NVL-655 exhibits antitumor activity in lorlatinib-resistant and intracranial models of ALK-rearranged NSCLC

ALK receptor tyrosine kinase can be aberrantly activated by gene rearrangement or point mutation to drive tumor cell proliferation, survival, and metastasis. ALK rearrangements are detected in up to 5% of advanced non-small cell lung cancer (NSCLC), and up to 40% of patients present with brain metastases at diagnosis. Crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are FDA-approved tyrosine kinase inhibitors for ALK-positive NSCLC. However, durability of response to these treatments is partly limited by mutations in ALK that confer resistance. The G1202R solvent front mutation is commonly observed in patients that have progressed on crizotinib, ceritinib, alectinib, or brigatinib. Patients with tumors harboring G1202R have responded to lorlatinib, but many have relapsed after acquiring compound mutations such as G1202R/L1196M and G1202R/G1269A. Another challenge with lorlatinib is central nervous system (CNS) adverse events attributed to inhibition of tropomyosin receptor kinase B (TRKB), a kinase structurally related to ALK. NVL-655 is a novel preclinical brain-penetrant ALK inhibitor with selectivity over TRKB. We previously reported that NVL-655 inhibits ALK G1202R, G1202R/L1196M, G1202R/G1269A, and G1202R/L1198F in vitro; has favorable kinome and ALK-vs-TRKB selectivity profiles; and shows antitumor activity in a Ba/F3 EML4-ALK variant 1 (v1) G1202R/L1196M xenograft model. Here we report results of a broader preclinical characterization of NVL-655 across ALK models, including an intracranial model. NVL-655 was observed to induce regression in a HIP1-ALK patient-derived xenograft model, an EML4-ALK v1 human cancer cell line-derived model (NCI-H3122), and Ba/F3 xenograft models expressing EML4-ALK v1 G1202R and G1202R/G1269A. Pharmacodynamic (PD) biomarker analyses supported in vivo ALK inhibition by NVL-655. Furthermore, NVL-655 was observed to reduce tumor size and prolong survival by more than 4-fold in a mouse intracranial tumor model of Ba/F3 EML4-ALK v1 G1202R/L1196M luciferase. In conclusion, NVL-655 has a preclinical profile that we believe supports its potential to address a medical need for patients with ALK-positive disease, including those with G1202R compound mutations. We believe the findings presented here support the evaluation of NVL-655 for the treatment of patients with ALK-driven disease.Citation Format: Anupong Tangpeerachaikul, Amit Deshpande, Nancy E. Kohl, Joshua C. Horan, Henry E. Pelish. NVL-655 exhibits antitumor activity in lorlatinib-resistant and intracranial models of ALK-rearranged NSCLC [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P244.