Mouse-human co-clinical trials demonstrate superior anti-tumour effects of buparlisib (BKM120) and cetuximab combination in squamous cell carcinoma of head and neck

Abstract

Background: Recurrent 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).

Methods: Fifty-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.

Results: For 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.

Conclusions: The buparlisib/cetuximab combination has significant promise as a treatment strategy for R/M SCCHN.

Clinical trial registration: NCT01527877.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1. Clinical response the patients enrolled in clinical trial.

a, b Best tumour volume change from baseline in patients with at least one post-baseline measurement a for buparlisib monotherapy, and b for the buparlisib/cetuximab combination phase. c Kaplan–Meier curves for progression-free survival. (d) Kaplan–Meier curve for overall survival. (e) Duration of response.

Fig. 2. Drug responses of PDX models and corresponding patients.

a Buparlisib, cetuximab and buparlisib/cetuximab tested in PDX models. b Correlation between patient YHIM-01 and PDX treated with buparlisib. c Rapid progression of patient YHIM-02 and PDX under buparlisib monotherapy. d Response of patient YHIM-07 to buparlisib/cetuximab therapy after progression under buparlisib monotherapy. After one cycle of buparlisib, the neck node progressed; however, it improved after the addition of cetuximab. Pink arrowhead indicates the measurable target tumour lesions.

Fig. 3. Genetic alteration profile in patient-derived xenograft models.

a Somatic mutations in known cancer-related genes based on the Cancer Gene Census for all seven PDX models (first panel); mutation rates for all seven PDX models (second panel); relative proportions of functional consequences (third panel); and signatures (fourth panel). b Genome-wide somatic copy number alteration profiles of seven PDX models using whole-exome sequencing data. Asterisks indicate the cases with NS/S (nonsynonymous/synonymous) ratios less than 2.0.

Fig. 4. In vitro experiments for cell proliferation in the PDX models showing synergy of buparlisib/cetuximab.

a Comparison of gene expression profiles between buparlisib, cetuximab, buparlisib/cetuximab and control in PDX models YHIM-05, -06 and -07, showing that genes associated with apoptosis and cell-cycle arrest were significantly upregulated by combination therapy. b Cell viability as a function of drug treatment of cell lines from PDX models YUX-06 and -07). c Expression of genes related to cell-cycle progression (cyclins B, D and E) and apoptosis (cleaved PARP, cleaved caspase-3 and cleaved-7) in YUX-06 and -07. d IHC showing proliferative (Ki67) and apoptotic (TUNEL) markers in YHIM-06 and -07. e Flow cytometry showing apoptosis in YUX-06 and -07.