AACR 2018: Selective Inhibitor Shows Early Promise in Patients With RET-Altered Cancers
BLU-667, a next-generation inhibitor that selectively targets the oncogenic receptor tyrosine kinase RET, was well tolerated and had broad clinical benefit in patients with advanced cancer that had progressed on previous therapies, including multikinase inhibitor therapy. Proof-of-concept data from an ongoing phase I clinical trial were presented at the 2018 American Association for Cancer Research (AACR) Annual Meeting (Abstract CT043).
“RET-altered cancers across multiple tumor types represent a high medical need, as there are no approved agents that selectively target this oncogene,” said Vivek Subbiah, MD, Assistant Professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, and Associate Medical Director, The Clinical Center for Targeted Therapy, The University of Texas MD Anderson Cancer Center. “Current therapies for RET-altered cancers are restricted to multikinase inhibitors and chemotherapy, which are nonspecific and display significant off-target toxicity. In an effort to revolutionize treatment for these cancers, BLU-667 was designed to specifically target oncogenic RET fusions and activating mutations.”
Response to BLU-667
Prior preclinical work found that BLU-667 potently inhibits oncogenic RET and displays antitumor activity in a variety of RET-driven cancers, Dr. Subbiah noted. In addition, the inhibitor was 100 times more selective for the RET kinase relative to more than 350 human kinases tested, and it potently inhibited gatekeeper mutations shown to confer resistance to multikinase therapies, he explained.
Dr. Subbiah and colleagues tested BLU-667 in an open-label, first-in-human study. As of February 13, 2018, they had enrolled 43 patients with unresectable, advanced solid tumors, with 26 patients having RET-mutant medullary thyroid cancer, 15 patients having non–small cell lung cancer (NSCLC) with RET fusion, and two patients with non-RET cancers. Patients had a median of one prior antineoplastic therapy; prior therapies ranged from zero to eight treatments.
BLU-667 doses ranging from 30 to 400 mg were administered orally every day. The maximum tolerated dose was not reached.
BLU-667 demonstrated broad antitumor activity with a best overall response rate of 37% in the 30 patients with RET alterations who received doses ≥ 60 mg and had at least 1 postbaseline response assessment. Patients with NSCLC and medullary thyroid cancer had best overall response rates of 45% and 32%, respectively. As of the data cutoff, 33 of 43 enrolled patients remained on study.
BLU-667 was well-tolerated; grade 1 constipation was the most commonly reported adverse event (23%). Three dose-limiting toxicities were documented, and there were no grade 4 or 5 adverse events. The dose-escalation portion of the trial is still underway.
“This ongoing phase I study has shown proof of concept of this selective RET inhibitor,” said Dr. Subbiah. “Although it’s very early in clinical testing, we observed promising antitumor activity in NSCLC and [medullary thyroid cancer].”
He continued, “Precision targeted therapy with RET inhibition can have a powerful impact in patients whose cancer is induced by these oncogenic drivers, even in early clinical trial testing. I encourage all [patients with cancer] to undergo genomic testing, as tumors with rare genomic aberrations may have effective drugs that are in clinical trials that could be beneficial to them.”
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