Radius Health’s Investigational Drug RAD1901 Selected as One of Informa and Kantar Health’s 2014 Top 10 Most Interesting Oncology Projects to Watch (Press release Radius, NOV 17, 2014, View Source [SID:1234501004])

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On November 17, 2014 Clovis Oncology reported that they have entered into a clinical trial collaboration with GlaxoSmithKline to evaluate a novel combination therapy targeting mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) (Press release Clovis Oncology, NOV 17, 2014, View Source;p=RssLanding&cat=news&id=1990475 [SID:1234500975]). 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).

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"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 mutation, 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.

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.

On November 17, 2014 Deciphera Pharmaceuticals reported the presentation of preclinical data that demonstrated that altiratinib (DCC-2701) inhibited tumor growth and invasion in a bevacizumab resistant glioblastoma mouse model (Press release Deciphera Pharmaceuticals, NOV 17, 2014, View Source [SID:1234500972]). Altiratinib, a kinase inhibitor that targets multiple selected kinases MET, TIE2, VEGFR2 and TRK, is currently in Phase 1 clinical development for the treatment of invasive solid tumors and received Orphan Drug Status from the U.S. Food and Drug Administration for the treatment of glioblastoma. The data on altiratinib were presented at the 19th Annual Scientific Meeting and Education Day of The Society for Neuro-Oncology held November 13-16, 2014, in Miami.

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"Altiratinib is differentiated in its ability to inhibit MET and TRK kinases while also providing balanced inhibition of the tumor microenvironment within a single oral therapeutic," said Michael D. Taylor, PhD, Deciphera’s President and Chief Executive Officer. "This balanced inhibitory profile demonstrates the power of Deciphera’s switch pocket technology to design advanced kinase inhibitor therapies to simultaneously block multiple cancer signaling mechanisms in the tumor cell and the tumor microenvironment to prevent growth and spread of cancer."
"These data demonstrated that altiratinib inhibited tumor growth and invasion both in vitro and in vivo. Based on these results, we believe the combination of altiratinib and anti-VEGF therapy may provide a new strategy to overcome antiangiogenic therapy resistance and prolong overall survival in patients with glioblastoma," said John F. de Groot MD, Associate Professor, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center and presenting author. "We look forward to further exploring the potential of altiratinib in refractory glioblastoma, an area of significant unmet medical need."

In an oral presentation titled, "The Novel c-MET inhibitor altiratinib (DCC-2701) inhibits tumor growth and invasion in a bevacizumab resistant glioblastoma mouse model," John F. de Groot, MD and colleagues from the Brain Tumor Center at MD Anderson Cancer Center described data that demonstrated altiratinib, either alone or in combination with anti-VEGF therapy (bevacizumab), inhibited tumor growth, epithelial-mesenchymal transition (EMT) progression and invasion both in vitro and in vivo, compared with anti-VEGF therapy alone:

• Altiratinib, alone or in combination with bevacizumab treatment, dramatically suppressed EMT and tumor invasion in vivo. This anti-invasive effect correlated with decreased N-cadherin and vimentin levels.

• In vivo, microvascular density associated with evasive revascularization induced by bevacizumab, was significantly inhibited in the groups treated with altiratinib and altiratinib plus bevacizumab, compared with control or the group treated with bevacizumab alone.

• Similarly, F4/80+ bone marrow derived macrophage cell infiltration was significantly suppressed in the groups treated with altiratinib and altiratinib plus bevacizumab, compared to control or the group treated with bevacizumab alone.