Spira, Alexander IAlexander ISpiraPaz-Ares, LuisLuisPaz-AresHan, Ji-YounJi-YounHanJIN-YUAN SHIHMascaux, CélineCélineMascauxRoy, Upal BasuUpal BasuRoyZugazagoitia, JonJonZugazagoitiaKim, Yu JungYu JungKimChiu, Chao-HuaChao-HuaChiuKim, Sang-WeSang-WeKimNadal, ErnestErnestNadalGil-Bazo, IgnacioIgnacioGil-BazoMurphy, Sean PSean PMurphyAnderson, Bailey GBailey GAndersonXia, YichuanYichuanXiaWang, GeorgeGeorgeWangBauml, Joshua MJoshua MBaumlChioda, MarcMarcChiodaSimoes, JairoJairoSimoesMahadevia, Parthiv JParthiv JMahadeviaLopes, GilbertoGilbertoLopes2025-05-142025-05-142025-01-24https://scholars.lib.ntu.edu.tw/handle/123456789/729285Introduction: Amivantamab, an EGFR-MET bispecific antibody, is approved for multiple indications in EGFR-mutated advanced NSCLC as monotherapy or combined with other agents. Intravenous amivantamab is associated with a 67% infusion-related reaction (IRR) rate. Methods: The phase 2 SKIPPirr study (NCT05663866) enrolled participants with EGFR-mutated (exon 19 deletion or exon 21 L858R) advanced NSCLC after progression on osimertinib and platinum-based chemotherapy who received intravenous amivantamab plus oral lazertinib (amivantamab-lazertinib), a third-generation tyrosine kinase inhibitor. Aiming to mitigate IRRs, four independent prophylactic approaches were evaluated using Simon's two-stage design with an expansion stage if a cohort passed both stages: oral dexamethasone 4 mg twice daily given on cycle (C) 1 day (D) −1 (two doses); oral dexamethasone 8 mg twice daily given on C1D−2, C1D−1, and the morning of C1D1 (five doses); oral montelukast 10 mg once daily given on C1D−4, C1D−3, C1D−2, C1D−1, and C1D1 (five doses); subcutaneous methotrexate 25 mg (one dose) given anytime between C1D−7 and C1D−3. The primary end point was C1D1 IRR incidence. Results: As of June 24, 2024, 68 participants were treated across all cohorts. The dexamethasone 8 mg cohort passed stages 1 and 2 proceeding to the expansion stage, with 24 additional participants treated. At C1D1, nine of 40 participants (22.5%) experienced IRRs, resulting in an approximately threefold decrease versus historical data (67.4%). By the end of C3, 10 of 41 participants (24.4%) in the dexamethasone 8 mg cohort experienced IRRs (grades 1–2, except one grade 3 on C2D1). Amivantamab-lazertinib's safety and efficacy were consistent with previous reports. Conclusions: Prophylaxis with 8 mg oral dexamethasone meaningfully reduced IRRs and can be readily implemented in clinical practice.enAmivantamabDexamethasoneInfusion-related reactionsNSCLCProphylaxisjournal article10.1016/j.jtho.2025.01.01839864547