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Fong Cao
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-44 - BLU-667 Demonstrates Robust Activity in RET Fusion-Driven Intracranial Tumor Models (ID 2057)
10:15 - 18:15 | Author(s): Fong Cao
- Abstract
Background
Oncogenic RET fusions and mutations have been identified in several cancer types including non-small cell lung cancer (NSCLC), papillary thyroid cancer and medullary thyroid cancer. Current treatment of RET-altered cancers is generally limited to multikinase inhibitors (MKIs) designed to target other kinases, and chemotherapy, which often have limited efficacy and carry significant off-target toxicities. BLU-667 is an investigational oral precision therapy that is a potent and highly selective inhibitor of oncogenic RET fusions and mutations (IC50 = 0.4 nM) and has demonstrated tumor growth inhibition and RET signaling abrogation in numerous subcutaneous models of RET-driven disease (Subbiah et al. 2018). Early phase 1 results with BLU-667 have demonstrated promising clinical activity in both RET fusion and RET mutant-driven tumors. As brain metastases occur in up to half of patients with NSCLC, we developed several preclinical intracranial models of RET-driven disease and demonstrate robust activity of BLU-667 in this setting.
Method
KIF5b-RET-Ba/F3 cells engineered to express luciferase or CCDC6-RET CRC PDX tumors were implanted intracranially in Balb/c nude mice. Efficacy was determined by survival or imaging after luciferin tail vein injection. Pharmacodynamic confirmation of RET kinase inhibition was assessed by immunoblot or qRT-PCR of RET pathway transcriptional markers DUSP6 and SPRY4 in harvested tumors.
Result
In RET fusion-driven intracranial mouse tumor models, oral BLU-667 treatment demonstrated significant survival benefit at well tolerated doses. This benefit occurred with BLU-667 doses (10 or 30 mg/kg BID) also shown to be efficacious in subcutaneous RET-driven tumor models and at drug exposures below those achieved at the recommended phase 2 dose in humans (400 mg) established in the BLU-667 phase 1 clinical trial. BLU-667 activity was consistent in both KIF5b-RET and CCDC6-RET fusions, the most common RET fusions found in NSCLC. Pharmacodynamic analysis of intracranial tumor tissue after BLU-667 treatment confirmed dose dependent inhibition of RET pathway signaling (P-RET, P-SHC) and >90% downregulation DUSP6 and SPRY4, consistent with full pathway inhibition. In intracranial Ba/F3-KIF5b-RET tumors expressing luciferase, imaging analysis established near complete inhibition of tumor growth in mice treated with BLU-667.
Conclusion
In intracranial tumor models driven by KIF5b-RET or CCDC6-RET fusions, BLU-667 inhibits RET kinase activity and increases survival. These data suggest BLU-667 has promise as an investigational agent for RET fusion NSCLC with or without brain metastasis. As such, BLU-667 is currently being evaluated in a clinical trial for patients with RET-driven solid tumors including NSCLC (NCT03037385) with registrational intent.