Palbociclib for Breast Cancer Inches Toward FDA Approval

Alexander M. Castellino, PhD

January 21, 2015

Hormone-directed drugs (e.g., tamoxifen, aromatase inhibitors, and fulvestrant) are at the cornerstone of treating postmenopausal women with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer.

Until recently, targeted agents have provided disappointing results in these patients. Then in 2012, the mTOR inhibitor everolimus (Afinitor) was approved in combination with exemestane for treating ER-positive, HER2-negative advanced breast cancer that recurs on standard therapies.

Now, attention is focusing on another targeted agent — palbociclib (under development by Pfizer), a cyclin-dependent kinase (CDK) 4/6 inhibitor — with speculation that it is approaching approval for this patient population on the basis of data from a phase 2 study.

The phase 2 study was initially reported at the San Antonio Breast Cancer Symposium in December 2012, and then at the American Association for Cancer Research meeting in April 2014.

The results show that palbociclib in combination with letrozole resulted in a significantly longer progression-free survival in the first-line treatment of ER-positive, HER2-negative advanced breast cancer — almost doubling progression-free survival compared with letrozole alone.

The final data from this phase 2 study — the PALOMA-1/TRIO-18 study — were published in the January issue of Lancet Oncology.

In an accompanying podcast, corresponding author Dennis J. Slamon, MD, PhD, director of clinical and translational research at the Jonsson Comprehensive Cancer Center, University of California at Los Angeles, indicated that the study provides further proof that targeted therapies still hold promise for improved efficacy.

If we can identify the right target and show that it plays a role in the pathogenesis and can inhibit it appropriately, we can develop therapies that are more effective and less toxic than traditional cytotoxic approaches to these cancers, he said.

These data are exciting, real, and speak to the fact that palbociclib is efficacious, Dr Slamon told Medscape Medical News.

Similar data are being reported in studies using other CDK 4/6 inhibitors, and we are certain the signal is there, he added. He was referring to abemaciclib (under development by Lilly), another CDK 4/6 inhibitor that has shown similar results in early phase 1 clinical studies in the same patient population.

"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 Gnant, MD, Guenther G. Steger, MD, and Rupert Bartsch, MD, from the Breast Health Center, Comprehensive Cancer Center, Medical University of Vienna, in an accompanying comment.

However, Clifford A. Hudis, MD, chief of the Breast Medicine Service at the Memorial Sloan Kettering Cancer Center in New York City, was more cautious in emphatically endorsing these data.

The idea of CDK inhibition has been around for a while, but this is the first phase 2 randomized clinical trial with data showing that inhibiting CDK 4/6 in the setting of aromatase inhibition could be promising, he told Medscape Medical News.

"This is always a tough moment. We tend to be optimistic and enthused," he commented, but added that "we are also cautious because we have been misled in the past with data from phase 2 studies."

Eric P. Winer, MD, chief of the division of women's cancers in the Susan F. Smith Center at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School in Boston, also shared his optimism, but indicated that he would wait for data from the phase 3 study before drawing firm conclusions.

The findings from the PALOMA-1 study do not come as a surprise; we have seen these data at international meetings, Dr Winer said. There is a lot of enthusiasm around palbociclib and the CKD 4/6 inhibitors in general, he told Medscape Medical News. He noted that there are two phase 3 studies with palbociclib that are in progress, and "we are awaiting results from these."

The PALOMA-1 Study

PALOMA-1 was a phase 2 open-label study undertaken in women with ER-positive, HER2-negative advanced breast cancer who had not received any 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 on the basis of ER-positive and HER2-negative 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 in a 1:1 ratio to palbociclib and letrozole or to 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 on the basis of 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 3 weeks followed by 1 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.

Tumor assessment — CT or MRI of the chest, abdomen, and pelvis — was done at each center at screening and every 8 weeks thereafter.

Progression-free survival was the primary end point of the study.

Extended Progression-free Survival With Palbociclib Plus Letrozole

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

Median progression-free survival was almost double for women on the combination of palbociclib and letrozole — 20.2 months vs 10.2 months for those on letrozole alone (= .0004).

Objective response rate was higher for women receiving the combination of palbociclib and letrozole: 43% vs 33% for letrozole alone (= .13).

For patients showing a complete or partial response, duration of response was higher for women receiving the combination of palbociclib and letrozole: 20.3 vs 11.1 months for letrozole alone.

However, as of 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. The incidence of grade 3/4 neutropenia was 54% for palbociclib and letrozole and 1% for letrozole; the incidence of grade 3 leukopenia was 19% for palbociclib and letrozole and 0% for letrozole.

