Background: Standard treatments for locally advanced larynx cancers include concurrent cisplatin/radiation therapy, or induction chemotherapy followed by radiation therapy alone, with the goal of organ preservation. Both strategies have been shown to achieve similar laryngectomy-free survival (LFS), but failed to improve overall survival (OS) compared with radiation therapy alone or surgery followed by radiation therapy. Although cisplatin given concurrently with radiation therapy is commonly used for organ preservation, there are concerns regarding long-term outcomes, such as late toxicities. Pembrolizumab with chemotherapy has been shown to improve OS in recurrent/metastatic head and neck squamous cell carcinomas (HNSCCs). Additionally, pembrolizumab combined with radiation therapy has been shown to be safe in locally advanced HNSCC. LACOG 0720 is designed to evaluate a pembrolizumab-based, cisplatin-free, and concurrent chemoradiation therapy-free regimen for larynx preservation, in an attempt to improve outcomes and avoid late toxicities. Methods: LACOG 0720 is a phase 2, single-arm, multicentric trial assessing patients with newly diagnosed squamous cell carcinoma of the larynx (glottic or supraglottic) and clinical stages III, IVA, or IVB (AJCC 8th Ed.). Patients with large volume T4 disease (invasion through the cartilage or extension > 1 cm to the base of the tongue) or T1 disease are excluded. Patients receive 3 cycles of induction chemo-immunotherapy (carboplatin AUC6, paclitaxel 175 mg/m², and pembrolizumab 200 mg, IV every 21 days [q21D]), followed by concurrent radioimmunotherapy (Intensity-modulated radiation therapy with pembrolizumab 200 mg IV q21D for 3 cycles), followed by consolidation immunotherapy (pembrolizumab 200 mg IV q21D for 11 cycles). The primary endpoint is two-year LFS rate. Secondary endpoints include two-year larynx dysfunction-free survival, OS, overall response rate, short-term and long-term toxicities, causes of death, patterns of failure, and quality of life. Predictive biomarkers of response and survival will be evaluated as exploratory analysis. The sample size was calculated based on the primary endpoint. Using the Chi-square Test for One Proportion and considering a one-sided 10% significance level, 39 patients are needed to achieve 80% power to detect the difference between the null hypothesis; that the true laryngectomy-free survival at two years is 59%, and the alternative hypothesis that the laryngectomy-free survival at two years is 75%. From Feb 2022 to Feb 2023, 24 patients were enrolled in 10 Brazilian centers. Results are expected in July 2024. NCT04943445. Clinical trial information: NCT04943445.