Palbociclib Plus Letrozole as First-Line Therapy in Postmenopausal Asian Women With Metastatic Breast Cancer: Results From the Phase III, Randomized PALOMA-2 Study

Abstract

PURPOSE In PALOMA-2, palbociclib plus letrozole significantly improved progression-free survival (PFS) as initial treatment of estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer. We assessed the benefit of palbociclib plus letrozole in Asians. PATIENTS AND METHODS Of 666 enrolled postmenopausal women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (no prior treatment of advanced disease), 95 were Asian. Patients were randomly assigned 2:1 to receive palbociclib plus letrozole or placebo plus letrozole. The primary end point was investigator-assessed PFS. Secondary end points were overall survival, objective response, patient-reported outcomes, pharmacokinetics, and safety. RESULTS Median PFS was significantly longer in Asian patients who received palbociclib plus letrozole versus placebo plus letrozole (25.7 months [95% CI, 19.2 months to not estimable] v 13.9 months [95% CI, 7.4 to 22.0 months]; hazard ratio, 0.48; 95% CI, 0.27 to 0.87; P = .007). The most common toxicities with palbociclib were hematologic and more frequent among Asians versus non-Asians: neutropenia (any grade, 95.4% v 76.8%; grade 3/4, 89.2% v 62.5%), leukopenia (43.1% v 38.3%; 32.3% v 23.5%), and thrombocytopenia (27.7% v 13.5%; 4.6% v 1.1%). No Asians had febrile neutropenia. Discontinuation rates as a result of adverse events were similar among Asian and non-Asian patients who received palbociclib plus letrozole (10.8% and 9.5%). In Asians, quality of life (QOL) was maintained with no significant differences observed between treatments from baseline in breast cancer–specific QOL and general health status scores. Change from baseline in EuroQol five dimensions index scores was significantly higher with palbociclib plus letrozole (0.013 v –0.069; P = .0132). Geometric mean palbociclib trough concentration values were higher in Asians versus non-Asians (93.8 v 61.7 ng/mL). CONCLUSION Consistent with the overall study population, the addition of palbociclib to letrozole significantly improved PFS in Asians. Hematologic toxicities were more frequent in Asians versus non-Asians but manageable with early dose modifications while maintaining QOL.

Hematologic adverse events following palbociclib dose reduction in patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer: pooled analysis from randomized phase 2 and 3 studies

“…The effect of palbociclib dose reduction on the frequency and severity of hematologic AEs regardless of ethnicity is supported by a previous analysis of PALOMA-2, in which higher rates of hematologic Table 3 Incidence of hematologic adverse events before/after palbociclib dose reduction from 100 to 75 mg AEs were observed in Asian versus non-Asian patients but were effectively managed with dose adjustments [17]. Higher rates of neutropenia may be due to a lower baseline ANC.…”

“…Subgroup analyses of PALOMA-2 and PALOMA-3 also demonstrated that Asian and non-Asian patients had similar PFS outcomes, even though Asian patients had more dose reductions [17]. This finding is likely due to higher palbociclib exposure in Asian versus non-Asian patients because of lower palbociclib clearance in Asian patients [10,17]. Dose modification due to AEs does not appear to negatively impact the efficacy of palbociclib plus ET in patients with HR+/HER2− ABC, but does reduce the severity and incidence of AEs.…”

“…In PALOMA-3, PFS was similar in patients receiving palbociclib plus fulvestrant regardless of whether they had ≥ 1 dose reduction or no dose reduction due to neutropenia [16]. Subgroup analyses of PALOMA-2 and PALOMA-3 also demonstrated that Asian and non-Asian patients had similar PFS outcomes, even though Asian patients had more dose reductions [17]. This finding is likely due to higher palbociclib exposure in Asian versus non-Asian patients because of lower palbociclib clearance in Asian patients [10,17].…”

Palbociclib with Letrozole in Postmenopausal Women with ER+/HER2− Advanced Breast Cancer: Hematologic Safety Analysis of the Randomized PALOMA-2 Trial

“…Findings in the present study showed that clinical characteristics, such as Asian ethnicity and low baseline absolute neutrophil counts, may increase the risk of developing grade 3/4 neutropenia. Additionally, an analysis of the Asian subgroup in PALOMA‐2 revealed that Asian patients had lower mean and median baseline absolute neutrophil counts compared with non‐Asians . These observations highlight the importance of closely monitoring these patients and intervening with dose adjustments when indicated.…”

Diagnostik und Therapie des HER2-negativen metastasierten Mammakarzinoms 2020 Empfehlungen für die tägliche Routine (Sponsor: Roche Pharma AG)

“…Von den sekundär metastasierten Pa tien ten sollten die primär oder de novo metastasierten Pa tien ten unterschieden werden, da es sich hier um In den letzten Jahren hat sich jedoch die Kombinationstherapie aus einer anti-hormonellen mit einer weiteren zielgerichteten Sub stanz als wesentlich wirksamer in der Behandlung des mBC herausgestellt. Neue Sub stanzen hemmen das Protein mammalian Target of Rapamycin (mTOR) oder die CDK4/6 [12][13][14][15][16][17]. Die im klinischen Alltag gängige Unterscheidung der beiden Subtypen Luminal A und B spielt jedoch für die Auswahl des Therapie ansatzes keine relevante Rolle.…”