Phase I Study of Fianlimab, a Human Lymphocyte Activation Gene-3 (LAG-3) Monoclonal Antibody, in Combination With Cemiplimab in Advanced Melanoma.

PURPOSE: Coblockade of lymphocyte activation gene-3 (LAG-3) and PD-1 receptors could provide significant clinical benefit for patients with advanced melanoma. Fianlimab and cemiplimab are high-affinity, human, hinge-stabilized IgG4 monoclonal antibodies, targeting LAG-3 and PD-1, respectively. We report results from a first-in-human phase-I study of fianlimab and cemiplimab safety and efficacy in various malignancies including advanced melanoma. METHODS: Patients with advanced melanoma were eligible for enrollment into four cohorts: three for patients without and one for patients with previous anti-PD-1 therapy in the advanced disease setting. Patients were treated with fianlimab 1,600 mg and cemiplimab 350 mg intravenously once every 3 weeks for up to 51 weeks, with an optional additional 51 weeks if clinically indicated. The primary end point was objective response rate (ORR) per RECIST 1.1 criteria. RESULTS: ORRs were 63% for patients with anti-PD-1-naïve melanoma (cohort-6; n = 40; median follow-up 20.8 months), 63% for patients with systemic treatment-naïve melanoma (cohort-15; n = 40; 11.5 months), and 56% for patients with previous neo/adjuvant treatment melanoma (cohort-16; n = 18, 9.7 months). At a median follow-up of 12.6 months for the combined cohorts (6 + 15 + 16), the ORR was 61.2% and the median progression-free survival (mPFS) 13.3 months (95% CI, 7.5 to not estimated [NE]). In patients (n = 13) with previous anti-PD-1 adjuvant therapy, ORR was 61.5% and mPFS 12 months (95% CI, 1.4 to NE). ORR in patients with previous anti-PD-1 therapy for advanced disease (n = 15) was 13.3% and mPFS 1.5 months (95% CI, 1.3 to 7.7). Treatment-emergent and treatment-related adverse events ≥grade 3 (G3) were observed in 44% and 22% of patients, respectively. Except for increased incidence of adrenal insufficiency (12%-G1-4, 4%-G3-4), no new safety signals were recorded. CONCLUSION: The current results show a promising benefit-risk profile of fianlimab/cemiplimab combination for patients with advanced melanoma, including those with previous anti-PD-1 therapy in the adjuvant, but not advanced, setting.

Utility of TTMV-HPV DNA in resolving indeterminate findings during oropharyngeal cancer surveillance.

OBJECTIVES: Clinical and imaging examinations frequently have indeterminate results during cancer surveillance, which can lead to overtreatment and cause psychological and financial harm to the patient. This study addresses the critical need to enhance diagnostic precision and decision-making in the management of HPV-associated oropharyngeal cancer. This study evaluated the utility of tumor tissue-modified viral (TTMV)-HPV DNA to resolve indeterminate disease status following definitive treatment for HPV-associated oropharyngeal cancer. MATERIALS AND METHODS: In this retrospective cohort, patients treated for HPV-associated oropharyngeal cancer at eight U.S. institutions and who received one or more TTMV-HPV DNA tests during post-treatment surveillance between February 2020 and January 2022 were included. RESULTS: Among 543 patients, 210 patients (38.7%; 210/543) experienced one or more clinically indeterminate findings (CIFs) during surveillance, with 503 CIFs recorded. Of those patients with an "indeterminate" disease status at a point during surveillance, 79 were associated with contemporaneous TTMV-HPV DNA testing. TTMV-HPV DNA testing demonstrated high accuracy (97.5%; 77/79) in correctly determining recurrence status. Patients whose disease status was "indeterminate" at the time of a positive TTMV-HPV DNA test were clinically confirmed to recur faster than those whose disease status was "no evidence of disease." Only 3% of patients (17/543) experienced indeterminate TTMV-HPV DNA tests during surveillance. Discordance between TTMV-HPV DNA tests and clinical results was minimal, with only 0.6% (3/543) of patients showing positive tests without recurrence. CONCLUSION: Our findings support the utility of circulating TTMV-HPV DNA in resolving indeterminate disease status and informing the subsequent clinical course.

