Nick Mulcahy

March 17, 2015

UPDATED March 19, 2015 // HOLLYWOOD, Florida — Clinicians will soon know whether palbociclib (Ibrance, Pfizer), the newly approved treatment for metastatic breast cancer, can deliver a significant improvement in overall survival in this setting — a rare achievement.

Results from a phase 3 trial of palbociclib will "definitely" be presented in December at the San Antonio Breast Cancer Symposium, but might be ready for presentation as early as June, at the American Society of Clinical Oncology annual meeting, said Ingrid Mayer, MD, clinical director of the breast cancer research program at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

She discussed palbociclib and new experimental therapies for advanced hormone-sensitive breast cancer here at the National Comprehensive Cancer Network (NCCN) 20th Annual Conference.

Palbociclib was approved by the US Food and Drug Administration (FDA) on the strength of open-label phase 2 trial data, which showed that progression-free survival with palbociclib plus endocrine therapy was double that seen with endocrine therapy alone.

The anticipated results from the phase 3 PALOMA-2 trial "will either confirm what we've seen with the phase 2 studies or disprove that [efficacy]," said Dr Mayer.

If the benefit is not replicated, "then the FDA will have to explain why they approved the drug without having the phase 3 results available," she noted.

The drug was granted breakthrough therapy designation by the FDA and received accelerated approval. These approvals are conditional and stipulate that drug developers must eventually present further proof of efficacy to maintain the approval.

Progression-free survival is the primary outcome of PALOMA-2. However, overall survival is a secondary outcome in the trial.

Dr Mayer pointed out that various other drugs, including everolimus (Afinitor, Novartis) in the recent phase 3 BOLERO-2 trial, have been a disappointment in terms of extending life. That is, they show a significant improvement in progression-free survival but fail to demonstrate a significant overall survival benefit. She called the everolimus overall survival data "a little disappointing." However, everolimus did demonstrate an improvement in overall survival, which has been called "clinically significant."

Everolimus, too, was approved by the FDA on the basis of progression-free survival data.

Palbociclib is specifically indicated for use with the aromatase inhibitor letrozole as first-line treatment in postmenopausal women with metastatic breast cancer that is estrogen-receptor-positive and HER2-negative.

Dr Mayer said that she has been repeatedly asked if she is using first-line palbociclib in "everybody" who meets these criteria.

I am not yet quite sold.

"The answer is still no. I am not yet quite sold that this is actually a strategy to be used for everybody," she reported.

She explained that there are still patients who are going to benefit "tremendously" from endocrine therapy (such as letrozole) alone in the first line.

Endocrine therapy alone is a good strategy for a patient who wants to preserve her quality of life, does not want to come in for frequent blood checks, and wants to avoid gastrointestinal toxicities, said Dr Mayer.

However, for patients who experience disease recurrence very quickly while being treated with adjuvant endocrine therapy, and who are therefore likely to have primary endocrine resistance, the use of palbociclib might be appropriate, she said.

Palbociclib acts as an inhibitor of cyclin-dependent kinases 4 and 6, which are involved in promoting the growth of cancer cells, Dr Mayer explained.

Patients being treated with palbociclib need careful blood monitoring because the drug can cause "severe myelosuppression," she reported.

This statement is a reference to results from the phase 2 PALOMA-1/TRIO-18 study, which the FDA used as a basis for its accelerated approval.

Of the 165 women enrolled in the study, 84 received palbociclib plus letrozole and 81 received letrozole alone.

All patients recevied the standard dose of oral letrozole 2.5 mg administered once daily. In addition, patients in the combination group received oral palbociclib 125 mg administered once daily for 3 weeks, followed by 1 week off treatment, in a 28-day cycle. Treatment continued until disease progression.

The PALOMA-1/TRIO-18 investigators reported that the incidence of grade 3/4 neutropenia was higher with the palbociclib and letrozole combination than with letrozole monotherapy (54% vs 1%), as was the incidence of grade 3 leukopenia (19% vs 0%).

On the plus side, median progression-free survival — the study's primary end point — was almost twice as long with the palbociclib and letrozole combination as with letrozole monotherapy (20.2 vs 10.2; = .0004).

Notably, the interim median survival difference between the combination and monotherapy groups was not significant (37.5 vs 33.3 months).

At the time of the FDA approval, some experts had hesitations about palbociclib because of its toxicity.

Physicians have to make a judgment call in balancing cost and toxicity with progression-free survival, Clifford A. Hudis, MD, chief of breast medicine service at the Memorial Sloan Kettering Cancer Center in New York City, told Medscape Medical News at that time. It is important to know how the phase 3 study will pan out, he added.

It was a surprise that the FDA would not wait for phase 3 data before proceeding with an approval, 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 in Boston.

"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.

Dr Mayer reports financial relationships with Genentech and Novartis.

National Comprehensive Cancer Network (NCCN) 20th Annual Conference. Presented March 14, 2015.


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