ALKOVE-1: Efficacy and safety of neladalkib in patients with advanced <i>ALK</i> + NSCLC.

Abstract

8503 Background: Neladalkib is an investigational ALK TKI designed for inhibition of ALK single and compound resistance mutations, brain penetrance, and sparing TRK. We report the first analyses of phase 2 TKI pre-treated patients (pts) and preliminary data in TKI-naïve pts with ALK + NSCLC . Methods: The global, single arm phase 1/2 ALKOVE-1 trial (NCT05384626) enrolled pts with advanced/metastatic ALK + NSCLC. Key study endpoints are objective response rate (ORR, RECIST v1.1 by BICR), duration of response (DOR), intracranial ORR (IC-ORR) and safety. Efficacy analyses included TKI pre-treated pts who initiated neladalkib 150 mg QD by 30 Sep 2024 or all treated TKI-naïve pts. Data cut: 29 Aug 2025. Results: 656 pts with ALK + NSCLC received neladalkib. Efficacy-evaluable TKI pre-treated pts (n=253) had received a median of 3 prior anticancer therapies (range 1-11, 51% prior chemo). 78% of pts received ≥2 (range 2-5) prior ALK TKIs, of whom 91% had prior lorlatinib. 19% had single or compound ALK G1202R resistance mutations. 40% had CNS disease by BICR. ALK TKI pre-treated results are reported in the Table. In a preliminary analysis of TKI-naïve pts, ORR was 86% (38/44, 2 uPRs); 12-month DOR rate was 91%. IC-ORR was 78% (7/9) with no CNS progression events as of data cutoff. Conclusions: In this ALK TKI pre-treated data set, neladalkib demonstrated clinically meaningful activity, including in pts with CNS disease, ALK G1202R single or compound mutations, and prior lorlatinib. Encouraging preliminary activity was also observed in TKI-naïve pts. Neladalkib’s safety profile was consistent with its ALK-selective, TRK-sparing design. Clinical trial information: NCT05384626 . Efficacy Parameter (RECIST v1.1, BICR) All ALK TKI Pre-treated± chemo ALK TKI Pre-treated,Lorlatinib-naïve ± chemo ORR % (n/N)95% CI 31 (79/253) a, b 26, 37 46 (29/63) c 33, 59 % DOR ≥ 12 m (95% CI) / 18 m (95% CI) d 64 (51, 75) / 53 (34, 68) 80 (58, 91) / 60 (19, 85) G1202R Mutation ORR % (n/N)95% CI 68 (32/47) e,f 53, 81 83 (10/12)52, 98 % DOR ≥ 12 m d (95% CI) 80 (61, 91) 77 (34, 94) Intracranial Activity IC-ORR % (n/N)95% CI 32 (29/92) g, h 22, 42 63 (15/24) g 41, 81 % IC-DOR ≥ 12 m d (95% CI) 71 (48, 85) 92 (57, 99) m, months; NE, not estimable. a Includes 2 unconfirmed partial responses (uPRs). b Pts with prior lorlatinib: ORR 26% (50/190, including 2 uPRs) and mDOR 17.6 m (95% CI: 6.9, NE). c Pts with 1 prior 2 nd generation ALK TKI (alectinib, n=44; brigatinib, n=2) ± chemo: ORR 48% (22/46) and DOR ≥ 12 m of 74% (95% CI: 48, 88). d Estimated by Kaplan-Meier analysis. e Single or compound G1202R resistance mutations may be present. f Includes 1 uPR. g Includes 2 IC-uPRs. h Pts with prior lorlatinib: IC-ORR 21% (14/68) and IC-DOR ≥ 12 m of 55% (95% CI: 26, 77).