Background: Amivantamab (ami) plus lazertinib (laz) demonstrated antitumor activity in EGFR-mutated advanced NSCLC. Subcutaneous (SC) ami administration takes ≤7 mins and has low infusion-related reaction (IRR) rates. PALOMA-3 (NCT05388669) evaluated SC ami+laz vs IV ami+laz for pharmacokinetics (PK), efficacy, and safety among pts with EGFR Ex19del or L858R-mutated advanced NSCLC and disease progression on osimertinib and platinum-based chemotherapy. Methods: SC ami at 1600 mg (2240 mg, ≥80 kg) was manually injected weekly for the first 4 weeks, then every 2 weeks; IV ami was given at the approved dose of 1050 mg (1400 mg, ≥80 kg). Laz was orally dosed at 240 mg daily. Co-primary PK noninferiority endpoints were trough concentration (C_trough on Cycle [C] 2 Day [D] 1 or C4D1) and C2 area under the curve (AUC_D1-D15). Key secondary endpoints were objective response rate (ORR; noninferior) and progression-free survival (PFS). OS was a predefined exploratory endpoint. Prophylactic anticoagulation was recommended for the first 4 months (mo) of treatment. Results: In total, 418 patients (pts) were randomized (SC, n = 206; IV, n = 212); 416 received ≥1 dose. Overall, median age was 61 years, 67% were female, 61% Asian, and median 2 prior lines. At a median follow-up of 7.0 mo, PALOMA-3 met both co-primary endpoints. Geometric mean ratios (GMRs) comparing SC ami+laz vs IV for C_trough were 1.15 (90% CI, 1.04–1.26) for C2D1 and 1.43 (90% CI, 1.27–1.61) for C4D1. GMR for C2 AUC_D1-D15 was 1.03 (90% CI, 0.98–1.09). ORR was 30.1% (95% CI, 24–37) in the SC arm and 32.5% (95% CI, 26–39) for IV (relative risk, 0.92; P= 0.001), meeting the noninferiority criteria. Median duration of response (DoR) was longer for SC ami+laz vs IV (median, 11.2 vs 8.3 mo among confirmed responders). A favorable PFS trend was observed for SC ami+laz over IV (median, 6.1 vs 4.3 mo; HR, 0.84; P= 0.20). OS was notably longer for SC ami+laz vs IV (HR, 0.62; 95% CI, 0.42–0.92; nominal P= 0.017). At 12 mo, 65% were alive in the SC arm vs 51% for IV. IRRs were ~5-fold lower in the SC arm: 13% vs 66% for IV, primarily grade 1-2 (0.5% vs 4% grade ≥3, respectively). Overall, 81% received prophylactic anticoagulants, with VTE reported by 9% in the SC arm vs 14% for IV. Across both arms, VTE incidence was 10% for pts who received prophylactic anticoagulants vs 21% for pts who did not. Severe bleeding risk was low among all pts receiving anticoagulants (1% grade ≥3). Conclusions: SC ami demonstrated noninferior PK and ORR compared to IV. Unexpectedly, DoR, PFS, and OS were longer in the SC arm vs IV, suggesting that the route of administration or formulation may affect outcomes. The safety profile was improved for SC ami, with lower IRR and VTE rates. Prophylactic anticoagulation can be safely implemented and reduces VTE risk. Clinical trial information: NCT05388669.