BLU-667, Selective RET Inhibitor, Demonstrates Antitumor Activity in NSCLC with RET Fusion

BLU-667, a novel inhibitor of RET, elicited responses in more than 50% of patients with RET fusion–positive advanced non–small-cell lung cancer (NSCLC), according to data from an ongoing phase 1 clinical trial presented at ASCO 2019.

Among 48 evaluable patients who received treatment with a daily starting dose of 400 mg of BLU-667, 1 patient had a complete response (CR) and 27 had a partial response (PR), for an overall response rate (ORR) of 58%, reported Justin F. Gainor, MD, Director of Targeted Immunotherapy, Massachusetts General Hospital, Boston.

In May 2019, the FDA granted BLU-667 breakthrough therapy designation for the treatment of patients with RET fusion–positive NSCLC that has progressed after platinum-based chemotherapy.

RET rearrangements generate oncogenic RET fusion protein in up to 2% of patients with NSCLC. “In contrast to other oncogenic RET fusions in NSCLC, such as ALK, ROS1, and NTRK, there are currently no FDA-approved selective RET inhibitors to date,” said Dr Gainor.

Early efforts to target RET focused on multikinase inhibitors that had relatively modest efficacy but substantial toxicity stemming from off-target effects. BLU-667 was designed to potently and selectively inhibit RET alterations and RET resistance mutations, Dr Gainor said.

The data presented at the meeting were from the expansion phase of the ARROW study, in which patients with NSCLC and RET fusion received treatment with a starting dose of 400 mg daily. The data came from 2 of the expansion cohorts, which included patients who received previous platinum therapy and platinum-naïve patients.

A total of 40% of the study population had brain metastases. Patients enrolled had received a me­dian of 2 previous lines of therapy, including treatment with checkpoint inhibitors (39%) and a multikinase inhibitor (18%).

Dr Gainor presented results from 120 patients (median age, 60 years), 91 of whom had received platinum-based therapy. The most common RET fusion partner was KIF5B (66% of patients), followed by CCDC6 (13% of patients); 19% of the patients had an unknown fusion partner.

In addition to the 28 responding patients among the overall cohort, 18 patients had stable disease, for a disease control rate of 96%. Among the 35 evaluable patients who had received platinum therapy, there was 1 CR and 20 PRs, for an ORR of 60%. Fourteen patients had stable disease, resulting in a disease control rate of 100%. Five of 7 (71%) treatment-naïve patients had confirmed PRs.

Most responses occurred at the time of the first scan at week 8. Some 82% of responding patients continued to receive treatment as of data cutoff. The median duration of response has not been reached. The pattern of tumor response was similar among patients with and without exposure to a checkpoint inhibitor.

“BLU-667 retained activity across all RET fusion genotypes, including patients with KIF5B as the RET fusion partner,” Dr Gainor said. “Importantly, BLU-667 was also active regardless of CNS [central nervous system] involvement.”

In total, 7 of 9 (78%) patients with intracranial metastases had shrinkage of measurable untreated metastases. The 2 patients who did not have CNS tumor shrinkage had unknown RET fusion partners. Across the entire preliminary efficacy population, “no patients at a 400-mg starting dose had progression due to new CNS involvement,” Dr Gainor said.

Treatment-related adverse events were generally low grade and reversible. The most common adverse events of any grade included neutropenia (26%), increased aspartate aminotransferase levels (20%), and constipation (17%). The most common grade 3 or higher adverse events included neutropenia (13%), hypertension (10%), and anemia (4%).

“These data support expansion of the ARROW trial in treatment-naïve NSCLC patients and continued enrollment of other RET-altered solid tumor groups,” said Dr Gainor.

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