A Quick Overview of CDK4/6 Inhibitor Palbociclib

JULY 12, 2018
First-in-class drug palbociclib (Ibrance, Pfizer) works by inhibiting cyclin-dependent kinases (CDK) 4 and 6 to inhibit downstream signaling pathways.

This, coupled with G1 phase cell cycle arrest, prevents progression to the S phase responsible for DNA replication and diminishes cellular proliferation.1
The oral capsule is approved for treatment of HR-positive and HER2-negative advanced or metastatic breast cancer in 2 settings: in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or in combination with fulvestrant in women with disease progression following endocrine therapy.2

The above indications were based on the PALOMA clinical trials.
PALOMA-1 was a 1:1, randomized, open-label, Phase 2 trial that compared palbociclib + letrozole (n=84) to letrozole alone (n=81). The primary endpoint was progression-free survival. Median progression-free survival in the combination group was 20.2 months, nearly double the median progression-free survival of the letrozole alone group at 10.2 months. The findings from this trial prompted the FDA to grant accelerated approval of this first CDK4/6 inhibitor.3
PALOMA-2 was a 2:1, randomized, double-blind, Phase 3 trial with 444 patients randomized to palbociclib plus letrozole and 222 patients randomized to placebo plus letrozole. Median progression-free survival was 24.8 months in the palbociclib-letrozole group and 14.5 months in the placebo-letrozole group.4
PALOMA-3 was a 2:1, multicenter, randomized, double-blind, Phase 3 trial that compared palbociclib and fulvestrant to placebo and fulvestrant. Median progression-free survival was 9.5 months in the palbociclib-fulvestrant group and 4.6 months in the placebo-fulvestrant group.5
All of the above trials used a 125-mg dose of palbociclib given once daily for 3 weeks, which was followed by an off week.
The most frequently reported adverse reaction in PALOMA-2 and PALOMA-3 was neutropenia, with 80% or higher occurrence of all grades of neutropenia in each trial. 2.5% of patients in PALOMA-2 and 0.9% of patients in PALOMA-3 experienced febrile neutropenia (1.8% across both studies). Other adverse reactions of all grades with an incidence of 10% or greater included alopecia, anemia, diarrhea, fatigue, leukopenia, nausea, rash, stomatitis, thrombocytopenia, and vomiting.2  
Palbociclib is administered as 3 weeks (21 days) on 1 week (7 days) off therapy. These 4 weeks constitute 1 cycle. The drug is available in 75-, 100-, and 125-mg oral capsules. They must be swallowed whole and taken with food to minimize variability in absorption.  
Moderate and strong CYP3A inducers can decrease palbociclib exposure by as much as 85%. If unable to avoid strong inhibitors, reduce the palbociclib dose. Because of these drug interactions, it is important that patients alert providers if they are starting or stopping any medications or herbal products.2
Because of the above-mentioned myelosuppression, providers must obtain a baseline complete blood count (CBC) prior to initiating palbociclib therapy. Monitor the CBC again on Day 15 of the first 2 cycles and as clinically indicated. No dose adjustment or holding of therapy is required, unless the patient develops Grade 3 or 4 toxicities, irrespective of whether these toxicities are hematologic or non-hematologic. When resuming therapy after toxicity, palbociclib should be re-initiated at the next available lower dose. For example, if the patient was previously taking 125 mg daily, they should be re-started on the 100-mg capsule.2
As a result of the CYP3A activity, pharmacists should counsel patients to avoid grapefruit products. Patients should be instructed on how to monitor their body temperature at home and the gravity of presenting for emergency care if their temperature reaches 100.4 F or greater. Additionally, patients should be educated on the importance of not becoming pregnant while taking palbociclib and to use reliable contraception for at least 2 weeks after the end of treatment. In case of a missed dose, patients should not double up and should take their next dose as scheduled.2 

1. De Groot AF, Kujipers CJ, Kroep JR. CDK4/6 inhibition in early and metastatic breast cancer: A review. Cancer Treat Rev. 2017;60:130-138. doi: 10.1016/j.ctrv.2017.09.003. 
2. Ibrance [prescribing information]. New York, NY: Pfizer, Inc; 2017. accessdata.fda.gov/drugsatfda_docs/label/2017/207103s004lbl.pdf. Accessed July 12, 2018.
3. Finn RS, Crown JP, Lang I, 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(1):25-35. doi: 10.1016/S1470-2045(14)71159-3. 
4. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925-1936.
5. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17(4):425-439. doi: 10.1016/S1470-2045(15)00613-0. 

Jola Mehmeti, PharmD, MBA
Jola Mehmeti, PharmD, MBA
Jola Mehmeti is a 2018 PharmD graduate from the UConn School of Pharmacy. She is a PGY1 Clinical Research Pharmacy Resident at Michigan Medicine. Connect with her on LinkedIn or send a message to contact@jolamehmeti.com.