|Year : 2016 | Volume
| Issue : 4 | Page : 1220-1223
Palbociclib: A new hope in the treatment of breast cancer
R Priyadharsini Palanisamy
Department of Pharmacology, JIPMER, Puducherry, India
|Date of Web Publication||7-Feb-2017|
R Priyadharsini Palanisamy
4/431-A, Kurinji Street, Kalaivanar Nagar, Puducherry - 605 006
Source of Support: None, Conflict of Interest: None
Breast cancer being one of the common cancers has high morbidity and mortality. Despite the conventional treatment, the burden of the disease increases year after year. There is a need for newer drugs that target the different mechanisms in the pathogenesis. The interaction of cyclins with cyclin dependent kinases (CDKs) plays a major role in the abnormal cell cycle in cancer and it is considered to be an important target. Palbociclib is a CDK inhibitor currently approved for the treatment of breast cancer. The preclinical studies with breast cancer lines were sensitive to palbociclib and the clinical trials phase I, phase II (PALOMA 1), and phase III (PALOMA 2, 3, PENTELOPE, PEARL) showed that the drug was efficacious when combined other conventional drugs for breast cancer. Palbociclib was also been tested in various other germ cell tumors, melanoma, multiple myeloma, glioblastoma multiforme etc., The major adverse effect of the drug includes hematological toxicity mainly neutropenia, gastrointestinal adverse effects.
Keywords: Breast cancer, cyclin dependent kinase inhibitor, palbociclib, PALOMA
|How to cite this article:|
Palanisamy R P. Palbociclib: A new hope in the treatment of breast cancer. J Can Res Ther 2016;12:1220-3
| > Introduction|| |
Breast cancer is the most common cancer in women with a higher incidence rate in both developed and developing countries. As per the WHO statistics, there were 508,000 deaths worldwide in the year 2011. Around 50% cancer cases and 58% deaths occurs in the developing countries. The risk factors for the disease include family history of breast cancer, inherited mutations of BRCA1 and BRCA2 genes, drug induced, and elderly age. The current treatment options include chemotherapy, surgery, and radiotherapy. The identification of the biomarkers has paved the way for diagnosis, staging, prognosis, and personalized treatment in breast cancer. The hormone receptor (ER+), progesterone receptor, and HER2 status are the most important biomarkers that have an impact on the treatment. There is a need for new drugs that will reduce the morbidity and mortality of breast cancer patients. Palbociclib is a selective cyclin dependent kinase (CDK) 4/6 inhibitor approved as a new drug for the treatment of ER+ and HER2− breast cancer.
| > Nonselective Cyclin Dependent Kinase Inhibitors|| |
The nonspecific CDK inhibitors such as roscovitine and flavopiridol had less anti-cancer property and significant toxicity. These inhibitors blocked the activity of the multiple CDKs that are involved in various processes such as transcription and translation. The disadvantages of the nonselective inhibitors has increased the demand for identifying drugs with less off-target effects.
| > Mechanism of Cyclin Dependent Kinase 4/6 inhibitors in Cancer Therapy|| |
The phases of the normal cell cycle which include G0, S, G1, M, G2 has two major check points in preventing the cell from undergoing abnormal replication. The check point is essential for the progression in cell cycle and any cell which does not satisfies the check point will enter into the G0 phase. The check point G1-S is controlled by the interaction between CDK and cyclin proteins. The interaction of cyclin D with CDK 4/6 results in the hyper phosphorylation of Rb (tumor suppressor) gene and mediates the progression through S phase. In cancer there is aberrant cell cycle control, abnormal expression of growth factors, growth factor receptors, which stimulates the cells to produce high levels of cyclin D. The mechanisms in G1-S check point are disrupted. It was noted that the levels of cyclin D (dominant oncogene) was amplified in 15–20% of the breast cancers but the exact prognostic significance is not much known. The three CDK inhibitors that entered the clinical trials were palbociclib, LEE011 and abemaciclib, palbociclib is a CDK4, CDK6 inhibitor which inhibits the Rb phosphorylation and abnormal cell replication in the breast cancer. The other tumors where palbociclib has a role are melanoma, multiple myeloma, glioblastoma multiformae (GBM) etc.,,,
| > Preclinical Studies|| |
PD 0332991 was tested in forty seven human breast cancer cell lines and the various methods used to analyze the efficacy of the compound were transcript micro assay analysis, proliferation assay, multiple drug effect analysis, and western blot analysis. The cancer cell lines with ER positivity and amplified HER status showed high sensitivity to PD 0332991 and the nonluminal cell lines were resistant., The human breast tumor tissues were analyzed for the therapeutic response of the drug PD 0332991. The inhibitor was ineffective in the tumors lacking Rb tumor suppressor. Rb status is essential for the action of the drug PD 0332991 and loss of Rb is associated with CDK4 independent state.,
PD 0332991 was tested in hormone refractory and hormone sensitive (tamoxifen resistant and tamoxifen sensitive) breast cancer tissues. The endocrine therapy resistance is a major problem in the treatment of breast cancer and it influenced around 50% of the affected patients. There was inactivation of Rb mediated transcription in the endocrine therapy resistant models. PD 0332991 was effective in activating Rb thereby reducing the hormone resistance. Palbociclib showed a reduction in the phosphorylation of Rb in cultured cancer cell within 4 h of exposure and the maximum effect was attained at 16 h. Breast cancer cell lines-palbociclib was active against the ER+ cancer cell lines.
