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The prognosis of patients (pts) with recurrent/metastatic head and neck squamous cell carcinoma (SCC) is poor (median overall survival [OS] 10–13 mo), and effective treatments are needed. The cell-adhesion molecule Nectin-4 is expressed in a majority of HNCs. EV is a Nectin-4–directed antibody–drug conjugate approved as monotherapy in previously treated locally advanced or metastatic (la/m) urothelial carcinoma (UC) and, in the US, with pembrolizumab for previously untreated la/mUC ineligible for cisplatin. EV was evaluated in previously treated HNC in EV-202 (NCT04225117). In this open-label phase 2 study, pts with la/m solid tumors enrolled in tumor-specific cohorts. In this cohort, pts had HNC not amenable to curative-intent treatment, radiographic progression on/after the last regimen, progression/relapse/discontinuation for toxicity after 1 platinum-based therapy for la/m disease, and ≤2 lines of cytotoxic therapy in the la/m setting. Pts had received prior programmed cell death protein 1/ligand 1 (PD-1/L1) inhibitor unless contraindicated. Pts received intravenous EV 1.25 mg/kg on days 1, 8, and 15 of each 28-d cycle (C) until disease progression or discontinuation criteria were met. Primary endpoint was confirmed objective response rate (ORR) per investigator assessment. Secondary endpoints were duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) per investigator assessment; OS; and safety/tolerability. Exploratory endpoints included immunogenicity, pharmacokinetic parameters, and pt-reported outcomes. As of April 11, 2022, 46 pts were enrolled; median follow-up was 9.3 mo. Median age was 65 y, 87.0% of pts were men, and 52.2% had ≥3 prior lines of systemic therapy in the metastatic setting. Forty-five pts had SCC; 1 had adenocarcinoma. Confirmed ORR was 23.9%; DCR was 56.5%. Median time to response was 1.7 mo. Median DOR was not estimable. Median PFS and OS were 3.9 and 6.0 mo, respectively. Common treatment-related adverse events (TRAEs) were alopecia (28.3%), fatigue (26.1%), and peripheral sensory neuropathy (23.9%). Grade ≥3 TRAEs occurring in >1 pt were anemia and decreased neutrophil count (both n=2). TRAEs of special interest were skin reactions (45.7%), peripheral neuropathy (32.6%), dry eye (6.5%), and hyperglycemia (4.3%). No antitherapeutic antibodies against EV were detected. Serum EV decreased substantially from end-of-infusion concentrations before subsequent doses in C1, while plasma concentration of free monomethyl auristatin E (drug component of EV) remained high between days 1 and 15 of C1. Median global pain assessment score was 4/10 at baseline, with numeric reduction in scores (indicating pain improvement) in C3 and beyond. EV demonstrated antitumor activity with manageable AEs in pts with heavily pretreated HNC post-platinum and PD-1/L1 inhibitor. [ABSTRACT FROM AUTHOR]

The purpose of the study was to define whether circulating tumor DNA (ctDNA) can be used as a measure to detect minimal residual disease (MRD) following surgical intervention in high-risk positive patients for head and neck squamous cell carcinoma (HNSCC). IRB approval was obtained through our institution. Patients with HNSCC with surgical resection of their tumor were enrolled. Of these, 28 patients had ctDNA levels determined post-operatively (n = 28) using the Signatera test. Data were extracted from electronic medical records by trained abstractors. The patient cohort (20 male and 8 female) had an average age of 67.0 ± 9.82 years at the time of surgery. Patients were assessed using The Eastern Cooperative Oncology Group (ECOG) functional scores, with 17.9% scoring 0, 75.0% scoring ECOG 1, and 7.14% of patients with ECOG 2 or 3. All patients had primary laryngeal or oral cavity cancer, including gingival, tongue, and mandibular. The study had two patients with pathologic Stage I cancer, three with Stage II, five with Stage III, eleven with Stage IVA, and seven with Stage IVB. One patient received neoadjuvant chemotherapy prior to surgery. There were 19 high-risk positive cancers, defined as positive extranodal extension or positive margins during surgery. 