ABSTRACT Purpose The neutrophil‐to‐lymphocyte ratio (NLR) is a prognostic marker in cancers treated with immune checkpoint inhibitors (ICI), reflecting the link between inflammation and cancer immune response. This study examines NLR's prognostic value in head and neck squamous cell carcinoma (HNSCC) patients receiving neoadjuvant ICI therapy, focusing on its potential as an independent predictor of overall survival (OS) and disease‐free survival (DFS). Methods We conducted a retrospective cohort study including three neoadjuvant trials: durvalumab ± metformin, nivolumab ± tadalafil, or nivolumab ± BMS‐986205 from 2017 to 2022. Pre‐treatment NLR was calculated using absolute neutrophil and absolute lymphocyte counts obtained before neoadjuvant ICI initiation. The optimal pre‐treatment NLR cut‐off was identified using receiver operating characteristic (ROC) curve analysis. OS and DFS were assessed using Kaplan–Meier and multivariable Cox proportional hazards regression models. Results A total of 97 patients met inclusion criteria. NLR < 4.14 was associated with improved overall survival (HR 0.07, 95% CI 0.01–0.30, p < 0.001) and DFS (HR 0.21, 95% CI 0.08–0.54, p = 0.001) compared to NLR ≥ 4.14. NLR < 4.14 remained independently associated with improved OS (HR 0.14, 95% CI 0.02–0.78, p = 0.025) and DFS (HR 0.25, 95% CI 0.07–0.87, p = 0.030) on multivariable Cox regression. The survival benefit of NLR < 4.14 persisted after sub‐stratification for p16 status, ICI pathologic response status, and ICI trial. Conclusion Low NLR was independently associated with improved OS and DFS among patients with HNSCC who received neoadjuvant ICI. These findings suggest the potential utility of the NLR in improving patient selection.

QuestionAfter neoadjuvant immune checkpoint inhibition (ICI), is achieving a pathologic treatment response associated with improved overall and/or disease-free survival in mucosal head and neck squamous cell carcinoma (HNSCC)?FindingsIn this systematic review and meta-analysis of 11 studies including 368 adult patients (aged >= 18 years) with mucosal HNSCC, both partial pathologic response (<= 50% residual viable tumor) and major pathologic response (<= 10% residual viable tumor) were associated with improved disease-free survival.MeaningThese findings suggest that pathologic treatment response may be a possible surrogate end point for disease-free survival in patients receiving neoadjuvant ICI for mucosal HNSCC. ImportanceNumerous phase 2 trials have evaluated the efficacy of neoadjuvant immune checkpoint inhibition (ICI) for mucosal head and neck squamous cell carcinoma (HNSCC), using some degree of pathologic treatment response as a primary or secondary end point. However, whether pathologic treatment response is a meaningful surrogate end point for survival has yet to be determined.ObjectiveTo systematically assess the association between pathologic treatment response and overall survival (OS) and disease-free survival (DFS) after neoadjuvant ICI.Data SourcesA systematic search of the PubMed, OVID Medline, Embase, CINAHL, and Cochrane databases was performed from January 1, 2000, through May 31, 2025.Study SelectionPeer-reviewed studies investigating neoadjuvant ICI for the treatment of mucosal HNSCC in patients 18 years and older were identified. Full-length English-language articles that presented pathologic treatment response and survival data (OS and/or DFS) and any association between the 2 were included.Data Extraction and SynthesisThree blinded reviewers independently extracted study characteristics, pathologic treatment response data, and survival data, including hazard ratios (HRs) and CIs when available, according to PRISMA guideline. Data were compiled for statistical analysis to calculate DFS, OS, and HRs using a random-effects model. The I2 index was used to report data heterogeneity.Main Outcomes and MeasuresHRs for the association of pathologic treatment response with DFS and OS.ResultsEleven trials involving 451 patients met inclusion criteria, with 368 patients included in this meta-analysis. Nine nonrandomized and 2 randomized studies were included, including 7 cohort studies, 2 randomized clinical trials, and 2 retrospective cohort studies, each with a different neoadjuvant ICI regimen. Pooled analysis demonstrated that overall (primary tumor plus lymph node) partial pathologic response (PPR; <= 50% residual viable tumor; HR, 0.53; 95% CI, 0.28-0.97; I2 = 2.1%) and major pathologic response (MPR; <= 10% residual viable tumor; HR, 0.34; 95% CI, 0.12-0.93; I2 = 0.0%) were both associated with improved DFS up to 2 years. PPR and MPR were not associated with improved OS. Nine of 11 studies were at low risk of bias.Conclusions and RelevanceStudy findings suggest that overall PPR and MPR are associated with improved DFS. These data provide additional support for the potential use of pathologic treatment response as a surrogate for DFS after neoadjuvant ICI in resectable mucosal HNSCC. This systematic review and meta-analysis assesses the association between achievement of a pathologic treatment response and improvement in disease-free survival in head and neck squamous cell carcinoma (HNSCC).

