treatment for women with HR+/HER2- metastatic breast cancer.

Comparing the effectiveness of palbociclib + letrozole vs. letrozole alone in reallife

The presented retrospective, observational analysis used electronic health records of HR+/HER2- metastatic breast cancer patients enrolled in the Flatiron health analytic database who were treated with either first line palbociclib + letrozole (N= 772) or letrozole alone (N= 658). Patients initiated their treatment between February 2015 and February 2019. At the time of the analysis, the median followup was 24.2 months. The primary outcome of the s tudy consisted of real-world PFS (rwPFS), with rwOS as a secondary objective. Comparative analyses were con ducted using three statistical methods: an un ad justed analysis, a stabilized inverse probability treatm ent weighting (sIPTW) analysis and an ana lysis using propensity score matching (PSM). While the unadjusted analysis did not control for confounders, the two latter methods do balance baseline demographic and clinical characteristics between the two cohorts and adjust for differences in potential confounders.1 PSM is a statistical matching technique that aims at to eliminating or reduce bias in real-world studies caused by a lack of randomization. With this technique, every patient in the experimental cohort is matched to a patient with similar characteristics in the control group. Patients for whom no match is found are excluded from the analysis.14 Also sIPTW is a statistical method that is being used to minimize bias in real-world studies. In contrast to PSM, however sIPTW uses a pseudo-population in which all patients are weighed according to the inverse of their probability to receive a certain treatment (based on the propensity score).14,15 As a result, sIPTW enables all eligible subjects to be included, preserving the overall sample size of original data.16 In the study at hand, this sIPTW approach was used as the primary analysis.

Palbociclib + letrozole associated with a consistent rwPFS and rwOS benefit over letrozole alone

In the overall study population, patient and disease characteristics differed substantially between the palbociclib + letrozole and letrozole alone groups. In fact, patients in the palbociclib + letrozole cohort were generally younger and had better performance status. This cohort was also characterized by a higher incidence of visceral disease and patients tended to have a greater number of metastatic sites. After sIPTW adjustment these characteristics were generally well-balanced. It was also the case between propensity score-matched cohorts.1 In the unadjusted analysis a median rwPFS of 19.7 months was reported with palbociclib + letrozole, which is significantly longer than the 11.9 months median rwPFS seen with letrozole alone (HR[95%CI]: 0.59[0.51-0.67]; p< 0.0001). This finding was solidified when the sIPTW method was used. In this analysis, palbociclib + letrozole and letrozole alone were associated with a median rwPFS of 20.0 and 11.9 months, respectively. This translates into a statistically significant 42% reduction in the risk of disease progression or death for patients treated with palbociclib and letrozole compared to letrozole alone (HR[95%CI]: 0.58[0.49-0.69]; p< 0.0001) . In a subsequent sensitivity analysis using the PSM method (N= 928), similar results were found with a median rwPFS of 20.2 and 11.9 months for palbociclib + letrozole and letrozole alone, respectively (HR[95%- CI]: 0.54 [0.46–0.65]; p< 0.0001).1 Importantly, the rwPFS benefit obtained from adding palbociclib to letrozole was consistently seen across different subgroups, irrespective of age, the presence of visceral metastases and whether or not patients had bone-only disease (Figure 2).1

Figure 2. Consistent rwPFS benefit of palbociclib + letrozole vs. letrozole alone after sIPTW across the different subgroups.1

In terms of OS, the unadjusted analysis revealed a median rwOS of 40.3 months for patients treated with letrozole alone, while the median was not yet reached for patients receiving palbociclib + letrozole (HR[95%CI]: 0.63[0.54-0.75]; p< 0.0001). Also in the sIPTW-adjusted analysis, the median rwOS was not yet reached for patients who received palbociclib + letrozole as compared to 43.1 months for patients in the letrozole alone cohort (HR[95%CI]: 0.66[0.53– 0.82]; p= 0.0002) (Figure 3). At the three-year landmark, of follow-up, 64.8% of patients in the palbociclib group were still alive as compared to 53.2% in the letrozole group. As for rwPFS, PSM results for rwOS confirm the findings of the sIPTW analysis. The benefit in rwOS obtained with palbociclibletrozole also proved to be consistent in most of the investigated subgroups.1

Conclusions

In this comparative effectiveness analysis, first-line palbociclib + letrozole was associated with a significantly longer rwPFS and rwOS than letrozole alone in a heterogeneous population and among various patient subgroups. The rwPFS benefit of palbociclib + letrozole over letrozole alone in this analysis (HR: 0.58) is consistent with what has been reported in the PALOMA-2 trial (HR: 0.56).6,7,1 As such, these findings further support the use of palbociclib in combination with an aromatase inhibitor as a first-line treatment for patients with HR+/HER2− metastatic breast cancer.

