Phase 1 trial and biomarker analysis of Buparlisib with weekly Cisplatin and Radiotherapy in high risk locally advanced squamous cell cancer of the Head and Neck.

Abstract Purpose: We evaluated the pan-PI3K inhibitor buparlisib with weekly cisplatin and radiotherapy among patients with locally advanced (LA) squamous cell cancer of the head and neck (SCCHN) and tobacco history. Patients and Methods: Patients with stage III/IV LA-SCCHN (AJCC7), ≥10 pack-year tobacco use treated with curative intent were enrolled. Patients received buparlisib during a 2-week run-in phase and during standard 70Gy of radiotherapy plus weekly cisplatin. An exploratory analysis of genomic sequencing was performed on biopsy specimens Results: Twenty-three patients were enrolled (n=17 at the MTD (buparlisib 40 mg daily, CDDP 30mg/m2/week)). Ninety-one percent (21/23) had stage IV disease. HPV was detected in 15 of 18 cases with oral/oropharyngeal disease. 5 patients suffered recurrences of whom 3 had activating mutations along the PI3K pathway. In 5 patients whose disease responded during the 2 week run-in phase with buparlisib alone, 3 of 4 with sequencing data showed loss-of-function mutations in either Tumor Necrosis Factor Receptor Associated Factor 3 (TRAF3), and/or Cylindromatosis Lysine Deubiquinatinase (CYLD). Preclinical studies with mutations in TRAF3 or CYLD via CRISPR/Cas9 knockout in HPV+SCCHN cells demonstrate that loss of TRAF3 or CYLD may sensitize SCCHN cell lines to PI3K through mechanisms other than blocking NFκb pathway. Conclusions: Buparlisib with CRT was feasible and active, though escalation to the standard weekly cisplatin dose of 40 mg/m2 was not possible. Our data suggests that TRAF3/CYLD mutant SCCHN may be susceptible to PI3K inhibition whereas PI3K pathway activation appeared to be associated with poor outcomes in this limited dataset.

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Publication Details

Journal
Clinical Cancer Research
Published
2026-09-09
DOI
https://doi.org/10.1158/1078-0432.ccr-21-3677
Primary Topic
Head and Neck Cancer Studies
Type
article
Field-Weighted Citation Impact
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article

Phase 1 trial and biomarker analysis of Buparlisib with weekly Cisplatin and Radiotherapy in high risk locally advanced squamous cell cancer of the Head and Neck.

Jochen H. Lorch, Kee‐Young Shin, Jonathan D. Schoenfeld, Ravindra Uppaluri et al.
Clinical Cancer Research
Head and Neck Cancer Studies
article

Phase 1 trial and biomarker analysis of Buparlisib with weekly Cisplatin and Radiotherapy in high risk locally advanced squamous cell cancer of the Head and Neck.

Jochen H. Lorch, Kee‐Young Shin, Jonathan D. Schoenfeld, Ravindra Uppaluri, Jennifer Marie Spangle, Laura A. Goguen, Glenn J. Hanna, Mofei Liu, Kristine Wong, Guilherme Rabinowits, A. O’Neill, Ethan Harris, Roy B. Tishler, Umair Mahmood, Alec Kacew, Patricia McHugh, Danielle N. Margalit, Robert I. Haddad, Bose Kochupurakkal, Lynette M. Sholl, Tom Thomas, Julian Huang, Kimberly Austin, Nicole G. Chau
article en

Abstract

Abstract Purpose: We evaluated the pan-PI3K inhibitor buparlisib with weekly cisplatin and radiotherapy among patients with locally advanced (LA) squamous cell cancer of the head and neck (SCCHN) and tobacco history. Patients and Methods: Patients with stage III/IV LA-SCCHN (AJCC7), ≥10 pack-year tobacco use treated with curative intent were enrolled. Patients received buparlisib during a 2-week run-in phase and during standard 70Gy of radiotherapy plus weekly cisplatin. An exploratory analysis of genomic sequencing was performed on biopsy specimens Results: Twenty-three patients were enrolled (n=17 at the MTD (buparlisib 40 mg daily, CDDP 30mg/m2/week)). Ninety-one percent (21/23) had stage IV disease. HPV was detected in 15 of 18 cases with oral/oropharyngeal disease. 5 patients suffered recurrences of whom 3 had activating mutations along the PI3K pathway. In 5 patients whose disease responded during the 2 week run-in phase with buparlisib alone, 3 of 4 with sequencing data showed loss-of-function mutations in either Tumor Necrosis Factor Receptor Associated Factor 3 (TRAF3), and/or Cylindromatosis Lysine Deubiquinatinase (CYLD). Preclinical studies with mutations in TRAF3 or CYLD via CRISPR/Cas9 knockout in HPV+SCCHN cells demonstrate that loss of TRAF3 or CYLD may sensitize SCCHN cell lines to PI3K through mechanisms other than blocking NFκb pathway. Conclusions: Buparlisib with CRT was feasible and active, though escalation to the standard weekly cisplatin dose of 40 mg/m2 was not possible. Our data suggests that TRAF3/CYLD mutant SCCHN may be susceptible to PI3K inhibition whereas PI3K pathway activation appeared to be associated with poor outcomes in this limited dataset.

Clinical Cancer Research
Northwestern University (US), Brigham and Women's Hospital (US), BC Cancer Agency (CA), Emory University (US), Morristown Medical Center (US), Moffitt Cancer Center (US), University of Illinois Chicago (US), University of Chicago (US), Northwestern University (PH), Dana-Farber Cancer Institute (US), Dana-Farber Brigham Cancer Center (US)
Good health and well-being
Openalex Percentile: Top 8%
Head and Neck Cancer Studies
DOIOpen Access PDFOpenAlex
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