Neutropenia management with palbociclib in Japanese patients with advanced breast cancer.
ABSTRACT: BACKGROUND:The cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib, in combination with endocrine therapy (ET), significantly prolonged progression-free survival in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- ABC) in PALOMA-2 and PALOMA-3. Neutropenia and palbociclib dose reductions/interruptions occurred more frequently in the Japanese versus overall populations. We evaluated neutropenia patterns, palbociclib dose management, and clinical responses after dose reduction in Japanese patients in PALOMA-2 and PALOMA-3 and a single-arm Japanese phase 2 study. METHODS:PALOMA-2 and the Japanese phase 2 study enrolled postmenopausal women with estrogen receptor-positive, HER2- ABC who had not received prior systemic therapy for advanced disease; PALOMA-3 enrolled women with HR+/HER2- ABC, regardless of menopausal status, whose disease had progressed after prior ET. Palbociclib (125 mg/day) was administered 3 weeks on/1 week off. Dose reduction/interruption, cycle delay, tumor response, and laboratory-assessed neutropenia were analyzed in Japanese patients who received palbociclib. RESULTS:A total of 101 Japanese patients received palbociclib?+?ET. Among Japanese patients in the 3 studies, the frequency of all-grade/grade 3/grade 4 neutropenia was 94%/53%/34%, 100%/69%/21%, and 100%/67%/26%, respectively. Twenty (63%), 28 (67%), and 15 (56%) patients required palbociclib dose reduction. Dose interruption or reduction did not affect palbociclib treatment duration, and durable tumor response was observed despite dose reduction. CONCLUSION:Neutropenia was manageable with dose modifications, without affecting palbociclib treatment duration or efficacy. TRIAL REGISTRATION:Pfizer (NCT01740427, NCT01684215, NCT01942135).
Project description:BACKGROUND:PALOMA-2 confirmed that first-line palbociclib + letrozole improved progression-free survival (hazard ratio, 0.58; 95% confidence interval, 0.46-0.72) in postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). This analysis evaluated palbociclib-associated hematologic adverse events (AEs) and provides insight on managing these AEs. MATERIALS AND METHODS:Postmenopausal women with ER+/HER2- ABC were randomly assigned 2:1 to letrozole (2.5 mg daily continuously) plus oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments were performed at baseline, days 1 and 15 (first two cycles) and day 1 of subsequent cycles, and included white blood cell, platelet, and absolute neutrophil count (ANC). RESULTS:PALOMA-2 randomized 666 women to palbociclib + letrozole (n = 444) or placebo + letrozole (n = 222). Neutropenia was the most common AE (95.3%) with palbociclib (grade 3, 55.6%; grade 4, 11.5%) and was managed by dose modifications; progression-free survival was similar between patients who experienced grade ? 3 neutropenia versus those who did not. Median (range) time to onset of neutropenia with palbociclib + letrozole was 15 (12-700) days (grade ? 3, 28.0 [12-854] days); median duration of each neutropenia episode grade ? 3 was 7.0 days. Asian ethnicity and low baseline ANC were associated with increased risk of grade 3/4 neutropenia with palbociclib (p < .001). CONCLUSION:Palbociclib + letrozole was generally well tolerated. Neutropenia, the most frequently reported AE in women with ER+/HER2- ABC, was mostly transient and manageable by dose modifications in patients who experienced grade ? 3 neutropenia, without appearing to compromise efficacy. (Pfizer; NCT01740427) IMPLICATIONS FOR PRACTICE: Palbociclib demonstrated an acceptable safety profile in PALOMA-2 in women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) receiving first-line palbociclib + letrozole. Although hematologic adverse events (AEs) are typically expected with anticancer therapies and are often clinically significant, palbociclib-related hematologic AEs, particularly neutropenia (most frequent AE), were transient/manageable by dose reduction, interruption, or cycle delay, which is in contrast to the more profound neutropenia associated with chemotherapy. Palbociclib dose adjustments decreased hematologic AE severity without appearing to compromise efficacy, supporting palbociclib + letrozole as a first-line treatment for ER+/HER2- ABC.
