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Investigational Compound CO-1686 Named ‘Breakthrough Therapy’ for NSCLC

FDA submission expected in 2015

The FDA has granted a “breakthrough therapy” designation for the investigational agent CO-1686 (Clovis Oncology, Inc.) as monotherapy for the treatment of second-line epidermal growth factor receptor (EGFR)-mutant non–small-cell lung cancer (NSCLC) in patients with the T790M mutation.

CO-1686 is an oral, targeted covalent (irreversible) inhibitor of the cancer-causing mutant forms of EGFR currently being studied for the treatment of NSCLC. The compound was designed to target selectively both the initial activating EGFR mutations and the T790M resistance mutation while sparing wild-type (normal) EGFR at anticipated therapeutic doses. Therefore, the agent may have the potential to treat NSCLC patients with EGFR mutations as both a first- and second-line therapy with a reduced toxicity profile compared with that of current EGFR inhibitors.

The FDA’s “breakthrough therapy” designation was granted as part of the 2012 FDA Safety and Innovation Act. The designation is intended to expedite the development and review of drugs to treat serious or life-threatening medical conditions when preliminary clinical evidence demonstrates that the drug may provide substantial improvement on at least one clinically significant endpoint compared with available therapies.

The FDA’s decision was based on interim efficacy and safety results from the ongoing phase I/II TIGER2 study of CO-1686, presented in March at the 4th European Lung Cancer Conference in Geneva, Switzerland. In this study, the investigators observed an objective response rate in 14 (64%) of 22 evaluable T790M-positive patients. CO-1686 was well tolerated, with one patient discontinuing treatment because of adverse events. There was no evidence of systemic wild-type EGFR inhibition.

The next update of study data on CO-1686 will be presented in a clinical science symposium titled “Targeting EGFR: The Next 10 Years,” to be held May 31 at the American Society of Clinical Oncology annual meeting in Chicago.

Subjects are currently being enrolled into two phase II expansion cohorts of the TIGER2 study in EGFR-mutant patients with the T790M mutation. Data from the expansion cohorts, combined with data from the TIGER2 study, in T790M-positive patients directly after progression on their first and only tyrosine kinase inhibitor (TKI) therapy, are expected to serve as the basis of a new drug application submission for CO-1686 by mid-2015.

Lung cancer is the most common cancer worldwide, with 1.7 million new cases annually. NSCLC accounts for approximately 85% of all lung cancers. The disease progresses rapidly, with a 5-year survival rate of less than 5% in patients with advanced NSCLC.

EGFR-activating mutations occur in approximately 10% to 15% of NSCLC cases in Caucasian patients and in approximately 30% to 35% of cases in East Asian patients. Patients with NSCLC show significant tumor responses to treatment with the first-generation EGFR inhibitors erlotinib (Tarceva, Genentech/Astellas Oncology) and gefitinib (Iressa, AstraZeneca) but ultimately progress on these therapies. Approximately 60% of treated patients develop acquired resistance from the T790M mutation.

Source: Clovis Oncology; May 20, 2014.

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