Objective Oral tongue squamous cell carcinoma (OTSCC) has traditionally affected older males with tobacco and alcohol exposure. Multiple population-based studies demonstrate a rising trend in OTSCC among younger individuals. Several studies indicate that young adults may experience higher rates of local recurrence and disease relapse. We sought to determine whether variations in somatic structural variants (SVs) and copy number variants (CNVs) could explain differences in clinical outcomes between young and old OTSCC patients. Study Design Retrospective cohort study. Setting Tertiary academic medical center. Methods Optical genomic mapping (OGM) was performed on DNA isolated from fresh-frozen tumors and whole blood from 8 patients younger than 40 and 13 patients older than 40 to identify tumor-specific SVs. Wilcoxon rank sum tests and contingency table analyses determined statistical significance of differences between old and young tumors. Results Mean ages of young and old patients were 35.6 ± 4.6 and 71.5 ± 9.2 years, respectively. Young patients were more likely to present with T3/T4 primary tumors (OR = 3.75) undergo chemoradiation (OR = 8.2), and experience recurrence (OR = 7.2). They were less likely to be female (OR: 0.23) and less likely to have tobacco (OR: 0.55) or alcohol use (OR: 0.3). Genomic analysis showed a trend to higher genomic instability and increased aneuploidy in OTSCC from young patients and higher frequencies of PTPR family gene deletions (OR: 2.7), particularly PTPRD (OR: 6.0). Tumors with these gene alterations exhibited significantly more SVs and CNVs (p < 0.05). Conclusion We found that PTPR family gene deletions, previously implicated in head and neck cancers, may contribute to genomic instability in young OTSCC.

Background Intraoperative free flap failure necessitates prompt intraoperative decision-making on alternative reconstructive strategies. In this study, we investigate the etiology and management of intraoperative flap loss.Methods Retrospective review between 2010 and 2024 at 6 institutions.Results There were 7423 free flaps performed with 46 instances of intraoperative flap failure (0.62%). The most common recipient subsite was oral cavity (27/46, 57%). Anterolateral thigh (ALT) was the most common flap type to fail (18/46, 39%), followed by the fibula (15/46, 32%). The most common reasons for total failure were clotting without observable vessel abnormality (12/35, 34.3%), poor quality perforator (11/35, 31.4%), and vessel spasm or intimal abnormality leading to clotting (8/35, 22.9%). The most common acute management was converting to an additional free flap intraoperatively (28/46, 60.9%).Conclusions Flap failure intraoperatively is rare. The majority of cases were acutely managed with an additional flap to provide defect coverage.

