Abstract
BackgroundRecurrent and/or metastatic squamous cell carcinoma of head and neck (R/M SCCHN) is a common cancer with high recurrence and mortality. Current treatments have low response rates (RRs).MethodsFifty-three patients with R/M SCCHN received continuous oral buparlisib. In parallel, patient-derived xenografts (PDXs) were established in mice to evaluate resistance mechanisms and efficacy of buparlisib/cetuximab combination. Baseline and on-treatment tumour genomes and transcriptomes were sequenced. Based on the integrated clinical and PDX data, 11 patients with progression under buparlisib monotherapy were treated with a combination of buparlisib and cetuximab.ResultsFor buparlisib monotherapy, disease control rate (DCR) was 49%, RR was 3% and median progression-free survival (PFS) and overall survival (OS) were 63 and 143 days, respectively. For combination therapy, DCR was 91%, RR was 18% and median PFS and OS were 111 and 206 days, respectively. Four PDX models were originated from patients enrolled in the current clinical trial. While buparlisib alone did not inhibit tumour growth, combination therapy achieved tumour inhibition in three of seven PDXs. Genes associated with apoptosis and cell-cycle arrest were expressed at higher levels with combination treatment than with buparlisib or cetuximab alone.ConclusionsThe buparlisib/cetuximab combination has significant promise as a treatment strategy for R/M SCCHN.Clinical Trial RegistrationNCT01527877.
Highlights
Recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M Squamous cell carcinoma of head and neck (SCCHN)) is a common cancer with high recurrence and mortality
This study showed that the pan-phosphatidylinositol 3kinase (PI3K) inhibitor buparlisib was insufficient for the treatment of patients with R/M SCCHN, even though PI3K pathway alterations are frequently caused by mutations associated with SCCHN.[7,8]
We conducted a mouse–human co-clinical trial, with patient-derived xenografts (PDXs) models derived from biopsied tumour samples of the patients enrolled in this Phase 2 clinical trial
Summary
Recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M SCCHN) is a common cancer with high recurrence and mortality. Based on the integrated clinical and PDX data, 11 patients with progression under buparlisib monotherapy were treated with a combination of buparlisib and cetuximab. Squamous cell carcinoma of head and neck (SCCHN) is the sixth most frequent cancer with a dismal prognosis and high mortality.[1] Low survival, in combination with the significant toxicity of current treatment strategies, emphasises the necessity for novel therapies.[2] In recurrent/metastatic SCCHN (R/M SCCHN), the only approved targeted therapy is cetuximab, a monoclonal antibody against the epidermal growth factor receptor (EGFR), with a response rate (RR) of 10–15%.3. Buparlisib combined with paclitaxel showed improved efficacy in the treatment of R/M SCCHN patients over paclitaxel alone, suggesting the importance of PI3K inhibition.[9] We conducted a Phase 2 study of buparlisib in R/M SCCHN
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