PALOMA-3: Basis of Expanded Labels for Ibrance, Faslodex

Alexander M. Castellino, PhD

March 08, 2016

Last year, the United States Food and Drug Administration (FDA) approved palbociclib (Ibrance, Pfizer Inc) in combination with letrozole (Femara, Novartis Pharmaceuticals Corporation) for the first-line treatment of postmenopausal women with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer on the basis of results of the PALOMA-1 trial.

Exactly 1 year later, on the basis of data from PALOMA-3, the FDA expanded the use of palbociclib — this time in combination with fulvestrant (Faslodex, AstraZeneca Pharmaceuticals LP) for the second-line treatment of advanced or metastatic breast cancer. The approval coincided with the publication on March 2 of PALOMA-3 in the Lancet Oncology.

Palbociclib is an oral selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6 and blocks cell cycle progression.

This approval expands the indication for fulvestrant — hormonal therapy that targets the ER through its blockade and degradation. In 2002, fulvestrant was approved as monotherapy for the treatment of postmenopausal women with hormone receptor (HR)–positive metastatic breast cancer that has progressed following other antiestrogen therapy.

This means that palbociclib and fulvestrant can now be used in combination for HR-positive, HER-negative metastatic breast cancer that has progressed on endocrine therapy.

"The new [Faslodex] indication provides another important treatment option for patients," said Dennis Slamon, MD, medical oncologist at the University of California, Los Angeles, in a press statement.

"The positive results of this study, which also included premenopausal women, showed that the combination of palbociclib and fulvestrant was effective for patients who had failed standard endocrine therapy," PALOMA-3 lead author Massimo Cristofanilli, MD, of the Robert H. Lurie Comprehensive Cancer Center, at Northwestern University in, Chicago, told Medscape Medical News.

"It is a safe combination, and a fraction of this population was also exposed to systemic chemotherapy," he said.

In an accompanying editorial, a trio of experts explained that the efficacy does not rely on other, established pathways.

"This benefit is not related to the degree of endocrine sensitivity assessed clinically (ie, previous endocrine response) or pathologically (ie, levels of expression of oestrogen and progesterone receptors) or to PI3K [phosphatidylinositol-3 kinase] mutational status," write Francesco Cognetti, MD, Paolo Malaguti, MD, and Daniele Alesini, MD, from the Regina Elena National Cancer Institute, Rome, Italy.

Furthermore, progression-free survival (PFS), the primary endpoint in the trial, was significantly better for patients receiving the palbociclib and fulvestrant combination regardless of menopausal status, site of metastasis, previous lines of endocrine therapy, and PIK3CA status.

Overall, in the 521-patient study, median PFS was longer for patients receiving the combination of palbociclib and fulvestrant vs fulvestrant alone (9.5 months vs 4.6 months; hazard ratio [HR]: 0.46; 95% confidence interval [CI]: 0.36 - 0.59; P < .0001); the patients receiving the combination had a 54% lower risk for disease progression.

Median follow-up was 8.9 months.

PALOMA-3 Study Details

PALOMA-3 was an international, prospective, randomized, double-blind, placebo-controlled phase 3 study that enrolled 521 women with HR-positive, HER-2 negative metastatic breast cancer who experienced disease progression on endocrine therapy. Menopausal status was not a factor in patient enrollment.

Patients were randomly assigned in a 2:1 ratio to receive palbociclib and fulvestrant (n = 347) or fulvestrant and placebo (n = 174). Fulvestrant 500 mg was administered intramuscularly on days 1 and 15 of cycle 1 and then on day 1 of subsequent cycles (28-day cycle). Palbociclib was provided orally at a daily dose of 125 mg for first 3 weeks of the 28-day cycle.

CT or MRI was used to assess tumors at baseline and every 8 weeks for the first year and every 12 weeks in subsequent years. Tumor tissue was obtained from a biopsy of patients with recurrent disease. Plasma samples were collected on days 1 and 15 of cycle 1 and after treatment termination to determine whether the presence of PIK3CA mutations could be used as a predictive biomarker.

The primary endpoint of the study was PFS in accordance with RECIST version 1.1.

