On December 13, 2021 APS reported the application for clinical trial of APS second generation RET inhibitor APS03118 without cancer limitation was accepted by the United States Food and Drug Administration (FDA) (Press release, Applied Pharmaceutical Science, DEC 13, 2021, View Source [SID1234613104]). APS03118 is an oral second-generation RET kinase inhibitor independently developed by APS. Preclinical studies indicated that APS03118 could effectively inhibit solvent frontier RET G810R/S mutation and was expected to overcome drug resistance of existing selective RET inhibitors.

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The approval of selective RET inhibitors brings significant improvements to the treatment of aberrant RET positive patients, including non-small cell lung cancer and thyroid cancer. However, the drug resistance of these first-generation selective RET inhibitors was reported recently. Compared with EGFR, ALK and other targets, there are no drugs targeting RET resistant mutations, and patients usually have disease progression again after experiencing effective treatment. The reported drug resistance mechanism is the on target mutation represented by the RET G810R/S solvent frontier mutations, which hinders the binding of first-generation RET inhibitors to the target and finally results in drug resistance. APS03118, with unique structural advantages, can effectively inhibit RET solvent frontier mutations and displays remarkable anti-tumor effect in multiple mouse models with good tolerance.