Purpose: Tumoral programmed cell death ligand-1 (PD-L1) expression is common in human papillomavirus (HPV)–associated head and neck squamous cell carcinoma (HNSCC). We assessed whether a DNA vaccine targeting HPV-16/18 E6/E7 with IL12 adjuvant (MEDI0457) combined with the PD-L1 inhibitor durvalumab could enhance HPV-specific T-cell response and improve outcomes in recurrent/metastatic HPV-16/18–associated HNSCC. Patients and Methods: In this phase Ib/IIa study, immunotherapy-naïve patients with ≥1 previous platinum-containing regimen (neoadjuvant/adjuvant therapy or for recurrent/metastatic disease) received MEDI0457 7 mg intramuscularly with electroporation on weeks 1, 3, 7, and 12, then every 8 weeks, plus durvalumab 1,500 mg intravenously on weeks 4, 8, and 12, then every 4 weeks, until confirmed progression and/or unacceptable toxicity. Coprimary objectives were safety and objective response rate (ORR; H0: ORR ≤ 15%); secondary objectives included 16-week disease control rate (DCR-16), overall survival (OS), and progression-free survival (PFS). Results: Of 35 treated patients, 29 were response evaluable (confirmed HPV-associated disease; received both agents). ORR was 27.6% [95% confidence interval (CI), 12.7–47.2; four complete responses, four partial responses]; responses were independent of PD-L1 tumor-cell expression (≥25% vs. 2-fold increase in tumor-infiltrating CD8+ T cells. Conclusions: MEDI0457 plus durvalumab was well tolerated. While the primary efficacy endpoint was not reached, clinical benefit was encouraging.

We hypothesized the combination of cetuximab and nivolumab would improve survival in recurrent and/or metastatic (R/M) HNSCC by providing synergy in cancer control and evaluated toxicities and efficacy of the combination. Effects of sequential administration of cetuximab and anti-Programmed Cell Death-1 checkpoint inhibitors (CPI) were also explored. Patients who failed at least one line of palliative treatment for incurable HNSCC were treated with cetuximab 500 mg/m² IV on Day (D)-14 as a lead-in followed by cetuximab 500 mg/m² IV and nivolumab 240 mg/m² IV on D1 and D15 every 28-D cycle. Electronic health record-derived real-world data (RWD) were used to explore sequential treatment effects of CPI and cetuximab. A total of 45 evaluable patients were analyzed, and 31/45 (69%) patients had prior exposure to either CPI or cetuximab. The only grade 4 treatment-related adverse event was cetuximab infusion reaction in one patient. The 1-year progression-free survival (PFS) and overall survival (OS) rates were 19% and 44%, respectively. Although patients with no prior CPI (23/45, 51%) showed a trend for more favorable PFS relative to patients with prior CPI (22/45, 49%), the improvement in the 1-year OS did not reach the statistical threshold. For evaluation of sequential CPI and cetuximab treatment effects, we selected RWD-cetuximab cohort with 173 patients and RWD-CPI cohort with 658 patients from 6862 R/M HNSCC. Our result suggested patients treated with RWD-cetuximab after RWD-CPI had worse OS compared to no prior RWD-CPI (HR 1.81, 95% CI 1.02–3.16). Our data suggest the combination of cetuximab and nivolumab is well tolerated. Optimal sequencing of cetuximab and CPI may have an impact in prognosis and requires further evaluation.

Laryngeal squamous cell carcinoma is the second most common head and neck cancer. Its pathogenesis is strongly associated with smoking. The management of this disease is challenging and mandates multidisciplinary care. Currently, accepted treatment modalities include surgery, radiation therapy, and chemotherapy—all focused on improving survival while preserving organ function. Despite changes in smoking patterns resulting in a declining incidence of laryngeal cancer, the overall outcomes for this disease have not improved in the recent past, likely due to changes in treatment patterns and treatment-related toxicities. Here, we review emerging concepts and novel strategies in the use of radiation therapy in the management of laryngeal squamous cell carcinoma that could improve the relationship between tumor control and normal tissue damage (therapeutic ratio).