Project description:BACKGROUND:In PALOMA-2, palbociclib-letrozole significantly improved progression-free survival (PFS) vs placebo-letrozole in women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced breast cancer (ABC) in the first-line setting. We evaluated the efficacy, safety, and pharmacokinetics of palbociclib in Japanese women in PALOMA-2. METHODS:In this phase 3 study, 666 postmenopausal women with ER+/HER2- ABC were randomized 2:1 to palbociclib (125 mg/day [3 weeks on/1 week off]) plus letrozole (2.5 mg daily) or placebo plus letrozole. A prespecified, exploratory, subgroup analysis of Japanese patients (n?=?46) was conducted to compare results with those of the overall population. RESULTS:At the February 26, 2016 cutoff, median PFS among the 46 Japanese patients was 22.2 months (95%CI, 13.6?not estimable) with palbociclib-letrozole vs 13.8 months (5.6?22.2) with placebo-letrozole (hazard ratio, 0.59 [95%CI, 0.26-1.34]). The most common adverse events (AEs) were hematologic and more frequent among Japanese patients than the overall population (neutropenia: 93.8% [87.5% grade 3/4] vs 79.5% [66.4%]; leukopenia: 62.5% [43.8%] vs 39.0% [24.8%]); no Japanese patients had febrile neutropenia. Palbociclib dose reductions due to toxicity (mainly neutropenia) were more common in Japanese patients (62.5% vs 36.0%); few permanently discontinued due to AEs. Although mean palbociclib trough concentration was higher in Japanese patients vs non-Asians (95.4 vs 61.7 ng/mL), the range of individual values of the Japanese patients was within that of non-Asians. CONCLUSIONS:These results from PALOMA-2 suggest that palbociclib-letrozole merits consideration as a first-line treatment option for postmenopausal Japanese patients with ER+/HER2? ABC. ClinicalTrials.gov: NCT01740427.
Project description:Background:The objective of this study was to review the pharmacology, efficacy, and safety of palbociclib, a first-in-class cyclin-dependent kinase 4/6 inhibitor, for the management of advanced breast cancer (ABC). Methods:Pharmacokinetics and drug interactions associated with palbociclib are described. Recent clinical trial data are reviewed, including patient-reported outcomes and subgroup analyses. Results:Palbociclib is indicated in combination with an aromatase inhibitor as initial endocrine therapy (ET) or with fulvestrant for patients with disease progression following ET for hormone receptor positive, human epidermal growth factor receptor 2 negative ABC or metastatic breast cancer. Palbociclib inhibits cyclin-dependent kinases 4/6, resulting in a blockade of phosphorylation of the retinoblastoma protein, which hinders the activation of transcription factors involved in S-phase entry, thereby arresting cell cycle progression at G1 phase. The efficacy and safety of palbociclib in combination with ET was established in three randomized trials (PALOMA-1, -2, and -3); all studies met their primary endpoint of significantly prolonging investigator-assessed progression-free survival versus ET alone. Findings were similar in subgroup analyses of the three PALOMA studies. Palbociclib plus ET also maintained health-related quality of life (QoL) compared with ET alone in PALOMA-2 and -3. A long-term safety profile for palbociclib, up to 3?years, has been established. Neutropenia, the most common any-grade and grade 3 or higher adverse event associated with palbociclib, is consistent with the drug's mechanism of action and can be effectively managed with dose interruption, dose reduction, or delay in starting treatment cycles. Conclusions:Palbociclib in combination with ET improved progression-free survival and QoL in patients with ABC, including in several patient subgroups.