15 of these 19 patients patients received adjuvant chemotherapy and radiation, with or without a platinum agent, depending on their chemotherapy eligibility. In these high-risk patients, 18 had data in the post-operative period, prior to adjuvant therapy, for which 61.1% had positive ctDNA. Conversely, there were 9 patients without high-risk features, of whom only two had positive MRD post-operatively, and two with disease recurrence. There was a significantly lower tumor recurrence in the patients without high-risk features compared to those with high-risk features (22.9% vs. 54.5%, respectively) which correlated with ctDNA. At the time of data collection, 7 patients had disease recurrence for which 5 were post-operative ctDNA positive. Two patients were ongoing adjuvant treatment and follow-up without recurrence data. ctDNA was detected frequently in the HNSCC patients with high-risk features post-operatively. Although we have a small number of the patients, the patients with recurrence following adjuvant treatment had high rates of positive ctDNA after the surgery. Therefore post-operative ctDNA for high-risk patients may be prognostic and considered in clinical trials designed for treatment intensification. [ABSTRACT FROM AUTHOR]

BCA101 is a first-in-class bifunctional EGFR/TGFβ inhibitor with a manageable safety profile and preliminary efficacy in advanced solid tumors (ESMO 2022 731MO). Pembrolizumab is approved for recurrent, metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the CPS≥1 population. Here we report updated results from the fully enrolled expansion cohort combining BCA101 + pembrolizumab as first line therapy in R/M HNSCC. This ongoing single-arm, multicenter dose expansion cohort enrolled patients (pts) with R/M HNSCC as part of a phase 1/1b trial. Pts with tumor PD-L1 CPS≥1 with no prior systemic therapy for R/M disease, ECOG 0-1, and measurable disease (RECIST v1.1) were eligible. Pts received BCA101 (1500 mg IV on days 1, 8, 15) with pembrolizumab (200 mg IV on day 1) every 21-days. Primary endpoint: safety; secondary endpoints: overall response rate (ORR), duration of response, progression-free survival (PFS), overall survival. Exploratory: molecular and immunologic predictors of response. Forty-two pts received at least one dose of study drug and 39 pts were evaluable for efficacy. Pts were more often men (30, 71%); median age: 63 (range: 31-84). Twenty pts (48%) had baseline PD-L1 CPS scores of 1-19 and 22 (52%) were ≥20. Oropharynx (20, 48%) [12/20 (60%) HPV/p16-positive] and oral cavity (13, 31%) were the most common subsites. Thirty-three pts (79%) had distant metastases. The ORR was 46% (5 CR, 13 PRs) with 57% (16/28) of HPV/p16-negative pts achieving response. Similar response rates were observed for HPV-negative pts with CPS scores 1-19 (54%, 7/13) and CPS≥20 (60%, 9/15), as well as in pts with distant metastasis (55%, 12/22) and locoregional disease (67%, 4/6). Median PFS (mPFS) continues to mature and currently has not been reached among HPV-negative pts with 13/28 responses ongoing (>30% for more than 6 months), with updates expected to be available at the time of the meeting. Grade 3+ treatment-related adverse events (TRAEs) were observed in 17/42 pts (40%). There were no treatment-related deaths. Acneiform rash was the most common TRAE of any grade (31/42, 74%). Permanent discontinuation of study treatment due to TRAEs was required in 6/42 pts (14%). BCA101 + pembrolizumab exhibits encouraging safety and anti-tumor activity in first line R/M HNSCC, particularly among HPV-negative pts in both CPS 1-19 and ≥20. Further investigation in HPV-negative pts is planned in a larger randomized study. Study funded by Bicara Therapeutics Inc. and conducted in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (NCT04429542). [ABSTRACT FROM AUTHOR]

Treatment of oropharyngeal cancer with definitive radiation/chemoradiation (RT/CRT) is an effective treatment and rapid regression of tumor can occur. Following treatment some patients will develop a pharyngeal ulcer which may or may not be associated with disease persistence. Data for the management of ulcers could improve post radiation care. From an IRB approved database of head and neck cancer cases at a tertiary care center, we reviewed patients with non-metastatic squamous cell carcinoma of the oropharynx treated curatively in non-operative fashion with RT/CRT between 1/1/2011 and 1/1/2022. Patients were reviewed for clinical, radiographic and laryngoscopic evidence of pharyngeal ulcer development following completion of radiation. Pharyngeal ulcer patients were evaluated for management strategy of the ulcer and associated complications and association with recurrence. A total of 45 patients with a pharyngeal ulceration following RT/CRT with a median follow up of 30.8 months were identified. The median age of patients was 60 (range 35-82) years, 80% of patients were caucasian, 82% were male, and 42% of patients were active smokers at the time of RT/CRT. 75% of patients had p16/HPV+ disease with T stages of T1/2, T3 and T4 of 44, 20 and 36% respectively. 