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Palbociclib Plus Fulvestrant in Korean Patients from PALOMA-3 With Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer

In the PALOMA-3 trial, the median progression-free survival (PFS) was longer among patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) treated with palbociclib plus fulvestrant than those treated with placebo plus fulvestrant. This subgroup analysis examined the efficacy and safety of palbociclib among Korean patients enrolled in PALOMA-3 (n = 43 [palbociclib group, n = 24; placebo group, n = 19]). In both groups, > 40% of patients were pre/perimenopausal at enrollment. The median PFS was significantly prolonged with palbociclib vs. placebo (12.3 [95% confidence interval (CI), 9.1–not estimable] vs. 5.4 months [95% CI, 1.9–9.2]; hazard ratio, 0.40 [95% CI, 0.19–0.83]; one-sided p = 0.005), and the confirmed objective response was 21.1% and 11.8%, respectively (odds ratio, 2.0 [95% CI, 0.24–24.8]). Neutropenia was the most common adverse event associated with palbociclib. Overall, palbociclib plus fulvestrant was effective and generally safe among Korean patients with HR+/HER2− ABC, regardless of menopausal status.


Data Availability
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Funding
This study was funded by Pfizer Inc. (NCT01942135). (ABC) [4]. Palbociclib was the first CDK4/6 inhibitor, in combination with letrozole in the first-line setting or fulvestrant in the second and later line settings, to be approved in many countries, including Korea [5][6][7]. Although accumulating evidence indicates that palbociclib has comparable clinical benefit in Asian and non-Asian patients [8,9], guideline for its use in Asian women remains unclear due to the limited clinical data [10].

