Iruplinalkib Elicits Significant PFS in ALK+ Advanced/Metastatic NSCLC

"Iruplinalkib may be a new treatment option for patients with advanced ALK-positive and ALK TKI–naïve NSCLC," according to Runxiang Yang, MD.

Patients with tyrosine kinase inhibitor (TKI)–naïve, locally advanced and metastatic ALK-positive non–small cell lung cancer (NSCLC) experienced a significant progression-free survival (PFS) benefit when receiving iruplinalkib (WX-0593) compared with crizotinib (Xalkori), according to findings form a prespecified interim analysis of the phase 3 INSPIRE trial (NCT04632758) presented at the 2023 World Conference on Lung Cancer (WCLC).¹

With a median follow-up of 23.98 months (range, 0-36.9) for iruplinalkib (n = 143) and 24.54 months (range, 0-33.2) for crizotinib (n = 149), the median PFS by independent review committee (IRC) assessment was 27.70 months (95% CI, 26.25-not evaluable [NE]) and 14.62 months (95% CI, 11.07-16.49), respectively (HR, 0.344; 95% CI, 0.226-0.523; P < .0001).

The IRC-assessed PFS in those with baseline central nervous system (CNS) metastases who received iruplinalkib (n = 37) was 21.95 months (95% CI, 18.23-NE) vs 11.01 months (95% CI, 7.46-14.72) with crizotinib (n = 44; HR, 0.242; 95% CI, 0.119-0.493; P < .0001). In those without CNS metastases at baseline, those given iruplinalkib (n = 106) experienced a median PFS of 28.32 months (95% CI, 27.56-NE) vs 16.46 months (95% CI, 12.88-18.43) in those who received crizotinib (n = 105; HR, 0.360; 95% CI, 0.236-0.548; P < .0001).

In the intention-to-treat population, iruplinalkib elicited an IRC-assessed ORR of 93% (95% CI, 87.5%-96.6%) vs 89.3% (95% CI, 83.1%-93.7%) with crizotinib (difference, 3.7%; P = .2694). The median time to objective response was 1.84 months in both the investigative arm (range, 0.5-11.1) and the control arm (range, 0.9-9.1). The median duration of response (DOR) with iruplinalkib was 26.78 months (95% CI, 25.79-NE) vs 12.88 months (95% CI, 10.97-14.72) with crizotinib (HR, 0.312; 95% CI, 0.215-0.452; P < .0001).

“Iruplinalkib may be a new treatment option for patients with advanced ALK-positive and ALK TKI–naïve NSCLC,” Runxiang Yang, MD, professor, chief physician, doctoral supervisor, and director of the Second Medical Oncology Department at Yunnan Cancer Hospital in China, said in a presentation of the data.

Although ALK TKIs have garnered regulatory approval for use in the frontline setting for advanced ALK-positive NSCLC, resistance inevitably develops after a few years of treatment. Preclinical data suggest that the ALK TKI, iruplinalkib, can inhibit wild-type ALK and have broad activity against resistance mutations such as L1196M and G1202R.

Moreover, previous data from the phase 2 INTELLECT study showed that iruplinalkib elicited an IRC-assessed ORR of 69.9% (95% CI, 61.7%-77.2%) with a median DOR of 14.4 months (95% CI, 13.1-NE) and a median PFS of 19.8 months (95% CI, 14.5-NE) in patients with crizotinib-resistant, ALK-positive NSCLC (n = 146).² Subsequently, in June 2023, China’s National Medical Products Association (NMPA) approved iruplinalkib for use in patients with ALK-positive, crizotinib-resistant or -intolerant, locally advanced or metastatic NSCLC.¹

The open-label, randomized, multicenter INSPIRE trial enrolled patients with stage IIIB/IV NSCLC who had ALK positivity that was centrally confirmed by FISH or another local NMPA-approved test. Patients were required to have an ECOG performance status of 0 or 1 and could not have prior exposure to an ALK TKI. They could have received up to 1 prior chemotherapy regimen.

