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).

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.

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.

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.

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.

Purpose: To evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of ficerafusp alfa (BCA101), a first-in-class bifunctional protein targeting EGFR and TGF-β, as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors. Patients and Methods: At escalating doses in a parallel 3 + 3 design, patients with EGFR-driven advanced solid tumors received weekly intravenous ficerafusp alfa as monotherapy (64–1,500 mg) or in combination (240–1,500 mg) with pembrolizumab (200 mg i.v. every 3 weeks). The primary objective was to determine safety/tolerability. Secondary objectives included assessment of pharmacokinetics, immunogenicity, and preliminary efficacy per investigator-assessed response. Exploratory analyses included pharmacodynamic biomarkers. Results: Among 61 patients (monotherapy, n = 46; combination, n = 15), the most common treatment-related adverse events included acneiform dermatitis (46%) and fatigue (20%) with monotherapy and acneiform dermatitis (73%), fatigue (53%), pruritus (40%), epistaxis (40%), and maculopapular rash (40%) with combination therapy. One patient had a dose-limiting toxicity with 1,250-mg monotherapy (grade 3 anemia and hematuria). The MTD was not reached in either cohort. With monotherapy, objective response was observed in one of 42 evaluable patients and 16 (38%) achieved stable disease. With combination therapy, four of 13 evaluable patients (31%) had a confirmed response, including one with head and neck squamous cell carcinoma refractory to anti–PD-1 therapy and cetuximab. Prolonged neutralization of plasma TGF-β1 was observed at doses ≥500 mg. Conclusions: Ficerafusp alfa exhibited a manageable safety profile and clinical activity as monotherapy and in combination with pembrolizumab, with exposure increasing proportionally at anticipated therapeutic doses. See related commentary by Choudhury et al., p. 4617