Single-agent palbociclib improves outcomes when added to existing endocrine therapy in patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer whose disease has progressed while on endocrine therapy.1 Findings from a phase 2 study known as TREnd demonstrated a longer duration of clinical benefit with the combination of palbociclib and endocrine therapy after endocrine therapy failure, reported Luca Malorni, MD, PhD, from the Medical Oncology Department, Hospital of Prato, Istituto Toscano Tumori, Firenze, Italy, at the 2017 meeting of the American Society of Clinical Oncology.
Palbociclib combined with endocrine therapy is approved for the treatment of HR-positive, HER2-negative metastatic breast cancer. Clinical data of palbociclib as a single agent in such patients are limited to heavily pretreated patients. Preclinical data suggest that adding palbociclib to endocrine therapy may partially reverse endocrine resistance, although this concept has yet to be tested in patients, said Dr Malorni.
TREnd was a randomized, open-label phase 2 study that enrolled 115 women with HR-positive, HER2-negative metastatic breast cancer who had disease progression despite endocrine therapy. The aim of the study, which was conducted in 8 centers in Italy, was to test the activity of palbociclib as a single agent in a moderately pretreated population of patients and in combination with the same endocrine therapy received before disease progression.
To be eligible, patients could have received 1 or 2 lines of endocrine therapy for metastatic disease. Fifty-seven patients were randomly assigned to palbociclib 125 mg daily (3 weeks on, 1 week off), and 58 patients were randomly assigned to receive palbociclib plus the same endocrine therapy they were receiving preprogression (an aromatase inhibitor or fulvestrant).
The primary end point was clinical benefit rate (CBR) defined as the combined rates of complete response, partial response, and stable disease for more than 6 months.
At baseline, approximately 75% of patients had visceral disease, and approximately 69% had received 1 line of prior endocrine therapy for metastatic disease. In each study group, 67% received study treatment as second-line endocrine therapy and 33% as third line.
Treatment was well-tolerated, with a median dose intensity of 100% in each arm. Twenty-three percent of cycles in the palbociclib plus endocrine therapy arm required dose reduction and 35% required a delay, compared with 13% and 28% of cycles in the palbociclib alone arm. As expected, dose reductions and delays were most often a result of hematologic toxicity.
The CBR was similar across both arms of the study: 54% for palbociclib plus endocrine therapy and 60% for palbociclib alone.
“This was clinically meaningful and superior to the prespecified cut point of 40% before both treatment arms can be declared active based on the study assumptions,” said Dr Malorni.
Most of the patients achieving clinical benefit had stable disease (44% with palbociclib plus endocrine therapy and 53% with palbociclib alone).
The median duration of clinical benefit was significantly longer for patients who received the combination of palbociclib plus endocrine therapy compared with palbociclib alone (11.5 vs 6 months; P = .0021).
There was a trend toward superior progression-free survival (PFS) with palbociclib plus endocrine therapy versus palbociclib as a single agent (10.8 vs 6.5 months; hazard ratio, 0.69; P = .12).
“The increase in PFS seen in the palbociclib plus endocrine therapy group was mostly confined to the subpopulation of patients who had received their prior endocrine therapy for longer than 6 months,” Dr Malorni said. In this group, the PFS was 11.5 months in the palbociclib plus endocrine therapy arm versus 6.5 months in the palbociclib single-agent arm (P = .02). The advantage in PFS for the combination was not observed in patients who did not receive benefit from prior endocrine therapy.
Adverse events, which were mostly hematologic in nature, were in line with previous studies. The rates of discontinuation due to adverse events were 9% in the palbociclib plus endocrine therapy arm and 6% in the palbociclib alone arm.
“Despite no difference observed in clinical benefit rate among the 2 study arms, the PFS and related subgroup analyses by duration of prior endocrine therapy does suggest that palbociclib could reverse acquired resistance to the same endocrine therapy used in the prior line of endocrine treatment,” Dr Malorni concluded.
1. Malorni L, Curigliano G, Minisini A, et al. A phase II trial of the CDK4/6 inhibitor palbociclib (P) as single agent or in combination with the same endocrine therapy (ET) received prior to disease progression, in patients (pts) with hormone receptor positive (HR+) HER2 negative (HER2−) metastatic breast cancer (mBC) (TREnd trial). Presented at the American Society of Clinical Oncology Annual Meeting; June 2-6, 2017; Chicago, IL. Abstract 1002.