Background: Amivantamab (ami), an EGFR and cMET bispecific antibody with immune cell-directing activity, and lazertinib (laz), a CNS-penetrant 3^rd-generation EGFR tyrosine kinase inhibitor have shown clinical activity in biomarker-selected patients (pts) with advanced NSCLC. Antitumor activity has been suggested to be improved when the agents are given in combination (Leighl Ann Oncol 2021;32:suppl_5, 1192MO). We examined the incidence of VTE, a common adverse event (AE) among pts with lung cancer, for those receiving ami monotherapy, laz monotherapy, and ami+laz to investigate if there is elevated risk and understand potential predisposing risk factors. Methods: CHRYSALIS (NCT02609776; ami monotherapy and ami+laz), CHRYSALIS-2 (NCT04077463; ami+laz), and LASER201 (NCT04075396; laz monotherapy) are ongoing open-label studies of locally advanced/metastatic NSCLC. Two descriptive, univariate risk analyses were performed, with the primary analysis including all treatment-emergent VTE events (grouped term) and a secondary analysis that excluded VTE events occurring after progression of disease (PD) or within 30 days prior to PD. Results: This analysis included 560 pts who received ami monotherapy, 536 ami+laz, and 252 laz monotherapy, predominantly in the TKI-relapsed setting. The incidence of VTE events of any grade was numerically higher in pts who received ami+laz (21%) than those who received ami (11%) or laz (11%) monotherapy. The median time to onset of the first VTE event was 84.5 days for ami, 79 days for ami+laz, and 170 days for laz. The majority (64%) of ami+laz pts had VTE events in the first 4 months. The most common VTE events by preferred term were pulmonary embolism and deep vein thrombosis. The incidence of grade ≥3 VTE events was comparable among pts receiving ami (5%), ami+laz (6%), and laz (6%), and there were no grade 5 VTE events for ami+laz. The overall incidence of serious VTE AEs was low (ami, 3%; ami+laz, 5%; laz, 4%). There were 6 discontinuations due to VTE, 1 (0.2%) ami, 2 (0.4%) for ami+laz, and 3 (1.2%) laz. In the primary analysis, age ≥60 years was a significant risk factor (P< 0.05). In the secondary analysis, age ≥60 years, ECOG performance status of 1 (vs 0), and response to therapy (partial response or better) were significant risk factors (P< 0.05). Conclusions: Lung cancer diagnosis is a known risk factor for VTE. In a review across clinical trials, single-arm cohort data suggest there is a numerically higher incidence of VTE for ami+laz compared with each monotherapy. Age ≥60 years, ECOG performance status, and response to treatment are potential risk factors. The relationship between response and VTE is emerging and may reflect possible immune or inflammatory-mediated mechanisms. Further efforts to understand VTE-associated risk factors in randomized clinical trials are ongoing. Clinical trial information: NCT02609776, NCT04077463, NCT04075396.