These findings provide further evidence of mTOR as a validated cancer target with potential clinical applicability in several different tumor types, said Ariad. Deforolimus demonstrated potent single-agent, antitumor activity in preclinical models of non-small cell lung cancer with a KRAS mutation.
Approximately 20% of non-small cell lung tumors have KRAS mutations, and these tumors typically do not respond well to epidermal growth factor receptor inhibitors, such as erlotinib. In a panel of more than 100 lung-cancer cell lines, deforolimus showed greater inhibition of tumor growth than erlotinib in 79% of cell lines tested and 84% of KRAS mutant cell lines, according to Ariad. Further, deforolimus potently inhibited the growth of erlotinib-resistant, KRAS-mutant tumors in three different mouse models.
These data lend support for the choice of patients with advanced non-small cell lung cancer whose tumors have a KRAS mutation as the target population for study in the ongoing randomized, double-blind, placebo-controlled Phase II clinical trial of oral deforolimus.
Deforolimus in combination with Merck’s anti-IGF-1R monoclonal antibody, MK-0646, licensed from Pierre Fabre Medicament, led to more effective pathway targeting and antitumor activity than with either investigational agent alone in several preclinical models, said Ariad.
The insulin-like growth factor-1 receptor (IGF-1R) is activated in many tumor types, leading to tumor-cell proliferation. IGF-1R functions, in part, through activation of mTOR. In the research presented, a genetic screen identified mTOR and IGF-1R as complementary drug targets. Testing in panels of cell lines and mouse models showed that combined treatment with these two investigational agents can provide significantly enhanced antitumor activity. The mechanism of this dual effect was confirmed as vertical-pathway synergy and blocking of feedback signaling between IGF-1R and mTOR.
These data support the ongoing Phase I study of oral deforolimus combined with MK-0646 in patients with advanced solid tumors, which is designed to evaluate the hypothesis of vertical-pathway synergy by inhibiting two targets in the PI3K-Akt-mTOR pathway. This multicenter study is aimed at determining the safety profile, tolerability and recommended doses for use in subsequent trials of the combination regimen.
Timothy Clackson, chief scientific officer of Ariad, said: “The single-agent activity of deforolimus observed in preclinical models provides a compelling rationale for our recently initiated Phase II clinical trial of deforolimus in patients with non-small cell lung cancer whose tumors have a KRAS mutation. These results are particularly important considering the limitations of available treatments for such patients.”