Among the MAPKi-treated patients, KDR Q472H homozygotes had shorter median progression-free survival (PFS, 3.3 vs 9.7 months, P = 0.009) than KDR wild type (WT). In patients treated with anti-PD-1-based therapies, response rates were lower in KDR Q472H variant patients compared to WT (P=0.012), with shorter median PFS (8.4 months vs not reached, P=0.0443)....VEGFR-2 blockade in a KDR Q472H B16 mouse melanoma model augmented the anti melanoma immune response. KDR Q472H cell lines displayed synergistic cytotoxicity with dabrafenib and lenvatinib, compared to KDR WT cells....melanoma patients with pathogenic germline variant KDR Q472H may be more resistant to both ICIs and MAPKi.