Negative Predictive Value of Circulating Tumor Tissue Modified Viral (TTMV)-HPV DNA for HPV-driven Oropharyngeal Cancer Surveillance.

PURPOSE: Human papillomavirus (HPV) is causally linked to oropharyngeal squamous cell carcinoma (OPSCC). Consensus guidelines recommend clinical exams and imaging in decreasing frequency as part of posttreatment surveillance for recurrence. Plasma tumor tissue modified viral (TTMV)-HPV DNA testing has emerged as a biomarker which can inform disease status during surveillance. EXPERIMENTAL DESIGN: This retrospective observational cohort study involved 543 patients who completed curative-intent therapy for HPV-associated OPSCC between February 2020 and January 2022 at eight U.S. cancer care institutions. We determined the negative predictive value (NPV) of TTMV-HPV DNA for recurrence when matched to physician-reported clinical outcome data (median follow-up time: 27.9 months; range: 4.5-154). RESULTS: The cohort included mostly men with a median age of 61 who had locoregionally advanced disease. HPV status was determined by p16 positivity in 87% of patients, with a positive HPV PCR/ISH among 55%; while pretreatment TTMV-HPV DNA status was unknown for most (79%) patients. Patients had a mean of 2.6 tests and almost half had three or more TTMV-HPV DNA results during surveillance. The per-test and per-patient sensitivity of the assay was 92.5% [95% confidence interval (CI): 87.5-97.5] and 87.3% (95% CI: 79.1-95.5), respectively. The NPV for the assay was 99.4% (95% CI: 98.9-99.8) and 98.4% (95% CI: 97.3-99.5), respectively. CONCLUSIONS: TTMV-HPV DNA surveillance testing yields few false negative results and few missed recurrences. These data could inform decisions on when to pursue reimaging following first disease restaging and could inform future surveillance practice. Additional study of how pretreatment TTMV-HPV DNA status impacts sensitivity for recurrence is needed.

The Inconsistent Assessment of Quality of Life in Patients Treated for Head and Neck Cancer with Anti-EGFR Inhibitors: A Systematic Scoping Review.

In patients receiving treatment for head and neck cancer (HNC), there is a correlation between quality of life (QoL) scores and treatment outcomes. Higher QoL scores have been associated with improved survival. Despite this, the assessment of QoL in clinical trials varies considerably. Three databases (Scopus, PubMed, and Cinahl) were queried for articles published in English between 2006 and 2022. Two reviewers (SRS and ANT) performed study screening, data extraction, and risk of bias assessment. The authors identified 21 articles that met the inclusion criteria. A total of 5961 patients were evaluated. QoL was reported as average scores for specific variables across five different surveys in 12 included articles. Supplemental QoL data were available in 10 included studies. Critical appraisal of studies indicated a high risk of bias due to the inclusion of trials. There is no standard method for reporting QoL data in clinical trials for HNC patients undergoing treatment with anti-EGFR inhibitors. Future clinical trials should standardize their method for assessing and reporting quality-of-life data to increase patient-centered care and refine treatment choices to optimize survival.

Randomized Phase II Trial of Ficlatuzumab With or Without Cetuximab in Pan-Refractory, Recurrent/Metastatic Head and Neck Cancer.

