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6078 Background: Severe oral mucositis (SOM) is a dose limiting toxicity during radiotherapy and cisplatin for head and neck cancers. The aim of this 4-arm randomized controlled pilot trial was to evaluate the efficacy of different schedules of a novel radioprotectant, RRx-001 versus standard-of-care (SOC), to reduce duration, time to onset and incidence of SOM in patients received cisplatin-based chemoradiotherapy (CRT) for oral cavity or oropharyngeal cancer (OCC). Methods: Patients with locally advanced OCC treated with definitive or postoperative CRT were randomized to receive RRx-001 by 15-minute intravenous infusion in one of three different schedules versus none. The days and severity of mucositis were prospectively evaluated. Oral mucositis was assessed weekly during and after CRT as well as 28 days after completion. The pre-specified efficacy endpoints were duration of grade 3-4 SOM, resolution of SOM, time to onset of SOM and incidence of SOM. Results: A total of 53 patients were enrolled between June 2018 and July 2019 across 11 institutions. Forty-five (out of 53) patients received study drug and were efficacy evaluable. RRx-001 were well tolerated with no associated serious adverse events. All RRx-001 arms numerically outperformed SOC on the pre-specified efficacy measures, and the greatest effect estimate was observed on Arm 1 (RRx-001 pretreatment only + CRT). The following endpoints favored treatment with RRx-001. Median SOM duration by treatment was 22 and 40 days for Arm 1 and SOC respectively. Time to onset of SOM was by 38 days (Arm 1) vs. 26 days (SOC). On Arm 1, 83% of patients had SOM resolution vs 60% on SOC). Gastrostomy requirement was reduced by 45%. No patients on Arm 1 developed grade 4 mucositis vs 30% developed grade 4 mucositis on the SOC arm. Furthermore, the incidence of oropharyngeal dysphagia, which can substantially impair nutrition, was reduced by treatment with RRx-001, occurring at 50% vs 70% for Arm 1 vs SOC respectively. Treatment with RRx-001 resulted in highly significant decrease in the duration of SOM through 60 Gy with a median SOM of 1 day vs 17 days for Arm 1 vs SOC respectively (Wilcoxon rank-sum test p < 0.001). Median cumulative cisplatin dose was significantly greater for RRx-001 Arm 1 than SOC (557.4 mg vs. 438 mg, Wilcoxon p = 0.025). Conclusions: Compared with SOC, SOM among RRx-001-treated patients given 3 different treatment schedules was less severe, of shorter duration, demonstrated delayed time to onset and resolved earlier. Overall, the incidence, duration and severity of SOM and dysphagia was reduced. The safety profile of RRx-001 was similar to SOC. These results will inform the design of a Phase 3 pivotal study of RRx-001 in the prevention of SOM in at-risk cancer patients. Clinical trial information: NCT03515538.

6031 Background: Salvage surgery for locally recurrent head and neck squamous cell carcinoma (rHNSCC) results in local control rates of 33-50% but only 20-40% of patients achieve long-term survival necessitating additional therapy (Haque et al., Oral Oncol. 2019). Many patients are ineligible for re-irradiation and chemotherapy alone after salvage surgeryhas shown no survival benefit. The clinical activity and tolerability of immune checkpoint inhibitors has been demonstrated in metastatic HNSCC, but the benefit after salvage surgery (SS) has not been studied. Here we report the results of a multi-center phase II investigation of nivolumab, a PD-1 inhibitor, after SS in recurrent HNSCC (NCT03355560). Methods: HNSCC patients undergoing curative-intent SS were enrolled to receive 6 months of nivolumab beginning 4-11 weeks after surgery. All received radiation with or without chemotherapy as prior definitive therapy and had no other curative treatment options at the time of surgery. Key exclusion criteria included: distant metastatic disease, gross residual disease, or a history of immunodeficiency, autoimmunity, or pneumonitis. The primary endpoint was 2-year disease-free survival (DFS) measured by Kaplan Meier curves. Safety was evaluated by CTCAE v5.0. Results: 39 patients were enrolled. Median age was 68 years (range, 49-85). 12/39 (31%) were female. 34/39 (87%) were white. Disease sites included oropharynx 9/39 (23%), oral cavity 14/39 (36%), and larynx 16/39 (41%). P16 status was 26% (+), 48% (-), and 26% (unknown). 17/39 (44%) had high risk pathologic features (positive margins or extranodal spread) at time of SS. 28/39 (72%) patients experienced treatment-related adverse events (TRAE), the most common of which were fatigue (26%), hypothyroidism (10%) and acneiform rash (13%). Grade 3-4 TRAEs were rare, occurring in 3/39 (8%) patients and included diarrhea, oral pain, neck pain, productive cough, stridor, and COPD exacerbation. 3/39 (8%) required treatment discontinuation and there were no grade 5 events. The 2-year DFS was 60% (95%CI 0.39-0.91). 2-year overall survival was 74% (95% CI 0.54-1). In single-cell multiplex cytokine analysis, patients who relapsed following adjuvant nivolumab had a significantly higher proportion of peripheral blood CD8 T cells which displayed a polyfunctional cytokine profile. IFN-γ and Granzyme were the dominant CD8 cytokines in both responders and non-responders, however CD8 expression of MIP1a and TNF-α were significantly higher in patients who ultimately relapsed. Conclusions: Nivolumab after salvage surgery in rHNSCC is well tolerated and shows promising antitumor activity in this high-risk patient population with unmet need. Immunotherapy after salvage surgery should be studied in randomized clinical trials. Clinical trial information: NCT03355560.

