Next-generation selective inhibitor BLU-667 demonstrated early promise for patients with RET mutations—a key driver across multiple cancers—according to proof-of-concept data presented from the ongoing phase I ARROW trial at the American Association for Cancer Research (AACR) Annual Meeting 2018, April 14-18.
Of the patients who received BLU-667 who had RET-altered solid tumors with measurable target lesions, 84 percent experienced a tumor reduction, including patients whose disease had progressed on prior multi-kinase therapy, immunotherapy and chemotherapy.
RET activating fusions and mutations drive multiple cancers, including non-small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC). RET fusions are implicated in approximately 1 to 2 percent of patients with NSCLC, while RET mutations are implicated in approximately 60 percent of patients with MTC. RET fusions have also been identified at low frequencies in colon and breast cancer.
Currently, there are no approved therapies that selectively target RET-driven cancers, though there are several approved multi-kinase inhibitors with RET activity being evaluated in clinical trials.
“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, lead investigator on the trial and assistant professor, the University of Texas MD Anderson Cancer Center, in a statement. “Current therapies for RET-altered cancers are restricted to multi-kinase 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.”
The ARROW clinical trial is taking place in two parts—a dose escalation portion and a global expansion portion.
As of the data cutoff date of April 6, 2018, 53 patients had been treated with BLU-667 in the dose escalation portion of the trial across multiple dose levels. This included 19 patients with NSCLC, 29 patients with MTC and five patients with other solid tumors.
Of these 53 patients, 27 patients had been previously treated with a multi-kinase inhibitor and 18 patients had been previously treated with an immunotherapy.
Forty patients with RET-altered tumors were evaluable for response assessment at the time the data were presented, including 14 patients with NSCLC, 25 patients with MTC and one patient with papillary thyroid cancer (PTC). Of the remaining 13 enrolled patients who were not evaluable for response assessment, two patients did not have RET-altered tumors, one patient died due prior to any response assessment and 10 recently enrolled patients had not yet been evaluated.
Preliminary overall response rates (ORR) were 50 percent in patients with NSCLC and 40 percent in patients with MTC. Across all evaluable patients, the preliminary ORR was 45 percent. Preliminary evidence of anti-tumor activity in the brain was also observed in metastatic NSCLC.
In the dose escalation portion, BLU-667 was observed to be well-tolerated, with common side effects including constipation, increased alanine aminotransferase and increased aspartate aminotransferase.
BLU-667 was discovered by researchers at Blueprint Medicine, a company focused on targeting previously unaddressed drivers of cancer and other debilitating diseases.
Based on the favorable tolerability and encouraging clinical activity observed for BLU-667 thus far, Blueprint Medicines initiated and is actively enrolling patients in the global expansion portion of the ARROW trial.
“We believe the safety, clinical activity and pharmacodynamic results from the dose escalation portion of the Phase 1 ARROW trial demonstrate compelling proof-of-concept for BLU-667,” said Andy Boral, MD., PhD., Chief Medical Officer at Blueprint Medicines, in a statement. “We are particularly encouraged by the consistency of these early BLU-667 data across multiple tumor types, RET alterations and prior lines of therapy. Based on these data, we are excited to rapidly advance the global expansion portion of the trial, which will further evaluate an optimized dose of BLU-667 across a broad patient population with a focus on durability of activity.”