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New Trial 'Justifies' FDA Nod for Ibrance

— Phase III study had almost identical results as pivotal trial

Ƶ MedicalToday

CHICAGO -- A large phase III clinical trial of palbociclib (Ibrance) has confirmed the phase II results that led to its approval.

The results of the placebo-controlled Paloma-2 trial -- a 10-month improvement in progression-free survival -- are "extremely gratifying," said , of the University of California Los Angeles, who presented the findings at the annual meeting of the American Society of Clinical Oncology here.

The bottom line, he said, is that the larger trial of palbociclib and letrozole (Femara) versus letrozole plus placebo in advanced breast cancer yielded almost exactly the same outcomes as the earlier study.

Those outcomes "represent the longest front-line improvement in progression-free survival seen to date in women with advanced HER2-positive breast cancer," Slamon said.

The presentation "very clearly justifies the approval in the U.S. of this agent," commented , of the University of Pittsburgh Cancer Institute, who was a discussant for the study.

The trial was well designed and well conducted, she said, and the outcomes are "everything you could possibly hope for."

"I'm sure that no one's happier than ... the FDA tonight," she said.

The drug is a cyclin-dependent kinase 4/6 (CDK-4/6) inhibitor and was the first in its class to be approved in the U.S.

In the normal state, CDK-4/6 facilitates progression from the growth phase of the cell cycle into the S-phase, which is associated with DNA synthesis. In breast cancer and many other types of cancer, activation of CDK-4/6 leads to loss of control over the cell cycle, contributing to the cascade of epigenetic and molecular events that results in the uncontrolled cell growth that typifies cancer.

Preclinical studies showed that inhibition of CDK-4/6 by palbociclib restored the normal cell-cycle process.

Early last year the FDA gave accelerated approval to the drug, in combination with letrozole, for the treatment of advanced, hormone receptor-positive postmenopausal breast cancer in women who have received no prior endocrine therapy, based on results of the phase II Paloma-1 study.

That randomized clinical trial showed that the combination of palbociclib and letrozole led to a doubling of median progression-free survival in advanced cancer from 10.2 months with letrozole alone to 20.2 months with the combination.

But the trial had only 165 participants and there was concern -- as with many new cancer drugs -- that the FDA should have had more evidence to back up its decision. The Paloma-2 trial had a similar randomized design but with 666 participants and a two-to-one randomization to the palbociclib and placebo arms.

As in the earlier trial, the primary endpoint of Paloma-2 was progression-free survival. The trial was conducted in 17 countries and at the data cutoff, on Feb. 26, 2016, there was a median of 23 months of follow-up for the palbociclib arm and 22.3 months for the placebo arm.

As assessed by the study investigators, Slamon said, the median progression-free survival was 24.8 months in the palbociclib arm and 14.5 months in the placebo arm, yielding a hazard ratio of 0.58, which was significant at P<0.0001.

In a blinded central review, the numbers were much the same, if not slightly better: a median of 30.5 months before progression for palbociclib patients and 19.3 months for placebo patients.

Importantly, Slamon noted, the benefit was similar for all of the pre-defined subgroups, regardless of such things as age, race, prior treatment, length of disease-free interval, type of disease, and performance status.

The objective response rates overall were 42% for palbociclib and 35% in the placebo arm, which did not reach statistical significance. But among women with measurable disease, the rates were 55% and 44%, respectively, and the difference was significant at P=0.013.

Those response rates, like the rates of progression-free survival, were similar to those seen in the Paloma-1 study, he noted.

Patients in the palbociclib arm had a greater incidence of neutropenia and leukopenia, Slamon reported. The overall incidence of serious adverse events was also higher in the palbociclib arm -- 19.6% versus 12.6% -- and 9.7% of palbociclib patients stopped therapy because of adverse events, compared with 5.9% in the placebo arm.