RET inhibitor for use in treating cancer having a RET alteration

Inventors

Evans Raab, Erica • Wolf, Beni B.

Assignees

Rigel Pharmaceuticals Inc

Abstract

Disclosed herein are methods for treating a subject afflicted with a cancer having an activating RET alteration by administering an effective amount of a selective RET inhibitor, e.g., Compound 1 or pharmaceutically acceptable salts thereof, including, e.g., administering an amount of 60 mg to 400 mg of the selective RET inhibitor once daily.

Core Innovation

The disclosure describes treating a subject with rearranged during transfection (RET)-altered thyroid cancer by orally administering Compound 1 (BLU-667) or a pharmaceutically acceptable salt once daily at specified doses, including 200 mg, 300 mg, or 400 mg, with emphasis on dosing regimens within about 300 mg to 400 mg. The disclosure further includes treating subjects with rearranged during transfection (RET)-mutant medullary thyroid cancer (MTC) and with rearranged during transfection (RET)-fusion thyroid cancer using the same general oral, once-daily Compound 1 approach. The document frames Compound 1 as a selective RET inhibitor in the setting of cancers driven by activating RET alterations.

The background problem addressed by the disclosure is that RET alterations function as oncogenic drivers in solid tumors, and that multikinase RET inhibitors are contrasted due to toxicity. The disclosure states that RET-altered solid tumors include RET-altered NSCLC and thyroid cancers, and it emphasizes the need for optimized dosing and schedules to sustain RET-pathway inhibition.

The disclosure provides pharmacodynamic and target-engagement rationale using downstream biomarkers, including DUSP6 and SPRY4 mRNA and effect markers including CEA, calcitonin, and KIF5B/TP53 ctDNA. Example results referenced in the document include planned or observed biomarker reductions consistent with sustained RET-pathway inhibition, and example patient responses described using tumor marker declines, partial responses under RECIST 1.1, and signals related to brain metastasis stability or response.

Claims Coverage

The provided claim set includes six independent claims. Across these claims, the inventive features focus on oral once-daily treatment of specific RET-altered thyroid cancer categories with Compound 1 (BLU-667) or pharmaceutically acceptable salts, using defined dose strengths and, in some claims, a multiple solid oral dosage form regimen with a fixed per-dosage-form amount.

Across the independent claims provided, the coverage centers on oral once-daily administration of Compound 1 (BLU-667) or pharmaceutically acceptable salts to treat RET-altered thyroid cancers, including RET-mutant MTC and RET-fusion thyroid cancer, using defined daily dose strengths (200 mg, 300 mg, or 400 mg) or, alternatively, a regimen using two or more solid dosage forms with a fixed 100 mg per form and pharmaceutically acceptable excipients.

Stated Advantages

Documented Applications