Palbociclib's Role in Endocrine-Resistant Breast Cancer

Roxanne Nelson

July 15, 2015

Palbociclib (Ibrance, Pfizer), the first CDK4/6 inhibitor to be approved for the treatment of breast cancer, has been welcomed by experts for its role in improving outcomes in patients with endocrine-resistant breast cancer.

The drug should a significant improvement in progression-free survival (PFS) when it was added to fulvestrant (Faslodex, AstraZeneca) in the phase 3 PALOMA 3 trial, as reported recently by Medscape Medical News. The addition of palbociclib to fulvestrant increased median PFS to 9.2 months in patients with estrogen receptor (ER)–positive/HER2-negative endocrine-resistant breast cancer compared with 3.8 months in the placebo-fulvestrant group (P < .001).

The overall survival data are still immature.

The full results have now been published in print in the July 16 issue of the New England Journal of Medicine.

But while these results are very promising, there are reasons to proceed with caution, experts comment in accompanying editorial

Editorialists Lisa A. Carey, MD, and Charles M. Perou, PhD, both from the University of North Carolina, Chapel Hill, point out that ER-positive breast cancer is biologically heterogeneous, and many patients do well long term, with minimal treatment, while using palbociclib adds considerable cost and toxicity to the treatment regimen.

"Ideally, we should seek to identify patients with an excellent prognosis with endocrine therapy alone as well as predictive biomarkers for palbociclib to have a benefit," they write.

But given the lack of biomarker selectively for palbociclib, the population cannot be sufficiently narrowed to those who may derive the most benefit, Dr Carey told Medscape Medical News.

She noted that patients could be receiving this drug, at a very high cost and risk for toxicity, but not derive much benefit, "and this is a problem for us as a community."

"In the meantime palbociclib is a reasonable addition to letrozole [Femara, Novartis] in the first-line setting if tolerated, given the progression-free survival advantage and its approval," she said. "Long term we must identify those patients who will do well without it, and those who truly benefit, and we cannot do either at this time."

Study Details

Results from the PALOMA-3 study have been public since early June 2015, when they were presented at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO) and simultaneously published online in the New England Journal of Medicine.

The improvement in PFS that was seen in this phase 3 study echoed the results seen in the earlier phase 2 PALOMA-1/TRIO-18 study, which were the basis for the accelerated approval of the drug, 2 months ahead of schedule.

For the PALOMA-3 study, Nicholas C. Turner, MD, PhD, from the Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom, and colleagues, enrolled 521 patients with advanced ER-positive, HER2-negative breast cancer that had relapsed or progressed during prior endocrine therapy.

Patients were randomly assigned 2:1 to receive palbociclib and fulvestrant or placebo and fulvestrant, and the primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, objective response, rate of clinical benefit, patient-reported outcomes, and safety.

The data cutoff date was December 5, 2014, for the interim analysis, and by then 195 events of disease progression or death had occurred (102 events in the palbociclib-fulvestrant group and 93 in the placebo-fulvestrant group). A total of 238 patients (68.6%) continue to receive treatment with palbociclib-fulvestrant and 75 patients (43.1%) with placebo-fulvestrant.

The trial met its primary end point at the interim analysis, showing a median PFS in favor of palbociclib: 9.2 months (95% confidence interval [CI], 7.5 months - not estimable) vs 3.8 months (95% CI, 3.5 - 5.5 months) with placebo-fulvestrant (hazard ratio for disease progression or death, 0.42; 95% CI, 0.32 - 0.56; P < .001).

Rates of overall objective response were 10.4% for patients receiving palbociclib and 6.3% for the fulvestrant-only group (P = .16).

The rate of clinical benefit (response or prolonged stable disease) at the interim analysis was 34.0% with palbociclib-fulvestrant and 19.0% with placebo-fulvestrant (P < .001).

However, the authors note that at the time of the interim analysis, overall survival data are still immature. A total of 28 patients have died: 19 (5.5%) in the palbociclib-fulvestrant group and 9 (5.2%) in the placebo-fulvestrant group.

The most common grade 3 or 4 adverse events observed in patients receiving palbociclib were neutropenia (62.0% vs 0.6% in the placebo-fulvestrant group), leukopenia (25.2% vs 0.6%), anemia (2.6% vs 1.7%), thrombocytopenia (2.3% vs 0%), and fatigue (2.0% vs 1.2%).

In addition, the rate of febrile neutropenia was identical in both groups (0.6%) and the rate of discontinuation due to adverse events was 2.6% with palbociclib and 1.7% with placebo.

At the ASCO annual meeting, experts applauded the drug as a welcome addition to the treatment armamentarium.

"It is exciting to have a novel, active, and well-tolerated biologic enter the treatment space," Erica Mayer, MD, assistant professor of medicine at Harvard Medical School, Boston, Massachusetts, told Medscape Medical News. "PALOMA 3 demonstrates efficacy in pretreated hormone receptor–positive breast cancer, suggesting the ability of CDK4/6 inhibition to overcome the challenge of endocrine resistance."

Conleth Murphy, MB, BCh, BAO, a medical oncologist at Bon Secours Hospital in Cork, Ireland, echoed those feelings. "This study is very important because it is the first phase 3 study to demonstrate efficacy in any setting for these agents…and represents the first phase 3 data supporting the use of this group of novel therapies in combination with endocrine therapy for women with hormone sensitive advanced breast cancer," said Dr Murphy.

The study was funded by Pfizer. Dr Turner has disclosed no relevant financial relationships, but several authors reported receiving fees from Pfizer, as well as other pharmaceutical companies; two authors are company employees. Dr Carey has disclosed no relevant financial relationships. Dr Perou reports receiving fees from Pfizer, G1 Therapeutics, Bioclassifier LLC, and GeneCentric Diagnostics and reports receiving royalties from a pending patent, licensed to Nanostring Technologies, related to gene expression profiles to predict breast cancer outcomes.

N Engl J Med. 2015;373:209-219, 273-274. Abstract Editorial


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