A NEW DRUG APPROVED BY FDA FOR BREAST CANCER

A new drug for the treatment of breast cancer with a novel mechanism of action, palbociclib (Ibrance, Pfizer) has been granted accelerated approval by the US Food and Drug Administration (FDA), two months ahead of schedule.

Palbociclib is indicated for use with the aromatase inhibitor letrozole as first-line treatment in postmenopausal women with metastatic breast cancer that is estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative.

The new drug acts as an inhibitor of cyclin-dependent kinases 4 and 6, which are involved in promoting the growth of cancer cells, the FDA noted.

"The addition of palbociclib to letrozole provides a novel treatment option to women diagnosed with metastatic breast cancer," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research.

The agency granted the drug breakthrough therapy designation because the sponsor demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies, the FDA said. It also received priority review, which provides for expedited review of drugs intended to provide a significant improvement in safety or effectiveness in the treatment of a serious condition or meet an unmet medical need.

Based on Phase 2 Data 

The accelerated approval is based on an open-label phase 2 data showing a significant improvement in progression-free survival (PFS).

The results from this phase 2 trial — the PALOMA-1/TRIO-18 study — were recently published in the January issue of The Lancet Oncology , and were reported by  Medscape Medical News at the time.

The trial was an open-label study undertaken in women with ER+/HER– advanced breast cancer who had not received any previous treatment. Of the 165 women enrolled in the study, 84 received palbociclib and letrozole, and 81 received letrozole alone.

Patients were enrolled in two cohorts: one cohort of patients was enrolled based on ER+ and HER2– receptor status. The second cohort was required to have tumors that had an amplification of cyclin D1, loss of p16, or both. Both cohorts were randomized 1:1 to palbociclib and letrozole, or letrozole alone.

Accrual to cohort 2 was stopped when an unplanned interim analysis showed that twice as many patients in the control group progressed in cohort 1 and came off the study. It was then decided that patient selection based on cyclin D amplification or p16 loss was not likely to improve patient outcome. A retrospective molecular analysis of tissues from patients in cohort 1 confirmed this.

Oral palbociclib 125 mg was given once daily for three weeks followed by one week off treatment in a 28-day cycle along with the standard dose of oral letrozole 2.5 mg once daily. Treatment continued until disease progression.

PFS was the primary endpoint of the study, and median PFS was almost double for women on the combination of palbociclib and letrozole — 20.2 months versus 10.2 for those on letrozole alone (P = .0004).

At data cut, women on palbociclib and letrozole had a median follow-up of 29.6 months, while those on letrozole were followed up for 27.9 months.

At this data cut, a median survival difference was not significant across the groups: 37.5 months for palbociclib and letrozole, and 33.3 months for letrozole alone.

The most common adverse events reported for the combination of palbociclib and letrozole were neutropenia, leukopenia, and fatigue. Incidence of grade 3/4 neutropenia was 54% for palbociclib and letrozole, and 1% for letrozole. Incidence of grade 3 leukopenia was 19% for palbociclib and letrozole, and 0% for letrozole.

"[The] results of this trial suggest a leap forward: doubling progression-free survival matters to our patients and is something that physicians have long been waiting to see," write Michael Gnat, MD, and colleagues from the Comprehensive Cancer Center, Breast Health Center, and Medical University of Vienna, Vienna, Austria, in an accompanying commentary.

"In a population that usually presents with few or no disease-related symptoms, the clinical relevance of prolonged progression-free survival can only be claimed when toxic effects are acceptable. Here, this seems to be the case," they write in their commentary.

However, other breast cancer experts approached by Medscape Medical News suggested that overall survival matters and waiting for data from ongoing phase 3 studies is important.

Two randomized phase 3 trials with palbociclib are ongoing: PALOMA-2, which is expected to have final data in October 2016; and PALOMA-3, which could finish sooner.

Although PFS is promising in the context of data from a phase 2 study, physicians have to make a judgment call in balancing cost and toxicity with PFS, Clifford A. Hudis, MD, Chief, Breast Medicine Service, Memorial Sloan Kettering Cancer Center, New York, told Medscape Medical News. It is important to know how the phase 3 study will pan out, he said.

Eric P. Winer, MD, chief of the Division of Women's Cancers in the Susan F. Smith Center for Women's Cancers at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, had thought that the FDA would wait for phase 3 data before proceeding with an approval. "I believe in the drug and am very encouraged, but I also believe in the scientific process. There is not sufficient rationale to make this drug available based on a phase 2, open-label trial," Dr Winer told Medscape Medical News last week.

Investigators Are Enthusiastic

The investigators who conducted the phase 2 study that led to the drug's approval are enthusiastic about the drug's potential. The subgroup of patients with ER+/HER2– tumors in this study represents the largest proportion of breast cancer cases, they note. This subgroup is traditionally treated with endocrine therapies, like tamoxifen or letrozole, they explain; palbociclib offers a novel approach.

"With the FDA approval, this study represents a potential practice-changing result," said study coauthor Dennis Slamon, MD, director of the Revlon/UCLA Women's Cancer Research Program and Clinical/Translational Research at the Jonsson Comprehensive Cancer Center in Los Angeles. "I believe palbociclib will now become a standard treatment approach for postmenopausal women with ER+/HER2– metastatic breast cancer," he said in a statement.

"What is really remarkable is that we doubled the median progression-free survival," commented Richard Finn, MD, the study's principal investigator and a researcher at the Jonsson Comprehensive Cancer Center. "That type of result is not often seen in cancer medicine."

"The magnitude of the observed benefit was very gratifying," added Dr Slamon, adding that it reminds him of the results seen 20 years ago in the initial studies on trastuzumab (Herceptin) in HER2+ breast cancers, which he was involved with.

The Wall Street Journal reports that palbociclib will sell for $9850 for a month's supply before discounts, adding that drug companies typically negotiate discounts with providers.

Pharmaceutical analysts predict the drug will be a blockbuster. Analysts at J.P. Morgan estimate the drug could generate $4 billion in sales in 2020, the newspaper reports.