First Selective RET Inhibitor Shows Efficacy in Multiple Cancers


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A first-in-human study provides proof of concept that a novel oral agent targeted to RET genetic alterations is safe and active in RET-driven cancers. The agent, called BLU-667, achieved durable disease control in patients with lung and thyroid cancers harboring the RET oncogene, according to the results of the phase I ARROW study reported at the 2018 Annual Meeting of the American Association for Cancer Research (AACR).1 The study was published online in Cancer Discovery to coincide with the presentation at the AACR meeting.2

“Tumor reductions and durable responses were observed in most patients, especially those whose cancers progressed with chemotherapy and multikinase inhibitors. Our study reported an overall response rate of 45% for RET-driven cancers, with responses of 50% for RET-fusion non–small cell lung cancer [NSCLC] and 40% for RET-mutant medullary thyroid cancer,” said lead author Vivek Subbiah, MD, Assistant Professor of Investigational Cancer Therapeutics, MD Anderson Cancer Center, Houston.


Today, 41 of the 51 patients remain on study. This is fantastic for a first-in-human trial.
— Vivek Subbiah, MD

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To date, no drug has been approved by the U.S. Food and Drug Administration to treat RET-driven cancers. “There is a critical unmet need for effective drugs against cancers that have the RET alteration. There are no highly selective RET inhibitors currently approved specifically for these RET-driven cancers. The current treatments for these cancers are limited to traditional chemotherapy and earlier generations of multikinase inhibitors. These options have had limited success, with often considerable side effects,” Dr. Subbiah explained.

BLU-667 is a novel designer drug targeted to RET-altered cancers. It is 100 times more selective for RET than other kinases and apparently is associated with fewer side effects affecting normal tissue.

RET is expressed in > 60% of medullary thyroid cancers, 20% of papillary thyroid cancers, and 1% to 2% of NSCLCs. The study enrolled 51 patients with diverse advanced RET-driven cancer types ineligible for surgery (RET mutations or fusions); of these patients, 29 had medullary thyroid cancer, 19 had NSCLC, 2 had papillary thyroid cancer, and 1 had paraganglioma. Patients enrolled in the trial failed to respond to a median number of 1 previous treatment (range, 0–8). BLU-667 was given in doses ranging from 30 to 600 mg, and the maximum tolerated dose was 400 mg/d.

Key Study Findings

The drug achieved broad antitumor activity. The best overall response rate was 45% in 40 patients treated at doses of 60 mg or higher and at least 1 baseline response assessment. Patients with NSCLC and medullary thyroid cancer had a best overall response rate of 50% and 45%, respectively. At data cutoff, 41 of the enrolled patients were still on study.

“Responses were seen regardless of tumor type or genotype or prior therapies or number of prior therapies,” he said. “This is what makes a doctor wake up in the morning to study this,” he said.

NOVEL THERAPY FOR RET-DRIVEN CANCERs

  • In a phase I, first-in-human study, BLU-667 appeared to be safe, with encouraging responses in RET-driven cancers, namely NSCLC and medullary thyroid cancer.
  • Compared with multikinase agents, BLU-667 is a designer drug specifically targeted to RET alterations.
  • Because the drug targets RET and not normal tissues, it has an improved side-effect profile compared with multikinase agents.
  • Future studies are needed to confirm these early findings.

Safety and toxicity were reasonable for a first-in-human study. There were no grade 4 or 5 adverse events; most were grade 1. “Today, 41 of the 53 patients remain on study. This is fantastic for a first-in-human trial,” Dr. Subbiah told the audience. He also pointed out that patients reported improved quality of life with BLU-667. “Response rate is just one side of the coin. Quality of life is another.”

“Overall, the data show the precision targeted therapy with next-generation kinase inhibitors can have a powerful impact for patients with RET-driven cancers. By offering a highly selective medicine tailored to this oncogenic driver, we hope this new therapy will enable patients to benefit from the recent advances in genomic profiling, which have revolutionized treatment options for patients with kinase-driven disease,” Dr. Subbiah concluded.

The global dose-expansion ARROW study is open for enrollment. The next step is a global phase II study enrolling multiple RET-driven cancer types in patients with advanced disease. ■

DISCLOSURE: Dr. Subbiah reported no conflicts of interest.

REFERENCES

1. Subbiah V, Taylor M, Lin J, et al: Highly potent and selective RET inhibitor, BLU-667, achieves proof of concept in a phase I study of advanced, RET-altered solid tumors. 2018 AACR Annual Meeting. Abstract CT043. Presented April 15, 2018.

2. Subbiah V, Gainor J, Rahal R, et al: Precision targeted therapy with BLU-667 for RET-driven tumors. Cancer Discov. April 15, 2018 (early release online).


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Formal discussant of the study on BLU-667, Alexander Drilon, MD, Clinical Director, Early Drug Development Service at Memorial Sloan Kettering Cancer Center, New York, was enthusiastic about these early results. “We’ve known about RET for more than 30 years. To date,...

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