BLU-667 Demonstrates Broad Activity in RET+ Advanced Solid Tumors

Vivek Subbiah, MD

According to the results from a phase I study, BLU-667, a next-generation tyrosine kinase inhibitor, was well-tolerated and demonstrated clinical benefit in patients with advanced,RET-altered solid tumors who had progressed on previous therapies. These findings were presented April 14 to 18 at the AACR Annual Meeting 2018 in Chicago, Illinois.

The receptor tyrosine kinaseRET, a rare driver of many diverse tumor types, includes more than 60% of medullary thyroid cancers (MTCs) and 10% papillary thyroid tumors, 1-2% non-small cell lung cancers (NSCLCs), and 1% of breast, colorectal, and esophageal cancers, as well as melanoma and leukemia. No approved therapies targetRETcurrently.

“Precision oncology has benefitted patients withEGFR, ALK, andROS1aberrations,” said Vivek Subbiah, MD, assistant professor in the Department of Investigational Cancer Therapeutics, Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center in Houston, Texas, during the AACR Annual Meeting. “Unfortunately, patients withRET-altered cancers have not benefitted from precision oncology targets to date.”

“The current drugs that have been used are repurposed multi-kinase inhibitors. They have decreased activity and increased off target toxicity. There was a need to design a selective drug for the RET pathway,” he added.

Currently in development by manufacturer Blueprint Medicines Corporation, BLU-667 is a highly potent and selective oral inhibitor targeting oncogenicRET-fusions, point mutations, and resistance mutations. Preclinical and early clinical validations were published today inCancer Discoveryfor BLU-667.

Since BLU-667 is much more selective forRETover other kinases and has proven effective in stopping genetic mutations that are related to resistance to multiple kinase therapy, BLU-667 was selected for this investigation, according to a press release issued by MD Anderson.

In ARROW trial, an open-label, first-in-human, phase I trial, Subbiah and colleagues aimed to define the maximum tolerated dose (MTD) of BLU-667, as well as the safety, pharmacokinetics (PK), and anti-tumor activity in patients with advanced,RET-altered solid tumors.

Fifty-one patients were enrolled with unresectable, advanced solid tumors, of which 29 patients were found withRET-mutant MTC, 19 with NSCLC withRETfusions, 2 with papillary thyroid cancer, and 1 with paraganglioma. There was a median of 1 prior anti-neoplastic therapy (range, 0-8) amongst the patients in this trial.

Patients were given BLU-667 orally at doses ranging from 30 mg to 400 mg daily on a 4-week cycle following a Bayesian Optimal Interval design. This allowed for additional accrual to dose levels declared safe. MTD was not reached in this trial.

Broad antitumor activity was found with this agent, showing a best overall response rate (ORR) of 37% (95% CI, 20%-56%) in patients withRET alterations who had received doses of ≥ 60mg and had at least 1 post-baseline response assessment (n = 30). Patients with NSCLC and MTC had a best ORR of 50% and 40%, respectively. Among those patients withRET-fusions and mutations, there was an ORR of 45%.

Overall, there were 40 evaluable patients, of which 1 had a complete response, 17 had partial responses, 20 reached stable disease, and 2 had progressive disease.

Subbiah, who is also the Associate Medical Director of the Clinical Center for Targeted Therapy, said these results are encouraging due to the broad anti-tumor activity seen regardless of tumor type; genomic aberration; fusion mutation; prior therapies that included immunotherapy, chemotherapy, and multi-kinase targeted therapy; and number of prior therapies in patients.

A rapid decline in blood and tumor biomarkers was found associated with anti-tumor activity, while PK showed rapid BLU-667 absorption (Tmax 2-4 hours), long half-life (> 12 hours), and exposure (AUC and Cmax) in the expected therapeutic range based on tumor xenograft models.

Overall, BLU-667 appeared to be well-tolerated amongst the patients, The most common adverse event (AE) was grade 1 constipation (23%). Grade 3 to 4 AEs were also found, including hypertension (8%) and neutropenia (4%). Researchers also noted AEs of increased ALT, fatigue, diarrhea, and a decrease in white blood cells (each 2%). Researchers recorded 3 dose-limiting toxicities. There were also no grade 4 to 5 AEs found in this trial.

After the data cutoff, 41 of 51RET-altered patients remained on the BLU-667 treatment. Subbiah said that this fantastic for a phase I study since patients had been receiving the drug in lower doses.

A dose escalation portion of this trial is currently enrolling globally. “ARROW dose escalation data validate BLU-667 as a promising precision therapy forRET-altered cancers,” Subbiah explained.

Louis M. Weiner, MD, press conference moderator, co-chair of the AACR Annual Meeting Clinical Trials Committee, and director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, acknowledged the empowering results from this trial, but said it also highlighted challenges commonly associated with precision medicine.

“The trial underscores the emerging necessity of molecular profiling of cancers to identify patients who might benefit from precision targeted therapy,” Weiner said. “The challenge associated with that is drug development is more complicated, and the molecular target is rarely found in these cancers. As a health care ecosystem, we need to find a way to find them and attack what might be considered mutational needles in a molecular haystack.”

Reference:

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. Presented at: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. Abstract CT043.