OBJECTIVE:To assess whether the Thyroid Informed Surgical Consent Augmenting Video (TISCAV) improves knowledge retention, reduces decisional conflict, alleviates anxiety, and enhances satisfaction in thyroidectomy decision-making compared to standard verbal consent. STUDY DESIGN:Randomized controlled trial. SETTING:Academic tertiary care center with urban outpatient and community-based clinics. METHODS:Forty-nine English-speaking adults scheduled for thyroid surgery were randomized to receive either standard verbal consent alone (control) or TISCAV followed by standard consent (intervention). Forty-three completed preoperative assessments and were included in the analysis. Knowledge was assessed before and after consent. Visual Analog Scale for Anxiety (VAS-A), Decisional Conflict Scale (DCS), and Satisfaction with Decision Scale (SDS) were measured preoperatively; SDS, Decision Regret Scale (DRS), and anxiety were reassessed at 22 and 100 days postoperatively. RESULTS:Both groups demonstrated significant knowledge gains post-consent (P < .0001), with no significant difference between groups (P = .1812). Patients with malignant/suspicious cytopathology had lower decisional conflict than those with benign findings (P = .03); scores in indeterminate cases trended similarly (P = .11). Among patients with indeterminate cytopathology, decisional conflict did not differ significantly (P = .06), while preoperative satisfaction was lower in the video group (P = .02); group differences resolved postoperatively (P ≥ .55). CONCLUSION:TISCAV and standard consent both improved knowledge acquisition. While video-based consent may transiently increase decisional conflict and reduce satisfaction among patients with indeterminate pathology, these effects did not persist postoperatively. Video tools may serve as a safe and accessible adjunct to verbal consent.

Abstract Introduction Head and neck squamous cell carcinoma (HNSCC) displays substantial immune heterogeneity that shapes response and prognosis to immune checkpoint inhibitor (ICI) therapy. Unlike biomarkers for response to ICI therapy, there is still no understanding of resistance mechanisms. To address this need, we performed baseline pathway enrichment analyses across TME subtypes and clinical outcomes. Using pairwise comparisons, we identified reproducible “breakpoints” within the Cancer Immunity Cycle (CIC) that inform future precision-therapeutic strategies. Methods Bulk RNA-sequences from TCGA HNSCCs HPV+ (n=94) and HPV- (n=415) and an our neoadjuvant ICI cohorts HPV+ (n=53) and HPV- (n=29) were assigned TME subtypes: Immune Enriched (IE), Immune Enriched Fibrotic (IEF), Fibrotic (F) and Depleted (D) using published signatures. Unbiased and supervised GSEA were performed, contrasting TME subtype pairs to identify enriched pathways mapping to CIC steps. Step activity was defined as Bioprocess Count × mean NES. Connectivity of CIRCOS plot chords, denoting interplay between steps, was quantified by shared processes × mean STRING signal for protein-protein interaction. CIRCOS plots were generated for TCGA and trial cohorts. Survival analyses used Cox and Kaplan-Meier models (p<0.05). Results HPV+ tumors exhibited a global reduction of stepwise CIC activities compared with HPV-tumors. As expected, CIC mapping revealed consistent low activity in antigen release (step 1) and antigen presentation (step 2), with variable loss of tumor cell killing (step 7) in F/D tumors. IE tumors maintained near-intact steps, IEF showed partial attenuation, whereas F showed breaks in steps 1-2, and D activity was minimal. CIC analysis revealed novel subpopulations within a given TME subtype, differentiated by survival. TCGA survival analyses showed statistically significant higher adaptive immune/TCR activity improved outcomes in IE tumors. In HPV- F tumors, a senescence/autophagy gene set linked to CIC predicted worse progression-free survival (HR=7.06, p=0.03). In contrast, HPV+ D tumors exhibited activity of a senescence gene set strongly associated with improved OS (HR=0.209, p<0.001). Phenotype-level survival (HPV-agnostic) showed significantly worse outcomes for F vs IE tumors. These patterns were reproducible in our clinical cohort. Future pathologic response to ICI mirrored CIC integrity, with higher response rates in IE/IEF, but did not reach statistical significance. Conclusion CIC modeling across independent cohorts reveals recurrent immune breakpoints in HNSCC, particularly in antigen release and presentation. This novel approach to parsing the TME and CIC activity may be valuable for predictive biomarker discovery, pertaining to response to ICI therapy. Citation Format: Sarah R. Harrington, Daniel Uralov, Sophia Linguiti, Hannah Kenny, Parvesh Kumar, Janvi J. Shukla, Marianna Nicodemi, Ian Argento, Emma J. Anisman, Eloise Freitag, Adam J. Luginbuhl, Larry Harshyne, Zhao Lin, Alban J. Linnenbach, Ubaldo E. Martinez-Outschoorn, Joseph M. Curry. Breaks in the cancer immunity cycle correlate with response-predictive HNSCC immune microenvironment phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4188.