The hematologic adverse effects did not require management with growth factors and resolved over the week when the patients were off palbociclib. This has much to do with the mechanism of action of the drug, Dr Slamon told Medscape Medical News.

Unlike cytotoxics that kill cells, palbociclib arrests cells in their growth. That's why we do not see febrile neutropenia or infection, or the same degree of very low white count troughs seen with chemotherapy, he added.

For Dr Gnant and his colleagues, these data are encouraging. "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 comment.

However, to others, overall survival matters, and waiting for data from phase 3 studies is important.

Dr Slamon indicated that it is too early to see survival differences, given that approximately 30 events have been recorded in each group. These patients are going to be followed for another 3 to 4 years, he told Medscape Medical News.

Although progression-free survival 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 progression-free survival, Dr Hudis told Medscape Medical News. It is important to know how the phase 3 study will pan out, he said.

The absence of a placebo can have an effect on the assessment of progression-free survival by the investigator, Dr Winer told Medscape Medical News. However, given the dramatic improvement in progression-free survival seen in the study, it is hard to imagine that this difference is entirely a result of investigator bias, he added.

"I am very hopeful that palbociclib will provide another important option for women with ER-positive, HER2-negative advanced breast cancer," Dr Winer said. He indicated that there will be substantial disappointment if the drug is ineffective in phase 3 studies and fails to obtain an approval.

The phase 3 multicenter study — the PALOMA-2 study — will take an approach similar to PALOMA-1 in 650 postmenopausal women with ER-positive, HER2-negative advanced breast cancer not on initial hormonal therapy (NCT01740427).

Several limitations of PALOMA-1 will be addressed in PALOMA-2. Whereas PALOMA-1 was an open-label study, PALOMA-2 is a randomized, double-blind, placebo-controlled study. In addition, tumor assessment will be done prospectively at a central facility, unlike PALOMA-1, where tumor assessment was done retrospectively at each center. Accrual in PALOMA-2 is complete. The study is ongoing and is expected to have final data in October 2016.

Another randomized, double-blind, placebo-controlled, phase 3 study — PALOMA-3 — will compare the combination of palbociclib and fulvestrant with fulvestrant alone in ER-positive, HER2-negative advanced breast cancer that has progressed on hormonal therapy (NCT01942135).

Because time to progression is long in patients not on initial hormonal therapy, Dr Winer indicated that data from PALOMA-3 may be available before those from PALOMA-2.

The Significance of Inhibiting CDK 4/6

CDKs belong to a family of kinases that, in conjunction with cyclins, plays a significant role in cell-cycle progression. CDK 4/6 interacts with cyclin D and is important for cells transitioning from the Gv(1) phase of the cell cycle to the S phase. Inhibiting CDK 4/6 arrests cells in the Gv(1) phase — called Gv(1) arrest.

But previous studies with CDK inhibition have been disappointing in breast cancer, so why does it work in this tumor subtype?

In his podcast, Dr Slamon explains the rationale for using CDK 4/6 inhibition in breast cancer. It was hoped that inhibiting cell-cycle progression would have an impact on some of the rapidly proliferating subtypes.

He admitted that that the preconceived notion was to see if CDK 4/6 inhibition would have an effect on triple-negative breast cancer — the fastest growing breast cancer subtype.

However, laboratory data with 51 breast cancer cell lines showed that the preconceived notion was incorrect. The greatest impact was seen in ER-positive luminal breast cancer cells; that's what provided the rationale to test palbociclib in ER-positive, HER2-negative breast cancer.

Available molecular data from these cell lines also showed that the Rb protein is expressed at high levels in these cells. The molecular and biologic data pointed to clinical trials in the direction of ER-positive, HER2-negative breast cancer, Dr Slamon told Medscape Medical News.

Dr Slamon also indicated that in the past, the pan-CDK inhibitors tested had a broad specificity. This study suggests that the narrow specificity for inhibiting CDK 4/6 matters. Although palbociclib was initially developed for hematologic malignancies, which show cyclin D amplification, attention turned to ER-positive, HER2-negative breast cancer, where the impact CDK 4/6 inhibition is significantly higher, he indicated.

Sufficient Data for Approval?

On the basis of interim data from PALOMA-1, palbociclib — now branded as Ibrance — received breakthrough therapy designation from the US Food and Drug Administration (FDA) in April 2013 for the first-line treatment of women with ER-positive, HER2-negative advanced breast cancer.

