The novel ALK tyrosine kinase inhibitor iruplinalkib has demonstrated potential for a difficult-to-treat subset of patients with non–small cell lung cancer (NSCLC), according to data presented at the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer.1
A preplanned interim analysis of the phase III INSPIRE study showed a nearly twofold improvement in progression-free survival with iruplinalkib vs crizotinib in patients with ALK-positive NSCLC who had not received previous ALK inhibitor treatment. Patients who received iruplinalkib had a median progression-free survival of 27.7 months vs 14.6 months on crizotinib (hazard ratio [HR] = 0.344). Iruplinalkib also demonstrated a higher objective response rate vs crizotinib (93.0% vs 89.3%) and improved intracranial objective response rate (90.9% vs 60.0%).
“Iruplinalkib may represent a new treatment option for patients with advanced ALK-positive and ALK [tyrosine kinase inhibitor]-naive NSCLC, demonstrating significant progression-free survival improvement and well-tolerated safety profiles without new adverse events,” said presenting author Runxiang Yang, MD, Professor, Chief Physician, Doctoral Supervisor, and Director of the Second Medical Oncology Department at Yunnan Cancer Hospital, China, and visiting scholar at The University of Texas MD Anderson Cancer Center, Houston.
Study Background
As Dr. Yang reported, ALK inhibitors have been approved by the U.S. Food and Drug Administration as a first-line treatment for advanced ALK-positive NSCLC, but resistance to these drugs inevitably develops a few years after treatment initiation. Iruplinalkib is a novel, potent ALK inhibitor with preclinical and clinical activity against ALK and ALK resistance mutations.
Iruplinalkib inhibitedALK and showed broad activity against ALK resistance mutations in preclinical studies, including L1196M and G1202R ALK mutations. Moreover, previous data from the phase II INTELLECT study showed that iruplinalkib elicited an independent review committee–assessed objective response rate of 69.9% (95% confidence interval [CI] = 61.7%–77.2%), with a median duration of response of 14.4 months (95% CI = 13.1 months–not estimable) and a median progression-free survival of 19.8 months (95% CI, 14.5 months–not estimable) in patients with crizotinib-resistant, ALK-positive NSCLC (n = 146).2
Iruplinalkib was approved in China in June 2023 for the treatment of ALK-positive, crizotinib-resistant or crizotinib-intolerable, locally advanced or metastatic NSCLC.
Phase III INSPIRE Trial
The open-label, randomized, multicenter INSPIRE trial enrolled patients with stage IIIB/IV NSCLC who had ALK positivity that was centrally confirmed by fluorescence in situ hybridization or another test approved by China’s National Medical Products Association. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1 and could not have prior exposure to an ALK inhibitor. They could have received up to one prior chemotherapy regimen.
Investigators randomly assigned 292 patients to receive iruplinalkib (daily dose of 180 mg with a 7-day lead-in at 60 mg daily) vs crizotinib (twice-daily dose of 250 mg). Treatment continued until disease progression, unacceptable toxicity, or discontinuation for other reasons. Patients were stratified according to prior chemotherapy regimens (0 vs 1), the presence of baseline central nervous system (CNS) metastases, and prior radiotherapy for CNS metastases.
The trial’s primary endpoint was independent review committee–assessed progression-free survival by Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included investigator-assessed progression-free survival, overall response rate, duration of response by independent review committee and investigator assessments, intracranial overall response rate, overall survival, and safety.
Outcomes Improved
Results of the preplanned interim analysis demonstrated significantly improved progression-free survival with iruplinalkib vs crizotinib. Patients randomly assigned to iruplinalkib had a median progression progression-free survival of 27.7 months vs 14.6 months with crizotinib (HR = 0.344).
In addition to the higher objective response rate (93.0% vs. 89.3%), responses to iruplinalkib were more durable. The median duration of response on iruplinalkib was 26.8 months vs 12.9 months on crizotinib.
Iruplinalkib also showed improved CNS efficacy compared with crizotinib. The intracranial overall response rate was 90.9% with iruplinalkib vs 60.0% with crizotinib. The duration of intracranial response was also more durable with iruplinalkib (median = 20.1 months vs 9.3 months).
Finally, safety and tolerability data demonstrated similar results between treatment arms. Any-grade treatment-related adverse effects were experienced by 98.6% of those in the iruplinalkib arm and 99.3% of those on the crizotinib arm. Serious treatment-related adverse events occurred in 14% of patients randomly assigned to iruplinalkib vs 10.7% in the crizotinib arm, but there were two fatal treatment-related adverse events in the crizotinib arm.
According to Dr. Yang, vomiting, constipation, sinus bradycardia, decreased white blood cell count, decreased neutrophil count, hypocalcemia, and peripheral edema were more common treatment-related adverse events in the crizotinib arm. Conversely, in the iruplinalkib group, more common treatment-related adverse events included elevated blood cholesterol, uric acid increase, hypertension, rash, abnormal hepatic function, and increased triglycerides.
“Iruplinalkib was well tolerated without new safety signals,” Dr. Yang concluded.
DISCLOSURE: Dr. Yang reported no conflicts of interest.
REFERENCES
1. Shi Y, et al: 2023 World Conference on Lung Cancer. Abstract OA03.05. Presented September 10, 2023.
2. Shi Y, et al: BMC Med 21:72, 2023.
