Palbociclib Dramatically Improves PFS in Updated Phase II Findings

Silas Inman @silasinman
Published: Monday, Apr 07, 2014

Dr. Richard Finn

Richard Finn, MD

The combination of palbociclib and letrozole more than doubled progression-free survival (PFS) and showed a promising 4.2-month trend toward improvement in overall survival (OS) for patients with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, according to results from the phase II PALOMA-1 trial that were presented at the 2014 AACR Annual Meeting.

In the 165-patient open-label study, the CDK 4/6 inhibitor palbociclib improved PFS by 20.2 months compared with 10.2 months for letrozole alone (hazard ratio [HR] = 0.488; P = .0004). The median OS was 37.5 months with palbociclib compared with 33.3 months with letrozole alone (HR = 0.813; 95% CI, 0.492-1.345; P = .2105). This first analysis of OS contained data from 61 patients (37%) and was not deemed statistically significant. A follow-up analysis of OS will be conducted once more events have accrued.

“The palbociclib and letrozole combination demonstrated a significantly improved clinical outcome for patients who had hormone receptor-positive, metastatic breast cancer in this phase II trial,” said the study’s lead author Richard S. Finn, MD, an associate professor of medicine at the University of California, Los Angeles (UCLA). “The point of a randomized, phase II study is to have evidence that gives us confidence to do a phase III study, and we think that this study proved the hypothesis that a combination of palbociclib and letrozole is better than letrozole alone in this subgroup of patients.”

Interim findings from the PALOMA-1 study culminated in a Breakthrough Therapy Designation from the FDA in April 2013. Pfizer, the company developing palbociclib, announced it is currently in discussions with the FDA to define the appropriate regulatory path forward for the drug.

In the phase II study, continuous daily letrozole was administered at 2.5 mg with or without palbociclib at 125 mg daily for 3 weeks followed by 1 week of rest until progression. One hundred and sixty-five postmenopausal patients with ER-positive, HER2-negative advanced breast cancer were randomized in a 1:1 ratio in two parts: Part 1 contained 66 patients and Part 2 had 99 patients. The primary endpoint was PFS by investigator assessment.

In the final analysis for PFS, the HR in Part 1 was 0.299 (95% CI, 0.156-0.572; P = .0001) and the HR in Part 2 was 0.508 (95% CI, 0.303-0.853; P =0.0046), for letrozole plus palbociclib compared with letrozole alone, respectively. For the two parts combined, the HR was 0.488 (95% CI, 0.319-0.748; P = .0004). Patients in Part 2 tested positive for CCND1 amplification and/or loss of p16, as possible markers of sensitivity to palbociclib. However, a correlation between these markers and outcomes was not found.

Dr. Dennis Slamon

Dennis Slamon, MD, PhD

In an interim analysis of the PALOMA-1 study presented in 2012 at SABCS, the combination resulted in a response rate of 45% compared with 31% for the monotherapy and the overall clinical benefit rate was 70% versus 44%.

The most commonly reported treatment-related adverse events in the combination arm were neutropenia, leukopenia, anemia, and fatigue. Altogether, 13% of patients discontinued treatment as a result of side effects in the palbociclib arm compared with 2% for letrozole.

“This is an exciting data set that shows a major clinical benefit for patients who have hormone receptor-positive, metastatic breast cancer,” said the study’s coauthor Dennis Slamon, MD, PhD, professor of medicine and director of the Revlon/UCLA Women’s Cancer Research Program. “The potential impact of this study could be huge. We are doing further phase III work with the drug, but the current data are as exciting as the initial studies we were involved in when testing Herceptin for HER2-positive breast cancers.”

Dr. Jose Baselga

José Baselga, MD, PhD

In a discussion of the results, Jose Baselga, MD, PhD, the physician-in-chief at Memorial Sloan Kettering Cancer Center and president-elect of AACR, called the results promising but cautioned against too much early optimism. He noted that several agents, including the PARP inhibitor iniparib, demonstrated promising phase II results and then were not successful in phase III studies. However, if these phase II results were duplicated in a larger clinical trial, palbociclib would become the standard of care for patients with ER-positive metastatic breast cancer, Baselga believes.

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