Introduction Current guidelines for the management of metastatic squamous cell carcinoma of unknown primary (SCCUP) recommend submission of suspicious primary sites for frozen section analysis (FSA). This study aims to investigate the diagnostic accuracy of FSA for identification of HPV-associated SCCUP. Methods A retrospective cohort study of patients with biopsy-proven p16-positive SCCUP who underwent diagnostic operation at two tertiary care institutions was performed. Sensitivity, specificity, PPV, and NPV of diagnostic FSA were assessed. Results 77 patients were included in analysis. 66 patients underwent definitive TORS (diagnostic TORS operation with subsequent neck dissection after identification of the occult primary tumor), 7 patients underwent diagnostic TORS (TORS to identify occult primary tumor, no neck dissection), and 4 patients underwent direct laryngoscopy and biopsy only. Primary tumors were identified in 63 patients (82%) with a mean tumor size of 1.1 cm. There was no significant difference in size between patients whose tumor was identified on FSA (mean 1.1 cm) and on permanent only (mean 0.9 cm) (p = 0.26). The sensitivity, specificity, PPV, and NPV of FSA for SCCUP was 86%, 100%, 100%, and 86%, respectively. Diagnostic frozen specimens included 52 direct laryngoscopy biopsies and 69 TORS excisions. In the biopsies, sensitivity was 100% and NPV was 100%, whereas in the TORS-excised specimens, sensitivity was 77% and NPV was 77%. Conclusions In this case series of 77 patients with SCCUP, the sensitivity and NPV of FSA for identification of the primary tumor was over 85%. FSA is valuable during diagnostic operation for SCCUP.

2577 Background: Standard treatment options for HNSCC include chemotherapy, radiation, surgery, and immunotherapy. Immune Checkpoint Inhibitors (ICI) are safe and improve survival in platinum-refractory and metastatic HNSCCs. Further studies are needed to efficiently stratify patients who may benefit from ICIs. MYC-V1 is a family of oncogenes, induced by MYC signaling, that is negatively correlated with response to ICI in HPV+ HNSCC. Non-invasive Biomarkers (NiBs) identifying patients with low MYC-V1 expression may aid in predicting response to ICIs. Small extracellular vesicles (sEVs) are membrane-bound mediators of intercell communication that are present in circulation, serving as a promising source of NiBs. The Let-7 family of tumor suppressors are negative regulators of the MYC-V1 gene family and exhibit low expression in HNSCC compared to healthy controls. Let-7 family members, such as Let-7d and Let-7c, may play a role in ICI responsiveness via PD-L1 and MYC mRNA degradation, respectively. Here, we analyze the miRNA profile of sEVs from patients enrolled in a randomized Phase I clinical trial undergoing Neoadjuvant Nivolumab therapy. (NCT03238365). Methods: Plasma was collected before and after treatment (N=24) with ICI. 12 patients were included and stratified based on HPV status (6 HPV-, 6 HPV+) and pathologic treatment response (pTR) (6 Responders [R], 6 Nonresponders [NR]). pTR >20% of tumor surface area as graded by two pathologists was R; 0% was NR. sEVs were isolated via immunoprecipitation targeting tetraspanins CD63/9/81. miRNA was isolated and NGS was performed. Analysis was performed using Python and Biomni. Log2FC (FC) compared expression levels between groups and a False Discovery Rate (FDR) <.05 was significant. Results: 189 miRNAs were detected in HNSCC sEVs. Analysis comparing HPV+ R vs NR revealed 48 miRNAs with significantly different levels between these pretreatment groups. 47 were more abundant in R; 1 was less abundant. miRNAs found at higher levels in HPV+ R include the Let-7 family. Let-7d was most abundant (FC: 2.26, FDR 0.04), with a family (Let-7a,b,d,f,g,i) FC range of 1.63-2.26 (FDR 0.03-0.05). Following treatment with ICI, HPV+ patients had increased Let-7c levels (FC 4.71, FDR 0.02) compared to pretreatment. Analysis of HPV– R vs NR showed 0 miRNA that met statistical significance. Conclusions: Here, we show that ICI-responsive HPV+ HNSCC is associated with high levels of circulating, sEV-contained Let-7 family members and that Let-7c is increased in response to ICI in those same patients. We propose that a MYC-V1-suppresive, PD-L1-destabilizing mechanism may be present in patients with higher than average Let-7 expression, conferring sensitivity to ICI, and that sEV-associated Let-7 levels may serve as NiBs to identify these patients as favorable ICI candidates prior to treatment.

