CHICAGO-The RET proto oncogene-targeted molecule BLU-667 was clinically active and had low and manageable toxicities in the ARROW study of patients with RET-altered thyroid cancers reported at the 2019 ASCO Annual Meeting (Abstract 6018).
"It has been very effective as an antitumor drug. Our data show significant responses in patients with medullary thyroid cancer, as well as differentiated thyroid cancer," said lead author Matthew H. Taylor, MD, from the Knight Cancer Institute, Oregon Health and Science University in Portland. "We found a very encouraging response rate between 56 and 63 percent of medullary thyroid cancer. And about 83 percent of the patients with differentiated thyroid cancer with a RET fusion have responded."
ARROW was conducted because no selective RET inhibitors had been approved, even though RET alterations had been recognized as targetable oncogenic drivers in more than 90 percent of advanced medullary thyroid cancer (MTC) and 20 percent of papillary thyroid cancers (PTC).
"RET is a gene that becomes either mutated or fused in a variety of different cancers, including medullary thyroid cancer, differentiated thyroid cancer, non-small cell lung cancer, [and in] other tumors as well," Taylor explained.
BLU-667 was described by the researchers as a "highly selective and potent" inhibitor of RET genes that had been mutated or fused. "One of the nice things about it is [that] it spares VEGFR2 and other related kinases. And that's what gives it a better tolerability profile," he noted.
Study Details
The ARROW study assessed response rates and toxicity from daily dosing of BLU-667 in 60 patients with mutated RET genes and five patients with RET-gene fusion. All the patients had advanced solid tumors. More than half of them had failed prior multikinase inhibitor therapy and had no further approved options.
In the study, 47 percent of the patients with medullary thyroid cancers who could be evaluated had objective responses. Two had complete responses. There were 21 partial responses and 25 patients who maintained stable disease. One patient had progressive disease. All but one of the responding patients continued treatment. In 15 of the patients, these responses lasted for at least 6 months.
In two out of four evaluable patients with PTC, partial responses were reported, and all of them were continuing treatment when the report was made after 8-11 months of therapy with BLU-667.
In MTC, the responses occurred regardless of multikinase resistance or RET genotype. Rapid plasma clearance of RET variants and marked reductions in CEA and calcitonin was observed.
"For the most part, the drug was well-tolerated by patients on the trial. None of [them] had to stop the drug because of side effects. We did see some patients having hypertension, some neutropenia. But these were all manageable either by a dose reduction or a brief interruption of the treatment," Taylor said.
The investigators concluded that treatment-related toxicity was generally low-grade and reversible, with 28 of patients having had grade 3 events. There were no grade 4 or 5 events and no events requiring discontinuation.
The investigators concluded that BLU-667 demonstrated potent, durable and broad antitumor activity, was well-tolerated in patients with MTC and PTC regardless of MKI resistance, and offered to significantly improve outcomes for patients with RET-altered thyroid cancers.
"My hope is that we'll see the day in the near future that this becomes FDA-approved as a first-line treatment option for patients with these cancers," Taylor.
Peter M. Goodwin is a contributing writer.
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