New Standard in ER+ Breast Cancer, but How to Proceed?

Nick Mulcahy

November 16, 2016

The results of the phase 3 trial of the oral therapy palbociclib (Ibrance, Pfizer) for the first-line treatment of estrogen receptor (ER)–positive, HER2-negative advanced breast cancer were published online November 16 in the New England Journal of Medicine.

Now it's up to clinicians to decide what to do with them.

The trial, known as PALOMA-2 (Palbociclib: Ongoing Trials in the Management of Breast Cancer–2), compared palbociclib plus letrozole with letrozole alone in postmenopausal women in this setting. The newly published results are impressive, experts have commented.

The median progression-free survival (PFS) was 24.8 months in the palbociclib-letrozole group (n = 444), as compared with 14.5 months in the letrozole alone group (n = 222) (hazard ratio for disease progression or death, 0.58; P < .001), report the authors, led by Richard Finn, MD, of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.

Monotherapy with an endocrine treatment such as letrozole is a long-standing standard for this patient population.

But these current results with palbociclib, which is a member of a new class of drugs known as cyclin-dependent kinase 4 and 6 inhibitors, expand the standard treatment options, says an expert.

"CDK4 and CDK6 inhibition in combination with antiestrogens is clearly a new standard for the treatment of advanced ER-positive breast cancer," writes Antonio Wolff, MD, of the Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, in an accompanying editorial.

These CDK4/6 inhibitors, which also include the still experimental ribociclib (Novartis) and abemaciclib (Eli Lilly), prevent cancer cells from dividing by blocking a key family of proteins (CDK4/6) responsible for cell growth.

However, in PALOMA-2, the improvement in PFS seen with adding palbociclib to letrozole was accompanied by additional toxicities – most notably, much higher rates of grade 3 or 4 neutropenia (66.4% of the palbociclib-letrozole group vs 1.4% in the letrozole alone group) and of grade 3 or 4 leukopenia (24.8% vs 0%), report the authors.

Furthermore, permanent discontinuation of treatment as a result of adverse events occurred in 9.7% of the palbociclib-letrozole group and in 5.9% of the letrozole alone group.

Also, one consideration in using palbociclib-letrozole combination therapy is money. "Palbociclib is costly," admit the study authors. The drug is approved for use in the United States in advanced disease in combination with letrozole (first line) and with fulvestrant (second line).

So, which ER-positive, HER2-negative advanced breast cancer patients should receive first-line CDK4/6 inhibition plus an endocrine therapy (such as letrozole)? And which should be started with first-line endocrine therapy alone?

Currently, palbociclib is the only CDK4/6 inhibitor approved in this setting by the US Food and Drug Administration.

Investigator Dr Finn told Medscape Medical News said that "palbociclib should have broad use in this population." He added that "the benefit was consistent across all subgroups we looked at."

Palbociclib should have broad use in this population. Dr Richard Finn

He further explained that there are currently no biomarkers to help identify likely palbociclib responders. "True, there are some women who can do very well with endocrine therapy alone, but we cannot really select them out," Dr Finn said.

Other oncologists may approach treatment options in this setting a bit differently.

In comments to Medscape Medical News, editorialist Dr Wolff said: "Physicians and patients should make decisions on a case-by-case basis. However, they must not feel obliged to always immediately start a CDK4/CDK6 inhibitor."

He explained that these newer drugs are not an option in many areas of the world, owing to access or costs, and that a CDK4/CDK6 inhibitor is "not fully devoid of side effects, even if they are modest."

They must not feel obliged to always immediately start a CDK4/CDK6 inhibitor. Dr Antonio Wolff

Currently, there are unknowns about the best course of action, said Dr Wolff.

"We do not have data on up-front vs delayed start of a CDK4/CDK6 inhibitor in terms of response, quality of life, and, ultimately, overall survival," he commented.

But he did describe a clinical scenario in which it seems fitting to delay use of a CDK4/CDK6 inhibitor.

"It may be fine to start endocrine therapy alone in a patient newly diagnosed with recurrent disease who is asymptomatic and has small volume of disease (perhaps limited to bone only and in limited areas) and who might have had a longer DFS [disease-free survival] before first manifestation of recurrence," Dr Wolff said.

He explained, "These are patients who may be more likely to still have endocrine-responsive disease and could have a robust response to just endocrine therapy, and use of a CDK4/CDK6 inhibitor might be reserved to those that do not show up-front benefit to endocrine therapy alone or quickly progress."

Last year at the annual meeting of the National Comprehensive Cancer Network, another clinician also had reservations about using palbociclib for "everybody" in the first-line setting of advanced ER+ disease, as reported by Medscape Medical News.

Ingrid Mayer, MD, of the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, said that 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 (necessary because of the possibility of myelosuppression, which can be "severe"), and wants to avoid gastrointestinal toxicities associated with palbociclib.

At the time of the NCCN conference, only the results from the earlier phase 2 trial were available, but the PFS data were similar to the new phase 3 results: 20.2 months for women who received palbociclib plus letrozole compared to 10.2 months for patients who received letrozole alone.

Recently, at the annual meeting of the European Society of Medical Oncology (ESMO), an investigator of ribociclib was more bullish about when to use a CDK4/CDK6 inhibitor.

Gabriel Hortobagyi, MD, PhD, from the University of Texas MD Anderson Cancer Center in Houston, commented that the results for both palbociclib and ribociclib are "paradigm changing in the sense that, historically, there have not been studies in metastatic breast cancer with this magnitude of benefit." He was referring to interim results from the MONALEESA-2 trial of ribociclib that were presented at ESMO, in which benefits were similar to those seen with palbociclib.

"I think there's room today for patients with asymptomatic HR+ metastatic breast cancer, perhaps especially those with comorbidities, to be treated with endocrine therapy alone, but that's not an evidence-based recommendation," he said.

"I think if you want the maximum benefit in metastatic HR+ breast cancer, you are pretty much going to select a combination with a CDK4/6 inhibitor as your first choice," he concluded.

Additional Study Details

In PALOMA-2, patients were randomly assigned in a 2:1 ratio to receive 125 mg of palbociclib per day, administered orally in 4-week cycles (3 weeks of treatment followed by 1 week off treatment), or matching placebo. All the patients received 2.5 mg of letrozole per day, administered orally (continuous treatment).

The median age of the patients was 62 years in the palbociclib-letrozole group and 61 years in the placebo–letrozole group.

Among all patients, 48.6% had visceral disease, 62.8% had received prior systemic therapy for breast cancer, and 37.2% had newly diagnosed advanced breast cancer. Notably, 56.3% had received prior adjuvant endocrine therapy, such as letrozole.

During the treatment period, 10 deaths occurred in the palbociclib-letrozole group (2.3%), and four deaths occurred in the placebo-letrozole group (1.8%).

The study was funded by Pfizer, Inc. Dr Finn is a consultant for Pfizer. Other authors have financial ties to the company.

N Engl J Med. 2016;375:1925-36, 1993-95. Abstract

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