Free flap reconstruction has become the standard of care for complex midfacial defects. Each reconstruction requires a highly individualized, defect-driven approach with special consideration to restoration of midface buttresses, orbital and skull base support, oronasal separation, and dental rehabilitation. The subscapular system of flaps is a workhorse of midface reconstruction and can meet the demands of virtually any defect as it allows for precise reconstruction of multiple buttresses with significant soft tissue availability. The fibula flap provides a reliable option for bony reconstruction, particularly when dental rehabilitation is desired. Adequate flap volume should be prioritized to support critical neurovascular structures and withstand radiation therapy. Pedicle management can be challenging due to the distance of flap inset from the neck vasculature and may require the use of small-caliber distant vessels, grafting, or flow-through techniques. Virtual surgical planning (VSP) allows for conceptualization of complex midfacial defects and facilitates reconstructive planning with the use of cutting guides, osteotomies, and customized hardware.

Importance:Numerous phase 2 trials have evaluated the efficacy of neoadjuvant immune checkpoint inhibition (ICI) for mucosal head and neck squamous cell carcinoma (HNSCC), using some degree of pathologic treatment response as a primary or secondary end point. However, whether pathologic treatment response is a meaningful surrogate end point for survival has yet to be determined. Objective:To systematically assess the association between pathologic treatment response and overall survival (OS) and disease-free survival (DFS) after neoadjuvant ICI. Data Sources:A systematic search of the PubMed, OVID Medline, Embase, CINAHL, and Cochrane databases was performed from January 1, 2000, through May 31, 2025. Study Selection:Peer-reviewed studies investigating neoadjuvant ICI for the treatment of mucosal HNSCC in patients 18 years and older were identified. Full-length English-language articles that presented pathologic treatment response and survival data (OS and/or DFS) and any association between the 2 were included. Data Extraction and Synthesis:Three blinded reviewers independently extracted study characteristics, pathologic treatment response data, and survival data, including hazard ratios (HRs) and CIs when available, according to PRISMA guideline. Data were compiled for statistical analysis to calculate DFS, OS, and HRs using a random-effects model. The I2 index was used to report data heterogeneity. Main Outcomes and Measures:HRs for the association of pathologic treatment response with DFS and OS. Results:Eleven trials involving 451 patients met inclusion criteria, with 368 patients included in this meta-analysis. Nine nonrandomized and 2 randomized studies were included, including 7 cohort studies, 2 randomized clinical trials, and 2 retrospective cohort studies, each with a different neoadjuvant ICI regimen. Pooled analysis demonstrated that overall (primary tumor plus lymph node) partial pathologic response (PPR; ≤50% residual viable tumor; HR, 0.53; 95% CI, 0.28-0.97; I2 = 2.1%) and major pathologic response (MPR; ≤10% residual viable tumor; HR, 0.34; 95% CI, 0.12-0.93; I2 = 0.0%) were both associated with improved DFS up to 2 years. PPR and MPR were not associated with improved OS. Nine of 11 studies were at low risk of bias. Conclusions and Relevance:Study findings suggest that overall PPR and MPR are associated with improved DFS. These data provide additional support for the potential use of pathologic treatment response as a surrogate for DFS after neoadjuvant ICI in resectable mucosal HNSCC.