Importance: Nasopharyngeal carcinoma (NPC) presents unique challenges in nonendemic regions, with varying patient characteristics and outcomes compared with endemic populations.Objective: To fill gaps in the current understanding of NPC by focusing on a US population, comparing patient characteristics and treatment outcomes with endemic populations, and identifying key factors to inform management and follow-up protocols in Western health care settings.Design, Setting, and Participants: This retrospective cohort study included patients with NPC treated at a single large US tertiary academic medical center from 2000 to 2023. The study analyzed patient demographics, tumor characteristics, treatment modalities, and survival outcomes. Data were analyzed from January to July 2024.Main Outcomes and Measures: Overall survival (OS), progression-free survival (PFS), and recurrence-free survival, stratified by patient characteristics, tumor types, Epstein-Barr virus (EBV) status, and p16 expression.Results: The sample included 159 adult patients with NPC (median [range] age, 53.5 [18-90] years; 117 [73.6%] male), with 23 African American patients (15.3%), 21 Asian patients (14.0%), and 106 White patients (70.7%). World Health Organization type III tumors predominated (88 patients [68.8%]), followed by type II (25 patients [19.5%]) and type I (15 patients [11.7%]). EBV positivity rates varied significantly by race (Asian: 13 patients [81.3%]; African American: 17 patients [63.0%]; White: 40 patients [47.0%]; P = .03) and WHO type (type III: 50 patients [72.5%]; type II: 10 patients [48.0%]; type I: 0 patients; P < .001). p16 status, a proxy for human papillomavirus status, did not vary by race but did vary by histopathologies (type III: 12 patients [28.5%]; type II: 12 patients [63.0%]; type I: 3 patients [43.0%]; P = .04). On Kaplan-Meier curves, stratifying p16 by EBV status eliminated its assumed association with OS. Multivariate analysis revealed that increasing age (hazard ratio [HR] per 1-year increase, 1.03 [95% CI, 1.00-1.05]; P = .04) and former smoking status (HR, 2.29 [95% CI, 1.03-5.10]; P = .04) were associated with inferior OS, while WHO type III tumors were associated with better OS compared with type I (HR, 0.38 [95% CI, 0.17-0.87]; P = .02). Male sex was associated with worse PFS (HR, 5.35 [95% CI, 1.23-23.30]; P = .03). For recurrence-free survival, former smokers (HR, 25.24 [95% CI, 2.56-249.23]; P = .006), current smokers (HR, 44.97 [95% CI, 2.27-892.10]; P = .01), and patients with advanced stages (IVa/b) (HR, 261.34 [95% CI, 3.96-17 258.06]; P = .009) had significantly increased risk.Conclusions and Relevance: This cohort study contributes to the evolving body of knowledge on NPC in nonendemic regions, finding a shift toward WHO type III tumors and underscoring the association of EBV status with survival outcomes, while highlighting the lack of association between human papillomavirus status and outcomes. Smoking history, advanced stage at diagnosis, male sex, and increasing age emerged as adverse factors. Notably, WHO type I tumors demonstrated particularly poor outcomes, highlighting the need for more intensive follow-up in this subgroup.

Trans-oral robotic surgery (TORS) has emerged as an important surgical treatment option in the management of human papillomavirus (HPV)-positive and -negative oropharynx cancer. However, treatment selection is paramount to ensure that patients will not require multimodality adjuvant therapy. In this study, we determined predictors of adjuvant therapy in TORS-treated patients. The National Cancer Database (NCDB) was used to identify patients with newly diagnosed clinical T1-T4, N0-N3 oropharyngeal squamous cell carcinoma who underwent TORS between 2010–2016. Kaplan–Meier survival analysis was used to estimate overall survival (OS). A total of 2999 patients were studied, and the five-year OS for the entire cohort was 82.5%, and for HPV-positive and -negative cohorts it was 88.3% and 67.9%, respectively (p < 0.001). Among all patients treated with TORS, 35.1% of patients received no additional treatment, 33.5% received adjuvant radiation alone (RT), and 31.3% received adjuvant chemoradiation. The N stage was pathologically upstaged in 629 (20.9%) patients after TORS. Patients treated at higher-volume centers were more likely to have negative surgical margins (OR: 0.96, 95% CI: 0.94, 0.98, p < 0.001), but this did not influence the receipt of adjuvant therapy. The high rate of adjuvant multimodality treatment after TORS suggests a need for improved patient selection. Limitations of this study, including lack of data on loco-regional control, progression free survival, acute and late toxicities, and utilization of pretreatment PET/CT imaging, should be addressed in future studies.