Here we present a case report of a SMARCA4-deficient Undifferentiated Tumor (SMARCA4-UT) lung carcinoma with additional microsatellite instability (MSI-H) treated with first-line pembrolizumab….A 63-year-old woman’s treatment for mediastinal SMARCA4-UT MSI-H, PDL1 low stage IIIC cT3 pN3 was retrospectively followed....She presented prior to late cycle 6 with significantly worsened functional status and hyperprogression apparent on repeat imaging....Despite MSI-H status and SMARCA4 deficiency, our patient which high tumor burden had a poor response to first line pembrolizumab with mixed response followed by hyperprogression.