Background: Palbociclib (PAL) is a selective and reversible oral cyclin-dependent kinase 4 and 6 inhibitor. Large randomized phase (ph) 2 and 3 trials showed significant improvement in progression-free survival (PFS) when PAL was combined with endocrine therapy (ET) vs ET alone in treatment (trt)-naive and previously treated hormone receptor?positive human epidermal growth factor receptor 2?negative (HR+ HER2–) advanced breast cancer (ABC) patients (pts). The median PFS with PAL+ET is >2 years as a first-line therapy for ABC and 11.2 mo in endocrine-resistant ABC. We evaluated the long-term safety in PALOMA-1, -2, and -3.

Methods: We analyzed the tolerability of PAL in combination with ET in 3 randomized trials. Pts untreated for ABC were randomized to receive PAL+letrozole (LET) vs LET alone in PALOMA-1 (ph 2, open-label; 1:1) or randomized to receive PAL+LET vs placebo (PBO)+LET in PALOMA-2 (ph 3, double-blind; 2:1). PALOMA-3 included pts who progressed on prior ET, randomized to receive PAL+fulvestrant (FUL) or PBO+FUL (ph 3, double-blind; 2:1). Safety assessments, including a complete blood count, were done at baseline, on D1 of each cycle, and on D14 of the first 2 cycles. We evaluated adverse events (AEs) by 6-mo intervals (out to 36 mo) and cumulatively (12-, 24-, and 36-mo time points), and assessed latency (event onset) of pertinent adverse drug reactions (ADRs) in all pts treated in PALOMA-1, -2, and -3.

Results: A total of 1352 pts were pooled for this analysis; 872 pts received PAL+ET (527 pts, PAL+LET; 345 pts, PAL+FUL). Median duration of trt was 421 days in PALOMA-1 (January 2015), 603 days in PALOMA-2 (February 2016), and 330 days in PALOMA-3 (July 2015). PAL+LET was received by 119 pts as first-line trt in PALOMA-1 and 2 for 24–<30 months and 11 pts were treated for >36 mo. PAL+FUL was received by 140 pts for >12 mo as second-line trt in PALOMA-3. The most commonly reported ADRs across all studies were neutropenia, fatigue, nausea, anemia, and leukopenia. The 6-mo-interval analyses of the most common (>15%) AEs (by preferred term [PT]) from PALOMA-1, -2, and -3 indicated that these AEs were reported with the highest frequency during the first 6-mo interval and typically decreased in incidence over time to 30–<36-mo; the most common hematologic AEs (clustered PTs) are shown (Table). The cumulative incidence of AEs after the first vs the second and third years showed similar frequencies of most AEs, including the most common ADRs.

Conclusions: Based on these long-term safety analyses, there is no evidence of specific cumulative or delayed toxicity resulting from prolonged trt with PAL+ET for HR+ HER2– ABC. This supports the ongoing investigation of PAL+ET in early breast cancer (NCT02513394).

Table. Pooled hematologic AEs: all grades and all causality clustered PTs reported for ≥10% of PAL+ET (LET/FUL)-treated pts

Time interval, mo 0–<6 6–<12 12–<18 18–<24 24–<30 30–<36 ≥36 
Patients, N 872 676 491 289 119 27 11 
TEAEs, %               
Neutropenia 75.7 58.6 49.3 49.8 42.9 37.0 54.5 
Leukopenia 40.0 27.4 16.7 11.8 7.6 11.1 18.2 
Anemia 20.8 12.7 10.0 11.1 9.2 11.1 18.2 
Thrombocytopenia 15.1 8.7 6.1 5.5 5.9 14.8 36.4 
Time interval, mo 0–<6 6–<12 12–<18 18–<24 24–<30 30–<36 ≥36 
Patients, N 872 676 491 289 119 27 11 
TEAEs, %               
Neutropenia 75.7 58.6 49.3 49.8 42.9 37.0 54.5 
Leukopenia 40.0 27.4 16.7 11.8 7.6 11.1 18.2 
Anemia 20.8 12.7 10.0 11.1 9.2 11.1 18.2 
Thrombocytopenia 15.1 8.7 6.1 5.5 5.9 14.8 36.4 

TEAEs=treatment-emergent adverse events.

Sponsor: Pfizer.

Citation Format: Diéras V, Rugo HS, Gelmon K, Finn RS, Cristofanilli M, Loi S, Colleoni M, Lu D, Gauthier E, Huang-Bartlett C, Turner NC, Schnell P. Long-term safety of palbociclib in combination with endocrine therapy in treatment-naive and previously treated women with HR+ HER2– advanced breast cancer: A pooled analysis from randomized phase 2 and 3 studies [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-07.