1509TiP - The 1825-EORTC, ALKALINE: Activity of lorlatinib based on ALK resistance mutations on blood in ALK positive NSCLC patients previously treated with second generation ALK inhibitor

Background

Optimal therapeutic sequence has not yet been established in patients with ALK positive advanced non-small cell lung cancer (aNSCLC) developing ALK resistant mutations after treatment with 1^st/2^nd generation(gen.) ALK inhibitors (ALKi). Treatment selection based on ALK resistance mutations may be a strategic approach for the decision-making process as each ALKi has a different spectrum of coverage of ALK mutations. Liquid biopsy (ctDNA) can provide a non-invasive option to identify resistant mechanisms. Lorlatinib is a 3^rd gen. ALKi that overcome ALK dependent resistance and being active against multiple ALK mutations that confer resistance to other inhibitors. ALKALINE aims to assess the activity of lorlatinib based on the presence of ALK mutations identified on ctDNA in patients progressing on 2^nd gen. ALKi. A preselection sub-study will assess the time of emergence of resistance mutations in blood in patients under treatment with 2^nd gen. ALKis.

Trial design

ALKALINE is a phase II, open-label, multicenter, single-arm study in 84 pts with ALK+ aNSCLC progressing on 2^nd gen. ALK TKI. ctDNA is performed before lorlatinib to stratify pts in 3 cohorts: A: if ≥ 1 ctDNA ALK mutations, B: non-ALK mutations and C: no ctDNA detected. Eligible patients receive lorlatinib until disease progression (PD), unacceptable toxicity or occurrence of any withdrawal criterion. Lorlatinib beyond PD is allowed if clinical benefit. Imaging, including brain MRI and ctDNA are performed every 2 months until week 40 and then 3 monthly. A prospective sub-study will assess the time to emergence of resistance mutations and its impact on outcomes in patient on treatment with 2^nd gen. ALKi. ctDNA is collected 3 monthly until PD to 2^nd gen. ALK inh. (RECIST v.1.1). Pts in the sub-study will enter the main study during PD based on RECIST v1.1. Primary endpoint is progression-free survival rate at 12 months in cohort A as assessed by Blinded Independent Central Review based on RECIST v1.1. Secondary objectives will evaluate activity in cohorts B and C, toxicity and patient reported outcomes. The estimated duration of the ALKALINE is 72 months, with an enrolment period of 42 months.

Clinical trial identification

EudraCT: 2019-003862-41; EU: 2022-502449-82-00; NCT04127110.

Editorial acknowledgement

Legal entity responsible for the study

EORTC.

Funding

EORTC.

Disclosure

All authors have declared no conflicts of interest.