A Phase 1b/2 Study of Alpelisib in Combination with Cetuximab in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Background: Alpelisib in combination with cetuximab showed synergistic anti-tumour activity in head and neck squamous cell carcinoma (HNSCC) models. Objectives: The recommended phase 2 dose (RP2D) was determined in a phase 1b dose-escalation study. Phase 2 evaluated anti-tumour activity with a randomised part in cetuximab-naïve patients and a non-randomised part in cetuximab-resistant patients. Patients and Methods: Alpelisib was administered in 28 d cycles as whole tablets, suspension from crushed tablets or suspension from dispersible tablets in patients with platinum-resistant, recurrent/metastatic HNSCC. Results: The RP2D determined for alpelisib was 300 mg/d. Alpelisib–cetuximab achieved an overall response rate of 25% and 9.9% and disease control rate of 75% and 43.7% in phase 1b and phase 2 studies, respectively. Median progression-free survival (PFS) per central review was 86 d for combination treatment and 87 d for cetuximab monotherapy (unadjusted HR 1.12; 95% CI 0.69–1.82; P > 0.05). When adjusted for baseline covariates [sum of longest diameters from central data, haemoglobin and white blood cell (WBC), the results favoured combination treatment (adjusted HR 0.54; 95% CI 0.30–0.97; P = 0.039). PFS per investigator assessment resulted in an unadjusted HR of 0.76 (95% CI 0.49–1.19; P > 0.05) favouring combination treatment. The median PFS in cetuximab-resistant patients was 3.9 months. Conclusions: The addition of alpelisib to cetuximab did not demonstrate a PFS benefit in cetuximab-naïve patients with advanced HNSCC. The alpelisib–cetuximab combination showed moderate activity in cetuximab-resistant patients, with a consistent safety profile. Clinical Trial Registration: ClinicalTrials.gov NCT01602315; EudraCT 2011-006017-34.