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

• Published in: The oncologist (Dayton, Ohio) Ohio), 2019-12, Vol.24 (12), p.1514-1525
• Main Authors: Diéras, Véronique, Harbeck, Nadia, Joy, Anil Abraham, Gelmon, Karen, Ettl, Johannes, Verma, Sunil, Lu, Dongrui R., Gauthier, Eric, Schnell, Patrick, Mori, Ave, Rugo, Hope S., Finn, Richard S.
• Format: Article
• Language: English
• Subjects: Breast Cancer; Hematologic; Neutropenia; Palbociclib; Safety
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.2019-0019

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 decreas