The randomized Phase IImulti-centerPALOMA-1 trial of palbociclib achieved its primary endpoint by demonstrating a statistically significant and clinically meaningful improvement in progression-free survival (PFS) for the combination of palbociclib (125 mg once daily for three out of four weeks in repeated cycles) and letrozole compared with letrozole alone (2.5 mg once daily on a continuous regimen) in post-menopausal women with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or newly diagnosed metastatic breast cancer.
Palbociclib, previously known PD-0332991, is an investigational oral targeted agent that selectively inhibits cyclin-dependent kinases (CDKs) 4 and 6 to regain cell cycle control and block tumor cell proliferation. The drug is being developed by Pfizer Oncology.
Loss of cell cycle control is a hallmark of cancer and CDK 4/6 are overactivated in numerous cancers, leading to loss of proliferative control. CDK 4/6 are key regulators of the cell cycle that trigger cellular progression from growth phase (G1) into phases associated with DNA replication (S). CDK 4/6, whose increased activity is frequent in estrogen receptor-positive (ER+) breast cancer (BC), are key downstream targets of ER signaling in ER+ BC. Preclinical data suggest that dual inhibition of CDK 4/6 and ER signaling is synergistic and has been shown to stop growth of ER+ BC cell lines in the G1 phase.
The final data suggest [that this drug has] the potential … to transform the standard of care for post-menopausal women with ER+ and HER2- advanced breast cancer…
Study Results
The progression-free survival is comprised of time from randomization to time of disease progression or death from any cause. PALOMA-1 was conducted in collaboration with theJonsson Cancer Center?s Revlon/UCLA Women?s Cancer Research Program.
?We are delighted with the final data, which suggest the potential for palbociclib to transform the standard of care for post-menopausal women with ER+ and HER2- advanced breast cancer. This is encouraging information for these women, who represent approximately 60% of the advanced breast cancer population,? noted Mace Rothenberg, MD 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.?
Adverse events observed for the palbociclib arm were consistent with the known adverse event profile for this combination. Detailed efficacy and safety data from PALOMA-1 will be submitted for presentation at the American Association for Cancer Research(AACR) Annual Meeting 2014 scheduled for April 5-9, 2014 in San Diego, CA, USA.
Breakthrough Therapy
Palbociclib was highlight at the at the CTRC-AACR 2012 San Antonio Breast Cancer Symposium (SABCS). At the 2012 meeting, 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. Based on the PALOMA-1 data presented by Finn, the drug received Breakthrough Therapy designation by the United States Food and Drug Administration(U.S. FDA) in April 2013, for the initial treatment of women with advanced or metastatic ER+, HER2- breast cancer.
In the initial part of the trial Finn and colleagues randomly assigned 66 postmenopausal women with metastatic estrogen receptor (ER)-positive breast cancer to either the combination of PD 0332991 and letrozole or to letrozole alone. The second part of the study involved 99 patients with ER-positive cancers determined by screening to have certain genomic alterations, specifically cyclin D1 amplification and/or p16 loss.
The results showed that progression-free survival was 26.1 months for those in the combination arm versus 7.5 months for patients treated with letrozole alone. There was also a 45% response rate with the combination treatment versus 31% with letrozole alone in patients with measurable disease. The clinical benefit rate was 70% with the combination treatment and 44% with letrozole alone.
The combination of PD 0332991 and letrozole was also well tolerated. The most common adverse events were neutropenia, leukopenia, anemia and fatigue. ?Importantly, this was uncomplicated neutropenia,? Finn noted in 2012. ?There was no evidence of febrile neutropenia.? Further more, after retrospectively analyzing the biomarkers for cyclin D1 amplification or p16 loss, the researchers found that ?ER positivity was the only biomarker we really needed to select patients who were most likely to benefit from PD 0332991.?
PALOMA-2
A randomized, global Phase III trial (PALOMA-2, also known as Study 1008) in this patient population is currently enrolling patients and is a randomized (2:1), multi-center, double blind study designed to evaluates palbociclib in combination with letrozole versus letrozole plus placebo as first-line treatment for post-menopausal patients with ER+, HER2- advanced breast cancer. A second phase III study, PALOMA-3 (also known as Study 1023) is a randomized (2:1), multi-center, double blind Phase III study that evaluates palbociclib in combination with fulvestrant versus fulvestrant plus placebo in women with hormone receptor-positive (HR+), HER2- metastatic breast cancer whose disease has progressed after prior endocrine therapy. [1] [2]
Additional studies
Other investigator-led studies of palbociclib in advanced/metastatic breast cancer and in early breast cancer are open and enrolling patients, including PENELOPE-B, a randomized (1:1), double blind, placebo-controlled Phase III study comparing palbociclib plus standard endocrine therapy to placebo plus standard endocrine therapy in patients with HR+, HER2-normal (also known as HER2-) early-stage breast cancer with certain features that suggest an increased risk for recurrence after completing pre-operative chemotherapy followed by surgery. This international study is sponsored by the German Breast Group (GBG). [3]
For more information:
[1] A Study of Palbociclib (PD-0332991) + Letrozole vs. Letrozole For 1st Line Treatment Of Postmenopausal Women With ER+/HER2- Advanced Breast Cancer (PALOMA-2) – NCT01740427 [Study Record Detail]
[2] Palbociclib (PD-0332991) Combined With Fulvestrant In Hormone Receptor+ HER2-Negative Metastatic Breast Cancer After Endocrine Failure (PALOMA-3) – NCT01942135 [Study Record Detail]
[3] A Study of Palbociclib in Addition to Standard Endocrine Treatment in Hormone Receptor Positive Her2 Normal Patients With Residual Disease After Neoadjuvant Chemotherapy and Surgery (PENELOPE-B) -NCT01864746 [Study Record Detail]
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