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Ref Type Abstract
PMID
Authors
Title 1253O Phase I/II ALKOVE-1 study of NVL-655 in ALK-positive (ALK+) solid tumours
Journal Vol Issue Date Pages Journal Short Title
Annals of Oncology 35 Supplement 2 September 2024 S802-S803 Ann Oncol
URL https://www.annalsofoncology.org/article/S0923-7534(24)02829-1/fulltext
Abstract Text Background NVL-655 is a potent, brain-penetrant, ALK-selective tyrosine kinase inhibitor (TKI) designed to address key limitations of prior generation ALK TKIs (1G, 2G, 3G); it demonstrates preclinical activity against diverse ALK fusions and resistance mutations, including lorlatinib-refractory compound mutations, while avoiding TRK inhibition, which is associated with neurologic toxicities. Methods The global ALKOVE-1 phase (ph) 1 (NCT05384626) enrolled pts with pretreated advanced ALK+ solid tumors. Key objectives were selection of a recommended ph 2 dose (RP2D), safety, and efficacy (RECIST 1.1, investigator assessment). Data cut: 23 March 2024. Results 133 pts (131 NSCLC, 2 other) received NVL-655 (15-200 mg orally once daily [QD]) in ph 1. Pts previously received a median of 3 (range: 1-8) prior anticancer therapies, including 2G ALK TKI or lorlatinib (100%), ≥1 2G ALK TKI & lorlatinib (79%), ≥3 ALK TKIs (46%), and chemotherapy (56%); 56% had a history of treated/untreated CNS metastases. A maximum tolerated dose was not reached. 150 mg QD was selected as the RP2D, providing favorable safety, activity and exposure exceeding targeted efficacy thresholds for ALK resistance mutations. Most common TRAEs were ALT increase (33%), AST increase (29%), constipation (15%), nausea (12%) and dysgeusia (11%); 2% discontinued due to TRAEs. Conclusions NVL-655 demonstrated encouraging efficacy & durability in heavily pretreated ALK+ NSCLC pts, including pts who exhausted available therapies (including lorlatinib), with ALK single and compound resistance mutations, and with CNS metastases. Safety was favorable, consistent with the ALK-selective, TRK-sparing design. Ph 2 enrollment is ongoing with registrational intent for previously treated pts. Clinical trial identification NCT05384626.

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