Phase III DIAMOND-2 Trial: Dirozalkib vs Crizotinib in Advanced ALK-Positive NSCLC

In the multicenter, randomized, open-label phase III DIAMOND-2 trial (NCT05204628), investigators compared dirozalkib—a selective anaplastic lymphoma kinase (ALK) inhibitor with intracranial activity against crizotinib-resistant mutations—with crizotinib in adult patients with ALK inhibitor-naïve, ALK-positive, advanced non-small-cell lung cancer (NSCLC). Eligible patients had received either no prior systemic therapy or had experienced disease progression or intolerance after one prior chemotherapy regimen. Participants were randomized 1:1 to dirozalkib 500 mg once daily (n = 137) or crizotinib 250 mg twice daily (n = 138) between January 24, 2022, and April 30, 2023. The primary endpoint was investigator-assessed progression-free survival (PFS).

At a median follow-up of 32.8 months for dirozalkib and 31.6 months for crizotinib (cutoff date May 31, 2025), dirozalkib significantly improved PFS. Median investigator-assessed PFS was 29.5 months (95% CI = 20.3 to not reached) in the dirozalkib cohort compared to 12.9 months (95% CI = 11.1 to 17.6) in the crizotinib cohort (HR = 0.47, 95% CI = 0.34 to 0.66; P < 0.001). PFS assessed by blinded independent central review was also significantly prolonged with dirozalkib at a median of 27.5 months versus 12.9 months (HR = 0.54, 95% CI = 0.39 to 0.74; P < 0.001). Grade ≥3 treatment-emergent adverse events were reported in 60.6% of dirozalkib-treated patients versus 72.5% of crizotinib-treated patients, with treatment discontinuation due to adverse events occurring in 2.2% and 7.2%, respectively. The authors concluded that dirozalkib showed a manageable safety profile and significantly improved PFS over crizotinib, supporting its role as a first-line therapy for ALK-positive advanced NSCLC.