Investigational CDK Inhibitor Extends Remission Time

Audrey Andrews

March 2013, Highlights - Emerging Therapies


San Antonio, TX—The addition of an oral investigational agent to letrozole (Femara) for the treatment of estrogen receptor (ER)-positive metastatic breast cancer more than tripled the time spent in remission compared with endocrine therapy alone, according to a study reported at the CTRC-AACR San Antonio Breast Cancer Symposium.

The agent, PD 0332991 (known as PD991), is a novel selective inhibitor of cyclin-dependent kinase (CDK) 4/6 that disables tumor-cell progression. In preclinical studies, PD991 inhibited cell growth and suppressed DNA replication. Preclinical studies also suggested the compound was synergistic when combined with tamoxifen (Nolvadex).

“Based on these observations, a phase 1/2 study was initiated, and we saw a dramatic improvement in progression-free survival [PFS] that was statistically and clinically meaningful with the addition of PD991 to letrozole,” said lead investigator Richard S. Finn, MD, Assistant Professor of Hematology/Oncology, University of California, Los Angeles (UCLA), and a researcher at Jonsson Comprehensive Cancer Center at UCLA. “The results confirm the preclinical observations made with PD991 in breast cancer models.”

In the first part of the current phase 2 clinical trial, the investigators randomly assigned 66 postmenopausal women with metastatic ER-positive breast cancer to letrozole alone or to letrozole plus PD991. In the second part of the study, 99 patients were screened for genomic alterations that may enhance the effect of the drug, specifically cyclin D1 amplification and/or p16 loss.

PD991 is given orally for 3 weeks on and 1 week off.

Patients Go 2 Years without Progression

Median PFS was 26.1 months in the combination arm versus 7.5 months with letrozole alone (P <.001).

Response rates were 45% with the combination and 31% with letrozole alone. The clinical benefit rates, which includes disease stability for 24 weeks, were 70% versus 44%, respectively, in the 2 cohorts.

After retrospectively analyzing the biomarkers for cyclin D1 amplification or for p16 loss, the researchers found that ER positivity was the only biomarker that was predictive of whether patients would benefit from taking PD991.

The combination was well toler­ated, although neutropenia, leukopenia, anemia, and fatigue were observed more often with the combination; however, there were no cases of febrile neutropenia.

“These conditions were uncomplicated and were managed with dose modifications and reductions,” Dr Finn noted. “Growth factors were
not required.”

Peter Ravdin, MD, PhD, Director of the Breast Health Clinic at the Cancer Therapy and Research Center of the University of Texas Health Science Center, San Antonio, told Value-Based Cancer Care, “These are some of the best results I have seen for quite a while. The patients were gaining almost 2 years of time before disease progression, which is really very striking.”

Although other CDK inhibitors are in development, PD991 stands out as the most effective so far, Dr Ravdin added. The tolerability appears good, but he cautioned that it is too early to be sure, because the study is based on a population of less than 200 patients.