Reference Detail

Ref Type

Journal Article

PMID

(38280448)

Authors

Shi Y, Chen J, Yang R, Wu H, Wang Z, Yang W, Cui J, Zhang Y, Liu C, Cheng Y, Liu Y, Shan J, Wang D, Yang L, Hu C, Zhao J, Cao R, Tan B, Xu K, Si M, Li H, Mao R, Li L, Kang X, Wang L

Title

Iruplinalkib (WX-0593) versus crizotinib in ALK TKI-naïve locally advanced or metastatic ALK-positive non-small cell lung cancer: interim analysis of a randomized, open-label, phase III study (INSPIRE).

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer			2024 Jan 25		J Thorac Oncol

URL

Abstract Text

Iruplinalkib (WX-0593) is a new-generation, potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) and has shown systemic and central nervous system (CNS) efficacy in ALK-positive non-small-cell lung cancer (NSCLC). We compared the efficacy and safety of iruplinalkib with crizotinib in ALK TKI-naïve, locally advanced or metastatic ALK-positive NSCLC patients.In this open-label, randomized, multicenter, phase III study, patients with ALK-positive NSCLC were randomly assigned to receive iruplinalkib 180 mg once daily (7-day run-in at 60 mg once daily) or crizotinib 250 mg twice daily. The primary endpoint was progression-free survival (PFS) assessed by Independent Review Committee (IRC) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints included PFS by investigator, objective response rate (ORR), time to response, duration of response, intracranial ORR and time to CNS progression by IRC and investigator, overall survival and safety. An interim analysis was planned after approximately 70% (134 events) of all 192 expected PFS events assessed by IRC were observed. Efficacy was analyzed in the intention-to-treat (ITT) population. Safety was assessed in the safety population, which included all randomized patients who received at least one dose of study drugs. This study is registered with Center for Drug Evaluation of China NMPA (CTR20191231) and Clinicaltrials.gov (NCT04632758).From 4 September 2019 to 2 December 2020, a total of 292 patients were randomized and treated; 143 with iruplinalkib and 149 with crizotinib. At this interim analysis (145 events), the median follow-up time was 26.7 months (range, 3.7-37.7) in the iruplinalkib group and 25.9 months (range, 0.5-35.9) in the crizotinib group. The PFS assessed by IRC was significantly longer among patients in the iruplinalkib group (median PFS, 27.7 months [95% CI, 26.3-NE] versus 14.6 months [95% CI, 11.1-16.5] in the crizotinib group; HR, 0.34 [98.02% CI, 0.23-0.52]; p<0.0001). The ORR assessed by IRC was 93.0% (95% CI, 87.5-96.6) in the iruplinalkib group and 89.3% (95% CI, 83.1-93.7) in the crizotinib group. The intracranial ORR was 90.9% (10/11, 95% CI, 58.7-99.8) in the iruplinalkib group and 60.0% (9/15, 95% CI, 32.3-83.7) in the crizotinib group for patients with measurable baseline CNS metastases. Incidence of grade 3 or 4 treatment-related adverse events was 51.7% in the iruplinalkib group and 49.7% in the crizotinib group.Iruplinalkib demonstrated significantly improved PFS and improved intracranial antitumor activity versus crizotinib. Iruplinalkib may be a new treatment option for patients with advanced ALK positive and ALK TKI-naïve NSCLC.

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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 rearrange	lung non-small cell carcinoma	sensitive	Iruplinalkib	Phase III	Actionable	In a Phase III trial (INSPIRE), Iruplinalkib (WX-0593) treatment in ALK-positive non-small cell lung cancer patients resulted in a significantly improved median progression free survival (mPFS) of 27.7 months, improved objective response rate (ORR) of 93.0% (133/143), and intracranial ORR of 90.9% (10/11) compared to a mPFS of 14.6 months (HR=0.34, p<0.0001), ORR of 89.3% (133/149), and intracranial ORR of 60.0% (9/15) with Xalkori (crizotinib) treatment (PMID: 38280448; NCT04632758).	38280448