Promising early phase clinical trials have led to the initiation of the phase III JUNIPER trial, which is assessing abemaciclib (LY2835219) for patients with previously treated KRAS-mutant lung cancer, a traditionally hard to treat genetic subtype.
KRAS-mutant lung cancer, a traditionally hard to treat genetic subtype.
JUNIPER is an open label phase III study currently recruiting patients with stage IV nonsmall cell lung cancer (NSCLC) with a detectableKRASmutation who have progressed following treatment with platinum-based chemotherapy (NCT02152631). Patients will be randomized to receive either abemaciclib or erlotinib, both with best supportive care.
“KRASmutations are common in patients with NSCLC, but there have been few clinical advances in our treatment for these patients,” said investigator Jonathan W. Goldman, MD, of the Department of Medicine, Hematology/Oncology, member of the Signal Transduction and Therapeutics Program Area at UCLA's Jonsson Comprehensive Cancer Center, who explored the drug in a phase I trial.
In the phase I study, 57 previously treated patients with advanced NSCLC were treated with abemaciclib twice daily. The median number of prior therapies was 4 and 29 patients hadKRASmutations. The response rate in the trial was 3.5%, and the disease control rate was 49%. In those withKRAS-mutant tumors, the disease control rate was 55% compared with 38% for those withKRASwild-type tumors.
The most common grade 3 adverse events were leukopenia (14%) and neutropenia (9%). There were no grade 4 adverse events in the study and less than 2% of patients discontinued treatment due to an adverse event.
“The results of the lung cohort of this study, which showed that abemaciclib could decrease tumor size in this patient population suggest further clinical investigation of abemaciclib as a single agent for the treatment of NSCLC is warranted, with a particular focus on those tumors with KRAS mutations,” Goldman said.
The JUNIPER study began in September 2014, and the estimated study completion date and estimated primary completion dates are April 2017 and October 2016 respectively. There are two primary outcome measures; progression free survival (PFS), measured from baseline to objective progression or death from any cause (estimated up to 31 months), and overall survival (OS), measured from baseline to the date of death from any cause (estimated up to 31 months).
Participants are being randomized to abemaciclib at 200 mg orally twice a day with best supportive care on days 1 to 28 or the active comparator erlotinib at 150 mg once daily with best supportive care on days 1 to 28. Treatment will continue until disease progression or unacceptable toxicity, and there will be short and long-term follow up.
The trial has an 80% statistical power to detect the superiority of the abemaciclib arm over the erlotinib arm for OS and PFS. An independent data monitoring committee will recommend stopping the study after 100 PFS events have occurred if the HR for PFS is greater than 0.95. The final OS analysis will be carried out when approximately 407 OS events have been documented, and interim safety analyses will be conducted every 6 months until the final OS analysis.
Secondary outcome measures include, overall response rates (complete response + partial response), the change in MD Anderson Symptom Inventory Lung Cancer Score, (patient reported changes in pain and disease-related symptoms), the PK of abemaciclib as shown by the area under the concentration curve, the change from baseline in European Quality of Life-5 Dimensions-5 Level Score, and the percentage of patients who are hospitalized as an indicator or resource utilization.
The study also aims to characterize the pharmacodynamic properties of abemaciclib, investigate biomarkers for abemaciclib and the disease, and relate them to clinical outcomes and specifically to abemaciclib.
Abemaciclib inhibits CDK4 and CDK6 at low nanomolar concentrations, and inhibits retinoblastoma protein phosphorylation, which induces G1 arrest and inhibits cell proliferation. In addition to lung cancer, the agent is also in phase III studies for patients with metastatic breast cancer. In October 2015, the agent received a breakthrough therapy designation from the FDA for patients with heavily pretreated refractory HR-positive advanced breast cancer.