Phase I study of ribociclib plus cetuximab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck

Abstract

Background: The majority of Human Papilloma Virus (HPV)‐negative squamous cell carcinoma of the head and neck (SCCHN) has inactivation of p16, an inhibitor of the Cyclin‐Dependent Kinases (CDK) 4 and 6, and 20‐30% present CCND1 amplification. These alterations promote cell cycle progression and tumor proliferation. EGFR upregulation could also induce elevation of cyclin D1 and CDK4. Cetuximab, an anti‐EGFR mAb, improves survival in combination with platinum‐based chemotherapy in recurrent SCCHN. This study is investigating the combination of ribociclib, an orally highly selective inhibitor of CDKs 4/6, and cetuximab in recurrent SCCHN. Methods: p16‐negative recurrent and/or metastatic SCCHN patients ( pts) who progress after platinum‐based chemotherapy were included in this phase 1 study. All the pts received cetuximab at the recommended dose (400 mg/m2 followed by 250 mg/ m2/week, IV), combined with ribociclib (3 weeks on/1 week off ), in a classical 3 + 3 dose‐escalation design. The first dose level of ribociclib was 400 mg/day and the second dose level 600 mg/day. The primary endpoint was to determine the maximum tolerated dose (MTD) of Ribociclib in combination with cetuximab. Results: Between April 2015 and January 2016, 10 pts (median age: 62.5 years; site location: larynx (2), hypopharynx (2), oropharynx (2), oral cavity (4)) were enrolled, including 6 pts previously treated with cetuximab. No dose limiting toxicities (DLTs) were observed at the first dose level. At the second dose level, 1 pt presented rapid disease progression and was therefore replaced as he could not be evaluated for toxicity. One pt out of 6 experienced DLT (Grade 4 thrombopenia lasting more than 7 days). The most common grade 3/4 treatment‐related adverse events were neutropenia (n = 2), anemia (n = 2), thrombopenia (n = 1), hypocalcemia (n = 2), hypokaliemia (n = 2), hypomagnesemia (n = 1) and hypoglycemia (n = 1). No objective responses were observed but 4 pts achieved a stable disease according to RECIST v1.1, including 2 pts previously treated with cetuximab. Conclusions: The MTD of ribociclib in combination with standard dose of cetuximab is 600mg daily (3 weeks on/1 week off ). An expansion cohort is currently ongoing.