93% of patients were treated with concurrent chemotherapy (74% cisplatin) to a median dose of 70 Gy (range 60-74 Gy). The median time to development of ulcer was 3.1 months (range 0.2-31.4 months). 19 patients (42%) underwent biopsy of their ulcer of whom 9 (47%) where found to have disease persistence. Ultimately thirteen patients (29%) had associated tumor persistence. Among the 32 patients with ulcer not associated with recurrence, 28 (87.5%) were p16/HPV+ and 90.6% has received chemotherapy. 3 ulcers (9.4%) were associated with exposed bone. Treatment of ulcers revealed 15 (46%) received antibiotics, 23 (72%) needed narcotics and 5 (16%) required feeding tube placement for pharyngeal rest. Three patients (9.4%) required surgical reconstruction to facilitate resolution. Overall, at time of last follow up 28 (88%) of ulcers not associated cancer had resolved with a median time to resolution of 3.6 months (range 1.3-75.2) months. The overall survival of the non-malignant ulcer group was 83% at 3 years compared to 28% in the patients with ulcers associated with persistent cancer. Pharyngeal ulceration is a significant potential complication of RT/CRT in oropharyngeal cancer. Ulceration is frequently identified around 3 months post treatment and when not associated with disease persistence has a high rate of resolution with conservative measures including antibiotics and pain control. Severe case may necessitate feeding tube and rarely surgical reconstruction. [ABSTRACT FROM AUTHOR]

Tumor mutational burden (TMB) is an emerging biomarker utilized in some cancers as a predictive tool to determine benefit to immune checkpoint inhibitor therapy and high TMB alone is an indication for pembrolizumab monotherapy, tumor agnostic. For head and neck squamous cell carcinoma (HNSCC), there is limited data utilizing TMB as a biomarker to predict response to PD-L1 inhibitors. This study assesses TMB score and progression of disease in HNSCC patients treated with immunotherapy. From an IRB-approved database, we retrospectively analyzed 51 patients treated between 2016 and 2023 with HNSCC who had at least one dose of pembrolizumab and known next generation sequencing (NGS). Patients were stratified between high TMB (≥10 mutations/Mb) and low (<10 mutations/Mb). Of the 51 patients, 40 (78%) had progression of disease while on pembrolizumab. The median TMB of those who progressed was 6.9 mutations/Mb. The median time to disease progression was 5.8 months. There were 37 patients who were classified as low TMB with a median 5.0 mutations/Mb. Of these 37, 29 (78%) had progression while on pembrolizumab with a median time to progression of 3.5 months. For the 14 patients with high TMB scores, the median was 12.0 mutations/Mb. Of these 14, 11 (79%) had progression while on pembrolizumab with a median time to progression of 5.8 months. There was no statistical difference in time to progression between high and low TMB cohorts (p=0.3483). Of the 11 (22%) without progression, all patients started pembrolizumab in the setting of recurrent HNSCC (7 metastatic, 4 locoregionally recurrent). The majority in this cohort are classified as having low TMB (n=8/11) with a median TMB of 5.0 mutations/Mb. Of the 10 patients who actively remain on pembrolizumab, they have been on pembrolizumab for a median of 14.7 months. A multivariable analysis revealed that TMB as a continuous variable (i.e., increase in TMB mutations), the risk of progression decreased (p=0.0238, HR 0.940). Although there was no statistical difference in time to progression between our high TMB and low TMB cohorts, a higher TMB score correlated with decreased risk of progression in our cohort of HNSCC patients. Further research is needed to better understand the utility of TMB as a biomarker in HNSCC. [ABSTRACT FROM AUTHOR]

Immunotherapy (IO) with cemiplimab or pembrolizumab is approved for treatment of metastatic or locally advanced cutaneous squamous cell carcinoma (cSCC). There is evidence of objective response to these anti-PD-1 agents in locally advanced cSCC. Cranial nerve (CN) involvement is seen in less than 5% of cSCC and is a poor prognostic factor. Radiotherapy (RT) can be used for locally advanced cSCC, however comprehensive delineation and eradication of perineural invasion can be challenging. To our knowledge, there are no published studies indicating how patients with CN involvement respond to IO. Patients were identified and retrospectively reviewed under an Institutional Review Board approved protocol at a tertiary care center. Selection criteria included histologically proven locally advanced cSCC of the head and neck cancer with CN involvement treated with IO. A total of 8 patients met inclusion criteria; demographic, disease, and treatment characteristics are summarized in Table 1. Most patients were men, with a median age at diagnosis of 74 years and had a median follow-up of 8.4 months. All received cemiplimab 350 mg intravenously every 3 weeks; 1 patient was initially treated with pembrolizumab, then transitioned to cemiplimab. 