The effect of the combination of anthracyclines and CDK 4/6 inhibitor was tested in triple negative breast cancer cell models. There was a synergistic cytostatic activity along with doxorubicin but doxorubicin mediated cell toxicity was antagonized by CDK 4/6 inhibition.,
PD 0332991 was tested in 21 GBM cell lines in which 16 out of 21 cell lines showed significant G1 cycle arrest. The 16 cell lines are those having Rb expression and the other 5 cell lines which did not show significant cell cycle arrest are the Rb inactivated ones. This study shows the necessity of the Rb expression for the cell lines to be sensitive to CDK 4/6 inhibitor. The blood brain barrier and the efflux transporters in the brain decrease the distribution of the anti-cancer agents in the tumor cells. It was observed that 75% of GBM tumors show a dysregulated CDK4 activity, and the extent of palbociclib distribution was studied in mice. The study concluded that palbociclib is less effective in the treatment of GBM because of BBB and the efflux transporters.
There was another study which stated that in the hepatoma cells the cell cycle progression was inhibited by using CDK 4/6 inhibitor and the need of Rb presence was also evaluated.
| > Phase I Clinical Trials|| |
The starting dose of the drug was assessed from the toxicity studies in dogs and rats. The dose that was estimated to appropriate in humans was 0.811 mg/kg in humans. Around 41 patients with Rb positive solid tumors were enrolled in the study and the objective was to evaluate the safety profile and maximum tolerated dose of the drug PD 0332991. The patients were treated in six cohorts with escalating doses (ranging from 25 to 150 mg once daily) of the drug for 21 days followed by a treatment for 7 days. The dose that recommended was 125 mg/day and neutropenia was the dose limiting toxicity.
The blood samples were collected from the patients on day 1 and day 8 of the first cycle. They were collected at 1, 2, 7, 10 h postdose and the pharmacokinetic parameters such as t½, Cmax, c trough, area under the curve (AUC). At day 21 of cycle 1, the samples were also obtained from the expanded MTD cohort The pharmacokinetic parameters of day 21 after repeated multiple dosing of recommended phase II dose 125 mg are as follows t½ =26 h, Cmax = 97.4 ng/ml, C trough = 47 ng/ml, tmax = 5.5 h. AUC = 1733 ng h/ml.
The efficacy was not included as the primary end point of the study. Around 10 of 37 patients achieved good response with stable disease for more than 4 cycles according to the RECIST guidelines.
The major toxicity that was observed during the study was dose dependent neutropenia.
| > Phase II Clinical Trial|| |
The dose that was selected from phase I was 125 mg/day for 3 weeks followed by 1 week off period. A phase II study was conducted in 37 breast cancer patients who were treated with palbociclib alone. There were 6/37 triple negative breast cancer, 2/37 with HER2+ and 29/37 with ER+/HER− breast cancer. The progression free survival was 3.8 months and 1.2 months in the ER+ group and triple negative breast cancer group, respectively.,
A phase Ib/II study evaluating the safety and efficacy of palbociclib + letrozole over letrozole alone in 12 patients with ER+/HER− breast cancer. Around 9 out of the 12 patients had stable disease and 3/12 patients showed partial response.
