More evidence for selective RET inhibition in RET-altered cancers
medwireNews: A report of two patients with advanced tumors harboring alterations in the RET gene who responded to treatment with the selective inhibitor LOXO-292 highlights that the clinical actionability of RET mutations, say researchers.
The article – published in the Annals of Oncology – follows the presentation of the phase I ARROW trial of a different targeted RET inhibitor, BLU-667, at the American Association for Cancer Research Annual Meeting 2018 in Chicago, Illinois, USA, this month. BLU-667 showed promising activity in the trial, with 18 of 40 evaluable patients achieving an objective response at data cutoff.
Vivek Subbiah (The University of Texas MD Anderson Cancer Center in Houston, USA) – an author on the ARROW trial and the current report – told medwireNews that “RET inhibitor therapies thus far have largely centered around multikinase inhibitors that have been repurposed to treat patients with RET alterations.”
But the response to these multikinase inhibitors is “disappointing” and treatment is often associated with “significant off-target toxicity,” he said.
LOXO-292 is a highly selective, small molecule inhibitor of RET, explain the authors of the case report, adding that it was given to two patients who had failed multiple lines of treatment, including with multikinase inhibitors, due to “clinical urgency.”
One patient had medullary thyroid cancer, with a RET M918T mutation and an acquired RET V804M gatekeeper resistance mutation, that had metastasized to the liver, while the other patient had KIF5B–RET fusion-positive non-small-cell lung cancer (NSCLC) with brain metastases. Both patients had highly symptomatic disease, including severe calcitonin-related diarrhea, abdominal pain, and fatigue in the thyroid cancer patient, and confusion and gait imbalance in the NSCLC patient.
Treatment with LOXO-292 was initiated at a dose of 20 mg twice daily for both patients, with pharmacokinetics-guided dose escalation to a final dose of 160 mg twice a day for the thyroid cancer patient and to 100 mg twice daily for the NSCLC patient.
Both patients responded to therapy as assessed by RECIST, with the thyroid tumor shrinking by 54% after 6.9 months of treatment and the lung tumor by 57% after 2 months. LOXO-292 treatment also led to the resolution of multiple intracranial metastases in the latter patient and to the improvement of symptoms in both patients.
At the time of reporting, the patient with thyroid cancer has remained on treatment for more than 7 months, but the NSCLC patient chose to discontinue treatment after 5 months against medical advice.
Commenting on the ARROW trial and this study, Subbiah said that we have learned that “[p]recision-targeted therapy with RET inhibition can have a powerful impact in patients whose cancer is induced by these oncogenic drivers, even in early clinical trial testing.”
And the “[g]ood news for RET-altered cancer patients is that we have two novel selective RET inhibitors that show significant clinical activity,” he continued.
Subbiah concluded: “I encourage all cancer patients to undergo genomic testing, as tumors with rare genomic aberrations may have effective drugs that are in clinical trials that could be beneficial to them.”
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