RET Inhibitor May Be Effective in RET-Altered Thyroid Cancers

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RET inhibitor LOXO-292 was well tolerated and demonstrated high antitumor activity against RET-altered thyroid cancers.
RET inhibitor LOXO-292 was well tolerated and demonstrated high antitumor activity against RET-altered thyroid cancers.
The following article features coverage from the American Thyroid Association (ATA) 2018 meeting. Click here to read more of Cancer Therapy Advisor's conference coverage.

RET inhibition with LOXO-292 was well-tolerated and demonstrated high antitumor activity among patients with advanced RET-fusion or -mutated thyroid cancer, according to results from a phase 1/2 trial presented at the 88th Annual Meeting of the American Thyroid Association in Washington, D.C.1

RET aberrations are common in papillary and medullary thyroid carcinomas (PTC; MTC), but multikinase inhibitors demonstrate modest efficacy. The aim of this trial was to evaluate the safety and preliminary efficacy of the RET inhibitor LOXO-292.

The ongoing international, phase 1/2 trial has treated 38 patients with PTC, MTC, or poorly differentiated thyroid cancer as of April 2, 2018. All patients had tumors harboring RET fusions or mutations. Patients received 20 mg to 240 mg of LOXO-292 once or twice daily in 28-day cycles in a 3 + 3 design. The primary end point was maximum tolerated dose (MTD) or recommended dose determination and the secondary end points included safety, objective response rate (ORR), and duration of response (DoR).

Most adverse events (AEs) were grade 1 or grade 2 in severity. Common AEs included fatigue in 20% of patients, diarrhea in 16%, constipation in 15%, dry mouth in 12%, nausea in 12%, and dyspnea in 11%.

Patients with RET-fusion PTC or poorly differentiated disease demonstrated an ORR of 100%. The ORR was 45% for patients with MTC. A reduction in tumor volume occurred in 82% of patients with MTC, and 86% demonstrated a sustained decrease of at least 50% in calcitonin levels.

The median DoR was not yet reached, with the longest response ongoing at 5 months. Most patients remained on treatment (95%).

In 100% and 85% of patients with RET fusions or mutations, respectively, there was a rapid and sustained decrease of at least 50% in RET variants, as measured by cell-free DNA.

The authors concluded that these data suggest that “LOXO-292 is well tolerated and has marked antitumor activity in RET-altered thyroid cancer patients, including those with resistance to prior multikinase inhibitors.” A phase 2 trial is currently actively enrolling patients; that trial will investigate the efficacy of a 160 mg dose of LOXO-292 twice daily.

Read more of Cancer Therapy Advisor's coverage of the ATA 2018 meeting by visiting the conference page.

Reference

  1. Wirth LJ, Cabanilla ME, Sherman E, et al. Clinical activity of LOXO-292, a highly selective RET inhibitor, in patients with RET-altered thyroid cancers. Presented at: the 88th Annual Meeting of the American Thyroid Association; Washington, D.C.: October 3-7, 2018. Abstract short call oral 6.

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