Abstract 1469: TPX-0131, a potent inhibitor of wild type ALK and a broad spectrum of both single and compound ALK resistance mutations

Abstract

Three generations of ALK inhibitors are approved for the treatment of ALK+ NSCLC but their efficacy is often limited by ALK resistance mutations. The solvent front mutation G1202R and gatekeeper mutation L1196M are major resistance mechanisms to the first two generations of inhibitors. Patients treated with second generation inhibitors are reported to progress with multiple mutations on separate alleles (mutations in trans). In contrast, 35 - 48% of patients treated with lorlatinib progress with multiple mutations on the same allele (compound mutations, mutations in cis). TPX-0131 is an ALK inhibitor with a compact macrocyclic structure designed to bind completely within the ATP binding boundary and overcome a spectrum of single and compound ALK resistant mutations. TPX-0131 was profiled against previous generations of ALK inhibitors both in vitro and in vivo. In biochemical assays, TPX-0131 potently inhibits (IC50 <10 nM) wild type (WT) ALK and 26 ALK mutations (single and compound). Cell proliferation assays of WT, single mutations, and compound mutations were used to evaluate TPX-0131 relative to previous generations of ALK inhibitions (crizotinib, alectinib, brigatinib, ceritinib, lorlatinib). TPX-0131 is more potent against WT EML4-ALK (IC50 = 0.4 nM) than previous generations of ALK inhibitors (2-fold, lorlatinib; 10 - 30-fold, second generation inhibitors; >100-fold, crizotinib). TPX-0131 potently inhibits EML4-ALK harboring a G1202R solvent front mutation (IC50 = 0.2 nM) which is >100-fold more potent than previous generations of ALK inhibitors. TPX-0131 potently inhibits ALK harboring a gatekeeper mutation (IC50 = 0.5 nM) and is >10-fold more potent than previous generations of ALK inhibitors. TPX-0131 potently inhibits ALK with a L1198F hinge area mutation (IC50 = 0.2 nM) which is 87 - 3000-fold more potent than previous generations of ALK inhibitors. TPX-0131 is the most potent inhibitor against nine EML4-ALK double and triple compound mutations (6 with IC50 < 1 nM, 3 with IC50 1.6 - 14.9 nM). Evaluation of ALK phosphorylation as a pharmacodynamic marker in tumors showed potent ALK inhibition by TPX-0131 that correlated with TPX-0131 exposure. In Ba/F3 cell-derived xenograft tumor models with EML4-ALK mutations, TPX-0131 (2, 5, 10 mg/kg BID) demonstrated robust anti-tumor activity in the G1202R model (64%, 120%, 200% TGI), G1202R/L1198F model (complete regression, all doses), and G1202R/L1196M model (44%, 83% and 200% TGI). In contrast, lorlatinib (5 mg/kg BID) caused 31% TGI in the G1202R/L1198F model and did not have statistically significant TGI in the G1202R/L1196M model. Taken together, TPX-0131 is a next generation ALK inhibitor that has preclinical potency against WT ALK as well as a broad spectrum of acquired resistance mutations, especially compound mutations, which currently lack any effective ALK inhibitor therapy. Citation Format: Brion W. Murray, Dayong Zhai, Wei Deng, Evan Rogers, Xin Zhang, Jane Ung, Vivian Nguyen, Han Zhang, Maria Barrera, Ana Parra, Jessica Cowell, Dong Lee, Herve Aloysius. TPX-0131, a potent inhibitor of wild type ALK and a broad spectrum of both single and compound ALK resistance mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1469.

Novel therapeutic strategies for rare mutations in non-small cell lung cancer

“…Interestingly, the ORR was 54% in patients with ALK-resistant mutations (n = 28) 170 . TPX-0131, a next-generation ALK inhibitor, also exhibited preclinical potency against both wild-type ALK and a wide range of compound mutations, such as G1202R + L1198F, L1196M + L1198F, and G1202R + C1156F 171 . Recently, a relevant clinical trial (FORGE-1; NCT04849273) is ongoing.…”

Update on Lorlatinib: Role in Reducing the Risk of Disease Progression in ALK-Positive NSCLC

“… 29 A next-generation macrocyclic ALK inhibitor, TPX-0131, demonstrated anti-tumor activity in vivo in a range of single and compound mutants refractory to all approved ALK inhibitors and currently being studied in the phase 1 FORGE-1 trial. 30 With lorlatinib as the only third and latest generation of ALK TKIs for advanced ALK-positive NSCLC, additional studies are needed to find novel strategies to overcome its resistance upon progression.…”