A phase I, first-in-human study led by The University of Texas MD Anderson Cancer Centre reveals for the first time, an investigational drug that is effective and safe for patients with cancers caused by an alteration in the receptor tyrosine kinase (RET). The drug appears to be promising as a potential therapy for RET-driven cancers, such as medullary and papillary thyroid, non-small cell lung, colorectal and bile duct cancers, which have been historically difficult to treat.
The oral drug, BLU-667, is being investigated in a multi-centre, open label trial. The results from the trial were presented 15 April at the American Association for Cancer Research Annual Meeting 2018 in Chicago.
"There is a critical un-met need for effective drugs against cancers that have the RET alteration, as there are no highly potent inhibitors currently approved specifically for these RET-driven cancers," said Dr Vivek Subbiah, assistant professor of investigational cancer therapeutics. "The current treatments for these cancers are limited to traditional chemotherapy and earlier generations of multiple kinase inhibitors. These options have had limited success with often considerable side effects that significantly impact the patient's quality of life."
Subbiah's study is investigating BLU-667 as a novel precision-targeted drug that, through a proof-of-concept trial, has shown promising activity and disease control as a highly selective RET inhibitor. The drug targets RET-altered cancers with fewer side effects affecting non-cancerous organs.
RET is linked to half of all medullary thyroid cancers, 20% of papillary thyroid cancers and 1% to 2% of non-small cell lung cancers. Subbiah's team followed 43 patients with advanced tumours not eligible for surgery. The investigation also studied 26 patients with medullary thyroid cancer, 15 with non-small cell lung cancer and two with other RET-driven cancers.
"Tumour reductions and durable responses were observed in most patients, especially those patients whose cancer progressed with chemotherapy and multi-kinase inhibitors," said Subbiah. "Our study reported an overall response rate of 37% for RET-driven cancers, with responses of 45% for non-small cell lung cancer and 32% for medullary thyroid."
BLU-667 was chosen for investigation because it is 100 times more selective for RET than other kinases tested and has proved effective in stopping genetic mutations known as gatekeepers, which have been tied to resistance to multiple kinase therapy.
"Overall, the data show the precision targeted therapy with next-generation kinase inhibitors can have a powerful impact for patients with RET-driven cancers," said Subbiah. "By offering a highly selective medicine tailored for this oncogenic driver, we hope this new therapy will enable patients to benefit from the recent advances in genomic profiling that have revolutionised treatment options for patients with kinase-driven diseases."
Abstract
The receptor tyrosine kinase, rearranged during transfection (RET), is an oncogenic driver activated in multiple cancers including non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC) and papillary thyroid cancer (PTC). No approved therapies have been designed to target RET; treatment has been limited to multi-kinase inhibitors (MKIs) which can have significant off-target toxicities and limited efficacy. BLU-667 is a highly potent and selective RET inhibitor designed to overcome these limitations. In vitro, BLU-667 demonstrated ≥10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants. In vivo, BLU-667 potently inhibited growth of NSCLC and thyroid cancer xenografts driven by various RET mutations and fusions without inhibiting vascular endothelial growth factor receptor 2 (VEGFR-2). In first-in-human testing, BLU-667 significantly inhibited RET signaling and induced durable clinical responses in patients with RET-altered NSCLC and MTC without notable off target toxicity, providing clinical validation for selective RET targeting.
Authors
Vivek Subbiah, Justin F Gainor, Rami Rahal, Jason D Brubaker, Joseph L Kim, Michelle Maynard, Wei Hu, Qiongfang Cao, Michael P Sheets, Douglas Wilson, Kevin J Wilson, Lucian DiPietro, Paul Fleming, Michael Palmer, Mimi I Hu, Lori Wirth, Marcia S Brose, Sai-Hong Ignatius Ou, Matthew Taylor, Elena Garralda, Stephen Miller, Beni Wolf, Christoph Lengauer, Timothy Guzi, Erica K Evans
[link url="https://www.mdanderson.org/newsroom/2018/04/first-in-human-clinical-trial-of-new-targeted-therapy-drug-reports-promising-responses-for-multiple-cancers.html"]University of Texas MD Anderson Cancer Centre material[/link]
[link url="http://cancerdiscovery.aacrjournals.org/content/early/2018/04/12/2159-8290.CD-18-0338"]Cancer Discovery abstract[/link]