Congress report supported by Pfizer. The content of this report only reflects the views of the speakers during the congress – 210604 june 2021.

References

  1. DeMichele A, et al. Breast Canc Res 2021;23(1):37.
  2. Cardoso F, et al. Ann Oncol 2018;29(8):1634-57.
  3. https://www.ema.europa.eu/en/medicines/human/EPAR/ibrance
  4. Finn R, et al. Lancet Oncol 2015;16(1):25-35.
  5. Finn R, et al. Breast Cancer Res Treat 2020;183(2):419-28.
  6. Finn R, et al. N Engl J Med 2016;375(20):1925-36.
  7. Rugo H, et al. Breast Cancer Res Treat 2019;174(3):719-29.
  8. Turner N, et al. N Engl J Med 2015;373(3):209-19
  9. Loibl S, et al. Oncologist 2017;22(9):1028-38.
  10. Turner N, et al. N Engl J Med 2018;379(20):1926-36.
  11. Varlella L, et al. Breast Cnacer Res Treat 2019;176(2):429-34.
  12. Xi J, et al. J Natl Compr Cancer Netw 2019;17(2):141-7.
  13. Bui T, et al. Breast Cancer (Ackl.) 2019;13:1-6.
  14. Austin P. Multivariate Behav Res 2011;46(3):399-424.
  15. Pezzi A, et al. BMC Med Res Methodol 2016;16(1):150.
  16. Xu S, et al. Value Health 2010;13(2):273-7.

