Long-Term Pooled Safety Analysis of Palbociclib in Combination with Endocrine Therapy for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Updated Analysis with up to 5 Years of Follow-Up.

BACKGROUND: Previous studies demonstrated the tolerability of palbociclib plus endocrine therapy (ET). This analysis evaluated safety based on more recent cutoff dates and a longer palbociclib treatment exposure. PATIENTS AND METHODS: Data were pooled from three randomized studies of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC), including postmenopausal women who had not received prior systemic treatment for advanced disease (PALOMA-1/-2) and pre- and postmenopausal women who had progressed on prior ET (PALOMA-3). RESULTS: Updated cutoff dates were December 21, 2017 (PALOMA-1), May 31, 2017 (PALOMA-2), and April 13, 2018 (PALOMA-3). Total person-years of treatment exposure were 1,421.6 with palbociclib plus ET (n = 872) and 528.4 with ET (n = 471). Any-grade neutropenia and infections were more frequent with palbociclib plus ET (82.1% and 59.2%, respectively) than with ET (5.1% and 39.5%). The hazard ratios were 1.6 (p = .0995) for grade 3/4 infections, 1.8 (p = .4358) for grade 3/4 viral infections, 1.4 (p = .0001) for infections, and 30.8 (p < .0001) for neutropenia. Febrile neutropenia was reported in 1.4% of patients receiving palbociclib plus ET. Cumulative incidence of all-grade hematologic adverse events in both arms peaked during the first year of treatment and plateaued over the 5 subsequent years. Interstitial lung disease was reported in 13 patients receiving palbociclib plus ET and 3 receiving ET. CONCLUSION: This 5-year, long-term analysis demonstrated that palbociclib plus ET has a consistent and stable safety profile and is a safe treatment for patients with HR+/HER2- ABC. IMPLICATIONS FOR PRACTICE: Several treatments for patients with breast cancer are associated with long-term or latent adverse events. This long-term, 5-year analysis demonstrated that palbociclib plus endocrine therapy has a consistent and stable safety profile without cumulative or delayed toxicities. These results further support palbociclib plus endocrine therapy as a safe and manageable treatment in clinical practice for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer.

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.

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.

Palbociclib with Letrozole in Postmenopausal Women with ER+/HER2- Advanced Breast Cancer: Hematologic Safety Analysis of the Randomized PALOMA-2 Trial.

BACKGROUND: PALOMA-2 confirmed that first-line palbociclib + letrozole improved progression-free survival (hazard ratio, 0.58; 95% confidence interval, 0.46-0.72) in postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). This analysis evaluated palbociclib-associated hematologic adverse events (AEs) and provides insight on managing these AEs. MATERIALS AND METHODS: Postmenopausal women with ER+/HER2- ABC were randomly assigned 2:1 to letrozole (2.5 mg daily continuously) plus oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments were performed at baseline, days 1 and 15 (first two cycles) and day 1 of subsequent cycles, and included white blood cell, platelet, and absolute neutrophil count (ANC). RESULTS: PALOMA-2 randomized 666 women to palbociclib + letrozole (n = 444) or placebo + letrozole (n = 222). Neutropenia was the most common AE (95.3%) with palbociclib (grade 3, 55.6%; grade 4, 11.5%) and was managed by dose modifications; progression-free survival was similar between patients who experienced grade ≥ 3 neutropenia versus those who did not. Median (range) time to onset of neutropenia with palbociclib + letrozole was 15 (12-700) days (grade ≥ 3, 28.0 [12-854] days); median duration of each neutropenia episode grade ≥ 3 was 7.0 days. Asian ethnicity and low baseline ANC were associated with increased risk of grade 3/4 neutropenia with palbociclib (p < .001). CONCLUSION: Palbociclib + letrozole was generally well tolerated. Neutropenia, the most frequently reported AE in women with ER+/HER2- ABC, was mostly transient and manageable by dose modifications in patients who experienced grade ≥ 3 neutropenia, without appearing to compromise efficacy. (Pfizer; NCT01740427) IMPLICATIONS FOR PRACTICE: Palbociclib demonstrated an acceptable safety profile in PALOMA-2 in women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) receiving first-line palbociclib + letrozole. Although hematologic adverse events (AEs) are typically expected with anticancer therapies and are often clinically significant, palbociclib-related hematologic AEs, particularly neutropenia (most frequent AE), were transient/manageable by dose reduction, interruption, or cycle delay, which is in contrast to the more profound neutropenia associated with chemotherapy. Palbociclib dose adjustments decreased hematologic AE severity without appearing to compromise efficacy, supporting palbociclib + letrozole as a first-line treatment for ER+/HER2- ABC.