Author Contributions
The phase 3 PALOMA-3 trial showed significant improvement in progression-free survival (PFS) in the palbociclib plus fulvestrant group versus the placebo plus fulvestrant group in pre/perimenopausal and postmenopausal women with HR+/HER2− ABC, who had progressed on prior endocrine therapy [11,12]. The efficacy and safety of palbociclib in the Asian population of PALOMA-3 have previously been described. However, limited data exist on the use of palbociclib plus fulvestrant in patients from Korea with HR+/HER2− ABC as this combination was not covered by health insurance until after June 1, 2020. The aim of this study was to assess the efficacy and safety of palbociclib plus fulvestrant versus placebo plus fulvestrant among Korean patients enrolled in PALOMA-3 who had progressed after receiving prior endocrine therapy.
PALOMA-3 was a phase 3, international, multicenter, randomized, double-blind, placebocontrolled clinical study (NCT01942135); study design and inclusion/exclusion criteria were described previously [12]. The study was approved by an institutional review board or independent ethics committee at each study site and conducted according to the International Ethical Guidelines for Biomedical Research Involving Human Subjects, Guidelines for Good Clinical Practice, and the Declaration of Helsinki. All patients provided written informed consent. The efficacy and safety of palbociclib plus fulvestrant (AstraZeneca, Wilmington, USA) compared to that of placebo plus fulvestrant was analyzed among patients from Korea and the Asia-Pacific region (inclusive of Korea, Australia, Japan, and Taiwan). Patients were randomized 2:1 to receive palbociclib (125 mg) orally once daily (for 21 days followed by 7 days off treatment for each 28-day cycle [3 weeks on/1 week off schedule]) and fulvestrant (500 mg) intramuscularly (every 14 days for the first three injections and then every 28 days) or matching placebo and fulvestrant. Pre-and perimenopausal women received goserelin or a luteinizing hormone-releasing hormone (LHRH) agonist ≥ 4 weeks before randomization. If patients had not received goserelin as their LHRH before study enrollment, they were switched to goserelin for the duration of the study.
All outcomes were based on radiologic assessments of tumor burden and on the local radiologist's or investigator's assessment. Median PFS was defined as the time from randomization to the date of first documentation of objective progression of disease (PD) or death due to any cause in the absence of documented PD, whichever occurred first. Objective response (OR) was analyzed among patients with measurable baseline disease and was defined as a complete response (CR) or partial response (PR) according to RECIST v.1.1 from randomization until disease progression or death due to any cause. Clinical benefit response (CBR) was defined as CR, PR, or stable disease (SD) ≥ 24 weeks according to the RECIST v.1.1 between randomization and disease progression or death due to any cause. Adverse events (AEs) were classified using Medical Dictionary for Regulatory Activities (MedDRA) v.17.1; severity of the toxicities was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. AEs were summarized by treatment and frequency of patients experiencing treatment-emergent AEs (TEAEs) corresponding to body systems and MedDRA preferred term.
A data cutoff date of October 23, 2015, was used for PFS, best overall tumor response, and safety analyses. A data cutoff date of April 13, 2018, was used for subsequent systemic anticancer therapy analyses. The intent-to-treat population included all randomized patients; patient characteristics, efficacy endpoints, and subsequent systemic anticancer treatments were evaluated in this population. The as-treated population included all patients who received ≥ 1 dose of study treatment; treatment administration and safety were evaluated in this population. The Kaplan-Meier method was used to estimate median PFS. The Cox proportional hazards model was used to compute the hazard ratio and corresponding 95% confidence interval (CI). Odds ratios and the corresponding 95% CI were calculated using the exact Clopper-Pearson method.
A total of 114 patients from the Asia-Pacific region were treated in the PALOMA-3 trial (palbociclib plus fulvestrant group, n = 78; placebo plus fulvestrant group, n = 36; Table 1). Among the 43 patients from Korea, 24 received palbociclib plus fulvestrant, and 19 received placebo plus fulvestrant. A total of 32 (74.4%) Korean patients discontinued the study; 15 (62.5%) patients in the palbociclib group and 16 (84.2%) in the placebo group permanently discontinued due to objective disease progression or relapse, and one (4.2%) patient in the palbociclib group discontinued due to an AE. The median age of patients in the Korean cohort was 51.5 years in the palbociclib group, and 49.0 years in the placebo group, which was younger than the median age in the overall PALOMA-3 population (palbociclib group, 57.0 years; placebo group, 56.0 years) [12]. In both treatment groups, more than 40% of Korean patients were pre/perimenopausal at baseline. The median weight was similar among Korean patients regardless of treatment assignment (palbociclib group, 54.8 kg; placebo group, 55.7 kg), but was lower than that of the overall PALOMA-3 study population (palbociclib group, 67.2 kg; placebo group, 69.8 kg). The majority of Korean patients in each treatment group had documented sensitivity to prior hormone therapy (> 75%).
Similar to the results from the overall population of PALOMA-3, palbociclib plus fulvestrant was an effective treatment in Korean patients with HR+/HER2− ABC who progressed following prior endocrine therapy [13]. In this patient cohort, the median PFS was significantly prolonged in the palbociclib plus fulvestrant group compared to that in the placebo plus fulvestrant group, regardless of menopausal status, and the confirmed OR rate was greater with palbociclib combination treatment (21.1% vs. 11.8%). The CBR rate among patients in the palbociclib group was more than double of that observed in the placebo group (78.9% vs. 35.3%). Palbociclib plus fulvestrant was well tolerated, with neutropenia being the most frequently reported TEAE. Additionally, the efficacy and safety profile of palbociclib in Korean patients was consistent with that observed in the Asian-Pacific population.
Overall, Korean patients from PALOMA-3 were heavily pretreated. The majority of patients in either treatment group received prior chemotherapy (palbociclib group, 79.2%; placebo group, 89.5%) and had > 1 prior line of hormone therapy (palbociclib group, 79.2%; placebo group, 73.7%). Additionally, the majority of Korean patients had sensitivity to prior endocrine therapy. Recent subgroup analyses of PALOMA-3 showed that overall survival (OS) among patients with sensitivity to previous endocrine therapy was 10 months longer in the palbociclib plus fulvestrant group than that in the placebo plus fulvestrant group [14]. Additional subgroup analyses of PALOMA-3 suggest that endocrine sensitivity and the lack of prior chemotherapy for ABC are prognostic factors for OS [15].
The efficacy and safety results observed in Korean patients are generally similar to those observed in the overall population and in subgroup analyses of Japanese and Asian patients from PALOMA-3 [9,11,13,16]. The relative dose intensity for palbociclib was 88.3% in the Korean population and 91.7% in the overall population. In both populations, neutropenia was the most common TEAE with palbociclib therapy, although a higher percentage of Korean patients experienced any grade (95.8% and 80.9%) and grade 3/4 neutropenia (95.8% and 64.3%) than the overall PALOMA-3 population [13]. Palbociclib-associated neutropenia has been previously shown to be manageable by dose modification with no negative impact on efficacy [8,[17][18][19][20].
A notable difference between the Korean subgroup and the overall population of PALOMA-3 is the percentage of pre/perimenopausal women at study entry. In general, the percentage of premenopausal women with breast cancer is higher among Asian patients than among non-Asian patients. In the Korean population, 41.7% and 42.1% of patients were pre/ perimenopausal at baseline in the palbociclib and placebo groups, respectively; whereas in the overall population of PALOMA-3, 20.7% of patients in both treatment groups were pre/ perimenopausal [12]. The median PFS among pre/perimenopausal women in the overall and Korean population of PALOMA-3 was significantly longer in the palbociclib group than that in the placebo group, suggesting that palbociclib combination therapy was an effective option in this patient subgroup. In a subgroup analysis of the overall population, palbociclib plus fulvestrant was also effective in pre/perimenopausal patients with prior sensitivity to endocrine therapy (OS: 48.3 vs. 34.6 months; HR, 0.73 [95% CI, 0.37-1.46]; PFS: 13.6 vs. 5.6 months; HR, 0.38 [95% CI, 0.21-0.68]) [15].
In summary, palbociclib plus fulvestrant was an effective and generally safe treatment option in Korean patients with HR+/HER2− ABC whose disease progressed following prior endocrine therapy. The safety profile among Korean and Asian-Pacific patients was similar to that observed in the overall population enrolled in PALOMA-3.