Clovis Oncology, Inc. is collaborating with GlaxoSmithKline LLC to design a clinical trial that aims to evaluate a new combination therapy targeting mutant epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC).
This phase 1/ 2 clinical trial, scheduled for the first half of 2015, will evaluate the efficacy of administrating rociletinib combined with trametinib. It will assess both activity and safety of the combination therapy in patients suffering with EGFR mutant NSCLC, previously treated with an EGFR tyrosine kinase inhibitor (know as TKI). The goal is to understand if two oral drugs that aim at different cellular growth pathways (both active in this type of cancer) will increase clinical benefit.
The lead researcher for this specific combination assessment, Lecia Sequist, MD, Medicine Professor at Harvard Medical School, said in a press release: “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.”
“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 (…) 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,” Clovis Oncology’s CEO and President, Patrick Mahaffy added.
It is common for EGFR mutant NSCLC patients to develop some resistance to the EGFR TKI therapy; the mutation in the T790M gene is the primary mutation related with resistance and occurs in 60 percent of the patients that receive treatment with the first and second generation of EGFR inhibitors. Rociletinib acts by targeting several EGFR mutations, incuding L858R, Del19 and T790M. It has demonstrated positive and encouraging clinical activity and tolerability.
Another frequent resistance mechanism is the activation of the mitogen-activated protein kinase (MAPK) pathway; trametinib is an inhibitor of the MEK protein, present in the MAPK pathway, that inhibits growth factor-mediated signaling and, ultimately, cellular proliferation. This drug is FDA-approved as a single agent to treat unresectable or metastatic melanoma (V600K mutations or BRAF V600E).
The combination of rociletinib and trametinib increases anti-tumor activity as it was proved in pre-clinical models of T790M+ EGFR mutant NSCLC, that developed resistance to T790M inhibitors. Further, molecular data regarding this type of tumors will be analyzed, and along with a pharmacodynamic evaluation, will provide better insights into new treatment possibilities.
