Early disease progression in a phase I study of bortezomib (B), cetuximab (C), and intensity-modulated radiation therapy (IMRT) for squamous cell carcinoma of the head and neck (SCCHN).

Abstract

2575 Background: Preclinical studies combining proteasome inhibitor B and epidermal growth factor receptor (EGFR) inhibitor C, or B and RT, provided evidence for anti-tumor and radiosensitizing activity. These observations provided a rationale for a first-in-human phase I study combining B with standard concurrent C and IMRT in patients with advanced SCCHN. Methods: Cohorts of patients with chemo +RT naive stage IV or recurrent SCCHN were treated with escalating doses of B, (0.7, 1.0 and 1.3 mg/m2), given IV twice weekly on days 1, 4, 8 + 11 every 3 weeks. B + C 400 mg/m2 was started 1 week before, followed by B + weekly C 250 mg/m2 concurrent with IMRT 2Gy/5 days per week to 70 Gy. Results: 6 patients with stage IV and 1 with recurrent neck SCCHN were accrued; 6 had oropharyngeal and 1 had a laryngeal primary. 3 patients each received B 0.7 or 1.0 mg/m2, without dose-limiting toxicities, and 1 patient treated with B 1.3 mg/m2 was taken off study in week 5 due to recurring Gr 2 infusion reaction to C and progressive disease (PD). Expected Gr 3 toxicities included radiation mucositis (4), dermatitis (4), and rash (1). The study was terminated after 5/6 of the previously untreated patients had PD within one year, 2 in the lung and 3 locoregionally, despite 5 having better prognosis oropharyngeal SCCHNs (3 testing HPV+ before and 2 testing p16+ at the site of PD). The patient with a laryngeal primary had a CR and remains disease-free >10 months, and 1 patient each with PD were salvaged by surgery, or cisplatin and RT. In SCCHN cells, B was found to inhibit C and RT-induced degradation of EGFR, and enhance ERK1/2 pathway signaling and cell survival. Conclusions: The combination of B, C, and IMRT was well tolerated but resulted in a median progression free survival of <12 mos, which compared unfavorably to 17 mos reported for C+RT. Translational studies reveal B unexpectedly prevents C+RT induced EGFR degradation, enhancing tumor prosurvival signaling and radioprotection. Supported by NIHIntramural Project ZIADC-000016 and Millennium Pharmaceuticals. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium