Background Osimertinib is the established first-line standard of care for EGFR-mutated advanced non–small cell lung cancer (NSCLC); however, resistance—particularly via MET-driven pathways—remains a major clinical challenge. Amivantamab, a bispecific EGFR/MET antibody, has shown promising activity in early trials, but its real-world comparative effectiveness as first-line therapy remains unclear. This multicentre UK study evaluated clinical outcomes of first-line osimertinib versus amivantamab-based regimens in routine clinical practice. Methods This retrospective cohort study included adults with EGFR-mutated stage IIIB–IV NSCLC treated across five NHS tertiary oncology centres between 2019 and 2024. Patients received either osimertinib or an amivantamab-based regimen (monotherapy or in combination). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), CNS progression, objective response, toxicity, and post-progression therapy. Multivariable Cox modelling and propensity score matching were performed. Results A total of 512 patients met eligibility criteria (osimertinib n=412; amivantamab-based n=100). Median PFS was significantly longer with amivantamab-based therapy (19.8 vs 16.2 months; HR 0.79, 95% CI 0.63–0.98; p=0.032), and remained significant after multivariable adjustment (HR 0.76, p=0.036). No significant OS difference was observed (33.7 vs 29.4 months; HR 0.90, p=0.48). ORR was similar between groups (74.0% vs 69.7%; p=0.41). CNS progression occurred in 12.0% of the amivantamab group versus 15.8% with osimertinib. Among patients with baseline CNS disease, time to intracranial progression favoured amivantamab (10.9 vs 8.4 months; p=0.19). Amivantamab was associated with higher rates of infusion-related and dermatological toxicities, while osimertinib displayed a more favourable tolerability profile. Conclusions In UK real-world practice, first-line amivantamab-based therapy demonstrated a clinically meaningful PFS advantage over osimertinib, particularly among patients with MET-associated biology, though OS differences were not yet evident. These findings support the emerging role of early dual EGFR/MET inhibition and highlight the importance of comprehensive molecular profiling to optimise first-line treatment selection. Longer follow-up and prospective studies are warranted to refine sequencing strategies and confirm survival impact.