Palbociclib: A Novel Cyclin-Dependent Kinase Inhibitor for Hormone Receptor-Positive Advanced Breast Cancer.
OBJECTIVE
To review palbociclib, a novel small-molecule inhibitor of cyclin-dependent kinases 4 and 6, and its current place in therapy for the treatment of hormone receptor (HMR)-positive, human epidermal growth factor receptor 2 (Her2)-negative advanced breast cancer.


METHODS
Four phase I trials, 2 phase II trials, and 1 phase III trial were identified from May 2004 to May 2015 using PubMed, American Society of Clinical Oncology (ASCO) abstracts, and European Society of Medical Oncology (ESMO) abstracts.


RESULTS
In the first-line setting, the phase II PALbociclib: Ongoing trials in the Management of breast cAncer (PALOMA)-1 trial randomized patients to receive letrozole alone or letrozole plus palbociclib 125 mg daily for 3 weeks, followed by 1 week off, as initial therapy for advanced breast cancer. The investigator-assessed median progression-free survival (PFS) was 20. 2 months for the combination versus 10.2 months for letrozole alone (hazard ratio [HR] = 0.488; 95% CI = 0.319-0.748; 1-sided P = 0.0004). The ensuing Food and Drug Administration approval of palbociclib was given a "breakthrough therapy" designation, where preliminary evidence suggests substantial improvement over existing therapies for a serious or life-threatening disease. A confirmatory phase III trial, PALOMA-2, is under way. In patients who were previously treated with endocrine therapy for advanced breast cancer, the phase III PALOMA-3 trial randomized patients to fulvestrant plus palbociclib versus fulvestrant plus placebo. The investigator-assessed median PFS at the time of a preplanned analysis was 9.2 months with palbociclib-fulvestrant compared with 3.8 months with placebo-fulvestrant (HR = 0.42; 95% CI = 0.32-0.56; P < 0.001).


CONCLUSIONS
Palbociclib, the first-in-class CDK4/6 inhibitor, significantly extended PFS in combination with endocrine therapy in the first and subsequent lines of treatment for HMR-positive, Her2-negative advanced breast cancer.
The James Cancer Hospital at the Ohio State University, Columbus, OH, USA.
Neha S
NS
Mangini
The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
Robert
R
Wesolowski
The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
Bhuvaneswari
B
Ramaswamy
The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
Maryam B
MB
Lustberg
The James Cancer Hospital at the Ohio State University, Columbus, OH, USA michael.berger@osumc.edu.
Michael J
MJ
Berger
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D018572:Disease-Free Survival; D004958:Estradiol / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D000077289:Letrozole; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy; D009570:Nitriles / Q000008:administration & dosage; D010879:Piperazines / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage; D014481:United States
D018844:Cyclin-Dependent Kinases; D004958:Estradiol; D000077267:Fulvestrant; D000077289:Letrozole; D009570:Nitriles; D010879:Piperazines; D011725:Pyridines; D018719:Erb-b2 Receptor Tyrosine Kinases; D014230:Triazoles; C508053:ERBB2 protein, human; C500026:palbociclib
CDK inhibitor; PD-0332991; advanced breast cancer; fulvestrant; letrozole; palbociclib