2 patients received IO for recurrence of previously diagnosed locally advanced cSCC, 1 of which had prior treatment with cetuximab and RT. 6 patients presented with CN involvement at diagnosis, and the additional 2 at time of recurrence after previous non-IO therapy. 1 patient treated with IO was immunosuppressed due to CLL and also had nodal involvement. 4 patients received RT prior to IO, and 1 patient received stereotactic radiosurgery (SRS) concurrent with IO. 3 patients never received RT and all had clinical benefit with IO: 2 having stable disease (SD) and 1 partial response (PR). Overall, 4 patients had PR, 2 SD and 2 progressive disease (PD) as best response. 5 patients are alive at last follow up, 1 completed a full year of IO and is currently off treatment, and 4 remain on IO treatment. In this limited cohort of patients with locally advanced cSCC with CN involvement, IO has shown clinical benefit in 75% of the cases. All patients treated with IO alone demonstrated a clinical response, indicating IO can be an effective monotherapy. Given the challenges of RT with extensive perineural invasion, RT can be reserved in the event of local failure after IO. [ABSTRACT FROM AUTHOR]

Adenosquamous carcinoma of the head and neck (ASC-HN) is a rare and aggressive variant of squamous cell carcinoma (SCC). Limited data suggests inferior outcomes compared to conventional SCC. We report one of the largest single institutional experiences of this disease in patients treated definitively to further elucidate oncologic outcomes. Patients with non-metastatic ASC-HN treated definitively between 2003 and 2021 were identified retrospectively from an IRB approved database with histology verified by head and neck pathologists. All tumors of the oropharynx were tested for p16 and/or HPV to document HPV associated disease. For non-oropharyngeal lesions, a designation of HPV positivity required the presence of HPV DNA/RNA per CISH. Actuarial analyses were performed for PFS and OS. 29 patients with ASC-HN (72.4% male, 93.1% Caucasian) with median age of 66 (range 34-91) and a median follow up of 33 months (range 6.6-126.7) were identified. The most common primary tumor sites were: oropharynx (27.6%), oral cavity (20.7%), nasal cavity (17.2%), and larynx (17.2%). 3 patients had primaries in the hypopharynx, nasopharynx and parotid gland respectively. 11 patients (37.9%) were HPV positive of whom 8 had oropharyngeal primaries. The majority (n=23, 79.3%) were treated with primary surgery of whom 19 (82.6%) received adjuvant radiation (RT) to a median dose of 60 Gy (range 36-70 Gy) with 7 receiving concurrent chemotherapy. 6 patients were treated with definitive RT to a median dose of 70 Gy with two receiving concurrent chemotherapy. There were 10 recurrences (34.5%) which occurred at a median of 14.3 months (range 5.4-28) after diagnosis including 8 loco-regional and 2 distant recurrences. Recurrences were documented in patients with primary salivary gland, oral cavity, laryngeal, hypo-pharyngeal, and oropharyngeal tumors. 3 of the 10 recurrences were in patients with HPV positive disease. Among the 6 patients treated with definitive radiation or chemo-radiation no failures were observed. 9 patients (31%) were deceased at the time of analysis. Overall, 3-year PFS and OS were 54.2% and 72.9%, respectively. 3-year PFS and OS were 45.6% and 69.6% for primary surgery and 83.3% and 83.3% in the definitive RT group. 3-year PFS was 50% and 75% for HPV negative and positive patients respectively. In our single institutional experience of 29 patients with adenosquamous carcinoma of the head and neck there was a 34.5% recurrence rate. Loco-regional recurrence was the primary mode of failure. [ABSTRACT FROM AUTHOR]

