DIAMOND-2: Dirozalkib Improves PFS Versus Crizotinib in ALK+ NSCLC

Key Takeaways

• Among ALK inhibitor–naïve adults with advanced ALK-positive non-small-cell lung cancer at Chinese hospitals, dirozalkib prolonged progression-free survival compared with crizotinib.
• Intracranial response was more frequent with dirozalkib among participants with measurable brain metastases at baseline.
• Responses lasted longer with dirozalkib, although overall response rates were broadly similar between treatment groups.
• Fewer grade ≥3 treatment-emergent adverse events occurred with dirozalkib, and treatment-emergent adverse events led to discontinuation in 2.2% versus 7.2% with crizotinib.
• Overall survival data remain immature, and dirozalkib was not directly compared with newer ALK inhibitors.

Advanced anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) presents a dual challenge: controlling systemic disease and addressing the risk of brain metastases. For adults who have not received an ALK inhibitor, how dirozalkib compares with crizotinib when brain disease is already present remains a clinical question.

In the randomized, open-label DIAMOND-2 phase III trial of dirozalkib versus crizotinib, investigators enrolled 275 adults with advanced ALK-positive NSCLC at 52 hospitals in China. They assigned 137 to oral dirozalkib 500 mg once daily and 138 to oral crizotinib 250 mg twice daily. Allocation was 1:1, stratified by baseline brain metastases and previous chemotherapy; none had previously received an ALK inhibitor. The primary endpoint was investigator-assessed progression-free survival (PFS), measured from randomization to progression or death. Blinded independent central review (BICR) of PFS and intracranial response were secondary assessments.

Investigator-assessed median PFS was 29.5 months with dirozalkib versus 12.9 months with crizotinib. The hazard ratio was 0.47 (95% confidence interval 0.34–0.66); P<0.001.

BICR-assessed median PFS was 27.5 versus 12.9 months, with a hazard ratio of 0.54 (95% confidence interval 0.39–0.74); P<0.001. Overall response rates were broadly similar, but investigator-assessed responses lasted longer with dirozalkib.

Among participants with measurable brain metastases at baseline, investigator-assessed intracranial objective response was 92.3% with dirozalkib versus 11.1% with crizotinib; P<0.001. Trial eligibility specified asymptomatic, untreated brain metastases, so this result does not establish efficacy in symptomatic brain disease. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 60.6% versus 72.5%, respectively.

Serious events, dose interruptions, and dose reductions were also less frequent with dirozalkib, and treatment-emergent adverse events led to discontinuation in 2.2% versus 7.2% of patients; gastrointestinal symptoms and aminotransferase elevations were common with that drug, and grade 3 diarrhea occurred in 19.0% of dirozalkib recipients. Post hoc analyses of intracranial PFS and cumulative intracranial progression also favored dirozalkib.

Open-label treatment and investigator assessment of the primary endpoint leave room for assessment bias, although blinded review found a concordant PFS difference. Enrollment was confined to China, limiting geographic generalization. The subset with measurable brain metastases at baseline was small, and some intracranial findings arose from post hoc analyses. Overall survival was immature, so these findings do not establish a survival advantage. Dirozalkib’s lower rates of severe adverse events occurred despite longer median exposure (715 vs 391 days)

The investigators reported longer PFS and greater observed intracranial activity with dirozalkib than with crizotinib, alongside fewer severe TEAEs. Its comparative position against newer ALK inhibitors and the overall survival findings await further evidence.

Clinician Questions

Could patients with prior chemotherapy enter DIAMOND-2 for ALK-positive advanced NSCLC?

Adults with advanced ALK-positive NSCLC were eligible if they had received no prior systemic anticancer therapy or had progressed or become intolerant after one previous chemotherapy regimen. Prior ALK inhibitor exposure excluded patients from assignment to dirozalkib or crizotinib.

Were fatal treatment-emergent adverse events attributed to dirozalkib or crizotinib in DIAMOND-2?

Fatal treatment-emergent adverse events occurred among participants receiving dirozalkib and among those receiving crizotinib for advanced ALK-positive NSCLC, but investigators considered none treatment-related. Treatment-emergent does not itself establish causation.

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