Palbociclib, sold under the brand name Ibrance among others, is an anti-cancer medication used for the treatment of HR-positive and HER2-negative breast cancer. It was developed by Pfizer. 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. The most common side effects include neutropenia (low blood levels of neutrophils, a type of white blood cell that fights infection), infections, leucopenia (low white blood cell counts), tiredness, nausea (feeling sick), stomatitis (inflammation of the lining of the mouth), anemia (low red blood cell counts), diarrhea, alopecia (hair loss), and thrombocytopenia (low blood platelet counts). The most common severe side effects include neutropenia, leucopenia, infections, anemia, tiredness, and increased blood levels of liver enzymes (aspartate and alanine transaminases).
Medical uses Palbociclib is indicated for the treatment of adults with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy; or fulvestrant in people with disease progression following endocrine therapy. Palbociclib is indicated in combination with inavolisib and fulvestrant for the treatment of adults with endocrine-resistant, PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer, as detected by an FDA‑authorized test, following recurrence on or after completing adjuvant endocrine therapy. Palbociclib is indicated in combination with trastuzumab, with or without pertuzumab, and endocrine therapy for the maintenance treatment of adults with hormone receptor-positive, human epidermal growth factor receptor 2‑positive locally advanced or metastatic breast cancer following induction treatment.
Adverse effects The most common side effects include neutropenia (low blood levels of neutrophils, a type of white blood cell that fights infection), infections, leucopenia (low white blood cell counts), tiredness, nausea (feeling sick), stomatitis (inflammation of the lining of the mouth), anemia (low red blood cell counts), diarrhea, alopecia (hair loss), and thrombocytopenia (low blood platelet counts). The most common severe side effects include neutropenia, leucopenia, infections, anemia, tiredness, and increased blood levels of liver enzymes (aspartate and alanine transaminases). 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.
Mechanisms of resistance
Resistance to palbociclib FDA- and EMA-approval for palbociclib hinges upon the clinical trials' results regarding progression-free survival (PFS). However, though data has proven promising (one study had p-values very close to the significance threshold which, with further clinical trials, may be able to demonstrate statistical significance), there is as of 2019 no significant improvement evident in overall survival (OS) 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 (the direct downstream target of CDK4/6). Palbociclib is less effective in patients whose breast cancer cells overexpress cyclin E1 or E2, and Brk (breast tumor-related kinase). 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.
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