PURPOSE: Primary or acquired resistance to cetuximab, an antiepidermal growth factor receptor monoclonal antibody (mAb), minimizes its utility in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Aberrant hepatocyte growth factor/cMet pathway activation is an established resistance mechanism. Dual pathway targeting may overcome resistance. PATIENTS AND METHODS: This multicenter, randomized, noncomparative phase II study evaluated ficlatuzumab, an antihepatocyte growth factor mAb, with or without cetuximab in recurrent/metastatic HNSCC. The primary end point was median progression-free survival (PFS); an arm met significance criteria if the lower bound of the 90% CI excluded the historical control of 2 months. Key eligibility criteria were HNSCC with known human papillomavirus (HPV) status, cetuximab resistance (progression within 6 months of exposure in the definitive or recurrent/metastatic setting), and resistance to platinum and anti-PD-1 mAb. Secondary end points included objective response rate (ORR), toxicity, and the association of HPV status and cMet overexpression with efficacy. Continuous Bayesian futility monitoring was used. RESULTS: From 2018 to 2020, 60 patients were randomly assigned and 58 were treated. Twenty-seven versus 33 patients were allocated to monotherapy versus combination. Arms were balanced for major prognostic factors. The monotherapy arm closed early for futility. The combination arm met prespecified significance criteria with a median PFS of 3.7 months (lower bound 90% CI, 2.3 months; P = .04); the ORR was 6 of 32 (19%), including two complete and four partial responses. Exploratory analyses were limited to the combination arm: the median PFS was 2.3 versus 4.1 months (P = .03) and the ORR was 0 of 16 (0%) versus 6 of 16 (38%; P = .02) in the HPV-positive versus HPV-negative subgroups, respectively. cMet overexpression was associated with reduced hazard of progression in HPV-negative but not HPV-positive disease (P interaction = .02). CONCLUSION: The ficlatuzumab-cetuximab arm met significance criteria for PFS and warrants phase III development. HPV-negative HNSCC merits consideration as a selection criterion.

Anatomic Region of Cutaneous Melanoma Impacts Survival and Clinical Outcomes: A Population-Based Analysis.

PURPOSE: The objective was to determine the effects of the anatomic site of a cutaneous melanoma on the survival outcomes of diagnosed individuals. METHODS: We conducted a cross-sectional study using data from the Surveillance, Epidemiology, and End Results Program (SEER) Database from 2004-2014 and included 178,892 cases of individuals diagnosed with cutaneous melanoma. Overall survival (OS) for each anatomic site as well as associated demographics, primary site, stage, and pathologic prognostic factors (Breslow's depth of invasion (DOI), level of mitoses, and ulceration), were analyzed. RESULTS: Lower extremity melanoma (LEM) was the most likely to have locoregional nodal spread, yet head and neck melanoma (HNM) was the most likely to present at the most advanced stage of disease (IV). Independent of other factors, HNM was associated with the greatest risk of death (HR 1.90 [95% CI, 1.85-1.96]) compared to other sites, and males experienced worse overall survival (OS) (HR 1.74 [95% CI, 1.70-1.78]) compared to females. The last and greatest risk of death is associated with LEM and HNM, respectively. CONCLUSION: Given these survival differences, consideration should be given to incorporating the primary site of melanoma into staging to ensure treatment is efficacious as possible.

Programmed death 1 (PD-1) and ligand (PD-L1) inhibitors in head and neck squamous cell carcinoma: A meta-analysis.

Background: PD-1 and PD-L1 inhibitors have emerged as promising treatments for patients with head and neck squamous cell carcinoma (HNSCC). Methods: Systematic review and meta-analysis of PD-1 and PD-L1 inhibitors in HNSCC. Outcomes: median overall survival (mOS), median progression-free survival (mPFS), Response Evaluation Criteria in Solid Tumors (RECIST) and treatment-related adverse events (TRAEs). Results: Eleven trials reported data on 1088 patients (mean age: 59.9 years, range: 18-90). The total mOS was 7.97 months (range: 6.0-16.5). Mean mPFS for all studies was 2.84 months (range: 1.9-6.5). PD-1 inhibitors had a lower rate of RECIST Progressive Disease than PD-L1 inhibitors (42.61%, 95% confidence interval [CI]: 36.29-49.06 vs. 56.79%, 95% CI: 49.18-64.19, P < 0.001). The rate of TRAEs of any grade (62.7%, 95% CI: 59.8-65.6) did not differ. Conclusions: Meta-analysis shows the efficacy of PD-1 and PD-L1 inhibitors in HNSCC and suggests a possible difference in certain RECIST criterion between PD-1 and PD-L1 inhibitors. Future work to investigate the clinical significance of these findings is warranted.