NAME OF THE MEDICINAL PRODUCT: IBRANCE 75 mg, 100 mg and 125 mg hard capsules. QUALITATIVE AND QUANTITATIVE COMPOSITION: Each hard capsule contains 75 mg, 100 mg or 125 mg of palbociclib. Excipients with known effect: Each hard capsule contains 56 mg, 74 mg and 93 mg of lactose (as monohydrate) respectively. PHARMACEUTICAL FORM: Hard capsule. IBRANCE 75 mg hard capsules: Opaque, hard capsule, with a light orange body (printed “PBC 75” in white) and a light orange cap (printed “Pfizer” in white). The capsule length is 18.0 ± 0.3 mm. IBRANCE 100 mg hard capsules: Opaque, hard capsule, with a light orange body (printed “PBC 100” in white) and a caramel cap (printed “Pfizer” in white). The capsule length is 19.4 ± 0.3 mm. IBRANCE 125 mg hard capsules: Opaque, hard capsule, with a caramel body (printed “PBC 125” in white) and a caramel cap (printed “Pfizer” in white). The capsule length is 21.7 ± 0.3 mm. CLINICAL PARTICULARS: 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; or in combination with fulvestrant in women who have received prior endocrine therapy. In pre‑ or perimenopausal women, the endocrine therapy should be combined with a luteinizing hormone‑releasing hormone (LHRH) agonist. 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 recommended dose of letrozole is 2.5 mg taken orally once daily continuously throughout the 28‑day cycle. Please refer to the Summary of Product Characteristics of letrozole. Treatment of pre/perimenopausal women with the combination of palbociclib plus letrozole should always be combined with an LHRH agonist. 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 hereafter. IBRANCE recommended dose modifications for adverse reactions: Recommended dose: 125 mg/day. First dose reduction : 100 mg/day. Second dose reduction: 75 mg/day (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 IBRANCEIBRANCE dose modification and management – Haematological toxicities: CTCAE Grade 1 or 2: No dose adjustment is required. CTCAE Grade 3a: Day 1 of cycle: Withhold IBRANCE, until recovery to Grade ≤2, and repeat complete blood count monitoring within 1 week. When recovered to Grade ≤2, start the next cycle at the same dose. Day 15 of first 2 cycles: If Grade 3 on Day 15, continue IBRANCE at the current dose to complete cycle and repeat complete blood count on Day 22. If Grade 4 on Day 22, see Grade 4 dose modification guidelines below. Consider dose reduction in cases of prolonged (>1 week) recovery from Grade 3 neutropenia or recurrent Grade 3 neutropenia on Day 1 of subsequent cycles. CTCAE Grade 3 ANCb (<1,000 to 500/mm3) + Fever ≥38.5 ºC and/or infection: At any time: Withhold IBRANCE until recovery to Grade ≤2. Resume at next lower dose. CTCAE Grade 4a: At any time: Withhold IBRANCE until recovery to Grade ≤2. Resume at next lower dose. Grading according to CTCAE 4.0. ANC=absolute neutrophil counts; CTCAE=Common Terminology Criteria for Adverse Events; LLN=lower limit of normal. a 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 1000 ‑ <1,500/mm3; Grade 3: ANC 500 ‑ <1,000/mm3; Grade 4: ANC <500 mm3IBRANCE dose modification and management – Non-haematological toxicities: CTCAE Grade 1 or 2: No dose adjustment is required. CTCAE Grade ≥3 non‑haematological toxicity (if persisting despite medical treatment): Withhold until symptoms resolve to Grade ≤1 or Grade ≤2 (if not considered a safety risk for the patient). Resume at the next lower dose. 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. Special populations: Elderly: No dose adjustment of IBRANCE is necessary in patients ≥65 years of age. Hepatic impairment: No dose adjustments of IBRANCE are 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 Renal impairment: No dose adjustments of IBRANCE are 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. 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. It should be taken with food, preferably a meal to ensure consistent palbociclib exposure. Palbociclib should not be taken with grapefruit or grapefruit juice. IBRANCE capsules should be swallowed whole (should not be chewed, crushed, or opened prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact. Contraindications: Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 of the SmPC. Use of preparations containing St. John’s Wort. 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. 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. 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. 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. 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. Patients should be monitored for signs and symptoms of infection and treated as medically appropriate. 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. Renal impairment: IBRANCE should be administered with caution to patients with moderate or severe renal impairment with close monitoring of signs of toxicity. Concomitant treatment with inhibitors or inducers of CYP3A4: Strong inhibitors of CYP3A4 may lead to increased toxicity. 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. 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. 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. Lactose: This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose‑galactose malabsorption should not take this medicinal product. Sodium: This medicinal product contains less than 1 mmol (23 mg) sodium per capsule, that is to say essentially ‘sodium‑free’. 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. No dose adjustments are needed for mild and moderate CYP3A inhibitors. Effect of CYP3Ainducers: 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. 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. Effect of acid reducing agents: Under fed conditions (intake of a moderate‑fat meal), coadministration of multiple doses of the proton pump inhibitor (PPI) rabeprazole with a single dose of 125 mg IBRANCE decreased palbociclib Cmax by 41%, but had limited impact on AUCinf (13% decrease) compared with a single dose of 125 mg IBRANCE administered alone. Under fasting conditions, the coadministration of multiple doses of the PPI rabeprazole with a single dose of 125 mg IBRANCE decreased palbociclib AUCinf and Cmax by 62% and 80%, respectively. Therefore, IBRANCE should be taken with food, preferably a meal. 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 when palbociclib is taken with food. 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. In vitro studies with transporters: Based on in vitro data, palbociclib is predicted to inhibit intestinal P‑glycoprotein (P‑gp) 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). 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. List of adverse reactions: Adverse reactions that were reported in the pooled dataset of 3 randomised studies are listed below. The median duration of palbociclib treatment across the pooled dataset at the time of the final overall survival (OS) analysis was 14.8 months. The adverse reactions are listed by system organ class, frequency category and preferred terma (PT). 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. Further, the adverse reactions are listed by grade of severity (n (%), for all grades (A), grade 3 (3), grade 4 (4)). Adverse reactions based on pooled dataset from 3 randomised studies (N=872): Infections and infestations: Very common: InfectionsbA: 516 (59.2), 3: 49 (5.6), 4: 8 (0.9); Blood andlymphatic system disorders: Very common: NeutropeniacA: 716 (82.1), 3: 500 (57.3), 4: 97 (11.1); LeukopeniadA: 424 (48.6), 3: 254 (29.1), 4: 7 (0.8); AnaemiaeA: 258 (29.6), 3: 45 (5.2), 4: 2 (0.2%); ThrombocytopeniafA: 194 (22.2), 3: 16 (1.8), 4: 4 (0.5); Common: Febrile neutropenia A: 12 (1.4%), 3: 10 (1.1%), 4: 2 (0.2%); Metabolism and nutrition disorders: Very common: Decreased appetite A: 152 (17.4 %), 3: 8 (0.9%), 4: 0 (0.0%); Nervous system disorders: Common: Dysgeusia A: 79 (9.1%), 3: 0 (0.0%), 4: 0 (0.0%); Eye disorders: Common: Vision blurred A: 48 (5.5%), 3: 1 (0.1%), 4: 0 (0.0%); Lacrimation increased A: 59 (6.8%), 3: 0 (0.0%), 4: 0 (0.0%); Dry eye A: 36 (4.1%), 3: 0 (0.0%), 4: 0 (0.0%); Respiratory, thoracic and mediastinal disorders: Common: Epistaxis A: 77 (8.8%), 3: 0 (0.0%), 4: 0 (0.0%); ILD/pneumonitis,iA: 12 (1.4%), 3: 1 (0.1%), 4: 0 (0.0%); Gastrointestinal disorders: Very common: StomatitisgA: 264 (30.3%), 3: 8 (0.9%), 4: 0 (0.0%); Nausea A: 314 (36.0%), 3: 5 (0.6%), 4: 0 (0.0%); Diarrhoea A: 238 (27.3%), 3: 9 (1.0%), 4: 0 (0.0%); Vomiting: A: 165 (18.9%), 3: 6 (0.7%), 4: 0 (0.0%); Skin and subcutaneous tissue disorders: Very common: RashhA: 158 (18.1%), 3: 7 (0.8%), 4: 0 (0.0%); Alopecia A: 234 (26.8%), 3: N/A, 4: N/A;Dry skin: A: 93 (10.7%), 3: 0 (0.0%), 4: 0 (0.0%); Uncommon: Cutaneous lupus erythematosusiA: 1 (0,1), 3: 0 (0,0), 4: 0 (0,0) General disorders and administration site conditions: Very common: Fatigue A: 362 (41.5%), 3: 23 (2.6%), 4: 2 (0.2%); Asthenia A: 118 (13.5%), 3: 14 (1.6%), 4: 1 (0.1%); Pyrexia: A: 115 (13.2%), 3: 1 (0.1%), 4: 0 (0.0%); Investigations: Very common: ALT increased A: 92 (10.6%), 3: 18 (2.1%), 4: 1 (0.1%); AST Increased A: 99 (11.4%), 3: 25 (2.9%), 4: 0 (0.0%). ALT=alanine aminotransferase; AST=aspartate aminotransferase; ILD=interstitial lung disease; N/n=number of patients; N/A=not applicable. aPTs are listed according to MedDRA 17.1. bInfections includes all PTs that are part of the System Organ Class Infections and infestations. cNeutropenia includes the following PTs: Neutropenia, Neutrophil count decreased. dLeukopenia includes the following PTs: Leukopenia, White blood cell count decreased. eAnaemia includes the following PTs: Anaemia, Haemoglobin decreased, Haematocrit decreased. fThrombocytopenia 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. hRash includes the following PTs: Rash, Rash maculo‑papular, Rash pruritic, Rash erythematous, Rash papular, Dermatitis, Dermatitis acneiform, Toxic skin eruption. iAdverse drug reaction identified post marketing, ILD/pneumonitis includes any reported PTs that are part of the Standardised MedDRA Query Interstitial Lung Disease (narrow). Laboratory abnormalities that were observed in pooled datasets from 3 randomized studies are listed below. The laboratory abnormalities are listed by grade of severity (% for all grades (A), grade 3 (3), grade 4 (4)). Laboratory abnormalities observed in pooled dataset from 3 randomised studies (N=872): WBC decreased: IBRANCE plus letrozole or fulvestrant: A: 97.4, 3: 41.8, 4: 1.0; Comparator arms*: A: 26.2, 3: 0.2 4: 0.2; Neutrophils decreased: IBRANCE plus letrozole or fulvestrant: A: 95.6, 3: 57.5, 4: 11.7; Comparator arms*: A: 17.0, 3: 0.9, 4: 0.6; Anaemia: IBRANCE plus letrozole or fulvestrant: A: 80.1, 3: 5.6, 4: N/A; Comparator arms*: A: 42.1, 3: 2.3, 4: N/A; Platelets decreased: IBRANCE plus letrozole or fulvestrant: A: 65.2, 3: 1.8, 4: 0.5; Comparator arms*: A: 13.2, 3: 0.2, 4: 0.0; AST increased: IBRANCE plus letrozole or fulvestrant: A: 55.5, 3: 3.9, 4: 0.0; Comparator arms*: A: 43.3, 3: 2.1, 4: 0.0; ALTincreased: IBRANCE plus letrozole or fulvestrant: A: 46.1, 3: 2.5, 4: 0.1; Comparator arms*: A: 33.2, 3: 0.4, 4: 0.0. 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 above). 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 Federal Agency for Drugs and Health Products – Vigilance Department, Galileelaan – Avenue Galilée 5/03, 1210 Brussels (website: www.eenbijwerkingmelden.be www.notifieruneffetindesirable.be; e-mail: adr@fagg-afmps.be)MARKETING AUTHORISATION HOLDER: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Brussels, Belgium. MARKETING AUTHORISATION NUMBER(S): EU/1/16/1147/001 to EU/1/16/1147/009. DELIVERY: On medical prescription. DATE OF REVISION OF THE TEXT: 07/2021. Detailed information on this medical product is available on the website of the European Medicines Agency: http://www.ema.europa.eu/

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