Abemaciclib (LY2835219) is a drug being developed by Lilly Oncology for the treatment of a number of cancers, including non-small cell lung cancer (NSCLC).
How does abemaciclib work?
LY2835219 is a small molecule that works by blocking the action of two proteins called cyclin-dependent kinases (CDK): CDK4 and CDK6. These are involved in the checkpoint of cell division and therefore play a role in controlling how quickly cells multiply. In many cancers, including some non-small cell lung cancers, they are abnormally overactive, causing increased cell proliferation and tumor growth.
Abemaciclib inhibits the activity of CDK4 and CDK6, which are essential in triggering cell division. Blocking this causes “cell cycle arrest,” where the cells do not divide, leading to a reduction in cancer cells.
Based on the results of experiments conducted in mice, it is believed that NSCLC tumors with a particular alteration mutation called the KRAS mutation are reliant on CDK4 overactivation for progression. Therefore, abemaciclib could be effective in these types of tumors.
LY2835219 in clinical trials
An ongoing Phase 1 clinical trial (NCT01394016) is evaluating the correct dosage of abemaciclib and has so far demonstrated the safety and anti-tumor activity of the treatment.
Trial results were published in the scientific journal Cancer Discovery. This first-in-human study included patients with various tumor types, with 68 patients having advanced NSCLC, 29 of whom had confirmed KRAS mutations. Overall, although the treatment appeared to benefit all NSCLC patients, those with KRAS-mutation tumors experienced a greater increase in disease control rate.
LY2835219 is currently being tested in the JUNIPER Phase 3 clinical trial (NCT02152631). The randomized trial is comparing the efficacy of LY2835219 to Tarceva (erlotinib) in patients with stage 4 NSCLC tumors with a confirmed KRAS mutation, and that has continued to progress after platinum-based chemotherapy. The study is no longer recruiting patients and is expected to be completed by November 2018.
Lilly is also conducting a range of Phase 1 and 2 clinical trials to assess abemaciclib treatment in combination with other cancer drugs. Two of these trials (NCT02079636 and NCT02779751) are still recruiting participants, while one (NCT02411591) is due to be completed in November 2018. Unlike JUNIPER, these trials are not limited to KRAS-positive NSCLC tumors.
A randomized Phase 2 clinical trial (NCT02450539), assessing the effectiveness of LY2835219 in patients with squamous NSCLC treated with platinum-based chemotherapy, is also ongoing, and due to be completed in December 2017.
LY2835219 has been awarded breakthrough therapy designation by the U.S. Food and Drug Administration for the treatment of breast cancer.
Other information
A number of adverse side effects, including diarrhea, nausea, weight loss, fatigue, and blood abnormalities such as anemia have been observed in patients taking LY2835219 in the clinical trials.
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