Systematic review of neuroendocrine carcinomas of the oropharynx.

Data describing features and management of oropharyngeal neuroendocrine carcinomas (NEC) remain sparse. A systematic review was performed. Patients were stratified by treatment modality and examined for disease progression and survival outcomes. Ninety-four patients from 50 publications were included. Average age at diagnosis was 59.7 years (range 14-83). 73.4% were male. Most studies did not document HPV status. Forty patients (85.1%) were p16 positive, and 34 (85.0%) were HPV-ISH positive. Overall survival was 75.4% at 1 year, and 40.0% at 2 years. Of patients with locoregional disease, 33.8% developed distant metastasis. 12.5% of patients developed locoregional recurrence. Patients who developed distant metastases had worse overall survival (p = 0.0004). No significant difference was found between treatment modalities. Human papilloma virus may be associated with oropharyngeal NEC. Current treatments provide locoregional control, but distant metastases are common and confer low overall survival.

Phase II Clinical Trial of Neoadjuvant and Adjuvant Pembrolizumab in Resectable Local-Regionally Advanced Head and Neck Squamous Cell Carcinoma.

PURPOSE: Patients with resected, local-regionally advanced, head and neck squamous cell carcinoma (HNSCC) have a one-year disease-free survival (DFS) rate of 65%-69% despite adjuvant (chemo)radiotherapy. Neoadjuvant PD-1 immune-checkpoint blockade (ICB) has demonstrated clinical activity, but biomarkers of response and effect on survival remain unclear. PATIENTS AND METHODS: Eligible patients had resectable squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or oropharynx (p16-negative) and clinical stage T3-T4 and/or two or more nodal metastases or clinical extracapsular nodal extension (ENE). Patients received neoadjuvant pembrolizumab 200 mg 1-3 weeks prior to surgery, were stratified by absence (intermediate-risk) or presence (high-risk) of positive margins and/or ENE, and received adjuvant radiotherapy (60-66 Gy) and concurrent pembrolizumab (every 3 weeks × 6 doses). Patients with high-risk HNSCC also received weekly, concurrent cisplatin (40 mg/m2). Primary outcome was one-year DFS. Secondary endpoints were one-year overall survival (OS) and pathologic response (PR). Safety was evaluated with CTCAE v5.0. RESULTS: From February 2016 to October 2020, 92 patients enrolled. The median age was 59 years (range, 27-80), 30% were female, 86% had stage T3-T4, and 69% had ≥N2. At a median follow-up of 28 months, one-year DFS was 97% (95% CI, 71%-90%) in the intermediate-risk group and 66% (95% CI, 55%-84%) in the high-risk group. Patients with a PR had significantly improved one-year DFS relative to patients without response (93% vs. 72%, hazard ratio 0.29; 95% CI, 11%-77%). No new safety signals were identified. CONCLUSIONS: Neoadjuvant and adjuvant pembrolizumab increased one-year DFS rate in intermediate-risk, but not high-risk, HNSCC relative to historical control. PR to neoadjuvant ICB is a promising surrogate for DFS.

Neoadjuvant presurgical PD-1 inhibition in oral cavity squamous cell carcinoma.

Oral cavity squamous cell carcinoma (OCSCC) is a prevalent surgically treated subset of head and neck cancer with frequent recurrence and poor survival. Immunotherapy has demonstrated efficacy in recurrent/metastatic head and neck cancer. However, whether antitumor responses could be fostered by neoadjuvant presurgical immunotherapy remains unclear. Using a Simon's two-stage design, we present results of a single-arm phase-II trial where 12 patients with stage II-IVA OCSCC received 3 to 4 biweekly doses of 3 mg/kg nivolumab followed by definitive surgical resection with curative intent. Presurgical nivolumab therapy in this cohort shows an overall response rate of 33% (n = 4 patients; 95% CI: 12%-53%). With a median follow up of 2.23 years, 10 out of 12 treated patients remain alive. Neoadjuvant nivolumab is safe, well-tolerated, and is not associated with delays in definitive surgical treatment in this study. This work demonstrates feasibility and safety for incorporation of nivolumab in the neoadjuvant setting for OCSCC (ClinicalTrials.gov: NCT03021993).

