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Overview

Rociletinib (CO-1686) is a novel, oral, targeted covalent (irreversible) inhibitor of the cancer-causing mutant forms of epidermal growth factor receptor (EGFR) currently being studied for the treatment of non-small cell lung cancer (NSCLC). Rociletinib was designed to selectively target both the initial activating EGFR mutations and the T790M resistance mutation, while sparing wild-type, or normal EGFR at anticipated therapeutic doses, with an improved toxicity profile. Accordingly, it has the potential to be a first-line treatment in NSCLC patients with activating EGFR mutations and a second or later-line treatment in NSCLC patients who become resistant to EGFR-directed therapy due to the emergence of the T790M secondary mutation.

The TIGER program (Third generation Inhibitor of mutant EGFR lung cancER) is our accelerated clinical development program for rociletinib in patients with mutant EGFR NSCLC. We currently have several clinical trials ongoing or planned in the TIGER program:

  • TIGER-X is evaluating rociletinib in two groups of patients; the first in patients directly after progression on their first and only EGFR-directed TKI therapy, such as Tarceva® or Iressa®, who have developed the T790M mutation. The second group includes later-line T790M positive patients after progression on their second or later TKI therapy or subsequent chemotherapy.
  • TIGER1 is a randomized Phase 2/3 registration study versus erlotinib in newly-diagnosed patients; the Phase 2 portion is expected to initiate in mid-2014.
  • TIGER2 is a global registration study underway in T790M positive patients directly after progression on their first and only TKI therapy.
  • TIGER3 is a randomized, comparative study versus chemotherapy in patients with acquired TKI resistance, expected to initiate later in 2014.

Data from TIGER-X, combined with data from TIGER2, are expected to serve as the basis of an NDA submission for rociletinib by mid-2015.

We own global development and commercialization rights to rociletinib.

The U.S. FDA granted Breakthrough Therapy designation for rociletinib as treatment for mutant NSCLC in patients with the T790M mutation after progression on EGFR-directed therapy in May 2014.

For more information about the TIGER program, please visit: www.tigertrials.com or to participate in the trial, contact the Clovis Oncology Clinical Trial Navigation Service at 1-855-262-3040 or 303-625-5010 or clovistrials@emergingmed.com.

Lung Cancer and EGFR Mutations

Lung cancer is the most common cancer worldwide with 1.35 million new cases annually, with NSCLC accounting for almost 85 percent of all lung cancers. NSCLC progresses rapidly with a five-year survival rate in advanced NSCLC patients of less than five percent. EGFR activating mutations occur in approximately 10 to 15 percent of NSCLC cases in Caucasian patients and approximately 30 to 35 percent in East Asian patients. These patients often experience significant tumor response to Tarceva and Iressa, which are first-generation EGFR inhibitors. However, most patients ultimately progress on these therapies, with approximately 60 percent of patients developing acquired resistance from a second, "gatekeeper" mutation, T790M. Currently, no targeted therapies are approved for treatment of this mutation.

Design of rociletinib – a Targeted Covalent Drug

The most commonly used small molecule drugs, while able to inhibit the activity of disease-causing proteins, are generally only able to form transient binding interactions with the disease targets, and are thus considered reversible. A covalent drug, however, forms a strong and durable bond with its protein target, known as a covalent bond. Covalent drugs, such as rociletinib, are designed to form their covalent bond in a highly directed and controlled manner with a specific site on the disease target. Directed bond formation is key to achieving a distinct selectivity profile that is difficult to achieve with reversible small molecules. Rociletinib was designed to potently inhibit the mutant forms of EGFR, while sparing normal EGFR, providing efficacy without "off-target" side effects or side effects due to inhibition of normal receptor functions.

Development of a Companion Diagnostic

We are collaborating with QIAGEN on the development and commercialization of a companion diagnostic to identify patients with the T790M mutation. The diagnostic test will be developed in parallel with the clinical development of rociletinib, with the goal of filing a premarket approval (PMA) application with the FDA in a time frame that would allow for regulatory approval of the companion diagnostic concurrent with rociletinib approval.

Rociletinib Scientific Presentations