Iruplinalkib trumps crizotinib for ALK TKI-naïve NSCLC

02 Oct 2023 bởiAudrey Abella
Iruplinalkib trumps crizotinib for ALK TKI-naïve NSCLC

In the phase III INSPIRE study, the novel, potent ALK tyrosine kinase inhibitor (TKI) iruplinalkib conferred a progression-free survival (PFS) benefit in patients with TKI-naïve, locally advanced, or metastatic ALK+ non-small-cell lung cancer (NSCLC).

“In this prespecified interim analysis, iruplinalkib demonstrated significantly improved PFS compared with crizotinib [in this patient setting],” said Dr Runxiang Yang from Yunnan Cancer Hospital, China, who presented the findings at WCLC 2023.

In the intention-to-treat cohort, median PFS as assessed by an independent review committee (IRC) was nearly doubled in the experimental compared with the crizotinib arm (27.70 vs 14.62 months; hazard ratio [HR], 0.344, 98.02 percent confidence interval [CI], 0.226–0.523; plog-rank<0.0001). [WCLC 2023, abstract OA03.05]

Similarly, median PFS was significantly longer with iruplinalkib vs crizotinib, be it among patients with (21.95 vs 11.01 months; HR, 0.242, 95 percent CI, 0.119–0.493; plog-rank<0.0001) or without baseline central nervous system (CNS) metastases (28.32 vs 16.46 months; HR, 0.360, 95 percent CI, 0.236–0.548; plog-rank<0.0001).

Compared with the crizotinib arm, the iruplinalkib arm had a higher IRC-assessed objective response rate (ORR; 93 percent vs 89 percent) and markedly longer median duration of response (DoR; 26.78 vs 12.88 months; HR, 0.312, 95 percent CI, 0.215–0.452; plog-rank<0.0001).

A similar trend favouring iruplinalkib over crizotinib was seen in terms of intracranial ORR and median intracranial DoR in both subsets of patients with measurable CNS metastases (90.9 percent vs 60.0 percent; p=0.0974 [ORR] and 20.14 vs 9.26 months [DoR]) and measurable or non-measurable CNS metastases at baseline (57.9 percent vs 25.6 percent; p=0.0033 and 23.79 vs 9.26 months, respectively).

Iruplinalkib was well tolerated without new safety signals, Yang noted. The most frequent treatment-related adverse events (TRAEs) in both arms were increases in aspartate aminotransferase, alanine aminotransferase, and blood creatine phosphokinase. The most common grade 3/4 TRAEs tied to iruplinalkib were hypertension and abnormal hepatic function.

There were similar incidences of serious TRAEs (14 percent vs 11 percent), grade 3/4 TRAEs (52 percent vs 50 percent) and TRAEs leading to treatment discontinuation (6 percent vs 5 percent) and dose reduction (28 percent vs 33 percent) between the experimental and the crizotinib arm.

 

Resistance develops even after treatment initiation

In a phase II study evaluating advanced ALK+ NSCLC patients who have progressed after crizotinib therapy, iruplinalkib treatment led to a median PFS of ~20 months, an ORR of 70 percent, and a median DoR of 14.4 months. [BMC Med 2023;21:72]

Given the previously reported clinical activity of iruplinalkib, Yang and colleagues sought to compare it against crizotinib in ALK+ NSCLC patients who have not received previous ALK TKI treatment. A total of 292 patients (median age 55 years) with stage IIIB/IV NSCLC who were ALK TKI-naïve and have only had <1 prior chemo regimen were included in the analysis. They were randomized 1:1 to receive either oral iruplinalkib 180 mg QD (with a 7-day lead-in at a dose of 60 mg QD) or crizotinib 250 mg BID.

“Resistance to ALK TKIs inevitably develops a few years after treatment initiation … [Taken together, these findings imply that] iruplinalkib may be a new treatment option for advanced ALK+ and ALK TKI-naïve NSCLC,” Yang concluded.

In June 2023, iruplinalkib has been approved in China for the treatment of ALK+ crizotinib-resistant or intolerable, locally advanced, or metastatic NSCLC.