Immune Checkpoint Inhibitors for Advanced Cutaneous Squamous Cell Carcinoma: A Systematic Review with Meta-Analysis.

BACKGROUND: Results of early trials led to FDA approval of immune checkpoint inhibitors (ICIs) for advanced and recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (CSCC). Updated data from these trials are pending and extent of survival outcomes is undetermined. OBJECTIVE: The aim of this study was to assess the efficacy of ICIs in advanced CSCC, comprising locally advanced (LA), locoregionally advanced (LR), and recurrent or metastatic (R/M) disease. PATIENTS AND METHODS: A systematic review of four databases (PubMed, Scopus, OVID, Cochrane) and meta-analysis of proportions was performed. Phase I and II prospective clinical trials were included. RESULTS: Six trials evaluating cemiplimab (n = 3) and pembrolizumab (n = 3) were eligible for inclusion. Overall survival (OS) was not reached at data-cutoff. Pooled analysis of 392 patients demonstrated that ICIs conferred an objective response rate (ORR) of 42.43% (95% CI 37.53-47.45) and disease control rate (DCR) of 58.05% (95% CI 53.04-62.95). Patients with LR or distant metastatic lesions achieved equivalent ORRs and DCRs. Duration of response (DOR) was not reached in all trials and 92% of all responders continued to have therapeutic response at data cut-off. Tolerability was favorable, with only 27.12% (95% CI 10.89-47.38) of patients experiencing grade ≥ 3 adverse events. CONCLUSION: Surgical treatment of CSCC remains the guideline-based standard of care for curative intent of local, LA, and LR disease. ICIs demonstrate promising results for LA, LR, and R/M CSCC not amenable to surgery. Endpoints assessing survival and durability of response have not been reached, warranting additional trials exploring neoadjuvant or adjuvant therapy in combination with local treatment.

Development and Evaluation of a Navigation-Based, Multilevel Intervention to Improve the Delivery of Timely, Guideline-Adherent Adjuvant Therapy for Patients With Head and Neck Cancer.

PURPOSE: More than half of patients with head and neck squamous cell carcinoma (HNSCC) experience a delay initiating guideline-adherent postoperative radiation therapy (PORT), contributing to excess mortality and racial disparities in survival. However, interventions to improve the delivery of timely, equitable PORT among patients with HNSCC are lacking. This study (1) describes the development of NDURE (Navigation for Disparities and Untimely Radiation thErapy), a navigation-based multilevel intervention (MLI) to improve guideline-adherent PORT and (2) evaluates its feasibility, acceptability, and preliminary efficacy. METHODS: NDURE was developed using the six steps of intervention mapping (IM). Subsequently, NDURE was evaluated by enrolling consecutive patients with locally advanced HNSCC undergoing surgery and PORT (n = 15) into a single-arm clinical trial with a mixed-methods approach to process evaluation. RESULTS: NDURE is a navigation-based MLI targeting barriers to timely, guideline-adherent PORT at the patient, healthcare team, and organizational levels. NDURE is delivered via three in-person navigation sessions anchored to case identification and surgical care transitions. Intervention components include the following: (1) patient education, (2) travel support, (3) a standardized process for initiating the discussion of expectations for PORT, (4) PORT care plans, (5) referral tracking and follow-up, and (6) organizational restructuring. NDURE was feasible, as judged by accrual (88% of eligible patients [100% Blacks] enrolled) and dropout (n = 0). One hundred percent of patients reported moderate or strong agreement that NDURE helped solve challenges starting PORT; 86% were highly likely to recommend NDURE. The rate of timely, guideline-adherent PORT was 86% overall and 100% for Black patients. CONCLUSION: NDURE is a navigation-based MLI that is feasible, is acceptable, and has the potential to improve the timely, equitable, guideline-adherent PORT.