9515 Background: Surgical resection of locally advanced basal cell carcinoma of the head and neck (BCCHN) often carries significant morbidity. This phase II study seeks to investigate the response to neoadjuvant cemiplimab on surgical morbidity in BCCHN patients. Methods: In this prospective, nonrandomized, multicenter, phase II trial (NCT05929664), anti-PD1 and HHI-naive patients with resectable BCCHN received 2 to 6 cycles of cemiplimab (350mg IV Q21 days), followed by surgical resection or biopsy. Surgical plan at enrollment required functional organ sacrifice (orbit, eyelid, ear, nose, lip, or facial nerve). RECISTv1.1 tumor measurements were performed every 2 cycles to determine primary endpoints of ORR and DCR. Patients with PD (>20% growth) or SD with 5 to 20% growth at any assessment were offered HHI or surgery. Patients with CR at any assessment proceeded to surgery or directed biopsy. Secondary endpoints included: surgical benefit rate (SBR, defined as rate of functional organ preservation, determined by the investigator, comparing surgical resection to surgical plan at time of enrollment), rate of pCR, safety (CTCAEv5.0), and quality of life (FHNSI, FACE-Q and VFQ-25). Correlative studies include examination of the tumor immune microenvironment related to functional changes in immune cell composition. Results: Between August 2023 and September 2025, 33 patients were enrolled: 40-89 yo; 22 M/11 F; sites of disease included eyelid (n=17), orbit (n=4), nose(n=5), lip (n=1), facial nerve (n=1), ear (n=1), and scalp or cheek (n=5). 30 were evaluable: 23 (76.7%) completed 6 cycles. Among the remaining 7 patients, 1 experienced CR after 4 cycles; 1 was taken off therapy for grade 3 myalgia; 1 had SD with 5-20% growth and 2 had PD, and were taken to surgery per protocol; 2 chose surgery due to stagnant response after initial PR. 12 patients (40%) experienced a grade 1-2 treatment-related AE. 1 patient (3.33%) experienced a grade 3 treatment-related AE as above. The ORR was 66.67%. The DCR was 90.0%. Based on RECISTv1.1 criteria, 3.33% (n=1) had CR, 63.33% (n=19) had PR, 23.33% (n=7) had SD, and 10.0% (n=3) had PD as best overall response 8 patients (26.67%) achieved pCR. The SBR was 43.3%, with functional preservation of the eyelid (n=7), nose (n=2), lip (n=1), ear (n=1), or orbit (n=1). Conclusions: Neoadjuvant cemiplimab had an acceptable safety profile and shows promising efficacy in the treatment of advanced, surgically-resectable BCCHN. This novel approach may alleviate the morbidity of subsequent surgical resection. (NCT05929664 supported by Regeneron Pharmaceuticals, Inc.). Clinical trial information: NCT05929664 .

BACKGROUND:Flow-through flaps (FTFs) are an advanced technique in which a free flap is anastomosed to the pedicle of another free flap to reconstruct extensive head and neck defects when recipient vessels are scarce. METHODS:A multi-institutional cohort of FTFs used for head and neck reconstruction were reviewed. For comparison, FTF outcomes were compared to free flaps that required vein grafts (VG) to reach distant recipient vessels. RESULTS:A total of forty-two patients underwent surgery using a FTF configuration, including 32 simultaneous and 10 sequential FTFs. There were no instances of flap failure compared to a 7% flap failure rate in the VG group (n = 54). The overall postoperative complication rate was 28% compared to a 46% complication rate in the VG group (p = 0.093). CONCLUSION:FTFs are a reliable option for reconstruction of extensive head and neck defects when recipient blood vessel availability is limited.

