Iruplinalkib improves progression-free survival versus crizotinib in locally advanced or metastatic ALK-positive NSCLC

Results from a prespecified interim analysis of the phase III INSPIRE trial suggest that iruplinalkib, a novel ALK inhibitor, is more effective than crizotinib in patients with ALK TKI–naïve, locally advanced and metastatic ALK-positive non–small cell lung cancer. Patients who had received iruplinalkib demonstrated an improved progression-free survival and a higher objective response rate vs. crizotinib. Iruplinalkib also demonstrated greater efficacy in patients with central nervous system metastasis.

Iruplinalkib is a novel, potent ALK tyrosine kinase inhibitor (TKI) which demonstrated preclinical and clinical activity against wild-type ALK and ALK resistance mutations. As of June 2023, iruplinalkib is approved in China for the treatment of ALK-positive, crizotinib resistant or intolerable, locally advanced or metastatic NSCLC. At WCLC 2023, Prof. Yang presented the results of a prespecified interim analysis of the phase III INSPIRE study, aiming to compare the safety and efficacy and iruplinalkib with crizotinib in patients with ALK-positive NSCLC who had not received previous ALK TKI treatment.

Study design

The open-label, randomised, multicentre, phase III INSPIRE trial enrolled patients with stage IIIB/IV NSCLC who had ALK positivity that was centrally confirmed by FISH or by local NMPA-approved test. Patients were required to have an ECOG performance status of 0 or 1 and must be treatment-naïve to ALK-TKI. Up to one prior chemotherapy regimen was allowed. In total, 292 patients were randomly assigned (1:1) to receive iruplinalkib (180 mg daily with a 7-day lead-in at 60 mg daily) or crizotinib (twice-daily dose of 250 mg). Treatment was given until progressive disease, intolerable toxicity, or other reasons for discontinuation. Patients were stratified based on previous chemotherapy regimens (0 vs. 1), presence of baseline CNS metastases (yes vs. no), and prior radiotherapy to central nervous system (CNS) metastases (yes vs. no). Primary endpoint of the study was independent review committee (IRC)-assessed progression-free survival (PFS).

Results

After a median follow-up of 23.98 months for iruplinalkib (N= 143) and 24.54 months for crizotinib (N= 149), the median PFS by IRC assessment was 27.70 months and 14.62 months, respectively (HR[98.02%CI]: 0.344[0.226-0.523], p< 0.0001). The IRC-assessed PFS in those with baseline CNS metastases who received iruplinalkib (N= 37) was 21.95 months vs. 11.01 months with crizotinib (N= 44; HR[95%CI]: 0.242[0.119-0.493], p< 0.0001). In those without CNS metastases at baseline, patients in the iruplinalkib arm experienced a median PFS of 28.32 months, as compared to 16.46 months for those in the crizotinib arm (HR[95%CI]: 0.360[0.236-0.548], p< 0.0001). Furthermore, the objective response rate (ORR) was 93% for patients receiving iruplinalkib vs. 89.3% with crizotinib (difference, 3.7%, p= 0.2694). The median time to objective response was 1.84 months in both arms. The median duration of response (DOR) was more than two-fold longer with iruplinalkib as compared to crizotinib (26.78 vs. 12.88 months, HR[95%CI]:0.312[0.215-0.452], p< 0.0001). In patients with measurable CNS metastases at baseline, iruplinalkib (N= 11) elicited an intracranial ORR of 90.9%, as compared to 60.0% with crizotinib (N= 15). The median intracranial DOR was respectively 20.14 and 9.26 months.

The median duration of treatment with iruplinalkib was 23.92 months vs. 12.94 months with crizotinib. Grade 3-4 treatment-related adverse events (TRAEs) were reported by 51.7% of those in the iruplinalkib arm and 49.7% of those in the crizotinib arm. Serious TRAEs occurred in 14% of those assigned to the iruplinalkib vs. 10.7% of those assigned to crizotinib. Two fatal TRAEs were reported in the crizotinib arm, none in the iruplinalkib arm. Respectively 28.0% and 32.9% of patients in the iruplinalkib and crizotinib arms experienced a TRAE that required dose reduction. Treatment discontinuation due to TREAs was reported in respectively 5.6% and 4.7% of patients.

Conclusion

Iruplinalkib demonstrated significantly improved PFS vs. crizotinib in this pre-planned interim analysis. In addition, iruplinalkib showed high ORR and durable responses, with an improved CNS efficacy as compared to crizotinib. Finally, iruplinalkib was well tolerated, without any new safety signals. As such, iruplinalkib may be a new treatment option for patients with advanced ALK-positive and ALK TKI-naïve NSCLC.

Reference

Shi Y, et al. A Randomized, Phase 3 Study of Iruplinalkib (WX-0593) vs Crizotinib in Locally Advanced or Metastatic ALK+ Non-small Cell Lung Cancer (NSCLC). Presented at WCLC 2023; Abstract OA03.05.