NVL-655: a promising new option in pre-treated, drug-resistant ALK-mutated NSCLC

In the phase 1/2 ALKOVE-1 trial, the ALK-selective tyrosine kinase inhibitor (TKI) NVL-655 demonstrated promising safety and clinical activity in patients with heavily pre-treated ALK-positive non-small cell lung cancer (NSCLC).

NVL-655 is a new and potent, brain-penetrant, ALK-selective TKI designed to address key limitations of prior-generation ALK TKIs. It has demonstrated preclinical activity against different ALK mutations, including lorlatinib-refractory compound mutations, while avoiding TRK inhibition, which is associated with neurologic toxicities [1].

The phase 1/2 ALKOVE-1 trial (NCT05384626) enrolled 133 patients with pre-treated advanced ALK-positive solid tumours (131 NSCLC, 2 other) [2]. About half of the participants had secondary ALK mutations; 25% had 2 or more ALK mutations. The participants previously had received a median of 3 (range: 1–8) prior anti-cancer therapies, including a second-generation ALK TKI or lorlatinib (100%), ≥1 second-generation ALK TKI and lorlatinib (79%), ≥3 ALK TKIs (46%), and chemotherapy (56%); 56% had a history of CNS metastases.

The participants received NVL-655 at a once-daily dose of 15–200 mg orally in phase 1. A maximum tolerated dose was not reached and the recommended phase 2 dose was 150 mg, as it exceeded preset safety and efficacy thresholds. Dr Alexander Drilon (Memorial Sloan Kettering Cancer Center, NY, USA) presented the results of the 52 participants enrolled in phase 2 of the ALKOVE-1 trial.

Objective response rates were 38% (all paticipants), 55% (any ALK mutation), 71% (ALK G1202R mutation), and 80% (lorlatinib-naïve, any ALK mutation). The duration of response (DOR) was over 6 months in all participants and median DOR was not reached, regardless of ALK resistance mutation status. Intra-cranial response was 50% in lorlatinib-naïve and 15% in lorlatinib-treated participants.

The most common treatment-related adverse events (TRAEs) of any grade were ALT increase (34%), AST increase (30%), constipation (16%), dysgeusia (13%), and nausea (12%). TRAEs were mostly grade 1, and 2% of participants discontinued due to TRAEs.

Dr Drilon concluded that “the encouraging clinical activity of NVL-655 in this heavily pre-treated population supports further investigation in less heavily pre-treated patients with ALK-positive NSCLC.” Meanwhile, clinical trials are being initiated in the first-line setting.

1. Lin JJ, et al. Cancer Discov. 2024;Sept 13. DOI: 10.1158/2159-8290.CD-24-0231.
2. Drilon AE, et al. Phase I/II ALKOVE-1 study of NVL-655 in ALK-positive (ALK+) solid tumours. Abstract 1253O, ESMO Congress 2024, 13–17 September, Barcelona, Spain.

 

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Posted on 4 November 20244 November 2024