A phase II randomized open label study (PALOMA-1/TRIO 18) comparing the combination of palbociclib with letrozole versus letrozole alone was conducted in HER2− and ER+ breast cancers. The patients were enrolled in two cohorts; cohort 1-patients with HER2− and ER+ breast cancer and cohort 2 had patients with highly amplified levels of cyclin D and loss of p16. Around 66 patients were recruited in the cohort 1 and the progression free survival was higher (18.2 vs. 5.7) in the combined treatment when compared to the letrozole. The adverse events were observed in the combination group and they are mainly the hematological toxicities such as neutropenia and leucopenia. In second part of the study combining both cohorts, 165 patients were assigned to receive both treatments. The progression free survival (primary end point) was 20.2 months for the combined treatment group and 10.2 months for the letrozole group.,
| > Phase III Clinical Trials|| |
A phase III multicenter double blinded trial comparing the treatments palbociclib with letrozole versus letrozole with placebo in breast cancer patients (postmenopausal) with ER+/HER2 status. The primary outcome measures are the progression free survival and the secondary outcome measures are the probability of participant survival, overall survival, objective response, duration of response, and tumor tissue biomarkers.
A phase III multicenter double blinded placebo controlled trial comparing the efficacy of palbociclib with fulvestrant versus placebo with fulvestrant in HER2−, hormone receptor positive patients is ongoing. The primary outcome of the trial is progression free survival (10 months) and the secondary outcome is overall survival. The group treated with palbociclib and fulvestrant had higher median progression free survival with 9.2 months compared to 3.8 months with fulvestrant and placebo group. The adverse events were severe with palbociclib-fulvestrant group when compared with fulvestrant-placebo group. The major adverse reactions were neutropenia, anemia, thrombocytopenia and fatigue.,
Penelope B is a phase III randomized placebo controlled trial which compares the combination of palbociclib plus standard endocrine therapy versus combination of placebo + standard endocrine therapy. The patients recruited were the premenopausal and the postmenopausal women with hormone receptor positive HER2 normal breast cancer. The primary outcome measure is invasive disease free survival and the secondary outcome measures are distant disease free survival, overall survival, quality-adjusted life-year, compliance, safety, AUC, Cmax, and prognostic markers.
It is a phase III open label randomized study which compares the safety and efficacy of palbociclib + exemastine (intervention) and the active comparator capecitabine in patients with HR+/HER− breast cancer who did not respond to nonsteroidal aromatase inhibitors such as letrozole or anastrazole. The primary outcome is progression free survival for up to 36 months and the secondary outcome measures include clinical benefit rate, objective response rate, response duration, overall survival, and safety assessments.
| > Adverse Effects and Precautions|| |
The major adverse effects of palbociclib include neutropenia, infections, gastrointestinal infections, pulmonary embolism, and the embryo fetal toxicity. It is mandatory to take blood counts before starting the treatment and on day 14 of the first two chemotherapy cycles. The women in the reproductive age should be advised to take oral contraceptives till about 2 weeks after the end of the treatment.,
- Drug information: Palbociclib
- Brand name: Ibrance
- Dosage form: 125 mg capsule
- Dosage regimen: 125 mg oral dose once daily for 21 consecutive days followed by 7 days week off.
The dose recommendation and modification during the occurrence of adverse effects:
- Starting dose - 125 mg/day
- First dose reduction - 100 mg/day
- Second dose reduction - 75 mg/day.
The chances of adverse effects are common when the drug palbociclib is used with other strong CYPA4 inhibitors and, therefore, concomitant usage of both the drugs should be avoided. The dose of palbociclib has to be reduced to 75 mg/day.
The drug is advised to be taken along with the food to facilitate its absorption. Grape juice has to be avoided with palbociclib as grape juice can increase the blood levels of palbociclib.
10,055$ per bottle containing 21 capsules.
| > Conclusion|| |
Palbociclib was designated by the Food and Drug Administration as a break through therapy in April 2013. The drug was approved for the treatment of ER positive and HER− breast cancer in February 2015. There are around 36 studies that are either been completed or ongoing with palbociclib as a monotherapy or in combination. Among the studies, seven are trials involving hematological malignancies and 29 studies in the treatment of solid tumors.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Law ME, Corsino PE, Narayan S, Law BK. Cyclin-dependent kinase inhibitors as anticancer therapeutics. Mol Pharmacol 2015. pii: mol. 115.099325.
Dickson MA. Molecular pathways: CDK4 inhibitors for cancer therapy. Clin Cancer Res 2014;20:3379-83.
Hosford SR, Miller TW. Clinical potential of novel therapeutic targets in breast cancer: CDK4/6, Src, JAK/STAT, PARP, HDAC, and PI3K/AKT/mTOR pathways. Pharmgenomics Pers Med 2014;7:203-15.