PALOMA-3 Results

The trial was terminated early owing to a determination by an independent data monitoring committee that PALOMA-3 had met its primary endpoint. The report in the Lancet Oncology is based on final data analysis.

The median age of the patients was 57 years. Of patients enrolled, 79% were postmenopausal; 21% were pre- or perimenopausal. Forty-eight percent of the women received at least one previous endocrine therapy, 38% received two prior endocrine therapies, and 13% received at least three prior endocrine therapies. Thirty-four percent of patients received prior systemic chemotherapy for metastatic disease.

For patients with measurable disease at baseline, the confirmed overall response rate was higher for those receiving palbociclib and fulvestrant (24.6% vs 10.9% for fulvestrant alone). The median time of response was 112 days for patients receiving palbociclib and 57 days for those receiving fulvestrant.

However, when median PFS was analyzed on the basis of PIK3CA mutational status, the difference in PFS for patients with the PIK3CA mutations was not significant (5.8 months vs 9.2 months for no mutations; P = .94), regardless of treatment. Median PFS for patients receiving palbociclib and fulvestrant was similar regardless of PI3KCA mutational status (9.9 months for wild-type PI3KCA vs 9.5 months for PI3KCA mutations).

Overall survival (OS) was not reported for PALMOA-3. Dr Cristofanilli told Medscape Medical News that the number of deaths that occurred was not sufficient to determine OS.

The warnings and precautions of palbociclib, as noted in a recent company statement, include neutropenia, pulmonary embolism, and embryo-fetal toxicity. Most of the adverse events of grade 3 or 4 that occurred with the combination were neutropenia (65% vs 1% for fulvestrant); febrile neutropenia was uncommon. Leukopenia also occurred at a greater frequency in patients receiving the combination (28% vs 2% for fulvestrant). Serious adverse events occurred in 13% of patients in the palbociclib group vs 17% in the fulvestrant group; 4% of patients in the palbociclib group discontinued treatment (vs 2% in the fulvestrant group).

Significance for Women With Metastatic Breast Cancer

The National Comprehensive Cancer Network (NCCN) has provided a category 1 recommendation for the use of the combination of palbociclib and fulvestrant in postmenopausal women or for premenopausal women receiving luteinizing-hormone-releasing hormone agonist; these are the same patients who parpticipated in PALOMA-3.

"Single-agent fulvestrant is an accepted second-line option in these patients," Dr Cristofanilli said. Now palbociclib can be added for a more effective second-line option. In addition, the study provides support for use of this combination in premenopausal women for whom therapy with tamoxifen has failed, he further explained.

"We do use palbociclib as treatment for metastatic breast cancer," Eric P. Winer, MD, a medical oncologist at Dana-Farber Cancer Institute, in Boston, Massachusetts, told Medscape Medical News.

"If patients are starting on first-line therapy, we usually begin treatment with palbociclib. If patients have had a non-palbociclib-containing first-line regimen, we use it second line," he added. Referring to PALOMA-1 and PALOMA-3, he explained that there are data to support both approaches.

Dr Cristofanilli indicated that he usually uses the combination of palbociclib and letrozole for the first-line treatment of postmenopausal women with metastatic breast cancer and the combination of exemestane (Aromasin, Pharmacia and Upjohn) and everolimus (multiple brands) for second-line treatment in women with recurrent disease. In some cases, he uses fulvestrant, particularly if he is concerned about everolimus toxicity.

However, PALOMA-3 did not identify a subset of patients who may benefit more from the combination of palbociclib and fulvestrant. The analysis based on PIK3CA status was undertaken on the basis of observations that mutations in PIK3CA are associated with a lower rate of nodal and distant metastasis.

In PALOMA-3, it was not possible to identify a subset of patients who would achieve any superior clinical benefits on the basis of PIK3CA mutational status. "Since palbociclib affects cell cycle progression, it was not possible to identify clinical benefits with this marker," Dr Cristofanilli said.

"This failure could be because of tumour heterogeneity and further study into this issue is urgently needed,” the editorials explain.

The study was funded by Pfizer, Inc. Several PALOMA-3 authors have ties with industry, which are listed in the original article. Dr Cristofanilli and the editorialists have disclosed no relevant financial relationships.

Lancet Oncol. Published online March 2, 2016. Abstract, Editorial


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