Microscopic Extranodal Extension in HPV-Negative Head and Neck Cancer and the Role of Adjuvant Chemoradiation.

OBJECTIVE: Pathologic extranodal extension (ENE) is an important adverse feature for human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC), but the prognostic significance of microscopic ENE (ENEmi) and role of adjuvant concurrent chemoradiation (CRT) for ENEmi remain unclear. This study evaluates (1) the prognostic significance of ENEmi in HPV-negative HNSCC and (2) whether adjuvant CRT is associated with improved overall survival (OS) for these patients. STUDY DESIGN: Retrospective cohort study. SETTING: Commission on Cancer (CoC)-accredited facilities. METHODS: This retrospective cohort study included patients in the National Cancer Database from 2009 to 2015 with pathologic node-positive (pN+) HPV-negative HNSCC with either pathologic ENEmi or no ENE who had undergone margin-negative surgery. The association of ENEmi with OS was evaluated using Cox proportional hazard analyses. Analyses were repeated in patients with ENEmi receiving adjuvant therapy to evaluate the association of adjuvant CRT with OS. RESULTS: We included 5483 patients with pN+ HPV-negative HNSCC, of whom 24% had ENEmi. On multivariable analysis, ENEmi was associated with decreased OS relative to no ENE (adjusted hazard ratio [aHR], 1.43; 95% CI, 1.28-1.59). Among patients with ENEmi who received ≥60 Gy of adjuvant radiation therapy (RT) (n = 617), adjuvant CRT was not associated with improved OS relative to RT (aHR, 0.91; 95% CI, 0.66-1.27). CONCLUSION: For patients with HPV-negative HNSCC, pN+ with ENEmi is associated with worse OS than pN+ without ENE. However, for patients with ENEmi, concurrent CRT is not associated with improved OS relative to RT. The optimal adjuvant paradigm for ENEmi requires additional investigation.

Hobnail variant of papillary thyroid carcinoma: a systematic review and meta-analysis.

OBJECTIVE: The hobnail variant of papillary thyroid carcinoma (HVPTC) has emerged as a rare and aggressive variant of papillary thyroid carcinoma (PTC). We aim to determine the prevalence and clinicopathologic factors of HVPTC. METHODS: A systematic review of the literature for studies examining HVPTC was performed. Four databases (PubMed, Scopus, OVID, Cochrane library) were queried from inception of databases through March 20th, 2020. RESULTS: Sixteen studies with 124 cases of HVPTC were included. The mean age for all patients was 52.3 years. HVPTC had a prevalence of 1.08% out of all PTC cases, with a mean tumor size of 3.1 cm. In 62% and 50% of cases, lymphovascular invasion and extrathyroidal extension were present, respectively. Follow-up data, with a mean of 49.9 months, revealed a 66% rate of lymph node metastasis and 23% rate of distant metastasis. Tumors with ≥30% hobnail morphology had a 2.6-fold increased odds of developing lymph node metastasis compared with <30% hobnail morphology, however did not differ in rates of distant metastasis. Patients ≥55 years old had a 4.5-fold increased odds of distant metastasis and a 4.7-fold increased odds of lymphovascular invasion over patients <55. CONCLUSIONS: High rates of locoregional and distant disease as well as high-risk pathological factors reveal the aggressive nature of HVPTC. Diagnostic criteria regarding percentage of hobnail morphology requires further refinement. Further studies are warranted in order to better understand how recognition of this high-risk variant impacts clinical treatment.

Barriers to the Delivery of Timely, Guideline-Adherent Adjuvant Therapy Among Patients With Head and Neck Cancer.

