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

Abstract Palbociclib is a cyclin‐dependent kinase 4/6 inhibitor indicated for treatment of hormone receptor‐positive/human epidermal growth factor receptor 2‐negative advanced breast cancer in combination with endocrine therapy. We investigated the efficacy and safety of palbociclib in patients enrolled in North America during two‐phase 3 trials: PALOMA‐2 (n = 267, data cutoff: May 31, 2017) and PALOMA‐3 (n = 240, data cutoffs: April 13, 2018, for overall survival, October 23, 2015, for all other outcomes). In PALOMA‐2, treatment‐naïve postmenopausal patients with advanced breast cancer were randomized 2:1 to palbociclib (125 mg/d; 3 weeks on/1 week off [3/1]) plus letrozole (2.5 mg/d, continuous) or placebo plus letrozole. In PALOMA‐3, patients who progressed on prior endocrine therapy were randomized 2:1 to palbociclib (125 mg/d; 3/1) plus fulvestrant (500 mg, per standard of care) or placebo plus fulvestrant; pre/perimenopausal patients received ovarian suppression with goserelin. Palbociclib plus endocrine therapy prolonged median progression‐free survival vs placebo plus endocrine therapy in North American patients (PALOMA‐2: 25.4 vs 13.7 months, hazard ratio, 0.54 [95% CI, 0.40–0.74], P < .0001; PALOMA‐3: 9.9 vs 3.5 months, hazard ratio, 0.52 [95% CI, 0.38–0.72], P < .0001). Objective response and clinical benefit response rates were greater with palbociclib vs placebo in North American patients in both trials. While overall survival data are not yet mature for PALOMA‐2, median overall survival was increased in PALOMA‐3 (32.0 vs 24.7 months, hazard ratio, 0.75 [95% CI, 0.53–1.04]), though this did not reach statistical significance (P = .0869). Safety profiles in North American patients were similar to those of the overall populations; neutropenia was the most common treatment‐emergent adverse event. No new safety signals were observed. In summary, palbociclib plus endocrine therapy is an effective treatment option for North American women with hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer.

Objective response and clinical benefit response rates were greater with palbociclib vs placebo in North American patients in both trials. While overall survival data are not yet mature for PALOMA-2, median overall survival was increased in PALOMA-3 (32.0 vs 24.7 months, hazard ratio, 0.75 [95% CI, 0.53-1.04]), though this did not reach statistical significance (P = .0869). Safety profiles in North American patients were similar to those of the overall populations; neutropenia was the most common treatment-emergent adverse event. No new safety signals were observed. In summary, palbociclib plus endocrine therapy is an effective treatment option for North American women with hormone receptorpositive/human epidermal growth factor receptor 2-negative advanced breast cancer.

| INTRODUC TI ON
Breast cancer is the most common cancer diagnosis in women from developed countries. 1,2 Incidence and mortality vary across countries due partly to differences in screening, lifestyle, and effects of race and ethnicity on treatment response. 1,3,4 Understanding regional differences is critical to optimizing care. In the United States Approximately 60% to 70% of patients with ABC have hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) tumors. 6,7 In this setting, endocrine therapy (ET) is the preferred option for patients who are not symptomatic or in visceral crisis. 2,8 Recent advances have enabled the development of combination strategies to delay progression and limit resistance to monotherapy, including targeting the cyclin-dependent kinase (CDK) 4/6 pathway. [9][10][11][12] Palbociclib is a CDK4/6 inhibitor indicated in combination with an aromatase inhibitor as first-line treatment of ABC and in combination with fulvestrant for progressive disease following ET. 13 Full approval was based on the multinational phase 3 PALOMA-2 and PALOMA-3 trials. 14,15 Since the accelerated approval of palbociclib in 2015-based on the phase 1/2 PALOMA-1 study 16,17 CDK4/6 inhibitors in combination with ET have become a preferred treatment option for HR+/HER2− ABC. 2,8 Because palbociclib was first approved in North America, clinical use has been most extensive in this region. Therefore, it is of interest to examine the safety and efficacy of palbociclib in North American patients. We analyzed this subgroup using updated data from the PALOMA-2 and PALOMA-3 studies.

| Study design and patients
Detailed methods for both studies were previously published and are summarized in the Supplementary Information. 14,15,18 In PALOMA-2, all patients were postmenopausal. In PALOMA-3, patients were enrolled regardless of menopausal status.

| Data analyses
This analysis compared the efficacy of palbociclib plus ET with that of placebo plus ET in a subset of the intent-to-treat (ITT) population enrolled in the United States and Canada, regardless of ethnicity.
The primary end point in both trials was progression-free survival (PFS), defined as time from randomization to radiologically con- The Kaplan-Meier method was used to estimate median PFS and OS, with corresponding 95% confidence intervals (CIs). The Cox proportional hazard model was used to estimate hazard ratios (HR).
ORR and CBR were summarized in the ITT population with measurable disease at baseline, and corresponding 95% CIs were calculated.
No adjustments were made for multiple testing. of patients in the palbociclib and placebo arms, respectively, were pre/perimenopausal. Baseline demographics and disease characteristics were similar across treatment arms within each study (Table 1).

| Patient population
Sites of recurrence were similar between treatment arms within each study; the most common metastatic site was bone (Table 1).

| Efficacy
In both studies, palbociclib plus ET prolonged PFS in North American women compared with placebo ( Figure 1, Table 2).  ORRs were higher in North American patients receiving palbociclib vs those receiving placebo in PALOMA-2 (57% vs 52%) and PALOMA-3 (24% vs 9%) ( Table 2). North American patients in the palbociclib arms of both trials were also more likely to exhibit a CBR than patients in the placebo arms: 80% vs 67%, respectively, in PALOMA-2 and 58% vs 28%, respectively, in PALOMA-3.
In PALOMA-3, 46% of the palbociclib group and 61% of the placebo group received postprogression chemotherapy, with a median time to first chemotherapy of 15.2 and 7.4 months, respectively ( Figure 2B).

| Safety
Most North American patients experienced at least 1 AE (any grade) with palbociclib combination treatment ( Table 3). The most common any-grade and grade 3/4 AE in North American women in the palbociclib arm in both trials was neutropenia (Table 3). Febrile neutropenia was reported in 5 (3%) patients in the palbociclib arm (4 grade 3, 1 grade 4) in PALOMA-2 and 1 (0.6%) patient (grade 3) in PALOMA-3. Infections, fatigue, stomatitis, and alopecia, among others, were more common in palbociclib-treated patients ( Table 3).

| D ISCUSS I ON
In the PALOMA-2 and PALOMA-3 trials, palbociclib plus ET pro- One-sided unstratified log-rank test.
f One-sided, from exact test.
g Two-sided unstratified log-rank test.
Tumor response was similar with palbociclib in the overall and North American populations (Table 2) The safety profile of palbociclib plus ET in North American patients was similar to that in the overall population. In both populations, the most common any-grade and grade 3/4 AEs with palbociclib were hematologic (Table 3). Importantly, no new safety signals were observed in the North American population in either study at this later cutoff.

| CON CLUS ION
The present report is subject to several limitations, including its post hoc nature and small cohort size; moreover, analyses were not