When the final data became available in August 2014, Pfizer filed a New Drug Application with the FDA for the first-line treatment of postmenopausal women with ER-positive, HER2-negative advanced breast cancer.

In a January 8 press release, Pfizer said: The FDA "has informed Pfizer Inc. that at this time there is no plan for an Oncologic Drugs Advisory Committee meeting for [palbociclib]."

The company went on to indicate that the Prescription Drug User Fee Act goal date for a decision by the FDA is April 13, and said that it is currently in label discussions with the FDA.

This announcement prompted a flurry of speculation among pharmaceutical analysts that palbociclib is close to approval and that it could be approved on the basis of phase 2 data. The drug is considered to be one of the most important in Pfizer's developmental pipeline, and analysts are forecasting annual sales of $3 billion.

But is the approval of palbociclib in combination with letrozole for the first-line treatment of ER-positive, HER2-negative advanced breast cancer imminent? Medscape Medical News got mixed opinions.

Dr Winer believes "the FDA will need to wait for the phase 3 data before proceeding with an approval. The situation would be very different if there had been a significant survival difference in PALOMA-1."

"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. Any approval will need to wait for data from the phase 3 study," Dr Winer told Medscape Medical News.

We do not have the definitive evidence that this drug could transform the standard of care, but we have an exciting lead, Dr Hudis said. He indicated that it is unusual to set the standard of care on the basis of data from a phase 2 study.

However, Dr Slamon indicated to Medscape Medical News that he believes that the FDA may well approve the drug for ER-positive, HER2-negative advanced breast cancer on the basis of data from the phase 2 PALOMA-1 trial.

As a physician who advanced the HER2-trageted agent trastuzumab (Herceptin) in clinical practice, he is hopeful that palbociclib will experience similar success.

"Palbociclib offers a new standard of care for women with ER-positive, HER2-negative breast cancer who have waited for over four and a half decades for drugs based on an approach other than attacking just the estrogen/estrogen-receptor pathway," Dr Slamon told Medscape Medical News. We will no longer have to alternate between the traditional hormonal therapies as we are currently doing, he added.

If it is approved on the basis of data from PALOMA-1, it is not wrong to use it in patients, Dr Hudis commented. "We have to exercise judgment and be thoughtful in our approach," he told Medscape Medical News.

Dr Winer said that, although he may use it in some patients if approval were to be granted on the basis of these data, "there should not be a strong rush to use this drug until data from the phase 3 study become available."

Dr Slamon told Medscape Medical News: "Should this be confirmed in larger trials, it will represent a new standard of care for women with ER-positive breast cancer who have either developed de novo ER-positive breast cancer that can be treated with hormonal blockade and CDK 4/6 inhibition or who develop recurrence after treatment with hormonal blockade."

When asked about the accelerated approval of palbociclib, Dr Hudis indicated that it is appropriate to question the risk involved. On the basis of the safety profile, this is not the highest risk we are taking, he suggested.

Further Plans for Palbociclib

Further plans for palbociclib include more clinical trials in breast cancer, as well as investigations in other tumor types, the company revealed at a recent meeting.

At the J.P. Morgan Healthcare Conference on January 13, Mikael Dolsten, Pfizer's worldwide president for R&D, provided key milestones that palbociclib intends to achieve over the next few years.

The initial indication for the drug will be for women with ER-positive advanced breast cancer, he said. Data for women with recurrent breast cancer will be available from two trials — PALOMA-3 and PEARL — and studies in early-stage ER- positive, HER2-negative breast cancer (e.g., PENELOPE, PALLAS) should be completed by 2019, he indicated.

PALLAS will be an international study — a collaboration between the Breast Cancer Alliance in the United States, the Austrian Breast Cancer Study Group in Europe, with close involvement of the Breast International Group and PrECOG.

Expansion into other tumor types, including non-small cell lung cancer, head and neck cancer, melanoma, and pancreatic cancer, is expected over the next 4 years.

"We have invested heavily in the area around CDK 4/6 over the last couple of years and have been able to understand the molecular signatures and the type of preclinical data that support the strategy in the clinic to understand which indications are likely to succeed and how you combine palbociclib optimally to get the probability of the best response," Dolsten said.

This study was funded by Pfizer. Several study authors report being consultants, employees, and/or having financial relationships with Pfizer and other pharmaceutical companies. Dr Hudis reports being an unpaid consultant for Pfizer. Dr Winer is involved in the design of Pfizer's adjuvant study, PALLAS, in breast cancer, but receives no financial benefits from Pfizer.

Lancet Oncol. 2015;16:2-3, 25-35. Comment, Abstract

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