Palbociclib
Palbociclib, sold under the brand name Ibrance among others, is a medication developed by Pfizer for the treatment of HR-positive and HER2-negative breast cancer. It is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6. Palbociclib was the first CDK4/6 inhibitor to be approved as a cancer therapy.
Mechanism of action
It is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6.In the G1 phase of the cell cycle, mammalian 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. 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.
Administration
Palbociclib is taken daily orally with food in a cycle of 21 days of active medication, followed by a week of abstinence. Currently, palbociclib is prescribed as a combination therapy with either letrozole or fulvestrant. Patients should also not consume CYP3A inhibitors or inducers while taking palbociclib. FDA information also cautions against consuming grapefruit products while taking palbociclib, in order to avoid negative interactions.Approvals and indications
HR+ breast cancer
The drug was reviewed and approved under the Food and Drug Administration’s accelerated Priority Review and Breakthrough Therapy designation programs on February 3, 2015, as a treatment for patients with estrogen receptor positive advanced breast cancer. This was an accelerated approval.In March 2017, the FDA granted regular approval to palbociclib for hormone receptor positive, human epidermal growth factor receptor 2 negative advanced or metastatic breast cancer, in combination with an aromatase inhibitor.
A phase III trial, PALOMA-2, was fully enrolled by February 2015 and reported positive results in April 2016. The results of PALOMA-2 trial, published in 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.
The drug was approved for use in the European Union in November 2016 as a treatment for hormone receptor positive, human epidermal growth factor receptor 2 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.
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.
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. Leukopenia and anemia are also frequent among patients taking palbociclib. More than 10% of patients also experience side effects such as fatigue, nausea, diarrhea, respiratory infection, headache, thrombocytopenia, vomiting, and decreased appetite. 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.Mechanisms of resistance
Resistance to palbociclib
FDA- and EMA-approval for palbociclib hinges upon the clinical trials’ results regarding progression-free survival. However, though data has proven promising, there is as of 2019 no significant improvement evident in overall survival when taking palbociclib. For example, in the PALOMA-2 trial, more than 70% of patients who were treated with palbociclib and letrozole progressed by 40 months. This has impeded the drug's worldwide acceptance as economic analyses have not found palbociclib to be cost-effective.''De novo'' resistance
De novo resistance to palbociclib implicates a variety of targets both upstream and downstream of the CDK4/6 to Rb pathway. Overexpression of the transcription factor E2F2 is capable of promoting resistance to CDK4/6 inhibition more than just loss of Rb alone. Palbociclib is less effective in patients whose breast cancer cells overexpress cyclin E1 or E2, and Brk. Brk is an intracellular kinase that is overexpressed in 60% of breast cancers and whose amplification leads to increased phosphorylation of Y88 of the p27 protein, as well as increases the cyclin D and CDK4 activity, thereby rendering the cancer cells more resistant to palbociclib.A 2018 study found that mutations in a pathway completely unrelated to the CDK4/6-Rb axis are also implicated in resistance to palbociclib. Loss of the FAT1 tumor suppressor promoted resistance to CDK4/6 inhibitors through the Hippo pathway, a signaling pathway known to function as a tumor suppressor. Previously, FAT1 had been suggested to be a tumor suppressor and oncogene, though never before explicitly linked to resistance. The team found that FAT1 suppressed cells required significantly higher doses of CDK4/6 inhibitors in order to block proliferation of breast cancer cells in vivo.
Resistance due to endocrine therapy
Palbociclib is indicated in HR+, HER2- metastatic breast cancer cells. Because CDK4/6 inhibition acts directly downstream of the endocrine therapy targets, cross-therapy resistance could possibly develop as a result of patient progression on hormone-therapy. In general, however, endocrine-resistant tumors are able to maintain sensitivity to CDK4/6 inhibition, with particular success witnessed with patients given combination therapy of palbociclib with endocrine therapy. For example, the PALOMA-3 trial which studied the benefit of palbociclib and fulvestrant vs. fulvestrant alone found that the combined treatment regimen improved PFS in both patients with an ESR1 mutation and those with ESR1 wildtype ctDNA. Such results indicate that CDK4/6 inhibitors are effective irrespective of ESR1 mutation status, a marker that otherwise would reveal a patient to be endocrine-resistant.Certain manifestations of endocrine therapy resistance may further sensitize the breast cancer to CDK4/6 inhibitors. For example, deficiencies in mismatch repair caused by the MutL mutation in ER+ breast cancer evades CHK2-mediated inhibition of CDK4, thereby leading to endocrine resistance. CDK4/6 inhibitors, however, have been demonstrated to be highly effective in MutL-defective ER+ breast cancer cells, and MutL bears potential as a biomarker for identifying patients highly suitable for treatment with CDK4/6 inhibitors.
Other mechanisms of resistance
Researchers at the Dana Farber Institute found that breast cancer cells that developed resistance to palbociclib were resensitized to the drug after a seven-day "treatment holiday". Scientists linked the initial development of resistance to an increase in expression of CDK6, with the specific mechanism of CDK6 upregulation originating from suppression of the TGF-β pathway via the miR-432-5p microRNA. Scientists made this discovery after noticing that, in the lab, all breast cancer cells in the dish were found to acquire resistance at a similar time, a phenomenon contrary to classical models of acquiring resistance in which one or two cells become resistant and then expand to encompass more of the tumor as they divide. These palbociclib-resistance cells also did not contain a particular mutation, but rather became resistant and continued to spread this resistance to neighboring cells via exosomes. While the mechanism of this resistance has not yet been elucidated, it opens an avenue for further research into a completely novel method through which cancer cells acquire resistance. On the other hand, this suggests that patients which seemingly progress on palbociclib could benefit from longer-term treatment following a treatment holiday in which their tumors are "reset".There are a variety of means through which cancer cells become resistant to palbociclib, with mechanisms of resistance involving multiple targets and processes throughout the pathway in which palbociclib operates. Previous research estimates that breast cancer cells show adaptation against palbociclib as early as 72 hours post-treatment. Evidence for this was "shown to be mediated by non-canonical activation of cyclin D1/CDK2 complexes, which in turn induced a recovery of cyclin E2 expression and S-phase entry despite CDK4/6 inhibition" upstream of these two targets. Furthermore, it is estimated that approximately 10% of patients have primary resistance to CDK4/6 inhibitors. For example, patients who display evidence of functional Rb loss at baseline are not likely to benefit from CDK4/6 inhibition, nor are patients who display baseline evidence of increased cyclin E1 expression, or a high CCNE1/RB ratio.