A new inhibitor of the cyclin-dependent kinases CDK 4 and CDK 6, palbociclib, is being developed by Pfizer in several different forms of cancer
The cyclin-dependent kinases CDK 4 and CDK 6 are a pair of closely related kinases that enable tumour cell progression during phase G1 to phase S in the cell cycle, which is vital for DNA replication and cell division. A new inhibitor of both these kinases, palbociclib, is being developed by Pfizer in several different forms of cancer, including HER2-negative breast cancer, liposarcoma, non-small cell lung cancer, liver cancer, ovarian cancer, glioblastoma, refractory solid tumours and blood cancers.1
In one open label, nonrandomised Phase II study, 10 patients with inoperable, and recurrent or refractory advanced hepatocellular cancer who are intolerant or refractory to sorafenib were given 125mg of palbociclib orally every day for the first three weeks of a 28-day cycle until progression, unacceptable tolerability or death occurred.2 The most common side-effects were neutropoenia and thrombocytopoenia. Three subjects died from liver failure before disease progression occurred, three progressed after three to eight months, and two received additional therapy. The best progression-free survival was eight months.
In another Phase II trial, 29 patients with CDK-4 amplified advanced liposarcoma who had previously received systemic therapy were enrolled. Subjects were given oral 200mg doses of the drug daily for 14 consecutive days in 21-day cycles.3 The progression-free survival rate at 12 weeks was 70%, with a median progression-free survival date of 18 weeks at the data cut-off date. At the time of reporting seven patients remained on the study with stable disease, after 18 to 48 weeks of follow-up. Dose reductions because of toxicity-related adverse events were needed in about a quarter of the patients.
In an attempt to reduce toxicity, a further Phase II trial was carried out with a lower dose.4 Patients were given 125mg daily doses for 21 days in 28-day cycles. There was one partial response that lasted for more than a year, with grade 3 or 4 adverse events including anaemia, thrombocytopoenia and neutropoenia. However, unlike the previous Phase II trial, a dose reduction was required in only one patient. A Phase III trial is planned in this indication.
The furthest advanced indication is in oestrogen receptor positive, HER2-negative breast cancer.5 A Phase II trial comparing palbociclib plus letrozole with letrazole plus placebo showed that the two-drug combination gave significantly long progression-free survival versus letrozole alone – 26 months compared with 7.5 months, while being generally well tolerated. A randomised, multi-centre, double blind Phase III study is now being run in postmenopausal women with this form of cancer who had not received any previous systemic anticancer treatment for advanced disease. About 450 patients are being recruited, and will receive 125mg palbociclib plus 2.5mg letrozole every day on a three-week on, one-week off schedule, or 2.5mg daily doses of letrozole plus placebo. The aim is to prove significantly improved progression-free survival.
1. P.L. Toogood et al. J. Med. Chem. 2005, 48, 2388
2. S.J. Littman et al. J. Clin. Oncol. 2012, 30 (Suppl. 34), Abst. 321
3. M.A. Dickson et al. J. Clin. Oncol. 2012, 30 (Suppl. 34), Abst. 10002
5. R.S. Finn et al. J. Clin. Oncol. 2013, 31 (Suppl.). Abst. TPS65