Abstract P4-22-03: Palbociclib in combination with endocrine therapy in treatment-naive and previously treated elderly women with HR+, HER2– advanced breast cancer: a pooled analysis from randomized phase 2 and 3 studies

Abstract

Background: At least 40% of breast cancers are diagnosed in women ≥65 y old and most are hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-). Palbociclib (PAL) is an oral, small-molecule inhibitor of cyclin-dependent kinases 4 and 6. Randomized studies of PAL combined with endocrine therapy (ET) demonstrated significantly improved progression-free survival (PFS) in patients (pts) with treatment-naive and previously treated advanced breast cancer (ABC). Methods: We evaluated the efficacy of PAL+ET vs ET alone in pts aged ≥65-74 and ≥75 y across multiple pivotal randomized phase 2 and 3 studies. Safety and pharmacokinetics (PK) data (blood samples collected from pts in phase 1/2 [PALOMA-1] and phase 1 studies [NCT00141297 and NCT00420056]) for PAL+ET were pooled and compared across age groups. Pts who had not received treatment for ABC were randomized to receive PAL+letrozole (LET) or LET alone/with placebo (PBO; PALOMA-1, open-label/PALOMA-2, double-blind). Pts who had progressed on prior ET were randomized to receive PAL+fulvestrant (FUL) or PBO+FUL (PALOMA-3, double-blind). The primary endpoint for these studies was investigator-assessed PFS. Safety assessments and blood counts occurred at baseline and every 2 weeks for the first 2 cycles and on day 1 of subsequent cycles. Results: Among 872 pts treated with PAL+ET, 221 (25%) were aged ≥65-74 y and 83 (10%) were ≥75 y (PAL+LET: n=528, 162 and 56, respectively; PAL+FUL: n=347, 59 and 27). Median (range) treatment durations were 440 (1-1615) d, 502 (1-1615) d, and 459 (21-1404) d, respectively. Improvement in efficacy endpoints was seen with PAL+ET vs ET across all age groups (Table 1). Incidence of adverse events (AEs), serious AEs and discontinuations due to AEs were similar in the overall population (99%, 19%, 3%) and in pts aged ≥65-74 (99%, 25%, 5%) and ≥75 y (100%, 30%, 6%). Incidence of all grades and grade 3/4 neutropenia were also similar across age groups (overall: 67% and 54%; ≥65-74 y: 64% and 51%; ≥75 y: 77% and 60%). PK analysis showed no clinically relevant differences between arithmetic means, medians, and geometric means of the apparent oral clearance across age groups. Conclusions: PAL in combination with ET is an effective and well-tolerated treatment option for elderly pts with HR+/HER2- endocrine-sensitive and -resistant ABC. A dose adjustment based on age is not required. Sponsor: Pfizer Table 1. PFS in pts ?65-74 and ?75 y (ITT populations)OverallAged ≥65-74 yAged ≥75 yPALOMA-1/PALOMA-2PAL+LET vs528 vs 303162 vs 9456 vs 26LET/LET+PBO,* nHR (95% CI);0.53 (0.44-0.64);0.66 (0.45-0.97);0.31 (0.16-0.61);1-sided P value<0.00010.01620.0002Median PFS (95% CI), mo24.4 (22.0-26.2) vs27.5 (24.2-NR) vsNR (19.2-NR) vs13.6 (11.1-16.4)21.8 (16.3-31.3)10.9 (4.9-24.9)PALOMA-3PAL+FUL vs347 vs 17459 vs 3727 vs 6FUL+PBO, nHR (95% CI);0.46 (0.36-0.59);0.25 (0.14-0.45);0.87 (0.27-2.79);1-sided P value<0.0001<0.00010.4074Median PFS (95% CI), mo9.5 (9.2-11.0) vs16.1 (12.0-NR) vs13.6 (7.5-NR) vs4.6 (3.5-5.6)3.7 (1.9-5.3)7.4 (1.9-NR)HR=hazard ratio; ITT=intent to treat; NR=not reached. *Does not include 5 pts from phase 1 of PALOMA-1. Citation Format: Rugo HS, Turner NC, Finn RS, Joy AA, Verma S, Harbeck N, Moulder S, Masuda N, Im Y-H, Zhang K, Kim S, Sun W, Schnell P, Huang-Bartlett C, Slamon D. Palbociclib in combination with endocrine therapy in treatment-naive and previously treated elderly 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 P4-22-03.

Use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in older patients with ER-positive HER2-negative breast cancer: Young International Society of Geriatric Oncology review paper

“…In a pooled analysis of data from 872 patients enrolled in the randomized phase II and III studies (PALOMA-1, -2 and -3) investigating safety and efficacy of palbociclib plus letrozole or fulvestrant in ER-positive, HER2-negative breast cancer, 221 (25%) of the participants were aged 65–74 and 83 (10%) were aged 75+. 33 In the first-line setting for all patients, median PFS was 24.4 months (95% CI 22.0–26.2) in the combined palbociclib and letrozole group versus 13.6 months (95% CI 11.1–16.4) in the placebo and letrozole group with an HR of 0.53 (95% CI 0.44–0.64). In the pretreated group, median PFS was 9.5 months (95% CI 9.2–11.0) in the combined palbociclib and fulvestrant group versus 4.6 months (95% CI 3.5–5.6) in the placebo and fulvestrant group with an HR of 0.46 (95% CI 0.36–0.59).…”

Updates on managing advanced breast cancer with palbociclib combination therapy

“…36 A pooled analysis of data from elderly patients in the PALOMA-1, -2, and -3 studies showed that palbociclib combined with endocrine therapy versus endocrine therapy alone improved PFS in patients aged 65-74 years (HR 0.66; 95% CI 0.45-0.97; p = 0.0162) and those aged 75 years and over (HR 0.31; 95% CI 0.16-0.61; p = 0.0002). 55 Moreover, findings from the pooled analysis demonstrated no new safety concerns in elderly patients taking palbociclib. 55 Patients with hepatic or renal impairment Palbociclib exposure is not altered in patients with mild hepatic impairment [total bilirubin ⩽ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN, or total bilirubin >1.0-1.5 × ULN and any AST] or in patients with mild [60 ml/min ⩽ creatinine clearance (CrCl) <90 ml/min] or moderate renal impairment (30 ml/min ⩽ CrCl <60 ml/min) and therefore does not typically require dose adjustments.…”

“…55 Moreover, findings from the pooled analysis demonstrated no new safety concerns in elderly patients taking palbociclib. 55 Patients with hepatic or renal impairment Palbociclib exposure is not altered in patients with mild hepatic impairment [total bilirubin ⩽ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN, or total bilirubin >1.0-1.5 × ULN and any AST] or in patients with mild [60 ml/min ⩽ creatinine clearance (CrCl) <90 ml/min] or moderate renal impairment (30 ml/min ⩽ CrCl <60 ml/min) and therefore does not typically require dose adjustments. 8 Recently, palbociclib has also been studied in patients with moderate or severe hepatic impairment or severe renal impairment.…”