A total of 292 patients were randomly assigned 1:1 to receive iruplinalkib at a daily dose of 180 mg with a 7-day lead-in at 60 mg daily vs crizotinib at a twice-daily dose of 250 mg. Treatment continued until progressive disease, unacceptable toxicity, or other reasons for discontinuation were met.

Stratification factors included prior chemotherapy regimens (0 vs 1), presence of baseline CNS metastases (yes vs no), and prior radiotherapy for CNS metastases (yes vs no).

IRC-assessed PFS by RECIST v1.1 criteria served as the trial’s primary end point. Secondary end points included investigator-assessed PFS, ORR and DOR by IRC and investigator assessment, intracranial ORR by IRC and investigator assessment, overall survival, and safety.

The median age in both the iruplinalkib and crizotinib arms was 55 years (range, 25-76); 50.3% and 41.6% of patients, respectively, were male. Most patients had an ECOG performance status of 1 (78.3% vs 73.2%) and had stage IV disease at the time of study entry (89.5% vs 94.6%).

Per investigator assessment, 25.9% of those assigned to the iruplinalkib arm had CNS metastases present at baseline vs 29.5% of those assigned to crizotinib; 1.4% vs 2.7% of patients, respectively, received prior radiotherapy to those metastases. Additionally, 16.8% of patients in both arms previously received chemotherapy.

Additional data from the trial presented at the meeting showed that in patients with measurable CNS metastases at baseline, iruplinalkib (n = 11) elicited an intracranial ORR of 90.9% (95% CI, 58.7%-99.8%) vs 60% (95% CI, 32.3%-83.7%) with crizotinib (n = 15). The median intracranial DOR was 20.14 months (95% CI, 7.33-NE) in the iruplinalkib arm and 9.26 months (95% CI, 3.71-NE) in the crizotinib arm.

In patients with measurable or non-measurable baseline CNS metastases, iruplinalkib (n = 38) induced an intracranial ORR of 57.9% (95% CI, 40.8%-73.7%) vs 25.6% (95% CI, 13.0%-42.1%) with crizotinib (n = 39). The median intracranial DOR with iruplinalkib and crizotinib was 23.79 months (95% CI, 9.23-NE) and 9.26 months (95% CI, 3.71-NE), respectively.

At the time of data cutoff, 71 patients were still receiving treatment with iruplinalkib, and 28 patients were still receiving crizotinib. Of the 72 patients who discontinued iruplinalkib, the most common reason for discontinuation was radiologic disease progression (n = 53), followed by intolerance (n = 9), patient withdrawal (n = 4), death (n = 4), and clinical disease progression (n = 2).

The median duration of treatment with iruplinalkib was 23.92 months vs 12.94 months with crizotinib. Any-grade treatment-related adverse effects (TRAEs) were experienced by 98.6% of those in the iruplinalkib arm and 99.3% of those on the crizotinib arm; these effects were grade 3 or 4 in 51.7% and 49.7% of patients, respectively. Serious TRAEs occurred in 14% of those assigned to the iruplinalkib arm vs 10.7% of those assigned to the crizotinib arm. Two fatal TRAEs were reported in the crizotinib arm.

Moreover, 28% of those who received iruplinalkib experienced TRAEs that required dose reduction and 5.6% had TRAEs that resulted in treatment discontinuation; these rates were 32.9% and 4.7%, respectively, with crizotinib.

“Iruplinalkib was well tolerated without new safety signals,” Yang concluded.

References

1. Shi Y, Chen J, Yang R, et al. A randomized, phase III study of iruplinalkib (WX-05923) vs crizotinib in ALK TKI-naïve, locally advanced or metastatic ALK-positive non-small cell lung cancer (INSPIRE). Presented at: 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore, Republic of Singapore. Abstract OA03.05.
2. Shi Y, Chen J, Zhang H, et al. Efficacy and safety of iruplinalkib (WX-0593) in ALK-positive crizotinib-resistant advanced non-small cell lung cancer patients: a single-arm, multicenter phase II study (INTELLECT). BMC Med. 2023;21(1):72. doi:10.1186/s12916-023-02738-5