LY2835219 is a novel cell cycle inhibitor selective for the cyclin-dependent kinases CDK4 and CDK6 (CDK4/6), which act in a protein complex with D-type cyclins to enable G1 to S cell cycle progression. Preclinical models indicate this complex plays a critical role in breast cancer. We conducted a phase I study with expansion cohorts to evaluate the safety, pharmacokinetics, and antitumor activity of LY2835219 in 5 different tumor types: glioblastoma; melanoma; and cancers of the lung, colon/rectum and breast. In the expansion cohorts, LY2835219 was administered continuously at 150-200mg orally every 12 hours on Days 1-28 of a 28-day cycle. RECIST v1.1 was used to assess tumor response. The most common possibly related treatment-emergent adverse events across the expansion cohorts (n=132) included diarrhea (5% G3/4), nausea (3% G3/4), fatigue (2% G3/4), vomiting (2% G3/4) and neutropenia (11% G3/4). In the metastatic breast cancer (MBC) cohort, 47 patients with a median of 7 prior systemic regimens received therapy with LY2835219. Across all MBC patients, 9 achieved a best overall response of confirmed partial response (PR), 24 achieved stable disease (SD), 11 had progressive disease (PD), and 3 were not evaluable for response. Among the 36 HR+ patients, there were 9 confirmed partial responses for an ORR of 25%. In addition, 20 of these 36 HR+ patients (56%) had SD: 7 patients had SD < 24 weeks and 13 patients (including 2 patients with unconfirmed PR) had SD ≥ 24 weeks. The disease control rate (DCR = CR + PR + SD) was 70% for all patients and 81% for HR+ patients. The median PFS was 5.8 months for all patients and 9.1 months for HR+ patients, with 18 HR+ patients (including the 2 unconfirmed PRs) still on LY2835219 therapy (range: 2.8-15.5 months). In conclusion, LY2835219 demonstrates evidence of durable single-agent activity for women with MBC after multiple prior systemic regimens for metastatic disease, particularly for those women with HR+ tumors, and merits further clinical investigation in MBC.

Citation Format: Amita Patnaik, Lee S. Rosen, Sara M. Tolaney, Anthony W. Tolcher, Jonathan W. Goldman, Leena Gandhi, Kyriakos P. Papadopoulos, Muralidhar Beeram, Drew W. Rasco, Scott P. Myrand, Palaniappan Kulanthaivel, Lily Li, Martin Frenzel, Damien M. Cronier, Edward M. Chan, Keith T. Flaherty, Patrick Y. Wen, Geoffrey I. Shapiro. Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT232. doi:10.1158/1538-7445.AM2014-CT232