The results of the phase III PALOMA-2 study were presented at the 2018 Miami Breast Cancer Conference. According to the deep analysis, the CDK 4/6 inhibitor palbociclib showed significant efficacy in combination with the aromatase inhibitor letrozole in the frontline setting of estrogen receptor-positive, HER2-negative, postmenopausal metastatic breast cancer.
Richard S. Finn, MD
The results of the phase III PALOMA-2 study were presented at the 2018 Miami Breast Cancer Conference®. According to the deep analysis, the CDK 4/6 inhibitor palbociclib (Ibrance) showed significant efficacy in combination with the aromatase inhibitor letrozole (Femara) in the frontline setting of estrogen receptor (ER)-positive, HER2-negative, postmenopausal metastatic breast cancer.
The combination of palbociclib plus letrozole significantly improved median progression-free survival (PFS) versus placebo plus letrozole in the first-line setting for metastatic disease (24.8 versus 14.5 months; HR, 0.58; 95% CI, 0.46-0.72;P<.001). Investigators also concluded that palbociclib plus letrozole “consistently and significantly” prolonged median PFS compared to the placebo plus letrozole in all subgroups, regardless of prior adjuvant/neoadjuvant endocrine therapy or chemotherapy.
Median PFS in patients with prior endocrine therapy from the palbociclib-plus-letrozole group (n = 249) was 22.2 months versus 11.3 months for the placebo-plus-letrozole cohort (n = 126) (hazard ratio [HR], 0.53; 95% CI, 0.40-0.70). Objective response rate (ORR) was 33.7% versus 27.0%, respectively. The median PFS in the no-prior endocrine therapy group was 25.7 months for the palbociclib group (n = 195) versus 19.6 months for the control group (n = 96) (HR, 0.63; 95% CI, 0.44-0.90). The ORR rates were 52.8% and 44.8%, respectively.
Within the patients previously treated with chemotherapy, the median PFS was 22.4 months (n = 213) versus 13.7 months for the non-palbociclib group (n = 109) (HR, 0.53; 95% CI, 0.40-0.72). The ORRs were 36.2% versus 30.3%, respectively. In the no-prior chemotherapy subgroup, median PFS was 25.7 months (n = 231) versus 17.0 months (n = 113) (HR, 0.61; 95% CI, 0.44-0.84). ORR was 47.6% versus 38.9% for the palbociclib-plus letrozole versus control.
“In the subgroup analysis, we evaluated benefit based on prior endocrine and prior chemotherapy, both of which would have been given in the neoadjuvant or adjuvant setting," lead author of the subgroup analysis Richard Finn, MD, from the David Geffen School of Medicine at UCLA, toldTargeted Oncology. "The take-home message is that regardless of these prior therapies, there is still a significant improvement in PFS with the addition of palbociclib to letrozole.”
"Tolerability was similar across subgroups and was consistent with the known safety profile of palbociclib when combined with endocrine therapy," added the authors.
666 postmenopausal women enrolled in the study from February 2013 to July 2014 and were randomly assigned 2:1 to the palbociclib plus letrozole arm (n = 444) or the placebo plus letrozole arm (n = 222). Median age was between 58 and 65 years, and most of the patients were white (75%-81%) and non-Hispanic or Latino.
The most common of the prior endocrine therapies received by patients were tamoxifen (22%-84%), anastrozole (6%-23%), letrozole (4%-15%), and exemestane (2%-12%). The median average of the daily palbociclib dose was 125 mg across all subgroups; the median number of cycles was 18 versus 21 for those receiving prior endocrine therapy versus those who did not, and 19 versus 21 for prior chemotherapy versus without, respectively.
There was a clinical benefit rate of 81.5% (palbociclib) versus 66.7% (placebo) for the prior endocrine therapy patients, 89.2% versus 75.0% for no prior endocrine therapy, 81.7% versus 70.6% for prior chemotherapy, and 87.9% versus 69.9% for no prior chemotherapy.
Across the subgroups receiving palbociclib plus letrozole, the median duration of response was strongest among those with no prior therapy: 28.0 months for those with no prior endocrine therapy versus 22.5 months for pretreated patients, and 28.0 months for those with no prior chemotherapy versus 20.1 months for the pretreated group.
Investigators found tolerability to be consistent across all subgroups and in accordance with the known safety profile of palbociclib when combined with endocrine therapy. Neutropenia, infections, leukopenia, nausea, fatigue, and arthralgia (Table) were the most common treatment related adverse events (AEs).
Regardless of prior therapy or type of therapy if pretreated within all palbociclib plus letrozole groups, treatment emergent AEs of any grade leading to permanent discontinuation occurred in <10% of patients. All subgroups had permanent discontinuations due to grades 3 to 5 AEs ranged from 0.8% to 3.5%, and similar frequencies. There were no new/unexpected safety issues observed in the study.
Palbociclib has been investigated in several settings for patients with ER-positive advanced breast cancer. The CDK4/6 inhibitor has been approved in combination with an aromatase inhibitor as a frontline therapy and in combination with fulvestrant as a second-line therapy, both for postmenopausal women with HER2-negative, ER-positive metastatic breast cancer.
Table: Grades 3 to 5 Adverse Events
in Palbociclib-Plus Letrozole Subgroups
Prior Endocrine Therapy
n = 249
n = 195
n = 213
n = 231
Finn RS, Gelmon KA, Ettl J, et al. Impact of prior treatment on palbociclib plus letrozole efficacy and safety in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) first-line advanced breast cancer: a PALOMA-2 subgroup analysis. Presented at the 35th Annual Miami Breast Cancer Conference®(MBCC); March 8-11, Miami Beach, FL. Abstract 591.