Phase II Palbociclib Results Confirm Effectiveness in Breast Cancer

Mace Rothenberg, MD

Final results from the phase II PALOMA-1 trial continue to support the dramatic efficacy of palbociclib plus letrozole in postmenopausal patients with locally advanced or newly diagnosed estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, according to a statement released by Pfizer, Inc., the company developing the drug.

Palbociclib (formally PD-0332991) made a dramatic debut at the 2012 San Antonio Breast Cancer Symposium (SABCS) when Richard S. Finn, MD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, presented interim results from the PALOMA-1 trial. At this point, the combination of letrozole and palbociclib achieved a statistically significant median progression-free survival (PFS) of 26.1 months compared with 7.5 months for letrozole alone. Based on these interim findings, the FDA granted palbociclib a Breakthrough Therapy designation for the treatment of patients with breast cancer in April 2013.

“We are delighted with the final data, which suggest the potential for palbociclib to transform the standard of care for postmenopausal women with ER-positive and HER2-negative advanced breast cancer. This is encouraging information for these women, who represent approximately 60% of the advanced breast cancer population,” said Mace Rothenberg, MD, the senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology. “We will discuss these results with the FDA and other regulatory authorities to determine next steps, with the goal of bringing a much-needed new medicine to patients.”

Palbociclib is a novel oral selective inhibitor of cyclin-dependent kinase (CDK) 4 and 6, which play a role in regulating cell cycle progression. 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 ER-positive tumors.

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. Patients with postmenopausal 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. Data from the combination of both groups (n = 165) were presented at SABCS.

In this analysis, the median PFS was 26.1 months with letrozole plus palbociclib compared with 7.5 months for letrozole alone (hazard ratio [HR]=0.37; 95% CI, 0.21 — 0.63, P < .001). The combination resulted in a response rate of 45% compared with 31% for the monotherapy. The overall clinical benefit rate was 70% versus 44%, for the combination and single-agent, respectively.

The most commonly reported treatment-related adverse events in the combination arm were neutropenia, leukopenia, anemia, and fatigue. Overall, there was no evidence of febrile neutropenia with the combination.

“The dramatic improvement in progression-free survival with the combination is very encouraging and clinically meaningful,” Finn said, when results from the study were initially presented in December 2012. “These data represent a potential major advancement in our efforts to identify new medicines that target patients most likely to have an optimal response.”

Final results from the PALOMA-1 trial have been submitted for presentation at the AACR Annual Meeting in April.

Palbociclib is under investigation in a number of phase III clinical trials for patients with breast cancer. Following up on the PALOMA-1 trial, the PALOMA-2 investigation is examining treatment with letrozole in combination with palbociclib versus letrozole with placebo in postmenopausal women with ER-positive, HER2-negative advanced breast cancer who have not received prior systemic therapies (NCT01740427).

Additionally, the PALOMA-3 trial is attempting to demonstrate superiority of palbociclib in combination with fulvestrant over fulvestrant alone in women with HR-positive, HER2-negative metastatic breast cancer whose disease has progressed after prior endocrine therapy (NCT01942135). PFS is the primary endpoint of the study with overall survival and response as secondary endpoints.

Finn RS, Crown JP, Lang I, et al. Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (BC). Cancer Res 2012;72(24 Suppl):Abstract nr S1-6.