Updates on managing advanced breast cancer with palbociclib combination therapy.
ABSTRACT: 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: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: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:<h4>Objective</h4>In the PALOMA-2 trial, palbociclib in combination with letrozole prolonged progression-free survival (PFS) and exhibited an acceptable safety profile in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (ABC). This post hoc analysis of PALOMA-2 evaluated the efficacy and safety of palbociclib plus letrozole in patients with preexisting conditions grouped by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC).<h4>Methods</h4>Postmenopausal patients without prior treatment for ABC were randomized 2:1 to receive palbociclib (125 mg/d on a 3 weeks on/1 week off schedule) plus letrozole (2.5 mg/d, continuous) or placebo plus letrozole. Patients were grouped by the following MedDRA SOC preexisting conditions: gastrointestinal, musculoskeletal, metabolic, and vascular/cardiac. Median PFS was estimated by the Kaplan-Meier method, and treatment emergent adverse events (AEs) were compared between treatment arms within each preexisting condition subgroup.<h4>Results</h4>At baseline, 276 (41.4 %) patients had preexisting gastrointestinal disorders, 390 (58.6 %) had musculoskeletal disorders, 259 (38.9 %) had metabolic disorders, and 382 (57.4 %) had vascular/cardiac disorders. Baseline characteristics were similar between subgroups and between each arm within subgroups. Regardless of baseline preexisting condition, palbociclib plus letrozole prolonged PFS compared with placebo plus letrozole. Treatment-emergent AEs associated with palbociclib plus letrozole and dose modifications due to AEs were similar across preexisting condition subgroups.<h4>Conclusion</h4>This post hoc analysis of PALOMA-2 demonstrated a favorable effect of palbociclib on PFS and a safety profile consistent with previous observations, regardless of underlying preexisting condition. Pfizer Inc (NCT01740427).
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:<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: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: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: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:Purpose:To assess the efficacy and safety of cyclin-dependent kinases 4 and 6 inhibitors (CDKi) combined with endocrine therapy (ET) in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) and compare the efficacy of different CDKi (palbociclib, ribociclib, or abemaciclib). Materials and Methods:This study based on randomized Phase 2 or 3 trials of CDKi plus ET compared with placebo plus ET for women with HR+/HER2-ABC and identify relevant randomized clinical trials (RCTs) published prior to February 2020. The primary endpoint was progression-free survival (PFS), the secondary endpoints included overall survival (OS), objective response rate (ORR), clinical benefit response (CBR) and safety. The PROSPERO registry number is 42018081105. Results:The results from eight trials including 4580 participants were pooled. Evidence indicated that the PFS of CDKi group was significantly prolonged (hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.50-0.60, P < 0.01) compared with placebo group. The ORR and CBR were better (risk ratio [RR] 1.47, 95% CI 1.30-1.67, P < 0.01; 1.24, 95% CI 1.15-1.35, P < 0.01) in the CDKi group. The OS of CDKi group (HR 0.75, 95% CI 0.67-0.85, P < 0.01) was significantly longer than ET alone. Subgroup analyses confirmed that the benefit was consistent across most subgroups. Subgroup analyses showed no statistically significant difference of PFS among three CDKi: palbociclib vs ribociclib (HR 0.55, 95% CI 0.49-0.60, P = 0.34), palbociclib vs abemaciclib (HR 0.53, 95% CI, 0.47-0.59, P = 0.61), and ribociclib vs abemaciclib (HR 0.56, 95% CI, 0.51-0.62, P = 0.72). Treatment-related grade 3 or 4 hematologic adverse events (AEs) were more frequently in CDKi group. Conclusion:CDKi combined with ET can significantly prolong PFS and improve the ORR, CBR and OS in patients with HR+/HER2- ABC. However, the advantage of different CDKi has not been established.
Project description:<h4>Background</h4>This analysis investigated whether baseline characteristics affect the survival benefit derived from palbociclib-fulvestrant and the optimal timing of cyclin-dependent kinase 4/6 inhibitor therapy for advanced breast cancer (ABC) in patients from PALOMA-3.<h4>Patients and methods</h4>In total, 521 patients were randomized 2:1 to receive palbociclib (125 mg/day, 3/1 schedule)-fulvestrant (500 mg, intramuscular injection, on days 1 and 15 of cycle 1, and then day 1 of each subsequent cycle) or matching placebo-fulvestrant. Median overall survival (OS) and progression-free survival were estimated using the Kaplan-Meier method.<h4>Results</h4>Multivariable analysis identified endocrine sensitivity, nonvisceral disease, no prior chemotherapy for ABC, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 as significant prognostic factors for OS. Patients without chemotherapy for ABC had fewer prior lines of treatment in any setting and in the ABC setting versus patients with prior chemotherapy for ABC (two or fewer prior systemic therapies: 69% vs. 42%; no more than one prior line for ABC: 82% vs. 33%, respectively). Median OS was prolonged with palbociclib-fulvestrant in patients without prior chemotherapy for ABC (39.7 vs. 29.5 months; hazard ratio, 0.75; 95% confidence interval [CI]: 0.56-1.01) and was similar in patients with prior chemotherapy for ABC (25.6 vs. 26.2 months; hazard ratio, 0.91 [95% CI: 0.63-1.32]) versus placebo-fulvestrant.<h4>Conclusion</h4>Prognostic factors for OS included endocrine sensitivity, nonvisceral disease, ECOG PS of 0, and no prior chemotherapy for ABC. Exploratory analyses suggest improved OS with palbociclib-fulvestrant versus placebo-fulvestrant in patients with no prior chemotherapy for ABC, prior endocrine sensitivity, and fewer prior regimens of systemic therapy. (Clinical trial identification number: NCT01942135).<h4>Implications for practice</h4>Prognostic factors for overall survival in HR+/HER2- advanced breast cancer (ABC) include the absence of prior chemotherapy in the advanced setting, endocrine sensitivity, nonvisceral disease, and an ECOG performance status of 0. Improved overall survival benefit was observed with palbociclib-fulvestrant versus placebo-fulvestrant in patients (regardless of menopausal status or visceral involvement) with no prior chemotherapy for ABC, with prior endocrine sensitivity, and fewer prior regimens of systemic therapy. Progression-free survival was prolonged with palbociclib across subgroups (regardless of chemotherapy exposure in ABC). These exploratory findings suggest that patients may receive greater clinical benefit from palbociclib-fulvestrant if they receive the combination before chemotherapy in the advanced setting.