Mayer EL. Targeting breast cancer with CDK inhibitors. Curr Oncol Rep 2015;17:443.
Rocca A, Farolfi A, Bravaccini S, Schirone A, Amadori D. Palbociclib (PD 0332991): Targeting the cell cycle machinery in breast cancer. Expert Opin Pharmacother 2014;15:407-20.
Toogood PL, Harvey PJ, Repine JT, Sheehan DJ, VanderWel SN, Zhou H, et al.
Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J Med Chem 2005;48:2388-406.
Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, et al.
PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro
. Breast Cancer Res 2009;11:R77.
Sutherland RL, Musgrove EA. CDK inhibitors as potential breast cancer therapeutics: New evidence for enhanced efficacy in ER+disease. Breast Cancer Res 2009;11:112.
Dean JL, McClendon AK, Hickey TE, Butler LM, Tilley WD, Witkiewicz AK, et al.
Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo
analyses of human tumors. Cell Cycle 2012;11:2756-61.
Dean JL, Thangavel C, McClendon AK, Reed CA, Knudsen ES. Therapeutic CDK4/6 inhibition in breast cancer: Key mechanisms of response and failure. Oncogene 2010;29:4018-32.
Thangavel C, Dean JL, Ertel A, Knudsen KE, Aldaz CM, Witkiewicz AK, et al.
Therapeutically activating RB: Reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer 2011;18:333-45.
McClendon AK, Dean JL, Rivadeneira DB, Yu JE, Reed CA, Gao E, et al.
CDK4/6 inhibition antagonizes the cytotoxic response to anthracycline therapy. Cell Cycle 2012;11:2747-55.
Johnson N, Shapiro GI. Cyclin-dependent kinase 4/6 inhibition in cancer therapy. Cell Cycle 2012;11:3913.
Michaud K, Solomon DA, Oermann E, Kim JS, Zhong WZ, Prados MD, et al.
Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer Res 2010;70:3228-38.
Parrish KE, Pokorny JL, Mittapalli RK, Bakken K, Sarkaria JN, Elmquist WF. Abstract C81: BBB efflux pump activity limits brain penetration of palbociclib (PD0332991) in glioblastoma. Mol Cancer Ther 2013;12 Suppl 11:C81.
Rivadeneira DB, Mayhew CN, Thangavel C, Sotillo E, Reed CA, Graña X, et al.
Proliferative suppression by CDK4/6 inhibition: Complex function of the retinoblastoma pathway in liver tissue and hepatoma cells. Gastroenterology 2010;138:1920-30.
Flaherty KT, Lorusso PM, Demichele A, Abramson VG, Courtney R, Randolph SS, et al.
Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res 2012;18:568-76.
Cadoo KA, Gucalp A, Traina TA. Palbociclib: An evidence-based review of its potential in the treatment of breast cancer. Breast Cancer (Dove Med Press) 2014;6:123-33.
DeMichele A, Clark AS, Tan KS, Heitjan DF, Gramlich K, Gallagher M, et al.
CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+advanced breast cancer: Phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res 2015;21:995-1001.
Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al.
The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): A randomised phase 2 study. Lancet Oncol 2015;16:25-35.
Palbociclib ups PFS in HER2-/ER+breast cancer. Cancer Discov 2014;4:624-5.
Palbociclib (PD-0332991) Combined With Fulvestrant in Hormone Receptor+HER2-Negative Metastatic Breast Cancer After Endocrine Failure (PALOMA-3) – Full Text View – ClinicalTrials.gov. Available from: https://www.clinicaltrials.gov/ct2/show/NCT01942135
. [Last cited on 2015 Apr 30].
Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, et al.
Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 2015;373:209-19.
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 – Full Text View – ClinicalTrials.gov. Available from: https://www.clinicaltrials.gov/ct2/show/NCT01864746
. [Last cited on 2015 Jun 10].
Phase III Study of Palbociclib (PD-0332991) in Combination With Exemestane Versus Chemotherapy (Capecitabine) in Hormonal Receptor (HR) Positive/HER2 Negative Metastatic Breast Cancer (MBC) Patients With Resistance to Non-steroidal Aromatase Inhibitors – Full Text View – ClinicalTrials.gov. Available from: https://www.clinicaltrials.gov/ct2/show/NCT02028507
. [Last cited on 2015 Apr 30].
Gohil K. Pharmaceutical approval update. Pharm Ther 2015;40:251-87.
Aleem E, Arceci RJ. Targeting cell cycle regulators in hematologic malignancies. Front Cell Dev Biol 2015;3:16.