Trial Design & Participants
- Population: 1,074 patients with untreated, locally advanced or metastatic NSCLC harboring EGFR exon 19 deletion or L858R mutations.
- Arms (randomized 2:2:1):
- Amivantamab + lazertinib (bispecific EGFR/MET antibody + TKI)
- Osimertinib monotherapy (standard-of-care)
- Lazertinib monotherapy (experimental, unapproved)
Efficacy Outcomes
Progression-Free Survival (PFS)
- Amivantamab + lazertinib: median PFS 23.7 months
- Osimertinib: median PFS 16.6 months
- Risk reduction of ~30% (HR = 0.70; p < 0.001)
- Subgroup consistency: benefit seen across high-risk groups (e.g., TP53 co-mutations, baseline ctDNA, brain or liver metastases)
Overall Survival (OS)
- At median follow-up of 37.8 months:
- Combination arm: Median OS not reached; projected to exceed osimertinib by over 1 year
- Osimertinib: median OS ~36.7 months
- Hazard Ratio for death: ~0.75 (P < 0.005)
- 3-year survival: 60% (combination) vs. 51% (osimertinib)
- 42-month survival: 56% vs. 44%
Intracranial Control & Symptom Delay
- Intracranial PFS & duration of response significantly improved with combination therapy versus osimertinib
- Time to symptomatic progression: 43.6 months (combination) vs. 29.3 months (osimertinib); HR = 0.69
Safety Profile
- Common adverse events included rash, paronychia, hypoalbuminemia, dermatitis acneiform, stomatitis, decreased appetite, peripheral edema, and diarrhea.
- Most of these were grade 1–2, occurring early and generally reducing over time.
- No grade 4 or 5 adverse events reported. Dose interruptions were used effectively to manage toxicities, especially early in treatment.