Many solid tumors, including head and neck squamous cell carcinoma (HNSCC), are characterized by the dysregulation of metabolic functions, including accelerated glycolysis. This results in accumulation of intracellular lactate, which in turn leads to an increased expression of monocarboxylate transporters (MCT) family members to export lactate. The MCT 1 inhibitor AZD3965 has been developed as a targeted therapy, as it can increase intracellular lactate concentration resulting in tumor cell death, however translation into clinical trials has been challenging due to off target toxicity. The goal of this work was to develop a platform for targeted delivery of AZD3965 utilizing a surfactant stabilized microbubble (SE61) and ultrasound. AZD3965 was successfully loaded into SE61, resulting in a microbubble mean size of 1.58 +/- 0.08 mu m, a mean microbubble concentration of 5.58 +/- 1.44 x 108 microbubbles/mL and an average AZD3965 loading of 45.2 +/- 3.5 mu g/mL of SE61 microbubbles. The initial tolerability and ability to improve tumor control by ultrasound mediated microbubble delivery of the MCT 1 inhibitor to HNSCC tumor model was also evaluated in vivo. SE61 microbubbles loaded with AZD3965 were well tolerated, were imaged and successfully destroyed at tumor sites using ultrasound. Future studies will likely require a combination of multiple treatment doses, increased drug loading, and/or multiple inhibitors as no significant tumor response to treatment was observed in vivo. Overall, this study showed the feasibility of loading the MCT 1 inhibitor AZD3965 onto the SE61 microbubble platform for targeted ultrasound mediated delivery to HNSCC.

TPS9606 Background: Surgical resection of locally advanced basal cell carcinoma of the head and neck (laBCCHN) is often not feasible due to tumor size and proximity to vital structures with risk of significant deformity. Prior data suggest that neoadjuvant therapy could have a major impact on preserving critical structures, especially in the head and neck. The PD-1 inhibitor cemiplimab (REGN2810) has shown significant response rates for metastatic BCC after progression or intolerance of Hedgehog inhibitor (HHI) therapy. However, cemiplimab has not been investigated in the neoadjuvant setting for laBCCHN. To address this gap, this multi-center phase II study seeks to assess the response to neoadjuvant cemiplimab in the treatment of HHI-naïve laBCCHN. Methods: Patients with HHI-naive laBCCHN will receive response-adaptive, neoadjuvant IV cemiplimab 350mg every 3 weeks for an initial 2 cycles. The primary endpoint is the fraction of patients demonstrating clinical response after 2 cycles. All patients will undergo RECIST v1.1 response assessment by CT or MRI, and if not radiographically measurable, caliper measurement will be utilized to evaluate the primary endpoint. Those with RECIST v1.1 progression or stable disease with >5% growth will be considered non-responders and will proceed with surgery or other standard of care (e.g. HHI). Patients with stable disease (+5% to -20%) and RECIST v1.1 response will be considered responders and will continue to additional cycles of therapy and clinical assessment (imaging every 2 cycles, total cycles = 6). Patients with complete clinical response prior to completing 6 cycles may proceed to surgery for resection or biopsy of tumor site. Secondary endpoints include rate of functional organ preservation, pathologic response, safety, and quality of life. Correlative analyses will be performed on pre- and post-cemiplimab tumor specimens and peripheral blood samples to assess treatment-related changes in the immune microenvironment related to functional changes in immune cell composition. This study is open with 22 patients enrolled at the time of submission, with a planned total enrollment of 35 patients. Clinical trial information: NCT05929664 .

Supplementary Figure S5 from Immunostimulatory Cancer-Associated Fibroblast Subpopulations Can Predict Immunotherapy Response in Head and Neck Cancer

Supplementary Figure S3 from Immunostimulatory Cancer-Associated Fibroblast Subpopulations Can Predict Immunotherapy Response in Head and Neck Cancer

Figure s10. Hallmark pathway enrichment, cell cycle gene expression, and functional network analysis of differentially expressed genes in responders and nonresponders.

