Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up

Abstract

Purpose In the initial PALOMA-2 (NCT01740427) analysis with median follow-up of 23 months, palbociclib plus letrozole significantly prolonged progression-free survival (PFS) in women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) [hazard ratio (HR) 0.58; P < 0.001]. Herein, we report results overall and by subgroups with extended follow-up. Methods In this double-blind, phase 3 study, post-menopausal women with ER+/HER2− ABC who had not received prior systemic therapy for their advanced disease were randomized 2:1 to palbociclib-letrozole or placebo-letrozole. Endpoints include investigator-assessed PFS (primary), safety, and patient-reported outcomes (PROs). Results After a median follow-up of approximately 38 months, median PFS was 27.6 months for palbociclib–letrozole ( n = 444) and 14.5 months for placebo-letrozole ( n = 222) (HR 0.563; 1-sided P < 0.0001). All subgroups benefited from palbociclib treatment. The improvement of PFS with palbociclib-letrozole was maintained in the next 2 subsequent lines of therapy and delayed the use of chemotherapy (40.4 vs. 29.9 months for palbociclib–letrozole vs. placebo-letrozole). Safety data were consistent with the known profile. Patients’ quality of life was maintained. Conclusions With approximately 15 months of additional follow-up, palbociclib plus letrozole continued to demonstrate improved PFS compared with placebo plus letrozole in the overall population and across all patient subgroups, while the safety profile remained favorable and quality of life was maintained. These data confirm that palbociclib-letrozole should be considered the standard of care for first-line therapy in patients with ER+/HER2− ABC, including those with low disease burden or long disease-free interval. Sponsored by Pfizer; ClinicalTrials.gov: NCT01740427. Electronic supplementary material The online version of this article (10.1007/s10549-018-05125-4) contains supplementary material, which is available to authorized users.

CDK 4/6 inhibitor successful rechallenge after limiting hepatic toxicity

“…Endocrine therapy and CDK 4/6 inhibitor combinations have substantially prolonged progression-free survival making them a standard of care for advanced luminal breast cancer. [2][3][4][5][6][7][8] Increased transaminases have been described as adverse events in previous phase 3 trials (Table 1).…”

“…Here, for the first time, we report the case of a rechallenge of a CDK 4/6 inhibitor after serious liver toxicity. Endocrine therapy and CDK 4/6 inhibitor combinations have substantially prolonged progression‐free survival making them a standard of care for advanced luminal breast cancer . Increased transaminases have been described as adverse events in previous phase 3 trials (Table ).…”

“…Increased transaminases have been described as adverse events in previous phase 3 trials (Table ). Elevated ALAT (all grades) occurred in 6%‐15% of patients, including Grade 3 in 2%‐7.5% of patients . A pooled analysis of ribociclib studies revealed 7% Grade 3 ALAT increases, leading to permanent discontinuation of the treatment for the majority of patients .…”

Efficacy and safety of palbociclib plus endocrine therapy in North American women with hormone receptor‐positive/human epidermal growth factor receptor 2‐negative metastatic breast cancer

“…In the PALOMA‐2 and PALOMA‐3 trials, palbociclib plus ET prolonged PFS in the North American and overall populations (median PFS in PALOMA‐2: 25.4 and 27.6 months, respectively; PALOMA‐3: 9.9 and 11.2 months, respectively) and delayed treatment with cytotoxic chemotherapy. Updated data for North American patients from the PALOMA‐3 trial also indicated that OS was longer with palbociclib vs placebo (32.0 vs 24.7 months, HR, 0.75 [95% CI, 0.53–1.04]), P = .0869]), similar to results seen in the overall population (34.9 vs 28.0 months, HR, 0.81 [95% CI, 0.64–1.03]), P = .09]) …”

Drug repurposing for breast cancer therapy: Old weapon for new battle

“…Palbociclib (125 mg, 28-day cycle with aromatase inhibitor) is used as the targeted therapy against ER + /HER2 − advanced and metastatic breast cancer in conjunction with hormone therapy. The open label PALOMA (Palbociclib: Ongoing Trials in the Management of Breast Cancer) clinical trials were designed recently with either aromatase inhibitor (letrozole) (PALOMA-1 or PALOMA-2 Trials) [111,112] or Fulvestrant hormone therapies (PALOMA-3 trails) [113]. An improvement in the overall survival of metastatic breast cancer patients was reported in PALOMA-3 phase III clinical trials.…”