eXalt3

Background

Phase III, open-label RCT (eXalt3). N=290. Stage IIIB–IV ALK-positive NSCLC (IHC and/or FISH), no prior ALK inhibitor, ECOG PS 0–2, with or without CNS mets. First-line ensartinib vs crizotinib. Stratified by region, brain metastases, and ECOG PS.

Interventions and follow up

Arm A: Ensartinib 225 mg PO daily (N=144)
Arm B: Crizotinib 250 mg PO BID (N=146)
Primary endpoint: PFS by blinded independent central review (BICR)
mFollow up: 23.7 mo

Results

PFS (BICR): 25.8 mo vs 12.7 mo, HR 0.51 (95% CI 0.35–0.72; P<.0001)
ORR: 74.5% vs 66.4%
Intracranial ORR (baseline CNS disease): 63.6% vs 21.1%
CNS PFS: Significantly improved with ensartinib

Adverse events

Overall: Grade ≥3 AEs 51.7% (ensartinib) vs 55.5% (crizotinib)
Ensartinib-specific: Rash grade ≥3 12.6%, elevated ALT/AST 10.5%
Crizotinib-specific: Visual disturbance (all grades), QTc prolongation, nausea
Discontinuation: 13.3% vs 11.1%

Conclusions

Ensartinib delivered superior PFS (HR 0.51) and markedly better intracranial activity (ORR 64% vs 21%) vs crizotinib in 1L ALK-positive NSCLC, supporting it as an active next-generation ALK inhibitor.

Key Limitations

Crizotinib comparator no longer preferred — alectinib (ALEX) and lorlatinib (CROWN) are now preferred 1L. No head-to-head vs alectinib or lorlatinib. OS immature. Open-label design. Rash grade ≥3 in 12.6% may limit tolerability. Ensartinib was not approved by the FDA; regulatory pathway outside China not pursued.

Clinical Context

Ensartinib received NMPA (China) approval and is used in some Asia-Pacific markets for 1L ALK+ NSCLC. In the context of CROWN (lorlatinib) and ALEX (alectinib), it occupies a secondary role globally. Its intracranial activity is notable but eclipsed by lorlatinib/alectinib data. ESMO-MCBS score 4 vs crizotinib (less meaningful as crizotinib is no longer standard).

References