Background: HNSCC is the seventh most common cancer worldwide. Patients with R/M disease have limited treatment options and a poor prognosis. The USFDA has approved two ICI agents to treat R/M-HNSCC: pembrolizumab given as monotherapy or with platinum-based chemotherapy for first-line treatment of R/M disease and nivolumab (or pembrolizumab) monotherapy for treatment of disease that progressed on or after platinum-containing chemotherapy. In each setting, the ICI improved overall survival (OS); however, the absolute magnitude of the OS benefit was modest and most patients experienced disease progression within one year. There are no agents with regulatory agency-approval that are used to treat R/M-HNSCC that progressed on or after an ICI. Drugs commonly used in this setting have limited activity and include cetuximab (an epidermal growth factor receptor [EGFR] inhibitor), paclitaxel, docetaxel, a platinum, or 5-fluorouracil. Hence, there is an important unmet medical need to develop more effective treatments for R/M-HNSCC that progressed on or after an ICI. NRC-2694-A is an orally administered EGFR tyrosine kinase inhibitor, discovered and developed by NATCO Pharma Ltd., India. Based on the responses from Phase-I and Phase-II trials of NRC-2694-A in India, NAT2694US study is designed to evaluate the safety and efficacy of Oral NRC-2694-A in combination with paclitaxel in patients with R/M-HNSCC, who progressed on or after ICI therapy. Methods: NAT2694US is a multi-center, single-arm, Phase 2 study (NCI ClinicalTrials.gov Identifier: NCT05283226) with an estimated enrolment of 46 patients. Eligible patients are >18 years of age with an ECOG performance status of 0-2 and histologically confirmed unresectable, measurable R/M-HNSCC (of the oral cavity, oropharynx, hypopharynx, and larynx), radiological disease progression on or after ICI therapy, and no prior taxane for R/M disease. Patients receive 300 mg of oral NRC-2694-A once daily and 175 mg/m² of paclitaxel IV infusion once every 21-day cycle for 6 cycles or more. Tumor response assessment with CT/MRI scans is performed every 6 weeks. The primary endpoint is objective response rate (ORR) using RECIST v1.1 performed by the investigator. The study uses a Simon’s 2-stage design with ORR H₀: 30% and H₁: 50% using a one-sided Type-1 error rate = 0.05). In Stage 1, fifteen patients are to be enrolled for tumor assessment. If objective response is observed in at least 6 of these 15 patients, then Stage 2 would be opened with the inclusion of 31 additional patients, leading to a total enrolment of 46 patients. The observation of objective response in at least 19 of 46 patients would reject the null hypothesis in favour of the alternative hypothesis. Enrolment to the NAT2694US trial is currently ongoing in USA. Clinical trial information: NCT05283226.