BLU-667, a next-generation tyrosine kinase inhibitor, appeared to be well-tolerated and had broad clinical benefit among patients with advanced, RET
-altered solid tumors who progressed on prior therapies, according to phase I study findings presented at the AACR Annual Meeting 2018, held April 14 to 18 in Chicago, Illinois.
The receptor tyrosine kinase RET
is a rare driver of multiple, diverse tumor types including more than 60% of medullary thyroid cancers (MTCs), approximately 10% of papillary thyroid tumors, about 1% to 2% of non-small cell lung cancers (NSCLCs), and only about 1% of patients with esophageal cancer, breast cancer, melanoma, colorectal cancer, and leukemia.
Identifying the Need
To date, no approved therapies target RET potently and selectively.
“Precision oncology has benefitted patients with EGFR, ALK,
aberrations. Unfortunately, patients with RET
-altered cancers have not benefitted from precision oncology targets to date,” Vivek Subbiah, MD, assistant professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, the University of Texas MD Anderson Cancer Center in Houston, said during the AACR Annual Meeting press conference.
“The current drugs that have been used are repurposed multi-kinase inhibitors. They have decreased activity and increased off target toxicity,” he added. “There was a need to design a selective drug for the RET pathway.”
BLU-667, currently in development by Blueprint Medicines Corporation, is a highly potent and selective oral inhibitor that targets oncogenic RET
-fusions, point mutations, and resistance mutations. The preclinical and early clinical validation of the agent were also published today in Cancer Discovery.
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, which have been tied to resistance to multiple kinase therapy, according to an MD Anderson-issued press release.
In the open-label, first-in-human, phase I ARROW trial, Subbiah and colleagues aimed to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and anti-tumor activity of BLU-667 in advanced,RET
-altered solid tumors.
The researchers enrolled 51 patients with unresectable, advanced solid tumors which included 29 with RET
-mutant MTC, 19 with NSCLC with RET
fusions, 2 with papillary thyroid cancer, and 1 with paraganglioma. Patients had a median of 1 prior anti-neoplastic therapy (range, 0-8).
The researchers administered BLU-667 orally at doses ranging from 30 mg to 400 mg daily on a 4-week cycle following a Bayesian Optimal Interval design, which allowed additional accrual to dose levels declared safe. The MTD was not reached.
BLU-667 demonstrated broad antitumor activity with a best overall response rate (ORR) of 37% (95% CI, 20%-56%) in those withRET
alterations who received doses ≥ 60mg and had at least 1 post-baseline response assessment (n = 30). In particular, patients with NSCLC and MTC had a best ORR of 50% and 40%, respectively. Among those with RET
-fusions and mutations, the ORR was 45%.
Of the 40 evaluable patients, 1 experienced a complete response, 17 had partial responses, 20 patients achieved stable disease, and 2 patients had progressive disease.
Subbiah, who is also the Associate Medical Director of the Clinical Center for Targeted Therapy, noted these results are encouraging because this broad anti-tumor activity was seen regardless of tumor type; genomic aberration; fusion mutation; prior therapies that included immunotherapy, chemotherapy, and multi-kinase targeted therapy; and the number of prior therapies.
Rapid decline in blood and tumor biomarkers accompanied anti-tumor activity, and 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.
BLU-667 appeared well-tolerated, with grade 1 constipation as the most common adverse event (AE; 23%). Grade 3 to 4 AEs included hypertension (8%) and neutropenia (4%), as well as increased ALT, fatigue, diarrhea, and a decrease in white blood cells (each 2%). The researchers recorded 3 dose-limiting toxicities. No grade 4 to 5 AEs occurred.
At of the data cutoff, 41 of 51 RET-
altered patients remained on treatment. “This is fantastic for a phase I study because at a lower dose level, patients may not be getting the higher doses,” Subbiah said.
The dose escalation portion of the phase I trial is open and enrolling globally. “ARROW dose escalation data validate BLU-667 as a promising precision therapy for RET
-altered cancers,” he added.
Press conference moderator Louis M. Weiner, MD, co-chair of the AACR Annual Meeting Clinical Trials Committee and director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, acknowledged that the trial demonstrated empowering results, yet it also highlighted challenges 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,” he 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.”
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.