Abstract B154: Safety and preliminary activity of the selective ALK inhibitor NVL-655 in patients with ALK fusion-positive solid tumors
Authors: Lin Jessica J , Johnson Melissa , Felip Enriqueta , Ou Sai-Hong Ignatius , Besse Benjamin , Baik Christina , Mazieres Julien , Elamin Yasir , Reuss Joshua E. , Minchom Anna , Swalduz Aurelie , Pavlakis Nick , Liu Geoffrey , Gadgeel Shirish , Camidge D. Ross , Green Jennifer A , Shen Junwu , Soglia John , Sun Yuting , Zhu Viola W , Drilon Alexander 
Published: December 2023

Background: Oncogenic ALK alterations drive diverse tumor types, including ALK fusions in 3-5% of non-small cell lung cancers (NSCLCs). While 3 generations (1G, 2G, 3G) of ALK tyrosine kinase inhibitors (TKIs) are approved globally for ALK fusion-positive (ALK+) NSCLC, they are limited by acquired ALK resistance mutations, CNS relapses, and for the 3G TKI lorlatinib, neurologic adverse events attributed to off-target TRK inhibition. A rationally designed ALK TKI that overcomes these limitations is needed. Preclinically, NVL-655 is a brain-penetrant, ALK-selective, and TRK-sparing TKI that exhibits activity against diverse ALK fusions and resistance mutations, including lorlatinib-refractory compound mutations.

Materials and Methods: ALKOVE-1 (NCT05384626) is a global phase 1/2 trial of NVL-655. The ongoing phase 1 dose escalation enrolls patients (pts) with a previously treated ALK+ solid tumor, including NSCLC treated with ≥1 prior 2G or 3G ALK TKI. Primary objectives are to determine the safety/tolerability, recommended phase 2 dose (RP2D), and if applicable, the maximum tolerated dose (MTD). Additional objectives include assessments of pharmacokinetics (PK), pharmacodynamics, and preliminary activity by investigator-assessed tumor response (RECIST v1.1). Data cut: June 12, 2023.

Results: 57 pts (54 NSCLC, 3 other solid tumors) received NVL-655 orally at 15-200 mg once daily (QD). Pts previously received a median of 4 (range: 1-8) prior anticancer therapies, including a 2G or 3G ALK TKI (100%); ≥1 2G ALK TKI + lorlatinib (77%); ≥3 ALK TKIs (53%); and chemotherapy (60%). At baseline, 51% had a history of CNS metastases. 47% had known ALK resistance mutations and 32% had compound ALK mutations, as per available local testing or central analyses of baseline circulating tumor DNA (ctDNA). Treatment-related adverse events (TRAEs) were generally mild; most frequent were nausea (12%), transaminase elevation (12%), fatigue (9%), and constipation (7%). Grade ≥3 TRAEs were transaminase elevation (n=2), CPK elevation (n=1), and fatigue (n=1). NVL-655 PK analyses demonstrated dose-proportional exposure. Partial responses (PR) were observed in 45% (15/33; 8 pending confirmation) of efficacy-evaluable pts with ALK+ NSCLC (15-150 mg QD), in 65% (11/17) with baseline ALK resistance mutations, and in 41% (12/29) post-lorlatinib, including cases with compound resistance mutations. CNS activity, including complete resolution of CNS metastases, has been observed. ctDNA analyses showed reductions, including clearance, of ALK fusion and mutation variants. Neither the MTD nor RP2D has been identified; phase 1 continues.

Conclusions: NVL-655 has been well-tolerated up to 200 mg daily with favorable PK. Preliminary activity has been demonstrated in heavily pretreated pts with ALK+ NSCLC, including those who previously received 2G ALK TKI(s) + lorlatinib, with brain metastases, or with single/compound ALK resistance mutations.

Citation Format: Jessica J Lin, Melissa Johnson, Enriqueta Felip, Sai-Hong Ignatius Ou, Benjamin Besse, Christina Baik, Julien Mazieres, Yasir Elamin, Joshua E. Reuss, Anna Minchom, Aurelie Swalduz, Nick Pavlakis, Geoffrey Liu, Shirish Gadgeel, D. Ross Camidge, Jennifer A Green, Junwu Shen, John Soglia, Yuting Sun, Viola W Zhu, Alexander Drilon. Safety and preliminary activity of the selective ALK inhibitor NVL-655 in patients with ALK fusion-positive solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B154.