A Phase II Study of Nelfinavir plus Concurrent Chemoradiation for Advanced, HPV-Negative Squamous Cell Carcinoma of the Head and Neck

Abstract

<h3>Purpose/Objective(s)</h3> Locoregional control of advanced HPV-negative head and neck squamous cell carcinomas remains a challenge, with tumor hypoxia adversely affecting radiation efficacy and outcomes in patients treated with chemoradiation. Nelfinavir is a HIV protease inhibitor that has also shown promise as an anti-hypoxia agent, via decreasing tumor oxygen consumption. We conducted a single-arm, phase II study of Nelfinavir plus chemoradiation to assess whether Nelfinavir could improve locoregional control as a hypoxic radiosensitizer. <h3>Materials/Methods</h3> Patients with biopsy-proven AJCC v7 stage III or IV (excluding M1) HPV-negative squamous cell carcinomas of the oral cavity, oropharynx, larynx, or hypopharynx were eligible. Patients were treated with definitive chemo(bio)radiotherapy and received oral Nelfinavir (1250 mg twice a day), starting with a ‘lead-in' period of Nelfinavir for 10-14 days prior to initiation of chemoradiation, and continued during chemoradiation. PET/CT imaging to assess glucose metabolic activity (¹⁸F-FDG-PET) and hypoxia (¹⁸F-MISO or ¹⁸F-EF5) was obtained at baseline (prior to starting Nelfinavir), and again after Nelfinavir lead-in (prior to initiation of chemoradiation). The primary outcome was locoregional control, with secondary outcomes of distant metastasis-free survival, overall survival, and the effect of Nelfinavir on hypoxia and glucose metabolism as assessed via PET/CT. <h3>Results</h3> A total of 17 patients were enrolled with a median 2.72 year follow up. Patient characteristics are shown in Table 1. At most recent follow up, locoregional control was 76.5% (13/17 patients), with distant metastasis free survival of 70.6% (12/17 patients), and overall survival of 47.1% (8/17 patients). Three (17.6%) patients discontinued Nelfinavir due to toxicity, with elevated liver function tests in 2 (11.8%) and diarrhea in 1 (5.9%). <h3>Conclusion</h3> The addition of Nelfinavir to definitive chemoradiation shows promising locoregional control in HPV-negative locally advanced squamous cell carcinoma of the head and neck. These results compare favorably to patients with identified hypoxic head and neck cancers treated with chemoradiation alone (38% locoregional control, TROG 98.02 trial, Rischin et al. JCO 2006). These results warrant further investigation in cancers where locoregional control with standard approaches remains a limiting factor.