Introduction: Non-small cell lung cancer (NSCLC) is the most common lung cancer subtype and carries a poor prognosis, with 5-year survival around 4% in metastatic disease. EGFR mutations are the most clinically relevant driver alterations, present in roughly 11% of Austrian NSCLC cases. Two guideline-recommended first-line options for advanced NSCLC with common EGFR mutations (exon 19 deletions, exon 21 L858R) are amivantamab (intravenous or subcutaneous) plus lazertinib, and osimertinib plus platinum-based chemotherapy. This report assesses their comparative effectiveness, safety, and economic and organisational implications, including intravenous versus subcutaneous administration.

Methods: A systematic search covered Medline, Embase, the Cochrane Library and the HTA Database (INAHTA), supplemented by hand searching, with independent dual screening and extraction. Risk of bias in randomised controlled trials was assessed using Cochrane RoB v.2. An Austrian budget impact analysis used ex-factory prices and hospital cost data. Organisational aspects were synthesised narratively from the literature and expert consultation.

Clinical results: As no head-to-head trial comparing the two regimens was available, three indirect treatment comparisons (ITCs) were identified, two of which were part of the NICE and CDA-AMC HTA reports. Given limitations of the indirect evidence, the underlying pivotal phase 3 trials MARIPOSA (amivantamab plus lazertinib) and FLAURA2 (osimertinib plus chemotherapy), each comparing the respective combination with osimertinib monotherapy, were also considered descriptively, alongside one supportive single-arm study. Both regimens showed significant overall survival (OS) and progression-free survival benefits over osimertinib monotherapy in their respective pivotal trials with high response rates (83–86%). Direct comparison remains uncertain: MARIPOSA's median OS (amivantamab plus lazertinib) had not yet been reached versus FLAURA2's mature median (osimertinib plus chemotherapy). The ITCs reached differing conclusions, reflecting differences in methodology and underlying trials, and neither HTA report considered the indirect evidence sufficiently to resolve efficacy uncertainty. Grade ≥3 adverse events were frequent with both regimens but differed qualitatively: skin toxicity and venous thromboembolism (VTE) with amivantamab plus lazertinib, myelosuppression with osimertinib plus chemotherapy. Quality-of-life data were absent from both trials. Subcutaneous amivantamab was non-inferior to intravenous administration for objective response, with fewer infusion-related reactions and VTE events and improved patient-reported outcomes.

Economic aspects: Two economic analyses (NICE and CDA-AMC HTA reports) found no demonstrated incremental clinical benefit justifying the higher cost of amivantamab plus lazertinib at list prices. Favourable cost-effectiveness estimates relied on pricing assumptions and confidential discounts. The Austrian budget impact analysis estimated an annual cost of €207,250 per patient for amivantamab plus lazertinib versus €128,998 for osimertinib plus chemotherapy. Full substitution for 140 eligible patients annually would raise expenditure by roughly €10.96 million per year. This is a hypothetical scenario, not a forecast of actual expenditure, as real-world costs depend on treatment duration, market share, and negotiated prices.

Organisational aspects: Both regimens require intravenous treatment infrastructure, but delivery differs markedly. Osimertinib plus chemotherapy follows a standard three-weekly cycle with pre-hydration and antiemetic care, while amivantamab plus lazertinib demands more frequent infusions (biweekly), antithrombotic prophylaxis, and intensive VTE monitoring. This requires specialised capacity and a distinct toxicity-management learning curve. The subcutaneous formulation reduces the administration burden of amivantamab but does not substantially reduce prophylaxis and monitoring requirements. Real-world uptake of amivantamab plus lazertinib in Austria remains low.

Conclusion: Available evidence suggests no clear efficacy advantage of either regimen over the other, though the absence of direct comparative data leaves true differences uncertain. Safety profiles differ qualitatively rather than in overall burden. In Austria, amivantamab plus lazertinib entails substantially higher costs and organisational demands, only partly mitigated by the subcutaneous formulation. Treatment decisions should therefore consider costs, toxicity, organisational feasibility, and patient preferences. Registry data could help address remaining evidence gaps.