What are palbociclib and fulvestrant?
Palbociclib is an orally available inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Fulvestrant is an estrogen receptor antagonist, given by IM injections.
How do palbociclib and fulvestrant work?
CDK4/6 control the process of the cell entering the cell cycle from G1 to S phase, promoting cell division through interaction with cyclins. In addition, activation of the estrogen receptor also influences this process through interaction with cyclin D. By inhibiting CDK4/6, palbociclib inhibits the dysregulated cellular proliferation of breast cancer cells. Fulvestrant is an estrogen receptor antagonist, diminishing the effect of estrogen on the process, and has been shown to be effective when other endocrine treatments have failed.
What is this approved for?
Treatment of ER+/HER2- metastatic breast cancer after disease progression following endocrine therapy.
What is the basis for this approval?
The benefits of combination of palbociclib and fulvestrant were shown in the PALOMA3 trial; the preliminary results were published in 2015 and final analysis in 2016. The study participants included both premenopausal patients (if on goserelin) and postmenopausal patients with ER+/HER2- breast cancer who had progressed on previous endocrine treatments. In this trial, the median PFS in the palbociclib/fulvestrant arm was 9.5 months (95% CI 9.2-11.0), whereas in the fulvestrant-alone arm it was 4.6 months (95% CI 3.5-5.6) (Lancet Oncol 2016;17:425-439).
How do you administer this drug?
The initial dose of palbociclib is 125 mg PO daily on days 1-21 of each 28-day cycle. Dose reductions to 100 mg and then to 75 mg are needed if the patient has grade 3 or 4 hematologic toxicity. Palbociclib should be taken with food. Fulvestrant is given as IM injections 500mg Q2 weeks x 2 doses, then monthly thereafter.
Are there any premedications needed?
Nausea with palbociclib is not common; antiemetics are not routinely needed. Injections with fulvestrant can cause injection site pain, but pain medications are not commonly required.
What are the common side effects associated with palbociclib and fulvestrant (> or =10%)?
In the combination arm of the PALOMA3 study, the most common grade 3 or 4 toxicities were neutropenia, leukopenia, and thrombocytopenia. The most common all-grade toxicities include myelosuppression as noted, as well as infections, fatigue, nausea, headache, diarrhea, constipation, and hot flashes.
Are there any important drug interactions I should be aware of?
The combination of palbociclib and strong CYP3A4 inhibitors and inducers should be avoided, as the serum levels of palbociclib can be altered. If combination with strong CYP3A4 inhibitors (azole antifungals, protease inhibitors, verapamil, clarithromycin, others) is required, the palbociclib dose should be reduced to 75 mg daily, and the patient monitored closely for myelosuppression. There are no notable drug interactions with fulvestrant.
How do I adjust the dose in the setting of renal insufficiency?
The fulvestrant dose does not need to be adjusted in renal impairment. Palbociclib does not require a dosage adjustment for mild or moderate renal impairment, but it has not been studied in severe renal impairment.
How do I adjust the dose in the setting of hepatic insufficiency?
The dose of fulvestrant should be reduced to 250 mg in the setting of moderate hepatic impairment; it has not been studied in severe hepatic impairment. The dose of palbociclib does not require dose adjustments for mild hepatic impairment, but it hasn't been studied in moderate to severe liver dysfunction.
Practical tips
CBC should be monitored on day 1 and day 15 of the first two cycles, then monthly. If the dose needs to be held for myelosuppression, the blood counts usually improve in 1 week.
What should my patients know about palbociclib and fulvestrant?
Patients should take the palbociclib with food. Recommend patients record cycle start and stop dates on a calendar. Patients should avoid grapefruit and grapefruit juice.
What useful links are available regarding palbociclib and fulvestrant?
* http://labeling.pfizer.com/ShowLabeling.aspx?id=2191
* https://www.azpicentral.com (click on faslodex)
Any ongoing clinical trials related to palbociclib and fulvestrant?
Palbociclib is being investigated in first-line treatment of advanced breast cancer, with other endocrine therapies, and in pre- as well as postmenopausal patients. Please see http://www.clinicaltrials.gov for more information.
This monthly column focuses on noteworthy treatments and provides important information to assist oncologists in their day-to-day practice. To read more, visit http://bit.ly/2f4ktlD
LISA LOHR, PHARMD, BCOP, BCPS, is Clinical Pharmacist/ Oncology MTM and Oral Chemotherapy Monitoring Program, M Health Masonic Cancer Clinic (University of Minnesota/Fairview), Minneapolis. RAMASWAMY GOVINDAN, MD, Co-Director, Section of Medical Oncology, Professor of Medicine, Washington University School of Medicine, Alvin J. Siteman Cancer Center, serves as the Pharmacy Forum column physician advisor. SARA K. BUTLER, PHARMD, BCPS, BCOP, is Clinical Oncology Pharmacy Supervisor, Barnes-Jewish Hospital, St. Louis, Mo., and also serves as a Pharmacy Forum column co-editor. JANELLE E. MANN, PHARMD, BCOP, is an Investigational Drug Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as the Pharmacy Forum column co-editor.