Figure s6. Post-treatment changes in immune cell composition across spatial tumor compartments in responders and nonresponders

Importance:While neoadjuvant chemotherapy for head and neck squamous cell carcinoma dates to the earliest multidisciplinary approaches, the introduction of immune checkpoint inhibitors (ICIs) has renewed enthusiasm and research into its use. Although neoadjuvant therapy has remained mostly investigative through single-institutional clinical trials for mucosal head and neck squamous cell carcinoma, new data have emerged to support its use. Observations:A narrative review was conducted by the American Head and Neck Society to address current literature, evolving research, and gaps in knowledge surrounding neoadjuvant therapy. Neoadjuvant ICIs, most notably agents targeting anti-programmed cell death protein 1 (anti-PD-1), are a promising approach for bolstering antitumor immunity prior to ablating local structures. While neoadjuvant therapy may allow for an individualized approach, biomarkers to guide patient selection are limited. Potential benefits include de-escalation of subsequent treatment, but neoadjuvant therapy for curable disease also carries a small but real risk of progression and compromise of curative options. Measures of response include pathologic, clinical, and radiographic, but there are rapidly expanding capabilities in new diagnostics, such as circulating tumor DNA, with the emerging potential to provide objective quantification of disease burden. Further neoadjuvant strategies include response adaptive therapy, such as treatment selection/bioselection or modification of surgery, adjuvant therapy, or definitive treatment. Neoadjuvant ICI trials are summarized in this review. Optimized trial designs and additional research are needed to standardize surrogate outcomes and compare survival to standard treatment. Conclusions and Relevance:Neoadjuvant therapy can be an effective option for precision head and neck oncology bolstered by the advent of anti-PD-1 immunotherapy. However, tools for predicting and assessing treatment response remain limited. Further trials are evaluating adaptive strategies, combinations to increase efficacy, and comparisons to standard approaches.

Importance:Neoadjuvant immunotherapy shows promise in the treatment of head and neck squamous cell carcinoma (HNSCC). Pathologic treatment effect (pTE) is one way to assess response to treatment; however, the association of this response with survival outcomes is not yet clear. The current study sought to determine whether treatment response to neoadjuvant nivolumab, as measured by pTE, correlates with survival outcomes. Objective:To determine whether patients with HNSCC with pathologic response to neoadjuvant nivolumab have improved survival outcomes. Design, Setting, and Participants:A cohort study performing a pooled analysis of 2 multi-institutional neoadjuvant clinical trials (NCT03238365, NCT03854032) enrolling patients from July 2017 to January 2022, was performed. Patients with resectable HNSCC enrolled in 1 of 2 clinical trials and treated with neoadjuvant immunotherapy and surgical resection were included in the analysis. Patients were followed up for a median (range) of 36 (4-72) months. Analysis took place on April 15, 2024. Intervention:Patients were treated with neoadjuvant nivolumab with or without the addition of immunomodulating medications (tadalafil or indoleamine 2,3 dioxygenase inhibitor). Main Outcome and Measure:Pooled analysis was performed to plot Kaplan-Meier 3-year survival outcomes for pTE responders and low or nonresponders. A pTE response threshold was determined using recursive partitioning analysis. Results:Seventy-nine patients were included in the analysis, of whom 40 (51%) had human papillomavirus (HPV)-negative disease. Recursive partitioning analysis identified a pTE threshold of 57%, which was used to define pathologic responders vs low or nonresponders. Pathologic responders with HPV-negative disease had significantly improved disease-free survival (100% for responders vs 66.8% for low or nonresponders; 95% CI, 46.1%-80.6%) and overall survival (100% for responders vs 73.3% for low or nonresponders; 95% CI, 53.4%-85.7%). In patients with HPV-positive disease, disease-free survival was high for both responders (90%; 95% CI, 47.3%-98.5%) and low or nonresponders (92.4%; 95% CI, 72.8%-98.1%). Conclusion and Relevance:This cohort study found that patients with HPV-negative disease who are deemed pathologic responders (pTE >57%) to neoadjuvant nivolumab may have improved survival outcomes compared with those who are low or nonresponders. Not only does this suggest a role for using pathologic response as a surrogate marker, but it further highlights the neoadjuvant strategy in HNSCC as associated with improved survival.