Expanded Access Study of Palbociclib Plus Letrozole for Postmenopausal Women with HR+/HER2- Advanced Breast Cancer in Latin America for Whom Letrozole Therapy is Deemed Appropriate.

BACKGROUND AND OBJECTIVES: Palbociclib is a cyclin-dependent kinase 4/6 inhibitor that is approved in the United States for the treatment of hormone receptor‒positive (HR+)/human epidermal growth factor receptor‒2 negative (HER2-) advanced breast cancer (ABC). The objectives of this expanded access trial were to provide palbociclib in combination with letrozole to patients with HR+/HER2- ABC in Argentina, Brazil, Colombia, and Mexico who were candidates for letrozole therapy before commercial availability of palbociclib, and to evaluate the safety and tolerability of palbociclib plus letrozole. PATIENTS AND METHODS: Postmenopausal women aged ≥ 18 years with HR+/HER2- ABC were eligible to participate in this study. Patients received palbociclib 125 mg once daily (3/1 schedule) and letrozole 2.5 mg once daily (continuous schedule). Safety, objective response rate (ORR), and duration of treatment were evaluated. RESULTS: A total of 130 patients were treated with palbociclib plus letrozole (Argentina, n = 33; Brazil, n = 35; Colombia, n = 28; Mexico, n = 34). The most common treatment-emergent adverse events (TEAEs) of any grade were neutropenia (70.0%), leukopenia (34.6%), anemia (33.8%), decreased neutrophil count (27.7%), and thrombocytopenia (24.6%); 22.3% of patients required a palbociclib dose reduction due to adverse events (AEs). Serious AEs were reported in 32 patients (24.6%). The ORR was 24.8% (95% confidence interval 17.6‒33.2), and the median duration of treatment was 10.6 months (range 0.1‒29.3). CONCLUSION: Palbociclib in combination with letrozole was generally well tolerated with a clinically manageable safety profile; the observed ORR supported treatment benefit in Latin American women with HR+/HER2- ABC. TRIAL REGISTRY: ClinicalTrials.gov, NCT02600923.

This study was done to learn more about the safety of 2 medicines together for women with advanced breast cancer after menopause. All 130 women in the study had the most common kind of breast cancer and were from Argentina, Brazil, Colombia, and Mexico. Everyone took 2 oral medicines called palbociclib and letrozole during the study. The researchers looked for any side effects experienced by the women while taking these medicines together. Another goal of the study was to see how well the treatment worked. Blood tests showed 70.0% of women had a side effect where they had a lower number of a type of white blood cell called a neutrophil. In total, 34.6% of women had low levels of another white blood cell called a leukocyte. These blood test results can mean a person is more likely to get infections. Serious side effects were experienced by 24.6% of the women, which meant these were life-threatening, caused lasting problems, or they needed hospital care. To cope with their side effects, 22.3% of the women switched to a lower palbociclib dose; 24.8% of the women had an overall response, which meant they either had a decrease in their tumor size or all cancer signs disappeared from their body. The most common length of time in the study was 10.6 months and the longest time was 29.3 months. The results of this study support using palbociclib plus letrozole to treat women who live in Latin America with advanced breast cancer after menopause.

Progression-free Survival Outcome Is Independent of Objective Response in Patients With Estrogen Receptor-positive, Human Epidermal Growth Factor Receptor 2-negative Advanced Breast Cancer Treated With Palbociclib Plus Letrozole Compared With Letrozole: Analysis From PALOMA-2.

BACKGROUND: In PALOMA-2, palbociclib + letrozole significantly prolonged progression-free survival (PFS) versus placebo + letrozole in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced breast cancer (ABC). We investigated clinical outcomes of patients who achieved or did not achieve a confirmed objective response (OR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (data cutoff: May 31, 2017). PATIENTS AND METHODS: Postmenopausal patients untreated for ER+/HER2- ABC were randomized 2:1 to palbociclib + letrozole or placebo + letrozole. Median PFS, median duration of OR, baseline characteristics, and palbociclib exposure were compared in patients with or without OR by treatment arm. RESULTS: In the intent-to-treat population, OR was achieved by 194 (44%) of 444 and 77 (35%) of 222 patients in the palbociclib and placebo arms, respectively (odds ratio, 1.5; 95% confidence interval [CI], 1.0-2.1; P = .0156). Regardless of treatment, more OR than non-OR patients had de novo metastatic disease (47%-50% and 28%-31%, respectively) and no prior endocrine therapy (55% and 35%-37%, respectively). Rates of palbociclib dose reduction owing to adverse events were similar regardless of OR (41% and 38%, respectively). Among the patients with OR during the study, approximately 50% achieved OR within the first 3 months regardless of treatment. The median PFS was significantly prolonged with palbociclib + letrozole versus placebo + letrozole in patients with measurable disease in both OR (37.2 months; 95% CI, 28.1 months to not estimable vs. 27.4 months; 95% CI, 22.2-31.1 months; hazard ratio, 0.66; 95% CI, 0.47-0.94; P = .009) and non-OR groups (10.9 months; 95% CI, 8.2-11.2 months vs. 5.6 months; 95% CI, 5.3-8.3 months; hazard ratio, 0.72; 95% CI, 0.54-0.97; P = .016). CONCLUSIONS: Palbociclib + letrozole provided significant clinical benefit versus placebo + letrozole to patients with ER+/HER2- ABC regardless of achieving RECIST-defined OR. Pfizer; ClinicalTrials.gov: NCT01740427.

