TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutations

Abstract

Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, ALK inhibitors have become important treatments for a subset of patients with lung cancer. Each generation of ALK inhibitor showed improvements in terms of CNS penetration and potency against wild-type ALK, yet a key continued limitation is their susceptibility to resistance from ALK active-site mutations. The solvent front mutation (G1202R) and gatekeeper mutation (L1196M) are major resistance mechanisms to the first two generations of inhibitors while patients treated with the third-generation ALK inhibitor lorlatinib often experience progressive disease with multiple mutations on the same allele (mutations in cis, compound mutations). TPX-0131 is a compact macrocyclic molecule designed to fit within the ATPbinding boundary to inhibit ALK fusion proteins. In cellular assays, TPX-0131 was more potent than all five approved ALK inhibitors against wild-type ALK and many types of ALK resistance mutations, e.g. G1202R, L1196M, and compound mutations. In biochemical assays, TPX-0131 potently inhibited (IC 50 <10 nmol/L) wild-type ALK and 26 ALK mutants (single and compound mutations). TPX-0131, but not lorlatinib, caused complete tumor regression in ALK (G1202R) and ALK compound mutation-dependent xenograft models. Following repeat oral administration of TPX-0131 to rats, brain levels of TPX-0131 were ~66% of those observed in plasma. Taken together, preclinical studies show that TPX-0131 is a CNS-penetrant, next-generation ALK inhibitor that has potency against wild-type ALK and a spectrum of acquired resistance mutations, especially the G1202R solvent front mutation and compound mutations, for which there are currently no effective therapies.

Prediction of Resistant Mutations against Upcoming ALK-TKIs, Repotrectinib (TPX-0005) and Ensartinib (X-396)

“…L1196M + G1202R, a major repotrectinib-resistant mutation, is also discovered to be a lorlatinib-resistant mutation 13 . This mutant is highly resistant to all approved ALK-TKIs; however, we confirmed that a novel ALK-TKI, TPX-0131, was potent to this mutant 27 . If the efficacy and safety of TPX-0131 were demonstrated in a current clinical trial, this inhibitor would be an excellent treatment option for repotrectinib-resistant patients with the L1196M + G1202R mutation.…”

Review of Therapeutic Strategies for Anaplastic Lymphoma Kinase-Rearranged Non-Small Cell Lung Cancer

“…The fourth-generation ALK-TKIs are currently considered the most promising treatment for compound ALK mutation. Two fourth-generation ALK TKIs (TPX-0131 and NVL-655) are under development [ 88 , 89 , 90 , 91 ]. Both TPX-0131 and NVL-655 can inhibit acquired compound ALK mutations in addition to a wide spectrum of single ALK mutations.…”

Targeting ALK Rearrangements in NSCLC: Current State of the Art

“…Fourth-generation ALK TKIs such as TPX-0131 and NVL-655 have been developed, which are “double mutant active.” TPX-0131 is a compact macrocyclic inhibitor, which was designed to fit completely in the ATP-binding pocket. It may reduce the susceptibility to a variety of ALK TKI-resistant mutations, including solvent front, hinge region, gatekeeper, and compound mutations ( 82 ). Other than being sensitive to most single resistant mutations, TPX-0131 is effective for compound mutations such as G1202R+L1198F, G1202R+L1196M, L1196M+ L1198F, and G1202R+C1156F.…”