Targeted Therapy Reported For RET-Altered Tumours

Early results suggest proof of concept for a selective inhibitor of tumours with alterations to the receptor tyrosine kinase RET

medwireNews: First-in-human findings for the novel RET inhibitor BLU-667 have been reported for patients with unresectable advanced solid tumours with an oncogenic RET alteration.

Results from the phase I ARROW study were presented at the American Association of Cancer Research annual meeting 2018 in Chicago, Illinois, USA, and the foundational clinical findings have also been published in Cancer Discovery.

The open-label study was initiated after preclinical research showed that the inhibitor was more selective for the RET kinase relative to other kinases tested, including inhibition of known oncogenic alterations, some of which have previously been associated with multikinase resistance.

“This ongoing phase I study has shown proof-of-concept of this selective RET inhibitor,” commented presenting author Vivek Subbiah, from the University of Texas MD Anderson Cancer Center in Houston, USA.

“Although it’s very early in clinical testing, we observed promising antitumor activity in NSCLC [non-small-cell lung cancer] and MTC [medullary thyroid cancer]”, he said.

Vivek Subbiah reported findings for 29 patients with RET-mutated MTC, 19 patients with NSCLC with a RET fusion, two patients with papillary thyroid cancer with a RET fusion, and one patient with RET-mutated paraganglioma.

He described BLU-667 as being “well tolerated”. Safety analysis of 49 patients given doses of 30–400 mg/day showed that grade 1 constipation and alanine transferase elevation were the most common adverse events, each affecting 20% of patients, followed by grade 1 aspartate aminotransferase increase (16%) and peripheral oedema (12%).

A further 16% of patients experienced grade 3 treatment-related adverse events but there were no grade 4 or 5 side effects.

“BLU-667 has broad anti-tumour activity against RET-altered cancer”, the presenter summarised.

Of the 40 patients assessed for response at this time, one (3%) patient had a confirmed complete response to treatment, 17 (43%) had a partial response (10 of which have since been confirmed) and 20 (50%) had stable disease, with just two (5%) experiencing disease progression.

In all, 41 of the 51 patients with RET alterations remain on treatment at this time, he said, noting that these responses occurred across different tumour types and RET alterations, as well as in patients with or without a prior history of immunotherapy or multikinase inhibitor use.

“ARROW dose escalation data validate BLU-677 as a promising precision therapy for RET-altered cancers”, the presenter concluded, adding that the ARROW dose expansion cohort has now opened and is enrolling globally.

 

Reference

Subbiah V, Gainor JF, Rahal R, et al. Precision targeted therapy with BLU-677 for RET-driven cancers . Cancer Disc; Published Online 15 April 2018.
DOI: 10.1158/2159-8290.CD-18-0338

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