Palbociclib Dramatically Improves PFS in Updated Phase II Findings

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.

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.”

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.

Palbociclib is under investigation in a number of phase III clinical trials. The PALOMA-2 investigation is exploring treatment with letrozole in combination with palbociclib versus letrozole alone as a frontline treatment for postmenopausal women with ER-positive, HER2-negative advanced breast cancer (NCT01740427). Additionally, the PALOMA-3 trial is exploring palbociclib in combination with fulvestrant compared with fulvestrant alone in women with hormone receptor-positive, HER2-negative metastatic breast cancer whose disease has progressed after prior endocrine therapy (NCT01942135).

Inhibition of CDK 4/6 prevents DNA synthesis by prohibiting progression from G1 to S phase. Preclinical models showed preferential activity for the drug in ER-positive breast cancer, due in part to the intact retinoblastoma pathway that is common in these tumors. These promising findings have resulted in a number of agents being investigated across several clinical trials.

In a phase I expansion study, the CDK 4/6 inhibitor LY2835219 demonstrated promising single-agent activity in heavily pretreated patients with HR-positive metastatic breast cancer. At an interim analysis, the overall response rate was 25%, the clinical benefit rate was 61%, and the median PFS was 9.1 months with LY2835219.

In another analysis presented at the AACR Annual Meeting, the CDK4/6 inhibitor LEE011 added to letrozole or fulvestrant elicited an improved tumor response in HR-positive mouse models. Moreover, this study demonstrated that a regimen of LEE011, an anti-estrogen, plus a PI3K inhibitor (BKM120 or BYL719) resulted in robust tumor regression, representing an area for future clinical studies.

In December, Novartis, the company developing LEE011, initiated enrollment in a phase III clinical trial investigating LEE011. This study will combine the drug with letrozole for patients with untreated HR-positive, HER2-negative, metastatic breast cancer. The primary outcome measure will be PFS with OS and ORR as a secondary endpoint (NCT01958021).

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