Low-dose nivolumab with neoadjuvant chemotherapy and oral metronomic therapy in borderline resectable oral cavity squamous cell carcinoma: a phase II trial

Summary: Background: Non-surgical management of oral cavity squamous cell carcinoma (OSCC) has poorer outcomes compared to surgery. In borderline resectable tumors, historical neoadjuvant chemotherapy achieves surgical conversion in only about 40%. Combining low-dose immunotherapy and oral metronomic therapy (OMT) with chemotherapy may enhance resection rate and survival. Methods: Between April 2023 and April 2024, patients deemed ‘borderline resectable’ OSCC based on predefined criteria by a multidisciplinary tumor board were prospectively offered this Phase II single-arm interventional trial setting. Patients received two 21-day cycles of carboplatin, nab-paclitaxel, low-dose nivolumab, and six weeks of erlotinib, methotrexate, celecoxib, with additional cycle(s) if needed. Primary endpoint was R0 resection rate. Secondary endpoints were objective response rate, pathologic response, safety, event-free survival (EFS), and overall survival (OS). Immune biomarkers and Volumetric assessment were exploratory endpoints. The trial was prospectively registered in the Clinical Trial Registry of India (CTRI/2023/04/051617). Findings: Of 34 patients, all except one completed planned neoadjuvant therapy. After 2 cycles, 22 (66·6%) had partial response and 11 had stable disease; none progressed. Twenty six underwent surgery; 25 achieved R0 resection (25/33–75·7% conversion). Four of seven remaining patients received additional cycle(s); three subsequently achieved R0 resection. Overall conversion rate was 90·3% (28/31) excluding 2 patients who refused further treatment. Major pathological response occurred in 12 patients (41·4%), including four with pathological complete response. Grade ≥3 toxicities occurred in 5 of 34 patients (14·7%), with no treatment-related deaths. One patient had grade 4 diarrhea with grade 4 acute kidney injury. Interpretation: The NeoLOCUS regimen offers an affordable, outpatient chemo-immunotherapy approach that improves surgical conversion and pathological response in borderline resectable OSCC.