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Cranial base invasion involves the cranial nerves, causing various neurological symptoms and seriously affecting patients' quality of life. We encountered a 64-year-old woman with recurrent lip cancer with skull base invasion treated with nivolumab followed by cetuximab and paclitaxel (Cmab+PTX) combination chemotherapy. The therapy showed promising efficacy based on FoundationOne® CDx and achieved complete response (CR). The patient discovered an ulcer on the left side of her lip and visited our department in August 201X. She was diagnosed with left-sided lip cancer (squamous cell carcinoma, T1N0M0) and received external-beam radiation (70 Gy). However, primary-site recurrence was noted in December 201X, and she underwent tumor resection. In April 201X+ 2, she underwent neck dissection for cervical lymph node metastasis and postoperative radiation chemotherapy (60 Gy, two courses of CDDP). In February 201X+ 3, local recurrence due to tumor invasion into the middle skull base and ocular symptoms were noted. Therefore, eight nivolumab courses were administered; however, the primary tumor increased, and an oncogene panel test was performed. Based on EGFR amplification results, Cmab+PTX was administered. Recurrent metastasis is frequently associated with poor prognoses, and cytotoxic chemotherapy after immune checkpoint inhibitor therapy is effective in managing cancer recurrence and metastasis, as in the case of our patient. The patient's ocular symptoms disappeared, indicating CR. Six years have passed since the initial diagnosis, and there is no evidence of recurrence or metastasis. [ABSTRACT FROM AUTHOR]