Background: Amivantamab (ami), an EGFR-MET bispecific antibody with immune cell-directing activity, is approved as an intravenous (IV) formulation. IV ami + lazertinib (laz), a 3^rd-generation EGFR TKI, demonstrated superior progression-free survival (PFS) in patients (pts) with treatment-naïve, advanced EGFR-mutated NSCLC vs osimertinib (Cho AnnOncol 2023). Subcutaneous (SC) ami substantially reduced infusion-related reactions (16% vs 67%) and administration time (≤7 mins vs 2–4 hours) vs historical IV experience (Minchom JCO 2023). PALOMA-2 (NCT05498428) evaluated the efficacy, safety, and pharmacokinetics (PK) of first-line SC ami+laz. Methods: Cohorts 1 and 6 enrolled pts with treatment-naïve, EGFR Ex19del or L858R-mutated advanced NSCLC. Prophylactic anticoagulation for the first 4 months (mo) of treatment was recommended in cohort 1 and mandatory in cohort 6. SC ami was administered by manual injection in the abdomen at 1600 mg (≥80 kg: 2240 mg) weekly for the first 4 weeks and every 2 weeks thereafter. Laz was dosed orally at 240 mg daily. The primary endpoint was objective response rate (ORR) as assessed by the investigator per RECIST v1.1. Results: As of 6 Jan 2024, 68 and 58 pts were enrolled in cohorts 1 and 6, respectively. Overall, median age was 59 years, 60% were female, and 68% Asian. The median follow-up was 10 mo for cohort 1 and 6 mo for cohort 6. ORR (confirmed responses) in cohort 1 was 68% (95% CI, 55–79) by investigator and 72% (95% CI, 60–82) by independent central review. ORR in cohort 6 was 64% (95% CI, 49–78) and 73% (95% CI, 58–85), respectively. At data cutoff, 40/46 responders in cohort 1 and 29/29 responders in cohort 6 were receiving ongoing treatment. Best overall response rates (includes unconfirmed responses) were 81% (95% CI, 70–89) for cohort 1 and 76% (95% CI, 61–87) for cohort 6. Median time to response was 2 mo (range, 1.4–5.3). Median duration of response, PFS, and overall survival were not estimable. Administration-related reactions (ARRs) were reported in 13 (19%) pts in cohort 1 and 6 (11%) pts in cohort 6, all grade 1–2. EGFR- and MET-related AEs were primarily grade 1–2. Total of 71% of pts in cohort 1 and 100% in cohort 6 received prophylactic anticoagulation. Venous thromboembolic events (VTE) were reported in 18% and 7% of pts in cohorts 1 and 6, respectively. There were no dose reductions or discontinuations due to VTE. Rate of bleeding was 2% among pts receiving anticoagulation. Mean ami concentrations on cycle 2 day 1 were 328 µg/mL (n=49) in cohort 1 and 371 µg/mL (n=41) in cohort 6, consistent with historic IV levels. Conclusions: SC ami+laz showed a response rate similar to historic IV ami+laz in first-line EGFR-mutated NSCLC, with an improved safety profile that included significantly lower ARR rates. Further, prophylactic anticoagulation can be safely implemented and reduced incidence of VTE. Clinical trial information: NCT05498428.