Project description:BACKGROUND:Palbociclib improves outcomes for women with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- ABC). Dose reductions are recommended for the management of hematologic toxicities. A previous pooled analysis from the PALOMA clinical trials showed that 36.9% of patients required dose reduction, predominantly during the first 6?months of treatment and with decreasing frequency during subsequent 28-day treatment cycles (C). Previous data have shown that palbociclib dose reductions do not affect efficacy. This pooled, post hoc analysis evaluated the frequency of hematologic adverse events (AEs) before and after palbociclib dose reduction in PALOMA-1, PALOMA-2, and PALOMA-3. METHODS:This analysis evaluated the frequency of hematologic AEs 30?days before dose reduction and during each subsequent treatment from C1 to C6 among patients who required palbociclib dose reduction. Data were pooled from 3 randomized studies. PALOMA-1 was a phase 2, open-label study of postmenopausal patients untreated for ABC receiving palbociclib plus letrozole or letrozole alone. PALOMA-2 was a phase 3, double-blind study of postmenopausal patients untreated for ABC receiving palbociclib plus letrozole or placebo plus letrozole. PALOMA-3 was a phase 3, double-blind study of pre/perimenopausal or postmenopausal patients, whose disease progressed on prior endocrine therapy, receiving palbociclib plus fulvestrant or placebo plus fulvestrant. RESULTS:A total of 311 (35.5%) patients with HR+/HER2- ABC required a palbociclib dose reduction (93.6% due to AEs) from 125 to 100?mg. Mean patient age was 59.9?years, and 46.9% of patients had visceral disease. Median time to dose reduction was 70?days. The majority of dose reductions occurred within 3?months of starting palbociclib treatment. Incidences of all-grade and grades 3/4 hematologic AEs were lower following dose reduction. CONCLUSIONS:A decrease in frequency and severity of hematologic AEs, including febrile neutropenia, following palbociclib dose reduction was observed, supporting the recommended use of dose reduction in AE management. TRIAL REGISTRATION:These studies were sponsored by Pfizer. ClinicalTrials.gov: NCT00721409; registration date July 24, 2008. ClinicalTrials.gov: NCT01740427; registration date December 4, 2012. ClinicalTrials.gov: NCT01942135; registration date September 13, 2013.
Project description:<h4>Background</h4>Previous studies demonstrated the tolerability of palbociclib plus endocrine therapy (ET). This analysis evaluated safety based on more recent cutoff dates and a longer palbociclib treatment exposure.<h4>Patients and methods</h4>Data were pooled from three randomized studies of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC), including postmenopausal women who had not received prior systemic treatment for advanced disease (PALOMA-1/-2) and pre- and postmenopausal women who had progressed on prior ET (PALOMA-3).<h4>Results</h4>Updated cutoff dates were December 21, 2017 (PALOMA-1), May 31, 2017 (PALOMA-2), and April 13, 2018 (PALOMA-3). Total person-years of treatment exposure were 1,421.6 with palbociclib plus ET (n = 872) and 528.4 with ET (n = 471). Any-grade neutropenia and infections were more frequent with palbociclib plus ET (82.1% and 59.2%, respectively) than with ET (5.1% and 39.5%). The hazard ratios were 1.6 (p = .0995) for grade 3/4 infections, 1.8 (p = .4358) for grade 3/4 viral infections, 1.4 (p = .0001) for infections, and 30.8 (p < .0001) for neutropenia. Febrile neutropenia was reported in 1.4% of patients receiving palbociclib plus ET. Cumulative incidence of all-grade hematologic adverse events in both arms peaked during the first year of treatment and plateaued over the 5 subsequent years. Interstitial lung disease was reported in 13 patients receiving palbociclib plus ET and 3 receiving ET.<h4>Conclusion</h4>This 5-year, long-term analysis demonstrated that palbociclib plus ET has a consistent and stable safety profile and is a safe treatment for patients with HR+/HER2- ABC.<h4>Implications for practice</h4>Several treatments for patients with breast cancer are associated with long-term or latent adverse events. This long-term, 5-year analysis demonstrated that palbociclib plus endocrine therapy has a consistent and stable safety profile without cumulative or delayed toxicities. These results further support palbociclib plus endocrine therapy as a safe and manageable treatment in clinical practice for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer.
Project description:In the PALOMA-3 trial, the median progression-free survival (PFS) was longer among patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) treated with palbociclib plus fulvestrant than those treated with placebo plus fulvestrant. This subgroup analysis examined the efficacy and safety of palbociclib among Korean patients enrolled in PALOMA-3 (n = 43 [palbociclib group, n = 24; placebo group, n = 19]). In both groups, > 40% of patients were pre/perimenopausal at enrollment. The median PFS was significantly prolonged with palbociclib vs. placebo (12.3 [95% confidence interval (CI), 9.1-not estimable] vs. 5.4 months [95% CI, 1.9-9.2]; hazard ratio, 0.40 [95% CI, 0.19-0.83]; one-sided <i>p</i> =0.005), and the confirmed objective response was 21.1% and 11.8%, respectively (odds ratio, 2.0 [95% CI, 0.24-24.8]). Neutropenia was the most common adverse event associated with palbociclib. Overall, palbociclib plus fulvestrant was effective and generally safe among Korean patients with HR+/HER2- ABC, regardless of menopausal status.
