Phase I study results presented at the Annual Meeting of theAmerican Association for Cancer Research (AACR), being held in San Diego, CA, USA,April 5-9, 2014, demonstrates that a new oral drug called LY2835219, a cyclin-dependent kinases (CDKs) CDK4 and CDK6 inhibitor, shows early promise as monotherapy for patients with metastatic breast cancer, particularly for those with hormone receptor (HR)-positive disease.
Many tumors, including breast cancers, acquire alterations. These alterations can lead to the activation of cyclin-dependent kinases or (CDKs)?CDK4 and CDK6, gene amplifications (increases expression of various protein activators such as cyclin D), as well as genetic losses (reducing expression of protein inhibitors such as p16). These various 
mechanisms as well as loss of retinoblastoma (Rb) can lead to an enhanced proliferative potential by decreasing dependency on external growth factors and mitogenic signaling pathways, which are required to stimulate growth under normal conditions. [1][2]
?Preclinical evaluation [of the drug] indicated that LY2835219 may have a potential therapeutic application for the treatment of human cancers in which aberrant CDK-4/6 pathway enhances cancer cell growth,? explainedAmita Patnaik, M.D., associate director of clinical research atSouth Texas Accelerated Research Therapeuticsin San Antonio, Texas. ?When tested on various breast cancer types in preclinical studies, HR-positive cells were found to be highly sensitive to this drug.
?Approximately 80% of breast cancers are HR-positive,? added Patnaik. ?Although our study was not designed to compare patient outcomes based on HR status, the clinical benefit rate was 61% in our patients with HR-positive breast cancer, which means patients had disease control for longer than 24 weeks or had their tumors reduce in size by more than 30%. This is very encouraging, and warrants the initiation of future clinical trials in this setting where treatments are needed.?
These results indicate antitumor activity of LY2835219 in patients with HR-positive metastatic breast cancer…. and this warrants further evaluation in larger, confirmatory studies
In this phase I trial, Patnaik and colleagues tested LY2835219 as a single-agent treatment for five different types of tumors. Among the 132 patients enrolled across the five tumor types were 47 patients with metastatic breast cancer who had received about seven prior therapies. All patients received the drug orally every 12 hours for 28 days and were on 
this schedule until their tumors progressed or they had unacceptable side effects. Of the 47 patients with metastatic breast cancer, 36 had HR-positive disease.Of the 47 patients with metastatic breast cancer, nine (19%) had a partial response, and 24 patients (51%) had stable disease. Disease progressed despite treatment in 11 patients.
All of the nine patients who had a partial response, and 20 of the 24 patients who had stable disease had HR-positive disease, which meant that the partial response and stable disease rates for patients with HR-positive disease were 25% and 55%, respectively. The disease control rate, defined as the sum of complete responses, partial responses, and stable disease, was 81% for those with HR-positive disease, and progression free-survival was 9.1 months. ?These results indicate antitumor activity of LY2835219 in patients with HR-positive metastatic breast cancer, and the drug warrants further evaluation in larger, confirmatory studies,? Patnaik noted.
Eighteen patients with HR-positive breast cancer are still undergoing treatment with LY2835219, according to Patnaik. Based on the results of this study, the drug is being developed further for use against breast cancer.
This study was funded by Eli Lilly and Company. Patnaik has received research funding and honoraria from Eli Lilly.
For more information:
[1] Kim JK, Diehl JA. Nuclear cyclin D1: an oncogenic driver in human cancer. J Cell Physiol. 2009 Aug;220(2):292-6. doi: 10.1002/jcp.21791.[Article][PubMed]
[2] Choi YJ, Anders L. Signaling through cyclin D-dependent kinases. Oncogene. 2013 May 6. doi: 10.1038/onc.2013.137. [Article][PubMed]
Photo:Amita Patnaik, M.D.,Photo Courtesy:South Texas Accelerated Research Therapeutics.
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