LAUSR

Introduction: NVL-655 is a brain-penetrant, ALK-selective tyrosine kinase inhibitor (TKI) designed to maintain activity against ALK and ALK mutations that confer resistance to currently approved therapies, and to avoid neurological adverse events and dose-limiting toxicities associated with TRK inhibition. Brain metastases are common in ALK-positive non-small cell lung cancer (NSCLC), with an incidence of ~40% at diagnosis and ~60% after progressive disease on the first-generation ALK TKI (crizotinib) due to its limited brain penetration. Second- (ceritinib, alectinib, brigatinib, and ensartinib) and third-generation (lorlatinib) ALK TKIs have higher intracranial responses than crizotinib but are still limited by emergence of resistance mutations, most commonly G1202R-containing single and compound mutations. We previously reported that NVL-655 has intracranial activity in a preclinical model of Ba/F3 EML4-ALK v1 G1202R/L1196M. Here we further demonstrate the intracranial activity of NVL-655 in a preclinical patient-derived model harboring EML4-ALK v3 G1202R. Methods: The YU-1077 cell line was established from a patient with ALK-positive NSCLC after relapse on alectinib and was confirmed to harbor EML4-ALK v3 G1202R alteration. ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, ensartinib, lorlatinib, and NVL-655) were profiled against YU-1077 cells in 3-day viability assays and signaling assays. YU-1077 cells were intracranially implanted in Balb/c nude mice and treated with NVL-655 orally twice daily. Brain tumor burden was monitored weekly using magnetic resonance imaging (MRI). Results: NVL-655 suppressed the viability of YU-1077 cells bearing EML4-ALK v3 G1202R (IC50 < 1 nM) with potency >10-fold that of lorlatinib. NVL-655 at ≤10 nM fully inhibited ALK signaling as measured by ALK, ERK, and S6 phosphorylation, compared to ≥100 nM of lorlatinib required to achieve similar inhibition. Other ALK TKIs tested had limited activity against YU-1077 cells in viability and signaling assays, consistent with the G1202R mutation conferring resistance to first- and second-generation ALK TKIs. In mice intracranially implanted with YU-1077 cells, MRI scans confirmed rapid tumor regression upon treatment with 0.5 and 1.5 mg/kg NVL-655. Conclusion: Patient-derived models are widely viewed as among the most disease-relevant models for evaluating new therapies and drug resistance. Using a xenograft model derived from an alectinib-relapsed patient, we showed that NVL-655 had high intracranial activity against brain tumors bearing the ALK G1202R mutation that confers resistance to multiple ALK TKIs. NVL-655 is being evaluated in a Phase 1/2 clinical trial for patients with advanced NSCLC and other solid tumors harboring ALK rearrangement or activating ALK mutation (ALKOVE-1): NCT05384626. [J. Lee and M. Yu contributed equally.] Citation Format: Jii Bum Lee, Mi Ra Yu, Mi Ran Yun, You Won Lee, Seung Yeon Oh, Eun Ji Lee, Anupong Tangpeerachaikul, Henry E. Pelish, Byoung Chul Cho. Preclinical intracranial activity of NVL-655 in an alectinib-resistant patient-derived model harboring EML4-ALK fusion with G1202R mutation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4022.