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April 10th, 2014
Medscape
By: Roxanne Nelson

Investigative CDK Inhibitor Shows Promise in Breast Cancer

SAN DIEGO — Another investigational inhibitor of cyclin-dependent kinases (CDK) 4 and 6 has shown early activity and promise as a monotherapy for patients with metastatic breast cancer. The compound, known as LY2835219 (Eli Lilly), was particularly effective in hormone receptor (HR)–positive disease in a phase 1 trial presented here at the American Association for Cancer Research (AACR) 2014 meeting.

An investigational drug with the same novel CDK inhibitor action, palbociclib (Pfizer) was also highlighted at this meeting, with data from a phase 2 trial described as promising.

Presenting the data on LY2835219, lead author, Amita Patnaik, MD, associate director of clinical research at South Texas Accelerated Research Therapeutics in San Antonio, said that the clinical benefit rate was 61% in HR-positive patients, with a durable treatment effect. This translates to disease control for longer than 24 weeks or tumor reduction of more than 30%.

"Hormone receptor positivity is currently the best available biomarker to select patients with breast cancer most likely to benefit from treatment," Dr. Patnaik suggested. "LY2835219 warrants further investigation in larger, confirmatory clinical trials for women with breast cancer," she said.

CDK4/6 regulates G1 to S cell cycle progression by inactivating the retinoblastoma (Rb) tumor suppressor protein. This inhibition of CDK4/6 prevents phosphorylation of Rb protein and thereby induces strong G1 arrest in cancer cells.

LY2835219 is a novel cell cycle inhibitor selective for CDK4/6, and preclinical models indicate this complex plays a critical role in breast cancer. An initial phase 1 study identified early evidence of clinical activity and acceptable toxicity, and it was expanded to 5 tumor types: glioblastoma; melanoma; cancers of the lung, colon, and rectum; and metastatic breast cancer.

"A dose escalation study was presented last year at ASCO [American Society of Clinical Oncology]," said Dr. Patnaik, "and we looked at multiple cancers."

At this time, she noted that only the data on metastatic breast cancer would be presented.

Evidence of Response and Disease Control

The phase 1 study had expansion cohorts, in which LY2835219 was administered continuously at 150 to 200 mg orally every 12 hours on days 1 to 28 of a 28-day cycle. Among the 132 patients enrolled, 47 were women with metastatic breast cancer who had already received about 7 prior therapies. All patients received the drug orally every 12 hours for 28 days and remained on this schedule until disease progression or intolerable adverse events.

Of this group, 36 (76.6%) were HR positive, 9 (19.1%) were HR negative, and 2 (4.3%) had unknown status. Nine patients (19%) had a partial response and 24 patients (51%) experienced stable disease. Eleven patients had disease progression while receiving therapy.

All of the patients with a partial response and 20 of the 24 patients with stable disease had HR-positive disease. This extrapolated to a partial response rate of 25% and stable disease rates of 55% for patients with HR-positive disease.

The disease control rate was 80.6%, Dr. Patnaik pointed out, for women with HR-positive disease, and duration of progression-free survival was 9.1 months.
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The safety profile was similar for all patients. For the entire cohort of 132 patients, the most common possibly treatment-related emergent adverse events included diarrhea (5% for G3/4), nausea (3% for G3/4), fatigue (2% for G3/4), vomiting (2% for G3/4), and neutropenia (11% for G3/4).

The authors found that neutropenia occurrence was slightly higher in the breast cancer cohort (21.2%) than in patients overall. None of the patients discontinued treatment because of adverse events, said Dr. Patnaik.

In a discussion of the paper, Gary Schwartz, MD, chief of Columbia University Medical Center's Division of Hematology & Oncology, reiterated that this is an expansion study of the breast cancer cohort first presented at ASCO. "We do see that there is a high response rate of about 25% in hormone receptor positive breast cancer," he said, and the response was durable.

Overall, LY2835219 is highly active, and having a defined biomarker for it would facilitate drug development, Dr. Schwartz added.

This study was funded by Eli Lilly and Company. Dr. Patnaik has received research funding and honoraria from Eli Lilly.

Association for Cancer Research (AACR) 2014. Presented April 6, 2014. Abstract CT232
"Hormone receptor positivity is currently the best available biomarker to select patients with breast cancer most likely to benefit from treatment," Dr. Patnaik suggested. "LY2835219 warrants further investigation in larger, confirmatory clinical trials for women with breast cancer," she said.