Palbociclib Plus Letrozole Improves OS in ER+/HER2- Advanced Breast Cancer: PALOMA-2 Analysis

Based on phase 2 PALOMA-1 research results, PAL was the first cyclin-dependent kinase 4/6 (CDK4/6) inhibitor approved for ER+/HER2- ABC. Median progression-free survival (PFS) with PAL+LET against PBO+LET was 27.6 months versus 14.5 months; hazard ratio, 0.56 [95% CI, 0.46-0.69]; P<0.0001; PALOMA-2 is a randomized, double-blind, phase 3 trial in first-line ER+/HER2- ABC). OS data were immature during the time of the previous PFS study. The outcomes of OS are presented here. A randomized, double-blind, placebo-controlled trial of PAL (125 mg/d orally, 3/1 week regimen) plus LET (2.5 mg/d continuously) against PBO+LET in 666 postmenopausal women with ER+/HER2- ABC who had not undergone prior systemic therapy for advanced illness. Investigator-assessed PFS was the primary goal, and overall survival was a significant secondary endpoint. To have 80% power to detect a hazard ratio of 0.74 using a stratified log-rank test at a significance level of 0.025 (1-sided), the investigation needs 390 OS events.

The final OS analysis had to be performed as soon as enough events occurred. Median follow-up was 90 months, and as of the data cut-off date (November 15, 2021), 43 patients (10%) were still receiving PAL+LET, while 5 patients (2%) were receiving PBO+LET. In a study involving 405, the median overall survival (95% confidence interval) for those who had PAL+LET was 53.9 months (49.8-60.8), and those who received PBO+LET had 51.2 months (43.7 -58.9) (hazard ratio, 0.956 [95% CI, 0.777-1.177]; stratified 1-sided P=0.3378). This OS analysis was censored for patients unavailable for follow-up (21% in the PBO+LET arm versus 13% in the PAL+LET arm) due to withdrawal of consent or loss of contact. If these patients are excluded from the analysis, the median overall survival (OS) for PAL+LET is 51.6 months (46.9-57.1 months), and for PBO+LET, it is 44.6 months (37.0-52.3 months) (hazard ratio, 0.869 [95% CI, 0.706-1.069]). Eighty-one percent of patients in the PAL+LET arm and eighty-eight percent in the PBO+LET arm received post-study systemic medication; 12 % and 27% of patients who terminated treatment received a CDK4/6 inhibitor. Median overall survival (95% confidence interval) was 66.3 months (52.1-79.7) in the PAL+LET arm (n=179) and 47.4 months (37.7-57.0) in the PBO+LET arm (n=93) among patients with a disease-free interval (DFI) >12 months; hazard ratio, 0.728 (95% CI, 0.528-1.005). There were no new safety concerns found. PALOMA-2 improved PFS, which was the primary objective, but it did not increase OS, which was the secondary objective. Even though the results were not statistically significant, the fact remains that the PAL+LET had a more extended numerical advantage than the PBO+LET.

Source:https://meetings.asco.org/abstracts-presentations/208020

Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT01740427

Richard S. Finn, Hope S. Rugo, Veronique C Dieras, Nadia Harbeck, Seock-Ah Im, Karen A. Gelmon, Janice Maria Walshe, Miguel Martin, Mariana Chavez Mac Gregor, Eustratios Bananas, Eric Roland Gauthier, Dongrui Ray Lu, Sindy Kim, Dennis J. Slamon/Overall survival (OS) with first-line palbociclib plus letrozole (PAL+LET) versus placebo plus letrozole (PBO+LET) in women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ER+/HER2− ABC): Analyses from PALOMA-2/J Clin Oncol 40, 2022 (suppl 17; abstr LBA1003) DOI10.1200/JCO.2022.40.17_suppl.LBA1003