Palbociclib Plus Letrozole as First-Line Therapy in Postmenopausal Asian Women With Metastatic Breast Cancer: Results From the Phase III, Randomized PALOMA-2 Study.

PURPOSE: In PALOMA-2, palbociclib plus letrozole significantly improved progression-free survival (PFS) as initial treatment of estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. We assessed the benefit of palbociclib plus letrozole in Asians. PATIENTS AND METHODS: Of 666 enrolled postmenopausal women with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (no prior treatment of advanced disease), 95 were Asian. Patients were randomly assigned 2:1 to receive palbociclib plus letrozole or placebo plus letrozole. The primary end point was investigator-assessed PFS. Secondary end points were overall survival, objective response, patient-reported outcomes, pharmacokinetics, and safety. RESULTS: Median PFS was significantly longer in Asian patients who received palbociclib plus letrozole versus placebo plus letrozole (25.7 months [95% CI, 19.2 months to not estimable] v 13.9 months [95% CI, 7.4 to 22.0 months]; hazard ratio, 0.49; 95% CI, 0.27 to 0.87; P = .007). The most common toxicities with palbociclib were hematologic and more frequent among Asians versus non-Asians: neutropenia (any grade, 95.4% v 76.8%; grade 3/4, 89.2% v 62.5%), leukopenia (43.1% v 38.3%; 32.3% v 23.5%), and thrombocytopenia (27.7% v 13.5%; 4.6% v 1.1%). No Asians had febrile neutropenia. Discontinuation rates as a result of adverse events were similar among Asian and non-Asian patients who received palbociclib plus letrozole (10.8% and 9.5%). In Asians, quality of life (QOL) was maintained with no significant differences observed between treatments from baseline in breast cancer-specific QOL and general health status scores. Change from baseline in EuroQol five dimensions index scores was significantly higher with palbociclib plus letrozole (0.013 v -0.069; P = .0132). Geometric mean palbociclib trough concentration values were higher in Asians versus non-Asians (93.8 v 61.7 ng/mL). CONCLUSION: Consistent with the overall study population, the addition of palbociclib to letrozole significantly improved PFS in Asians. Hematologic toxicities were more frequent in Asians versus non-Asians but manageable with early dose modifications while maintaining QOL.

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

BACKGROUND: Palbociclib administered with endocrine therapy was tolerable when the overall incidence of toxicities was assessed separately for three PALOMA studies. This study analyzed pooled, longer-term PALOMA safety data longitudinally. METHODS: Data were pooled from three randomized phase II and III studies (ClinicalTrials.gov: NCT00721409, NCT01740427, NCT01942135) of hormone receptor-positive/human epidermal growth factor receptor 2‒negative advanced breast cancer patients. Front-line patients were randomly assigned to receive letrozole with/without palbociclib (PALOMA-1) or letrozole plus palbociclib/placebo (PALOMA-2). In PALOMA-3, patients with prior endocrine resistance received fulvestrant plus palbociclib/placebo. The cumulative event rates of adverse events (AEs), reporting up to 50 months of treatment, were assessed over time. RESULTS: Patients who received endocrine therapy (n = 1343) were included in this pooled analysis (872 were also treated with palbociclib, and 471 were not). The most common AEs with palbociclib plus endocrine therapy were neutropenia and infections (any grade, 80.6% and 54.7%, respectively), which were higher than in the endocrine monotherapy arm (any grade, 5.3% and 36.9%). The most common hematologic AEs (≥15.0% in the palbociclib arm) were more likely to be reported in the initial months of the study, after which time the cumulative event rate did not substantially increase. With palbociclib plus endocrine therapy, any grade AEs leading to permanent discontinuation over three years occurred in only 8.3% of patients. CONCLUSIONS: Based on these long-term safety analyses, there is no evidence of specific cumulative or delayed toxicities with palbociclib plus endocrine therapy, supporting the ongoing investigation of palbociclib plus endocrine therapy in early breast cancer (NCT02513394).