Treatment with erlotinib and pralatrexate resulted in stable disease for approximately 15 months in a patient with metastatic squamous cell carcinoma that harbored ERBB2 (S310F), ERBB4 (D609N), FBXW7 (R479Q), RB1 (E539*), and ARID2 (Q1194*) and amplification of EPHBI, PIK3CA, and SOX2. Here, ERBB2 is linked to metastatic squamous cell carcinoma.