Ravindra Uppaluri

Purpose: To determine the maximum tolerated dose (MTD) of the pan–class I PI3K inhibitor buparlisib (B) in combination with weekly cisplatin and radiotherapy (RT) 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 [American Joint Committee on Cancer (AJCC), Seventh Edition] and >10 pack-year tobacco use history were enrolled. Patients received B during a 2-week run-in phase and during chemoradiotherapy (CRT) consisting of standard 70 Gy of RT 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 [B 40 mg daily and cisplatin (CDDP) 30 mg/m2/week]}. Ninety-one percent (21/23) had stage IV disease. Human papillomavirus (HPV) was detected in 15 of 18 cases with oral/oropharyngeal disease. The median follow-up was 23 months. Recurrence was detected in five patients among whom four had evaluable tumor samples. Fifty-percent (2/4) of patients with evaluable tumor samples were characterized by activation of the PI3K pathway. In five patients whose disease responded during the 2-week run-in phase with B alone, 3 of 4 with sequencing data showed loss-of-function mutations in either tumor necrosis factor receptor–associated factor 3 (TRAF3) or cylindromatosis lysine deubiquitinase (CYLD). Preclinical studies with mutations in TRAF3 or CYLD modeled 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 the NF-κB pathway. Conclusions: Low-dose B with CRT was feasible and active in this high-risk cohort, although escalation to the standard weekly cisplatin dose of 40 mg/m2 was not possible. Our data suggest that TRAF3/CYLD-mutant SCCHN may be susceptible to PI3K inhibition with B, whereas PI3K pathway activation seemed to be associated with poor outcomes in this limited dataset.

Outcomes for patients with resectable head and neck squamous cell carcinoma (HNSCC) remain suboptimal despite multimodal therapy, with high rates of recurrence and patients suffering from toxicity of treatments. Immune checkpoint inhibitors, which have transformed the management of recurrent and metastatic disease, have been advanced into the perioperative and adjuvant settings. Recent phase III trials mark a turning point: the addition of adjuvant nivolumab improved disease‐free survival in pathologic high‐risk resected HNSCCs, while perioperative pembrolizumab significantly prolonged event‐free survival in resectable locally advanced HNSCCs, supporting a shift toward integrated perioperative immunotherapy strategies. Although the former approach fits into a conventional adjuvant framework, biological insights suggest that neoadjuvant delivery enables effective immune priming extending therapeutic approaches. Together, these advances redefine therapeutic strategies in resectable HNSCC and highlight the potential of perioperative immunotherapy to improve long‐term outcomes.

Quantification of PD-L1+ cell densities by multispectral imaging

Kaplan-Meier estimates of DFS by TP53 disruptive mutation status

Quantification of soluble serum analytes

Identification and visualization of circulating immune cell subsets by flow cytometry

Quantification of circulating immune cell subsets

Representativeness of Study Participants

Antibodies and dilutions used for multispectral imaging

Antibodies and dilutions used for spectral flow cytometry