PURPOSE: Delays initiating guideline-adherent postoperative radiation therapy (PORT) in head and neck squamous cell carcinoma (HNSCC) are common, contribute to excess mortality, and are a modifiable target for improving survival. However, the barriers that prevent the delivery of timely, guideline-adherent PORT remain unknown. This study aims to identify the multilevel barriers to timely, guideline-adherent PORT and organize them into a conceptual model. MATERIALS AND METHODS: Semi-structured interviews with key informants were conducted with a purposive sample of patients with HNSCC and oncology providers across diverse practice settings until thematic saturation (n = 45). Thematic analysis was performed to identify the themes that explain barriers to timely PORT and to develop a conceptual model. RESULTS: In all, 27 patients with HNSCC undergoing surgery and PORT were included, of whom 41% were African American, and 37% had surgery and PORT at different facilities. Eighteen clinicians representing a diverse mix of provider types from 7 oncology practices participated in key informant interviews. Five key themes representing barriers to timely PORT were identified across 5 health care delivery levels: (1) inadequate education about timely PORT, (2) postsurgical sequelae that interrupt the tight treatment timeline (both intrapersonal level), (3) insufficient coordination and communication during care transitions (interpersonal and health care team levels), (4) fragmentation of care across health care organizations (organizational level), and (5) travel burden for socioeconomically disadvantaged patients (community level). CONCLUSION: This study provides a novel description of the multilevel barriers that contribute to delayed PORT. Interventions targeting these multilevel barriers could improve the delivery of timely, guideline-adherent PORT and decrease mortality for patients with HNSCC.

Evaluating Adjuvant Therapy With Chemoradiation vs Radiation Alone for Patients With HPV-Negative N2a Head and Neck Cancer.

Importance: The American Joint Committee on Cancer staging system (Cancer Staging Manual, 8th Edition) for head and neck squamous cell carcinoma (HNSCC) now categorizes human papillomavirus (HPV)-negative HNSCC in a single positive lymph node smaller than 3 cm with pathologic extranodal extension (ENE) as N2a. The standard of care for pathologic ENE is adjuvant chemoradiation therapy (CRT). Whether adding chemotherapy concurrent with adjuvant radiation therapy improves survival in this clinical scenario is unknown. Objective: To assess whether adjuvant CRT relative to radiation therapy alone is associated with improved survival among patients with pN2a HPV-negative HNSCC with ENE. Design, Setting, and Participants: This retrospective cohort study included 504 patients with pN2a HPV-negative HNSCC with ENE who had undergone margin-negative surgery and adjuvant therapy. The patients were identified from the National Cancer Database from January 1, 2004, to December 31, 2015. Statistical analyses were conducted from September 1, 2019, to April 16, 2020. Main Outcomes and Measures: The primary end point was overall survival. The association of adjuvant CRT with overall survival was analyzed using univariate and multivariate Cox proportional hazards regression analyses. Planned subset analyses were conducted in patients younger than 70 years with no comorbidities (the subset most likely to be eligible for a clinical trial of cisplatin-based chemoradiation) and in patients with pT3/T4 disease classification. Results: Of 504 patients (mean [SD] age, 60.5 [12.7] years; 319 [63.3%] men; 434 [86.1%] White) with pN2a HPV-negative HNSCC with ENE who had undergone margin-negative surgery and adjuvant therapy, 298 patients (59.1%) received adjuvant CRT. For the overall cohort of patients with pN2a ENE, adjuvant CRT was not associated with improved overall survival relative to adjuvant radiation therapy alone in a multivariate analysis (adjusted hazard ratio, 0.98; 95% CI, 0.74-1.30). Adjuvant CRT was still not associated with improved overall survival in a subset analysis of 304 patients younger than 70 years with no comorbidities (adjusted hazard ratio, 0.98; 95% CI, 0.66-1.45) nor in a subset of 220 patients with pT3/T4 disease classification (adjusted hazard ratio, 1.03; 95% CI, 0.70-1.54). Conclusions and Relevance: This study found that for patients with pN2a HPV-negative HNSCC with ENE who underwent margin-negative surgery and adjuvant therapy, adding chemotherapy concurrent with adjuvant radiation therapy was not associated with improved overall survival. Additional research is necessary to identify the optimal treatment paradigm for this clinical scenario.

The Evolution of Care of Cancers of the Head and Neck Region: State of the Science in 2020.