Project description:Background:This report assesses the efficacy and safety of palbociclib plus endocrine therapy (ET) in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) with or without visceral metastases. Patients and methods:Pre- and postmenopausal women with disease progression following prior ET (PALOMA-3; N?=?521) and postmenopausal women untreated for ABC (PALOMA-2; N?=?666) were randomized 2 : 1 to ET (fulvestrant or letrozole, respectively) plus palbociclib or placebo. Progression-free survival (PFS), safety, and patient-reported quality of life (QoL) were evaluated by prior treatment and visceral involvement. Results:Visceral metastases incidence was higher in patients with prior resistance to ET (58.3%, PALOMA-3) than in patients naive to ET in the ABC setting (48.6%, PALOMA-2). In patients with prior resistance to ET and visceral metastases, median PFS (mPFS) was 9.2?months with palbociclib plus fulvestrant versus 3.4?months with placebo plus fulvestrant [hazard ratio (HR), 0.47; 95% confidence interval (CI), 0.35-0.61], and objective response rate (ORR) was 28.0% versus 6.7%, respectively. In patients with nonvisceral metastases, mPFS was 16.6 versus 7.3?months, HR 0.53; 95% CI 0.36-0.77. In patients with visceral disease and naive to ET in the advanced disease setting, mPFS was 19.3?months with palbociclib plus letrozole versus 12.9?months with placebo plus letrozole (HR 0.63; 95% CI 0.47-0.85); ORR was 55.1% versus 40.0%; in patients with nonvisceral disease, mPFS was not reached with palbociclib plus letrozole versus 16.8?months with placebo plus letrozole (HR 0.50; 95% CI 0.36-0.70). In patients with prior resistance to ET with visceral metastases, palbociclib plus fulvestrant significantly delayed deterioration of QoL versus placebo plus fulvestrant, whereas patient-reported QoL was maintained with palbociclib plus letrozole in patients naive to endocrine-based therapy for ABC. Conclusions:Palbociclib plus ET prolonged mPFS in patients with visceral metastases, increased ORRs, and in patients previously treated for ABC, delayed QoL deterioration, presenting a standard treatment option among patients with visceral metastases amenable to endocrine-based therapy. Clinical trial registration:NCT01942135, NCT01740427.
Project description:<h4>Objective</h4>The aim of this study was to assess the real-world effectiveness and tolerability of palbociclib combined with endocrine therapy for the treatment of hormone receptor positive (HR-positive), human epidermal growth factor receptor 2 negative (HER2-negative), advanced/metastatic breast cancer that progressed on previous endocrine therapy, and to compare these results with the outcomes of the PALOMA-3 clinical trial.<h4>Methods</h4>This study was a retrospective observational cohort study including all patients who started with palbociclib in the St. Antonius Hospital between September 1, 2016 and April 1, 2018 for the treatment of HR-positive, HER2-negative advanced/metastatic breast cancer that progressed on previous endocrine therapy. Individual patient data were collected from electronic medical records. Primary study outcomes were progression-free survival (PFS) and the number of permanent treatment discontinuations before disease progression due to adverse events (AEs). Secondary outcomes were the frequency of all (serious) AEs and the frequency of and reasons for dose reductions, -interruptions and cycle delays.<h4>Results</h4>A total of 46 patients were studied with a median follow-up of 13.0?months. Overall, the median PFS in real-world clinical practice was 10.0?months (95% confidence interval (CI) 4.9-15.1), compared with 9.5?months in PALOMA-3 (95% CI 9.2-11.0). Two patients discontinued treatment because of AEs. Neutropenia was the most frequent grade 3-4 AE, but with no febrile neutropenia events. Most AEs were managed with palbociclib dose modifications. Regarding these modifications, more cycle delays, less dose reductions, and less dose interruptions occurred in clinical practice compared with PALOMA-3 (59 vs 36%, 22 vs 34%, and 9 vs 54%, respectively). Patients who did not meet the PALOMA-3 study eligibility criteria (n?=?16) showed a lower median PFS of 5.5?months (95% CI 4.7-6.4).<h4>Conclusions</h4>The effectiveness and tolerability of palbociclib in real-world clinical practice corresponded well with the results obtained in the PALOMA-3 clinical trial. Despite the differences in dose modifications, this study suggests that there is no efficacy-effectiveness gap in this patient population.
