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Novel RET inhibitor BLU-667 offers promise for RET+ advanced NSCLC

Presented by
Dr Justin F. Gainor, Massachusetts General Hospital, USA
ASCO 2019
Phase 1, ARROW
Medical writer: Dave Levitan

The novel selective RET inhibitor BLU-667 demonstrated promising anti-tumour activity and was well tolerated in patients with RET fusion–positive advanced non–small cell lung cancer (NSCLC), according to a study presented on June 3 (Abstract 9008).

Approximately 1% to 2% of patients with NSCLC have tumours harboring RET fusions. “In contrast to other oncogenic fusions in NSCLC, such as ALK…there are currently no [U.S. Food and Drug Administration (FDA)]–approved selective RET inhibitors to date,” Justin F. Gainor, MD, of Massachusetts General Hospital, said, during the presentation of the results of the ongoing ARROW phase I dose-escalation and expansion study.

Patients with NSCLC have had low response rates to chemotherapy and immune checkpoint inhibition, and multikinase inhibitors have demonstrated low activity and high levels of off-target toxicity. BLU-667 potently and selectively inhibits RET with alterations and resistance mutants, according to preclinical research.

Dr. Gainor reported results from 120 patients with RET fusion–positive NSCLC who were treated with the dose that was established during the dose-escalation phase, 400 mg once daily; 91 of those patients had received prior platinum-based therapy. The most common RET fusion partner was KIF5B (66%), followed by CCDC6 (13%); 19% had an unknown fusion partner. The median age in the full cohort was 60, 49% of patients were male, and 40% had brain metastases.

The agent was reasonably well tolerated, and treatment-related toxicities were generally low-grade and reversible. The most common treatment-related toxicities of any grade included neutropenia (26%), increased aspartate aminotransferase (20%), and constipation (17%). The most common grade 3 or higher treatment-related adverse events included neutropenia (13%), hypertension (10%), and anaemia (4%). A total of 7% of the cohort discontinued BLU-667 due to treatment-related toxicities (pneumonitis, respiratory distress/hypoxemia, mucositis/colitis, and others).

A total of 48 patients were evaluable for response; they had enrolled as of November 2018 and had a scan for response evaluation as of April 2019. There was one complete response and 27 partial responses among those patients, for an objective response rate of 58%; 18 patients had stable disease, for a disease control rate of 96%. Among the 35 evaluable patients who had received prior platinum therapy, there was one complete response and 20 partial responses, for an objective response rate of 60%. In addition, there were 14 patients with stable disease, which resulted in a disease control rate of 100%. Five of seven patients who were treatment-naive had a confirmed partial response.

The responses were rapid in onset, with most occurring at the first scan at week 8. Most of the responding patients (82%) remained on treatment at the time of data cut off, and the median duration of response was not yet reached. The agent was active across RET fusion genotypes and regardless of prior checkpoint inhibition therapy. It was also active regardless of central nervous system involvement, and appeared to be active against intracranial metastases, with seven of nine patients (78%) experiencing shrinkage of measurable brain metastases. Dr. Gainor said that the two without such shrinkage had an unknown RET fusion partner.

“BLU-667 demonstrates broad and durable anti-tumour activity in patients with RET fusion–positive advanced NSCLC,” Dr. Gainor said, adding that the agent has been granted breakthrough therapy designation by the FDA. “Data support expansion of the ARROW trial in treatment-naive NSCLC patients and continued enrollment of other RET-altered solid tumour groups.”

Christine M. Lovly, MD, PhD, of Vanderbilt University Medical Centre, was the Discussant for the abstract. “ASCO 2019 has brought us hope for some of these elusive targets,” she said, noting that RET’s function in NSCLC has been known since the mid-1980s, though targeting it has proven extremely difficult in the past.

Dr. Lovly said questions remain regarding the best sequencing of this or other selective RET inhibitors, and whether they should be sequenced with multi-kinase inhibitors, checkpoint inhibitors, or chemotherapy. Importantly, she also said that encouraging genetic testing in NSCLC is crucial. “Thirty-three percent of patients [in this study] had a history of tobacco use,” she said. “Testing is not just for never-smokers; it should be broad-based in lung cancer.”

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