"We have seen significant activity in EGFR mutant NSCLC patients treated with rociletinib monotherapy, and so an important next step in our research is to examine rociletinib in combination with other targeted therapies that may also impact acquired resistance to EGFR inhibitors," said Lecia V. Sequist, MD, MPH, Massachusetts General Hospital Cancer Center and Associate Professor of Medicine at Harvard Medical School and the lead investigator for this combination study.
"As we continue to see compelling activity for rociletinib single-agent therapy at our selected dose, we look forward to exploring combination trials in both T790M-positive and T790M-negative patients," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "We believe that given the tolerability profile of rociletinib, particularly its lack of cutaneous toxicity, it may be a good candidate for combination therapy with trametinib, and other relevant targeted therapies. We intend to announce additional combination studies over the next few months."
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) pathway2. 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 activation3, and the combination of rociletinib and trametinib has been shown to restore MAPK pathway suppression, resulting in increased anti-tumor activity.
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.
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 to EGFR (L858R and Del19), while also inhibiting the primary resistance mutation, T790M, which develops in 60 percent of patients treated with first- and second-generation EGFR inhibitors.
As reported at ASCO earlier this year, rociletinib has demonstrated compelling efficacy in a heavily pre-treated, Western population of patients with acquired resistance to currently available EGFR inhibitors. In clinical trials to date, rociletinib is well-tolerated, without evidence of systemic wild-type EGFR inhibition. Inhibition of wild-type EGFR is associated with cutaneous (and other) toxicities such as acneiform rash, stomatitis and paronychia, all of which may significantly impact patients' quality of life and result in treatment discontinuation and patient distress. Clovis believes this aspect of rociletinib's clinical profile represents a significant point of differentiation from approved EGFR inhibitors and those currently in clinical development. In May of 2014, 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.
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.
About EGFR and Lung Cancer
Lung cancer is the most common cancer worldwide with 1.7 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 Asian patients. These patients experience significant tumor response with currently approved EGFR inhibitors 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, or "gatekeeper" mutation, T790M.
About Clovis Oncology
Clovis Oncology, Inc. is a biopharmaceutical company focused on acquiring, developing and commercializing innovative anti-cancer agents in the U.S., Europe and additional international markets. Clovis Oncology targets development programs at specific subsets of cancer populations, and simultaneously develops diagnostic tools that direct a compound in development to the population that is most likely to benefit from its use. Clovis Oncology is headquartered in Boulder, Colorado.
 Yu H, Arcila M and Rekhtman, et al. "Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR-Mutant Lung Cancers." Clin Cancer Res 2013; 19:2240-2247
 Cross D, Meador C, and Eberlein C at al. "Targeting resistance in EGFR-mutant non-small cell lung cancer (NSCLC)". European Society for Medical Oncology 2014 Congress, Abstract #7054
 Cortot A and Janne P. "Molecular mechanisms of resistance in epidermal growth factor receptor-mutant lung adenocarcinomas". Eur Respir Rev 2014; 23: 356-366
 Mekinist EU Summary of Product Characteristics. 2014.
 Romano E, Schwartz GK, Chapman PB, et al. "Treatment implications of the emerging molecular classification system for melanoma." Lancet Oncol. 2011;12(9):913-22.
To the extent that statements contained in this press release are not descriptions of historical facts regarding Clovis Oncology, they are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainties inherent in our clinical development programs for our drug candidates, the corresponding development pathways of our companion diagnostics, actions by the FDA, the EMA or other regulatory authorities regarding whether to approve drug applications that may be filed, as well as their decisions regarding drug labeling, and other matters that could affect the availability or commercial potential of our drug candidates or companion diagnostics, including competitive developments. Clovis Oncology does not undertake to update or revise any forward-looking statements. A further description of risks and uncertainties can be found in Clovis Oncology's filings with the Securities and Exchange Commission, including its Annual Report on Form 10-K and its reports on Form 10-Q and Form 8-K.