Date: 2014-11-17
Type of information: Clinical research agreement
Compound: combination of rociletinib (CO-1686) with trametinib
Company: Clovis Oncology (USA - CO) GSK (UK)
Therapeutic area: Cancer - Oncology
Type agreement: clinical research
Action mechanism: tyrosine kinase inhibitor/MEK inhibitor. Rociletinib is an oral, potent, mutant-selective inhibitor of epidermal growth factor receptor (EGFR) under investigation for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). Rociletinib targets the activating mutations of EGFR (L858R and Del19), while also inhibiting the dominant acquired resistance mutation, T790M, which develops in approximately 60 percent of patients treated with first- and second-generation EGFR inhibitors, while sparing wild-type, or “normal” EGFR at anticipated therapeutic doses. Accordingly, it has the potential to treat NSCLC patients with EGFR mutations both as a first-line or second-line treatment with a potentially reduced toxicity profile. Rociletinib was granted Breakthrough Therapy designation by the FDA in May 2014. Clovis announced on August 3 that it submitted its New Drug Application (NDA) regulatory filing to the FDA and submitted its Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) through the centralized procedure for rociletinib for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) who have been previously treated with an EGFR-targeted therapy. Trametinib is a MEK inhibitor which blocks the activity of a protein kinase called MEK4. This protein is present in the MAPK pathway, which regulates the normal growth and death of cells and plays a role in metastatic melanoma development. Some mutations in the BRAF gene can cause the MEK protein to stimulate cancer cell growth and survival5, therefore, inhibiting MEK can potentially slow down the growth of tumors in BRAF-mutant metastatic melanoma. All patients with EGFR mutant NSCLC eventually develop resistance to EGFR TKI therapy and T790M is the primary resistance mutation1, occurring in 60 percent of patients treated with first- and second-generation EGFR inhibitors. Rociletinib targets the activating mutations of EGFR (L858R and Del19) and the T790M mutation, and has demonstrated encouraging clinical activity and tolerability in Phase 1/2 studies of patients with EGFR mutant NSCLC. Another mechanism of acquired resistance in EGFR mutant NSCLC is through the activation of the mitogen-activated protein kinase (MAPK) pathway. Trametinib is an orally active inhibitor of mitogen-activated protein kinase (MEK), which plays a key role in downstream MAPK pathway signaling, and it thereby inhibits growth factor-mediated signaling and cellular proliferation. Trametinib as a single agent has been approved by the FDA for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. In preclinical models of T790M+ EGFR mutant NSCLC, acquired resistance to T790M inhibitors can occur through MAPK pathway activation, and the combination of rociletinib and trametinib has been shown to restore MAPK pathway suppression, resulting in increased anti-tumor activity.
Disease: mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC)
Details: * On November 17, 2014, Clovis Oncology and GSK announced that they have entered into a clinical trial collaboration to evaluate a novel combination therapy targeting mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC). The Phase 1/2 trial of rociletinib given in combination with trametinib is planned to start in 1H 2015. The trial is designed to assess the safety and activity of the combination in patients with EGFR mutant NSCLC who were previously treated with an EGFR tyrosine kinase inhibitor (TKI). This clinical trial is designed to test the hypothesis that the combination of two oral drugs targeting different cellular growth pathways, both often active in EGFR mutant NSCLC, will lead to augmented clinical benefit. Rociletinib is the core drug of the combination, and trametinib will be titrated in to first assess safety and then explore efficacy. Extensive tumor sampling will be performed to enable detailed molecular characterization of each patient’s tumor load, together with pharmacodynamic assessment of pathway inhibition. Integration of clinical data with molecular tumor data, both on and off drug(s), will enable robust understanding of observed clinical outcomes.
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