Project description:PURPOSE:This analysis evaluated the relationship between treatment-free interval (TFI, in PALOMA-2)/disease-free interval (DFI, in PALOMA-3) and progression-free survival (PFS) and overall survival (OS, in PALOMA-3), treatment effect in patients with bone-only disease, and whether intrinsic subtype affects PFS in patients receiving palbociclib. METHODS:Data were from phase 3, randomized PALOMA-2 and PALOMA-3 clinical studies of hormone receptor?positive/human epidermal growth factor receptor 2?negative (HR+?/HER2-) advanced breast cancer (ABC) patients receiving endocrine therapy plus palbociclib or placebo. Subpopulation treatment effect pattern plot (STEPP) analysis evaluated the association between DFI and PFS and OS. PFS by luminal subtype and cyclin-dependent kinase (CDK) 4/6 or endocrine pathway gene expression levels were evaluated in patients with bone-only disease; median PFS and OS were estimated by the Kaplan-Meier method. RESULTS:Median durations of TFI were 37.1 and 30.9 months (PALOMA-2) and DFI were 49.2 and 52.0 months (PALOMA-3) in the palbociclib and placebo groups, respectively. Among the PALOMA-2 biomarker population (n?=?454), 23% had bone-only disease; median PFS was longer with palbociclib versus placebo (31.3 vs 11.2 months; hazard ratio, 0.41; 95% CI 0.25?0.69). The interaction effect of bone-only versus visceral disease subgroups on median PFS with palbociclib was not significant (P?=?0.262). Among the PALOMA-3 biomarker population (n?=?302), 27% had bone-only disease. STEPP analyses showed that palbociclib PFS benefit was not affected by DFI, and that palbociclib OS effect may be smaller in patients with short DFIs. Among patients who provided metastatic tumor tissues (n?=?142), regardless of luminal A (hazard ratio, 0.23; 95% CI 0.11?0.47; P?=?0.0000158) or luminal B (hazard ratio, 0.26; 95% CI 0.12?0.56; P?=?0.000269) subtype, palbociclib improved PFS versus placebo. CONCLUSIONS:These findings support palbociclib plus endocrine therapy as standard of care for HR+?/HER2- ABC patients, regardless of baseline TFI/DFI or intrinsic molecular subtype, including patients with bone-only disease. TRIAL REGISTRATION:Pfizer (clinicaltrials.gov:NCT01740427, NCT01942135).
Project description:Palbociclib enhances endocrine therapy and improves clinical outcomes in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Because this is a new target, it is clinically important to understand palbociclib's safety profile to effectively manage toxicity and optimize clinical benefit.Patients with endocrine-resistant, HR-positive/HER2-negative MBC (n = 521) were randomly assigned 2:1 to receive fulvestrant (500 mg intramuscular injection) with or without goserelin with oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments at baseline and day 1 of each cycle included blood counts on day 15 for the first 2 cycles. Hematologic toxicity was assessed by using laboratory data.A total of 517 patients were treated (palbociclib, n = 345; placebo, n = 172); median follow-up was 8.9 months. With palbociclib, neutropenia was the most common grade 3 (55%) and 4 (10%) adverse event; median times to onset and duration of grade ?3 episodes were 16 and 7 days, respectively. Asian ethnicity and below-median neutrophil counts at baseline were significantly associated with an increased chance of developing grade 3-4 neutropenia with palbociclib. Dose modifications for grade 3-4 neutropenia had no adverse effect on progression-free survival. In the palbociclib arm, febrile neutropenia occurred in 3 (<1%) patients. The percentage of grade 1-2 infections was higher than in the placebo arm. Grade 1 stomatitis occurred in 8% of patients.Palbociclib plus fulvestrant treatment was well-tolerated, and the primary toxicity of asymptomatic neutropenia was effectively managed by dose modification without apparent loss of efficacy. This study appears at ClinicalTrials.gov, NCT01942135.Treatment with palbociclib in combination with fulvestrant was generally safe and well-tolerated in patients with hormone receptor (HR)-positive metastatic breast cancer. Consistent with the drug's proposed mechanism of action, palbociclib-related neutropenia differs in its clinical time course, patterns, and consequences from those seen with chemotherapy. Neutropenia can be effectively managed by a dose reduction, interruption, or cycle delay without compromising efficacy. A significant efficacy gain and a favorable safety profile support the consideration of incorporating palbociclib into the routine management of HR-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer.