Ibrance

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EF01. 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 Primary analysis (26 February 2016 cutoff) Updated analysis (31 May 2017 cutoff) IBRANCE plus letrozole (N = 444) Placebo plus letrozole (N = 222) IBRANCE plus letrozole (N = 444) Placebo plus letrozole (N = 222) Progression-free survival by investigator assessment Number of events (%) 194 (43.7) 137 (61.7) 245 (55.2) 160 (72.1) Median PFS [months (95% CI)] 24.8 (22.1, NE) 14.5 (12.9, 17.1) 27.6 (22.4, 30.3) 14.5 (12.3, 17.1) Hazard ratio [(95% CI) and p-value] 0.576 (0.463, 0.718), p< 0.000001 0.563 (0.461, 0.687), p< 0.000001 Progression-free survival by independent assessment Number of events (%) 152 (34.2) 96 (43.2) 193 (43.5) 118 (53.2) Median PFS [months (95% CI)] 30.5 (27.4, NE) 19.3 (16.4, 30.6) 35.7 (27.7, 38.9) 19.5 (16.6, 26.6) Hazard ratio (95% CI) and 1-sided p-value 0.653 (0.505, 0.844), p=0.000532 0.611 (0.485, 0.769), p=0.000012 OR* [% (95% CI)] 46.4 (41.7, 51.2) 38.3 (31.9, 45.0) 47.5 (42.8, 52.3) 38.7(32.3, 45.5) OR* measurable disease [% (95% CI)] 60.7 (55.2, 65.9) 49.1 (41.4, 56.9) 62.4 (57.0, 67.6) 49.7 (42.0, 57.4) CBR* [% (95% CI)] 85.8 (82.2, 88.9) 71.2 (64.7, 77.0) 85.6 (82.0, 88.7) 71.2 (64.7, 77.0) 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-2017) 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 sub-groups 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 PALOMA–2 study (intent-to-treat population; 31-May-2017 cutoff date) Visceral disease Non-visceral disease IBRANCE plus letrozole (N=214) Placebo plus letrozole (N=110) IBRANCE plus letrozole (N=230) Placebo plus letrozole (N=112) OR [% (95% CI)] 59.8 (52.9, 66.4) 46.4 (36.8, 56.1) 36.1 (29.9, 42.7) 31.3 (22.8, 40.7) TTR, Median [months (range)] 5.4 (2.0, 30.4) 5.3 (2.6, 27.9) 3.0 (2.1, 27.8) 5.5 (2.6, 22.2) 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). The results from the final OS analysis from the PALOMA-2 study are presented in Table 8. After a median follow-up time of 90 months, the final OS results were not statistically significant. The Kaplan-Meier plot of OS is shown in Figure 2. Table 8. PALOMA-2 (intent-to-treat population) – Final overall survival results Final Overall Survival (OS) (15 November 2021 Cutoff) IBRANCE plus letrozole (N=444) Placebo plus letrozole (N=222) Number of events (%) 273 (61.5) 132 (59.5) Number of subjects remaining in follow-up (%) 112 (25.2) 43 (19.4) Median OS (months [95% CI]) 53.9 (49.8, 60.8) 51.2 (43.7, 58.9) Hazard ratio (95% CI) and p-value † 0.956 (0.777, 1.177), p=0.6755 †* CI=confidence interval. * Not statistically significant. † 2-sided p-value from the log-rank test stratified by disease site (visceral vs. non-visceral) per randomisation. Figure 2. Kaplan-Meier plot of overall survival (intent-to-treat population) -PALOMA-2 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 (α=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 9. 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 9. The relevant Kaplan-Meier plots are shown in Figures 3 and 4, respectively. Table 9. Efficacy results – PALOMA-3 study (investigator assessment, intent-to-treat population) Updated analysis (23 October 2015 cutoff) IBRANCE plus fulvestrant (N=347) Placebo plus fulvestrant (N=174) Progression-free survival (PFS) Number of events (%) 200 (57.6) 133 (76.4) Median [months (95% CI)] 11.2 (9.5, 12.9) 4.6 (3.5, 5.6) Hazard ratio (95% CI) and p-value 0.497 (0.398, 0.620), p< 0.000001 Secondary efficacy endpoints OR [% (95% CI)] 26.2 (21.7, 31.2) 13.8 (9.0, 19.8) OR (measurable disease) [% (95% CI)] 33.7 (28.1, 39.7) 17.4 (11.5, 24.8) CBR [% (95% CI)] 68.0 (62.8, 72.9) 39.7 (32.3, 47.3) Final overall survival (OS) (13 April 2018 cutoff) Number of events (%) 201 (57.9) 109 (62.6) Median [months (95% CI)] 34.9 (28.8, 40.0) 28.0 (23.6, 34.6) Hazard ratio (95% CI) and p-value † 0.814 (0.644, 1.029) p=0.0429 †* 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. † 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 3. Kaplan-Meier plot of progression-free survival (investigator assessment, intent-to-treat population) – PALOMA-3 study (23 October 2015 cutoff) 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]). Figure 4. Kaplan-Meier plot of overall survival (intent-to-treat population) – PALOMA-3 study (13 April 2018 cutoff) Additional efficacy measures (OR and TTR) assessed in the sub-groups of patients with or without visceral disease are displayed in Table 10. Table 10. Efficacy results in visceral and non-visceral disease from PALOMA–3 study (intent-to-treat population) Visceral disease Non-visceral disease IBRANCE plus fulvestrant (N=206) Placebo plus fulvestrant (N=105) IBRANCE plus fulvestrant (N=141) Placebo plus fulvestrant (N=69) OR [%, (95% CI)] 35.0 (28.5, 41.9) 13.3 (7.5, 21.4) 13.5 (8.3, 20.2) 14.5 (7.2, 25.0) TTR, Median [months (range)] 3.8 (3.5, 16.7) 5.4 (3.5, 16.7) 3.7 (1.9, 13.7) 3.6 (3.4, 3.7) 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). Paediatric population An open-label, randomised Phase 2 portion of study A5481092 compared the efficacy of the combination of palbociclib with irinotecan (IRN) and temozolomide (TMZ) versus IRN and TMZ alone in the treatment of paediatric (2 to <18 years of age) and young adults (18 to 20 years of age) with r/r EWS for whom no standard therapy is available. The prespecified interim analysis was performed based on 33 event free survival (EFS) events (61.1% of 54 participants). The observed HR for palbociclib + IRN + TMZ compared to IRN + TMZ alone was 2.03 (95% CI: 0.902, 4.572; stratified 1-sided p-value=0.9621). 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).