Investors & Media
Publication Identifies Cyclin E as Key Resistance Pathway to Breast Cancer Treated by CDK4/6 Inhibitors and Thereby Amenable to Treatment by CYC065 CDK2/9 Inhibitor
-- PALOMA-3 study gene expression profiling shows that CDK2 is a key kinase bypass mechanism
after treatment with palbociclib plus hormone therapy --
-- Cyclin E is proposed as the first predictive biomarker of palbociclib efficacy --
“These data from a successful, randomized Phase 3 study identifies cyclin E as a biomarker of resistance of estrogen receptor positive, HER-2 negative breast cancer to palbociclib regimens. This supports and extends previous data showing that cyclin E is a resistance mechanism to HER-2 positive breast and uterine cancer treated with trastuzumab,” said
In the PALOMA-3 trial (NCT01942135), patients with endocrine therapy-pretreated, metastatic breast cancer were randomized to receive palbociclib + fulvestrant or placebo + fulvestrant. Out of 521 patients treated 302 had tumor tissue analyzed. Palbociclib efficacy was approximately halved in patients with high compared to low cyclin E1 expression in their tumors (median PFS of 7.6 vs. 14.1 months respectively). In contrast to cyclin E1 expression, the analysis showed that expression of cyclin D1, the molecular partner of CDKs 4 and 6 which are the targets of palbociclib, or PI3 kinase (PIK3CA) mutations were not predictive of efficacy for palbociclib plus hormone therapy.
The findings were further validated through a gene expression analysis of the Preoperative Palbociclib (POP) trial in 61 patients with untreated early-stage breast cancer receiving either palbociclib until the day before surgery or no treatment. High cyclin E expression was associated with lower absolute antiproliferative response to palbociclib (high 36%; intermediate 79%; low 80%; P = 0.005). Correlative analysis of PALOMA-3 data has identified cyclin E1 as the first potential biomarker that is predictive of the efficacy of palbociclib.
CYC065 is a highly-selective, orally- and intravenously-available, 2nd generation inhibitor of cyclin dependent kinases (CDK) 2 and 9. CYC065 is in an ongoing Phase 1, first-in-human study in patients with advanced solid tumors. In this study target engagement and durable suppression of the Mcl-1 biomarker were observed after a single dose of CYC065. Tumor shrinkage and stable disease were observed in four patients with cyclin E amplified advanced cancers. CYC065 is also being evaluated in a Phase 1 study in combination with venetoclax in patients with relapsed/refractory CLL. Preclinical data suggest that CYC065 may benefit patients with adult and pediatric hematological malignancies such as CLL, AML, ALL, B-cell lymphomas, multiple myeloma and certain cyclin E-addicted or MYC-amplified solid tumors, including HER2+ breast cancer, uterine serous carcinoma and neuroblastoma.
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