A new drug that targets not only common cancer-causing genetic mutations in patients with non-small cell lung cancer (NSCLC), but also a form of the mutation that causes resistance to treatment, has shown promising results in patients in a phase I/II clinical trial. The research was presented at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, in Barcelona, Spain.
Approximately 10% to 15% of white and 30% to 35% of Asian patients with NSCLC have a mutation in the epidermal growth factor receptor (EGFR), which can be successfully targeted with EGFR inhibitors called tyrosine kinase inhibitors (TKI), such as erlotinib, gefitinib, and afatinib. However, these patients will eventually develop resistance to EGFR TKI therapy.
A further EGFR mutation called T790M accounts for 60% of this acquired resistance. No currently approved therapies target T790M.
“Rociletinib (CO-1686) is a new and potent oral EGFR inhibitor designed to selectively target both the initial activating EGFR mutations as well as the T790M resistance mutation. This compound spares wild-type EGFR and this means that it causes far fewer toxic side effects than other EGFR inhibitors,” said Professor Jean-Charles Soria, MD, PhD, chairman of the Drug Development Department at Gustave Roussy Cancer campus, France.
Soria explained that rociletinib may benefit patients as a first-, second- or later-line treatment, and it has a reduced toxicity profile compared to current EGFR inhibitor therapies that cause acne-like skin rashes and paronychia.
Patients with advanced NSCLC with the EGFR mutation, with or without the T790M resistance mutation, were enrolled in the phase I/II clinical trial.
By October 2014, 179 patients had been treated at therapeutic doses (either 900 mg twice a day of freebase formulation, or 500 mg or more twice a day of HBr salt tablet). Preliminary results for all of these patients, including those with and without the T790M resistance mutation, include an overall response rate of 46% and a disease control rate of 84%.
Among the 56 patients who had the T790M resistance mutation and received the pivotal dose and formulation (625 mg twice a day) or the reduced dose of 500 mg twice a day, approximately 80% were treated immediately after their cancer progressed during treatment with a TKI. Among the 27 patients for whom CT data is available, 18 had a confirmed response to the treatment, giving an overall response rate of 67% and a median progression-free survival of 10.4 months.
Among an additional 11 evaluable patients who did not have the T790M mutation, four had a confirmed response to the treatment (overall response rate of 36%) and this group of patients had a median progression-free survival of 7.5 months.
Adverse side effects of rociletinib were manageable and included asymptomatic hyperglycemia, nausea, and diarrhea, and these were mostly grade 1 or 2. Only two patients had any form of rash, which was grade 1 and transient. The most common, grade 3 adverse event was hyperglycemia, which was observed in 14% of patients.
Soria stated that the data from the rociletinib clinical trials suggests success in targeting and overcoming resistance to EGFR inhibitors.