Cancers that arise in the head and neck region are comprised of a heterogeneous group of malignancies that include carcinogen- and human papillomavirus (HPV)-driven mucosal squamous cell carcinoma as well as skin cancers such as cutaneous squamous cell carcinoma, basal cell carcinoma, melanoma, and Merkel cell carcinoma. These malignancies develop in critical areas for eating, talking, and breathing and are associated with substantial morbidity and mortality despite advances in treatment. Understanding of advances in the management of these various cancers is important for all multidisciplinary providers who care for patients across the cancer care continuum. Additionally, the recent Coronavirus Disease 2019 (COVID-19) pandemic has necessitated adaptations to head and neck cancer care to accommodate the mitigation of COVID-19 risk and ensure timely treatment. This review explores advances in diagnostic criteria, prognostic factors, and management for subsites including head and neck squamous cell carcinoma and the various forms of skin cancer (basal cell carcinoma, cutaneous squamous cell carcinoma, Merkel cell carcinoma, and melanoma). Then, this review summarizes emerging developments in immunotherapy, radiation therapy, cancer survivorship, and the delivery of care during the COVID-19 era.

The neoadjuvant paradigm reinvigorated: a review of pre-surgical immunotherapy in HNSCC.

BACKGROUND: There remains up to a 50% recurrence rate in advanced p16- head and neck squamous cell carcinoma with current standard of care treatment. In an attempt to improve survival, multiple trials administering induction or neoadjuvant chemotherapy have been conducted but none demonstrated improved overall survival. The established efficacy of immune checkpoint inhibitors in the recurrent and metastatic setting has produced widespread interest in their neoadjuvant use. PURPOSE: To survey the landscape of active neoadjuvant immunotherapy trials in head and neck squamous cell carcinoma and summarize and synthesize currently available outcomes from these trials. CONCLUSIONS: Neoadjuvant immunotherapy has proven safe and well tolerated in head and neck squamous cell carcinoma with encouraging efficacy results, including relatively high rates of pathologic response. Ongoing studies offer an opportunity to study immune responses in vivo. PD-L1 positivity, high tumor mutational burden and infiltration of NK cells, CD8, CD26 and Tim3 positive lymphocytes at time of surgery have been correlated with pathologic responses. We await updated reports of disease free survival and overall survival data and results of ongoing phase III studies utilizing neoadjuvant immunotherapy to determine if this treatment paradigm will have a place in the standard of care treatment in head and neck squamous cell carcinoma.

Pembrolizumab-induced Hemophagocytic Lymphohistiocytosis: an immunotherapeutic challenge.

BACKGROUND: As the number of indicated malignancies for which immune checkpoint inhibitor therapy such as pembrolizumab grows the descriptions of associated immune-related adverse events (irAEs) increases as well. On rare occasions immunotherapy can lead to development of Hemophagocytic Lymphohistiocytosis (HLH) which is a potentially lethal inflammatory disorder characterized by histiocyte activation and cytokine storm. At this time no cases of HLH developing in head and neck squamous cell carcinoma (HNSCC) patients receiving pembrolizumab have been reported. CASE PRESENTATION: Here we describe the first documented case of pembrolizumab-induced HLH in a 61 year-old male with metastatic HNSCC after having received multiple prior cycles of pembrolizumab without event. Following cycle 14 the patient developed fever associated with new pancytopenia and transaminitis prompting hospital admission. Infectious workup was negative, his metastatic lesions were found to be stable, and there was no evidence of new malignancy. Further workup demonstrated hyperferritinemia and bone marrow biopsy demonstrated hemophagocytosis concerning for pembrolizumab-induced HLH. Etoposide and dexamethasone therapy was initiated leading to clinical improvement and safe discharge. CONCLUSIONS: Immunotherapy is a groundbreaking therapeutic intervention for patients with malignancy, however by nature of their mechanism carry a risk of inflammatory side effects. In rare circumstances these inflammatory reactions include potentially deadly syndromes such as HLH. As immunotherapeutics such as pembrolizumab become more widely utilized increased awareness of complications such as HLH is clinically relevant.