Overall survival results from the randomized phase 2 study of palbociclib in combination with letrozole versus letrozole alone for first-line treatment of ER+/HER2− advanced breast cancer (PALOMA-1, TRIO-18)

Abstract

Purpose Palbociclib is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, approved in combination with endocrine therapy for the treatment of women and men with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2− ABC). In the phase 2, open-label, PALOMA-1 trial, palbociclib plus letrozole significantly prolonged progression-free survival (PFS) versus letrozole alone (hazard ratio, 0.488; 95% CI 0.319-0.748; P = 0.0004; median PFS, 20.2 vs 10.2 months, respectively) in postmenopausal women with estrogen receptor-positive (ER+)/HER2− ABC. Here, we present the final overall survival (OS) and updated safety results. Methods Postmenopausal women with ER+/HER2− ABC were randomized 1:1 to receive either palbociclib (125 mg/day, 3/1 schedule) plus letrozole (2.5 mg/day, continuous) or letrozole alone (2.5 mg/day, continuous). The primary endpoint was investigator-assessed PFS; secondary endpoints included OS and safety. Results A total of 165 patients were randomized. At the data cutoff date of December 30, 2016 (median duration of follow-up, 64.7 months), the stratified hazard ratio for OS was 0.897 (95% CI 0.623-1.294; P = 0.281); median OS in the palbociclib plus letrozole and letrozole alone arms was 37.5 and 34.5 months, respectively. The median time from randomization to first subsequent chemotherapy use was longer with palbociclib plus letrozole than letrozole alone (26.7 and 17.7 months, respectively). The most frequently reported adverse event in the palbociclib plus letrozole arm was neutropenia (any grade, 75%; grade 3 or 4, 59%). Conclusions Palbociclib plus letrozole treatment led to a numerical but not statistically significant improvement in median OS. Pfizer Inc (NCT00721409)

Long-term Pooled Safety Analysis of Palbociclib in Combination With Endocrine Therapy for HR+/HER2- Advanced Breast Cancer

“…Currently, most of the safety data pertaining to CDK4/6 inhibitors received concomitantly during endocrine-based therapy for HR+/HER2- advanced breast cancer in women represent an evaluation after a relatively short follow-up period. The longest safety follow-up of any CDK4/6 inhibitor in the breast cancer setting is five years for palbociclib plus letrozole in the PALOMA-1 study (December 30, 2016, data cutoff), reported in conjunction with overall survival (12). Although these data were used to assess cumulative incidence annually over five consecutive years to reveal no new safety concerns, as a single study, it included only 83 patients, and, although informative, it must be viewed in that context.…”

Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

“…Palbociclib (Ibrance, Pfizer, NY, NY, USA) is the first-in-class CDK4/6i receiving an accelerated approval from FDA in February 2015, in combination with letrozole as initial therapy for postmenopausal women HR-positive, HER2-negative advanced, or metastatic BC, based on the results from the phase II trial PALOMA-1/TRIO-18, which showed a significant benefit in terms of progression-free survival (PFS) for combination therapy with palbociclib and letrozole over letrozole alone (median PFS 20.2 vs. 10.2 months, hazard ratio (HR) 0.49, p = 0.0004) [47]. Nevertheless, the trial cannot show a similar statistically significant increase of overall survival (OS), showing a median OS of 37.5 months in the palbociclib-letrozole group, as compared with 34.5 months in the placebo-letrozole group (HR 0.897, p = 0.281) [48]. These results were validated by conducting the phase III PALOMA-2 trial, which showed a final PFS of 27.6 months in palbociclib plus letrozolo arm, compared with 14.5 months in letrozole arm (HR 0.563, p < 0.001) and a clinical benefit rate (CBR) improved from 70.3% to 84.9% (p < 0.001) favoring palbociclib [49,50].…”

Hormone therapy for premenopausal women with metastatic breast cancer: combinations with cyclin-dependent kinase inhibitors

“…В первом же рандомизированном исследовании II фазы PALOMA-1 / TRIO-18 добавление палбоциклиба к летрозолу в 1-й линии терапии в 2 раза увеличило медиану ВБП, которая составила 20,2 мес для комбинации и 10,2 мес для одного летрозола (р = 0,0004), а также частоту объективного ответа (ЧОО) и клинической пользы (включает длительную стабилизацию болезни); выигрыш в отношении ВБП регистрировался во всех подгруппах пациенток и не зависел от экспрессии биомаркеров, продолжительность объективных ответов увеличивалась в 2 раза (20,3 мес против 11,1 мес) [18,19]. Отмечена также тенденция к увеличению ОВ в комбинированной группе: медиана ОВ достигла 37,5 мес против 34,5 мес, ОР 0,813, р = 0,42 [20].…”