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

• Type of Material: Article
• Authors: Albiruni R. Abdul Razak, UHN Princess Margaret Hospital; Hung-Ming Wang, Chang Gung Memorial Hospital at Linkou; Jang-Yang Chang, National Cheng Kung University Hospital; Myung-Ju Ahn, Sungkyunkwan University; Pamela Munster, University of California, San Francisco; George Blumenschein Jr., University of Texas, Houston; Benjamin Solomon, Peter MacCallum Cancer Centre; Darren Wan-Teck Lim, National Cancer Centre; Ruey-Long Hong, National Taiwan University Hospital; David Pfister, Memorial Sloan Kettering Cancer Center; Nabil F Saba, Emory University; Se-Hoon Lee, Seoul National University Hospital; Carla van Herpen, Radboud University Medical Center; Cornelia Quadt, Novartis Pharma AG; Douglas Bootle, Novartis Pharma AG; Lars Blumenstein, Novartis Pharma AG; David Demanse, Novartis Pharma AG; Jean-Pierre Delord, Institut Claudius Regaud
• Language: English
• Date: 2023-10-25
• Publisher: Springer Nature
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): https://doi.org/10.1007/s11523-023-00997-z
• Title of Journal or Parent Work: Targeted Oncology
• Volume: 18
• Issue: 6
• Start Page: 853
• End Page: 868
• Grant/Funding Information: This work was supported by Novartis Pharmaceuticals AG.
• Keywords: Alpelisib; cetuximab; RP2D; head and neck squamous cell carcinoma
• Research Categories: Health Sciences, Oncology; Biology, Cell

Abstract

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.