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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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ALK fusion ALK G1202R	lung non-small cell carcinoma	predicted - sensitive	NVL-655	Phase I	Actionable	In a Phase I trial (ALKOVE-1), NVL-655 treatment demonstrated activity in patients with ALK-positive non-small cell lung cancer (including patients with ALK fusion with or without secondary ALK mutations), with a response rate of 76% (22/29), a median duration of response (DOR) of 14.4 mo, DOR greater than 6 months in 88% of patients, and a response rate of 83% (10/12) at the RP2D dose of 150mg in patients harboring an ALK fusion with ALK G1202R (Ann Oncol (2024) 35 (suppl_2): S802-S803; NCT05384626).	detail...
ALK fusion	lung non-small cell carcinoma	predicted - sensitive	NVL-655	Phase I	Actionable	In a Phase I trial (ALKOVE-1), NVL-655 treatment demonstrated activity in patients with ALK-positive non-small cell lung cancer (including patients with ALK fusion with or without secondary ALK mutations), resulting in a response rate of 38% (39/103), a median duration of response (DOR) of 9.2 months, DOR greater than 6 months in 79% of patients, and a response rate of 39% (15/38) at the RP2D dose of 150mg (Ann Oncol (2024) 35 (suppl_2): S802-S803; NCT05384626).	detail...