Iruplinalkib Improves PFS Vs Crizotinib in Advanced ALK+ NSCLC

“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 tyrosine kinase inhibitor [TKI]-naïve NSCLC," according to the study authors.

Treatment with iruplinalkib (WX-0593) yielded improvements in progression-free survival (PFS) and intracranial control compared with crizotinib (Xalkori) among patients with locally advanced or metastatic ALK-positive non–small cell lung cancer (NSCLC), according to findings from the phase 3 INSPIRE trial (NCT04632758) published in the Journal of Thoracic Oncology.^1,2

The median PFS was 27.7 months (95% CI, 26.3-not evaluable [NE]) among patients who received iruplinalkib compared with 14.6 months (95% CI, 11.1-16.5) in the group treated with crizotinib according to an independent review committee (IRC) assessment (HR, 0.34; 98.02% CI, 0.23-0.52; P <.0001). The estimated PFS rate at 24 months was 60.9% (95% CI, 51.5%-69.1%) vs 24.5% (95% CI, 16.8%-33.0%) in each respective arm.

The median PFS based on investigator assessment was 27.7 months (95% CI, 24.0-NE) with iruplinalkib vs 14.8 months (95% CI, 11.1-16.6) with crizotinib (HR, 0.40; 95% CI, 0.29-0.56; P <.0001). Additionally, treatment with iruplinalkib yielded PFS improvements across patient subgroups, including those with liver metastases at baseline (HR, 0.20), central nervous system (CNS) metastases (HR, 0.24), and an ECOG performance status of 0 (HR, 0.27).

Among those with CNS metastases at baseline (n = 81), the median PFS was 22.0 months (95% CI, 18.2-NE) in the iruplinalkib arm vs 11.0 months (95% CI, 7.5-14.7) in those who received crizotinib (HR, 0.24; 95% CI, 0.12-0.49; P <.0001). At 24 months, the PFS rate in each respective arm was 49.0% (95% CI, 29.4-65.9%) vs 4.4% (95% CI, 0.3%-17.9%).

Additionally, the intracranial objective response rate (ORR) among patients with measurable CNS lesions (n = 26) was 90.9% (n = 10/11; 95% CI, 58.7%-99.8%) vs 60.0% (n = 9/15; 95% CI, 32.3%-83.7%) in each arm, and the median intracranial duration of response (DOR) was 20.1 months (95% CI, 7.3-NE) vs 9.3 months (95% CI, 3.7-NE).

“Results from this INSPIRE study provide evidence for potential global clinical studies of iruplinalkib,” the study authors wrote in the paper. “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 tyrosine kinase inhibitor [TKI]-naïve NSCLC.”

In the open-label INSPIRE trial, 292 patients were randomly assigned to receive iruplinalkib orally at 180 mg once a day following a 7-day lead-in period of 60 mg once daily (n = 143) or crizotinib orally at 250 mg twice a day (n = 149).

The trial’s primary end point was PFS according to IRC assessment based on RECIST v1.1 guidelines. Secondary end points included PFS by investigator assessment, ORR, time to response, DOR, intracranial ORR, time to CNS progression, overall survival (OS), and safety.

Patients 18 years and older with histologically or cytologically confirmed ALK-positive advanced, recurrent, or metastatic NSCLC were able to enroll on the trial. Additional eligibility criteria included having an ECOG performance status of 0 or 1, at least 1 measurable lesion based on RECIST v1.1 guidelines, and adequate organ function.

The median age was 55.0 years in both arms (range, 25-76). In the iruplinalkib and crizotinib arms, respectively, most patients had an ECOG performance status of 1 (78.3% vs 73.2%), stage IV disease (89.5% vs 94.7%), adenocarcinoma histology (98.6% vs 99.3%), and ALK-positive disease as confirmed by central laboratory assessment (81.1% vs 79.9%).

Across the overall population, the ORR per IRC assessment was 93.0% (95% CI, 87.5%-96.6%) with iruplinalkib vs 89.3% (95% CI, 83.1%-93.7%) with crizotinib. In each respective arm, the median DOR was 26.8 months (95% CI, 25.8-NE) vs 12.9 months (95% CI, 11.0-14.7; HR, 0.31; 95% CI, 0.22-0.45; P <.0001), with 61.5% (95% CI, 51.4%-70.1%) and 21.3% (95% CI, 13.5%-30.2%) of patients in each group estimated to have an ongoing response at 24 months.

CNS progression was observed in 7.0% of patients who received iruplinalkib compared with 12.8% of those in the crizotinib arm (incidence rate ratio, 0.24; 95% CI, 0.10-0.55). The 18-month incidence of CNS progression was 3.2% (95% CI, 1.0%-7.4%) vs 12.2% (95% CI, 7.3%-18.5%) in each arm.

The median OS was NE in both the iruplinalkib and crizotinib arms. The OS rates at 24 months were 85.6% (95% CI, 78.6%-90.5%) vs 84.0% (95% CI, 76.8%-89.0%) in each respective arm (HR, 0.95; 95% CI, 0.53-1.69; P = .8563).

Any-grade treatment-related adverse effects (TRAEs) in the iruplinalkib and crizotinib arms, respectively, included increased blood cholesterol (35.7% vs 8.7%), increased blood triglycerides (33.6% vs 14.1%), rash (23.1% vs 12.1), hypertension (18.2% vs 0.7%), and abnormal hepatic function (16.8% vs 6.7%). Additionally, grade 3 or higher TRAEs in the iruplinalkib arm included hypertension (9.1%) and abnormal hepatic function (9.1%); high-grade absolute neutrophil count decreases were observed in 14.1% of the crizotinib arm.

Overall, 17.5% of patients receiving iruplinalkib and 30.2% of those treated with crizotinib had treatment-emergent AEs leading to dose interruption. Additionally, 5.6% and 4.7% of patients in each respective arm had TRAEs resulting in treatment discontinuation.

References

1. Shi Y, Chen J, Yang R, et al. 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). J Thorac Oncol. 2024;25:S1556-0864(24)00033-9. doi:10.1016/j.jtho.2024.01.013.
2. Results of the phase III INSPIRE study on Qilu Pharmaceutical's Iruplinalkib Published in the Journal of Thoracic Oncology. Qilu Pharmaceutical Co., Ltd. News release. January 30, 2024. Accessed January 30, 2024. https://www.prnewswire.com/news-releases/results-of-the-phase-iii-inspire-study-on-qilu-pharmaceuticals-iruplinalkib-published-in-the-journal-of-thoracic-oncology-302047644.html