SAN DIEGO—Treatment with single-agent LY2835219, an oral inhibitor of cyclin-dependent kinases (CDK) 4 and 6, produced a clinical benefit rate of 61 percent in patients with hormone-receptor (HR)-positive metastatic breast cancer in a Phase I study reported here at the American Association for Cancer Research Annual Meeting (Abstract CT232) and highlighted by the meeting organizers in a news conference.
In the study, presented by Amita Patnaik, MD, Associate Director of Clinical Research at South Texas Accelerated Research Therapeutics (START) in San Antonio, clinical benefit was defined as disease control for longer than 24 weeks or a reduction in tumor size of more than 30 percent.
She noted that although the study was not designed to compare patient outcomes based on HR status, the findings are encouraging and warrant future clinical trials in patients with HR-positive breast cancer. The study was funded by Eli Lilly and Company, which provides Patnaik with research funding and honoraria.
The report covered one of five cohorts in a Phase I expansion trial with 132 patients. The safety, pharmacokinetics, and antitumor activity of LY2835219 are also being tested in glioblastoma, melanoma, and cancers of the lung and colon/rectum.
In each of the expansion cohorts LY2835219 was administered continuously at 150 to 200 mg orally every 12 hours on Days 1–28 of a 28-day cycle until disease progression or discontinuation due to adverse events.
The breast cancer cohort included 47 patients with metastatic breast cancer, 36 of whom had HR-positive disease. Patnaik said the breast cancer patients were heavily pretreated, with a median of seven prior therapies, and 40 percent had three or more metastatic sites.
In the breast cancer group, nine patients (19%) had a confirmed partial response, 24 (51%) had stable disease, and 11 had disease progression.
“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 percent and 55 percent, respectively,” Patnaik said.
Eighteen breast cancer patients with HR-positive disease are still undergoing treatment with LY2835219, Patnaik said, noting that the current estimated progression-free survival time is 9.1 months.
She said based on these results, LY2835219 is now being developed further for use against breast cancer.
Neutropenia Possibly a Class Effect
In a presentation at the 2013 American Society of Clinical Oncology Annual Meeting (Abstract 2500), researchers reported that LY2835219 had acceptable safety and early clinical activity as a single agent for patients with advanced cancer.
In Patnaik's presentation at the AACR meeting, the most common possibly related treatment-emergent adverse events reported across all 132 patients included diarrhea (5% grade 3/4), nausea (3% grade 3/4), fatigue (2% grade 3/4), vomiting (2% grade 3/4), and neutropenia (11% grade 3/4).
Importantly, no patient discontinued the drug due to toxicities, Patnaik said.
She said neutropenia may be a class effect with CDK inhibitors. Out of 11 breast cancer patients with decreases in tumor size of 30 percent or more, one patient had grade 2 neutropenia, four had grade 3, and one had grade 4.
But neutropenia is not essential for the drug's antitumor effect, Patnaik explained, adding that in most cases the neutropenia is reversible and manageable.
Other CDK-4/6 Studies
A report on another CDK-4/6 inhibitor, palbociclib (PD-0332991), was also presented at the AACR meeting (Abstract CT101; OT 5/10/14 issue).
In that Phase II study, called PALOMA-1, a regimen of palbociclib and the aromatase inhibitor letrozole significantly increased progression-free survival when administered as a first-line treatment in patients with ER-positive, HER2-negative metastatic breast cancer, compared with use of letrozole alone.
The palbociclib trial differed from the LY2835219 trial, though, in that LY2835219 was used as single agent.
Median progression-free survival for palbociclib was 20.2 months for 84 patients receiving the palbociclib-letrozole combination versus 10.2 months for the 81 patients receiving letrozole alone. Overall survival was trending in favor of palbociclib-letrozole, the researchers said, but the difference was not statistically significant.
The overall response rate for palbociclib-letrozole was 43 percent and median progression-free survival was 20.2 months
In the news conference Patnaik was asked whether the 19 percent response rate she reported, and the estimated 9.1 months progression-free survival, was reasonable, considering that the responses in the PALOMA-1 study were more than double that.
She said that it was, given LY2835219's use as a single-agent and also considering that patients in the trial were heavily pretreated, with a median of seven prior treatments.
Discussant: MDM2 Oncogene May Lead to Biomarker
The Discussant for the paper was Gary K. Schwartz, MD, Professor of Medicine, Division Chief for Hematology/Oncology, and Associate Director of the Herbert Irving Comprehensive Cancer Center of Columbia University Medical Center, who was also the Discussant for the report on LY2835219 at the 2013 ASCO Annual Meeting.
“What we did not know in 2013 was how hormonal status would affect the drug's activity, and how serious neutropenia would be,” Schwartz said. “We can now answer those questions.”
Schwartz said Patnaik's report here reinforces the dramatic effects of LY2835219 that were seen in earlier trials and now are seen in hormone-receptor positive breast cancer patients.
The durability of response is also impressive, he said, with some patients on study for over a year.
And while neutropenia is seen in about 20 percent of patients, it is reversible, short lived, and tolerable in these patients
Schwartz said in the future, having a predictive biomarker for sensitization would facilitate the drug's development.
He said CDK-4 inhibition-induced cellular senescence occurs in a subset of liposarcoma cell lines, which results in suppression of the MDM2 oncogene. MDM2 suppression in itself induces senescence and correlates with clinical benefit in liposarcoma.
Ongoing laboratory studies to understand the mechanism of MDM2 regulation by CDK-4 could lead to a predictive biomarker of clinical activity in breast cancer, liposarcoma, glioblastoma multiforme, and other tumor types, he concluded.