Pembrolizumab and nivolumab are approved in the treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). However, real-world effectiveness may vary from clinical trial efficacy, partly due to strict exclusion criteria. We reviewed the effectiveness of immunotherapy (IO) in recurrent/metastatic HNSCC at a single tertiary referral center. All HNSCC patients who received single-agent palliative IO for recurrent/metastatic disease were identified from the electronic medical record via ICD codes under an IRB approved protocol. Wilcoxon rank sums test and chi squared test of independence were used to compare characteristics between IO responders (any response) and non-responders (stable or progressive disease) respectively. Kaplan-Meier method was used to estimate overall (OS) and progression free survival (PFS). Multivariable cox proportional hazards method was used to identify predictors of OS. A total of 138 patients were identified with the following primary tumor sites: p16+ oropharynx (n=45), p16- oropharynx (21), oral cavity (29), larynx (21), hypopharynx (7), nasal/sinus (7), or unknown primary (8). Concurrent chemoradiation was given to 68.8% (95) of patients and palliative chemotherapy was given prior to IO in 26.1% (36). IO was given for unresectable recurrent or metastatic disease in 23.2% (32) and 76.8% (106) of patients respectively, with 95.7% (132) receiving pembrolizumab and 4.3% (6) receiving nivolumab. Median age was 64 years (IQR 58-71), with ECOG status of 0, 1, and 2 in 23.9% (33), 60.9% (84), and 15.2% (21) of patients respectively. Combined positive scores (CPS) were available in 45.7% (63) of patients, with 33.3% (46) having CPS≥1 and 23.9% (33) having CPS≥20. The median number of IO cycles received was 4 (IQR 2-7). Of the 96 patients who survived to undergo imaging after ≥3 cycles, 43.8% (42) of patients had progression, 15.6% (15) had stable disease, 36.5% (35) had partial responses, and 4.2% (4) had complete responses. There were no significant differences in age, time from definitive radiation to IO, or absolute lymphocyte count (ALC) at IO initiation between responders and non-responders. Median PFS from IO initiation was 3.2 months (95%CI 2.8-4.4) months while median OS from IO initiation was 6.6 months (4.7-10.3). In a multivariable model, ECOG status of 1 (HR=2.00, 1.16-3.45) or 2 (HR=3.03, 1.51-6.09) vs ECOG 0 and decreased ALC at IO initiation (100 cells/µL, HR=1.06, 1.01-1.12) were significant predictors of worse OS. In this real-world cohort, survival with palliative IO in HNSCC was similar to that in randomized control trials. Though ECOG status and ALC were significant predictors of OS, further work into predictors of OS mediated through evidence of tumor response is needed. [ABSTRACT FROM AUTHOR]

Adenosquamous carcinoma of the head and neck (ASC-HN) is a rare and aggressive variant of squamous cell carcinoma (SCC). Limited data suggests inferior outcomes compared to conventional SCC. We report one of the largest single institutional experiences of this disease in patients treated definitively to further elucidate oncologic outcomes. Patients with non-metastatic ASC-HN treated definitively between 2003 and 2021 were identified retrospectively from an IRB approved database with histology verified by head and neck pathologists. All tumors of the oropharynx were tested for p16 and/or HPV to document HPV associated disease. For non-oropharyngeal lesions, a designation of HPV positivity required the presence of HPV DNA/RNA per FISH. Actuarial analyses were performed for PFS and OS. 29 patients with ASC-HN (72.4% male, 93.1% Caucasian) with median age of 66 (range 34-91) and a median follow up of 33 months (range 6.6-126.7) were identified. The most common primary tumor sites were: oropharynx (27.6%), oral cavity (20.7%), nasal cavity (17.2%), and larynx (17.2%). 3 patients had primaries in the hypopharynx, nasopharynx and parotid gland respectively. 11 patients (37.9%) were HPV positive of whom 8 had oropharyngeal primaries. The majority (n=23, 79.3%) were treated with primary surgery of whom 19 (82.6%) received adjuvant radiation (RT) to a median dose of 60 Gy (range 36-70 Gy) with 7 receiving concurrent chemotherapy. 6 patients were treated with definitive RT to a median dose of 70 Gy with two receiving concurrent chemotherapy. There were 10 recurrences (34.5%) which occurred at a median of 14.3 months (range 5.4-28) after diagnosis including 8 loco-regional and 2 distant recurrences. Recurrences were documented in patients with primary salivary gland, oral cavity, laryngeal, hypo-pharyngeal, and oropharyngeal tumors. 3 of the 10 recurrences were in patients with HPV positive disease. Among the 6 patients treated with definitive radiation or chemo-radiation no failures were observed. 9 patients (31%) were deceased at the time of analysis. Overall 3 year PFS and OS were 54.2% and 72.9% respectively. 3 year PFS and OS were 45.6% and 69.6% for primary surgery and 83.3% and 83.3% in the definitive RT group. 3 year PFS was 50% and 75% for HPV negative and positive patients respectively. In our single institutional experience of 29 patients with adenosquamous carcinoma of the head and neck there was a 34.5% recurrence rate. Loco-regional recurrence was the primary mode of failure. [ABSTRACT FROM AUTHOR]