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Το IBRANCE (Palbociclib) έλαβε έγκριση στην Ευρώπη

Palbociclib, sold under the brand name Ibrance among others, is a medication for the treatment of HR-positive and HER2-negative breast cancerdeveloped by Pfizer. It is a selective inhibitor of the cyclin-dependent kinasesCDK4 and CDK6.[1][2] Palbociclib was the first CDK4/6 inhibitor to be approved as a cancer therapy.[3]

Mechanism of action

Further information: CDK inhibitor

It is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6.[1][2]

In the G1 phase of the cell cyclemammalian cells must pass a checkpoint, known as the restriction point “R”, in order to complete the cell cycle and divide. CDK4 and CDK6 complex with cyclin D drive the phosphorylation of the retinoblastoma protein, Rb, which allows the cell to pass R and commit to division.[4] Regulation of one or more proteins involved in this checkpoint is lost in many cancers. However, by inhibiting CDK4/6, palbociclib ensures that the cyclin D-CDK4/6 complex cannot aid in phosphorylating Rb. This prevents the cell from passing R and exiting G1, and in turn from proceeding through the cell cycle.[4]

Administration

Palbociclib is taken daily orally with food in a cycle of 21 days of active medication followed by 7 without. Currently palbociclib is prescribed as a combination therapy with either letrozole or fulvestrant.[5] Patients should also not consume CYP3A inhibitors or inducers while taking palbociclib. FDA information also cautions against consuming grapefruit products while taking palbociclib.[5]

Approvals and indications

HR+ breast cancer[edit]

The drug was reviewed and approved under the Food and Drug Administration’s (FDA) accelerated Priority Review and Breakthrough Therapy designation programs on February 3, 2015 as a treatment (in combination with letrozole) for patients with estrogen receptor positive (ER+) advanced breast cancer.[6] This was an accelerated approval.[7]

In March 2017, the FDA granted regular approval to palbociclib for hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative advanced or metastatic breast cancer, in combination with an aromatase inhibitor.[8]

A phase III trial, PALOMA-2, was fully enrolled by February 2015 and reported positive results in April 2016.[9] The results of PALOMA-2 trial (published November 2016) showed significantly longer progression-free survival in patients on palbociclib in combination with letrozole, compared to patients on letrozole and placebo. Progression-free survival was assessed by radiologically confirmed disease progression by RECIST criteria or death during the study. At the time of publication, there was insufficient data on overall survival, and a final analysis is planned after a total of 390 deaths occur per protocol and in agreement with regulatory agencies. Of note, it was noted that the addition of palbociclib caused higher rates of myelotoxic events in the study.[10]

The drug was approved for use in the European Union in November 2016 as a treatment for hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced or metastatic breast cancer either in combination with an aromatase inhibitor or, for women who have received prior endocrine therapy, in combination with fulvestrant. In pre- or perimenopausal women, a luteinizing hormone releasing hormone agonist should also be given.[11]

In December 2017, palbociclib, was accepted for use by the NHS after going through the Scottish Medicines Consortium‘s process for medicines used to treat very rare and end-of-life breast cancer.[12]

Adverse effects

A majority of patients taking palbociclib experience neutropenia, a condition where a patient has an abnormally low number of neutrophils. This side effect impacts the immune system, and is thus likely responsible for the second most common side effect, infection.[13] Leukopenia and anemia are also frequent among patients taking palbociclib.[13] More than 10% of patients also experience side effects such as fatiguenauseadiarrhearespiratory infectionheadachethrombocytopeniavomiting, and decreased appetite.[14][13] The FDA also indicates that patients should be vigilant to monitor themselves for any sign of pulmonary embolism. The FDA further cautions that women should be aware that the medication can have a harmful effect on a fetus, and thus should not be taken while pregnant.[5]

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