6006 Background: Patients with resected HNSCC, with high-risk (positive margins, extracapsular spread [ECE]) or intermediate-risk pathological features have an estimated 1-year DFS of 65% and 69%, respectively. Immune checkpoint blockade improved survival of patients with recurrent/metastatic HNSCC, and preclinical models indicate radiotherapy (RT) synergizes with anti-PD-1. Therefore, we administered the PD-1 inhibitor pembrolizumab (pembro) pre- and post-surgery with adjuvant RT +/- cisplatin in patients with resectable, locoregionally advanced (clinical T3/4 and/or ≥2 nodal metastases) HNSCC (NCT02641093). Methods: Eligible patients received pembro (200 mg I.V. x 1) 1-3 weeks before resection. Adjuvant pembro (q3 wks x 6 doses) was administered with RT (60-66Gy) with or without weekly cisplatin (40mg/m2 X 6) for patients with high-risk and intermediate-risk features, respectively. The primary endpoint was 1-year DFS estimated by Kaplan Meier curves. Safety was evaluated by CTCAE v5.0. Pathological response (PR) to neoadjuvant pembro was evaluated by comparing pre- and post-surgical tumor specimens for treatment effect (TE), defined as tumor necrosis and/or histiocytic inflammation and giant cell reaction to keratinaceous debris. PR was classified as no (NPR, < 20%), partial (PPR, ≥20% and < 90%) and major (MPR, ≥90%). Tumor PD-L1 immunohistochemistry was performed with 22c3 antibody and reported as combined positive score (CPS). Results: Ninety-two patients were enrolled. Seventy-six patients received adjuvant pembro and were evaluable for DFS. Patient characteristics included: median age 58 (range 27 – 80) years; 32% female; 88% oral cavity, 8% larynx, and 3% human papillomavirus negative oropharynx; 86% clinical T3/4 and 65% ≥2N; 49 (53%) high-risk (positive margins, 45%; ECE, 78%); 64% (44/69 available) had PD-L1 CPS ≥1. At a median follow-up of 20 months, 1-year DFS was 67% (95%CI 0.52-0.85) in the high-risk group and 93% (95%CI 0.84-1) in the intermediate-risk group. Among 80 patients evaluable for PR, TE scoring resulted in 48 NPR, 26 PPR and 6 MPR. Patients with PPR/MPR had significantly improved 1-year DFS when compared with those with NPR (100% versus 68%, p = 0.01; HR = 0.23). PD-L1 CPS ≥ 1 was not independently associated with 1-year DFS, but was highly associated with MPR/PPR (p = 0.0007). PPR/MPR in PD-L1 CPS < 1, ≥1 and ≥20, were estimated as 20, 55 and 90%, respectively. Grade ≥ 3 adverse events occurred in 62% patients with most common including dysphagia (15%), neutropenia (15%), skin/wound infections (10%), and mucositis (9%). Conclusions: PR to neoadjuvant pembro is associated with PD-L1 CPS≥1 and high DFS in patients with resectable, local-regionally advanced, HNSCC. Clinical trial information: NCT02641093.

e18551 Background: Treatment for locally advanced head and neck squamous cell carcinoma (HNSCC) involves a combination of surgery, chemotherapy, and radiotherapy (RT). RT for HNSCC is a known risk factor for the development of hypothyroidism. Recently, anti-PD1 therapies have been approved for recurrent and metastatic HNSCC and are moving to the forefront of HNSCC care. Similarly, thyroid dysfunction is a common immune-related adverse event following anti-PD1 therapy. Whether the addition of anti-PD1 to RT increases the likelihood of developing hypothyroidism remains unknown. Methods: The rate of hypothyroidism in HNSCC patients receiving RT (+/- chemotherapy and surgery) was compared to HNSCC patients receiving RT + anti-PD1 therapy either concurrently or after RT. Exclusion criteria were preexisting thyroid dysfunction, RT dose < 45 Gy and patients with incomplete treatment records. We defined clinical hypothyroidism as an elevation of TSH with low T3, T4 or elevation of TSH with symptoms requiring levothyroxine initiation. Hypothyroidism incidence was compared using Fisher’s exact test. Results: 153 patients were evaluated. In the RT group (N = 103), patients received RT +/- surgery or chemotherapy. 82/103 (80%) were male, median age was 57 and primary tumor groups included oropharynx 62/103 (60%), larynx 29/103 (28%), oral cavity 9/103 (9%) and other 3/103 (3%). In the RT + anti-PD1 group (N = 50), 36/50 (72%) were males, median age was 57 and primary tumor groups included oral cavity 19/50 (38%), oropharynx 17/50 (34%), larynx 8/50 (16%), and other 6/50 (12%). In the RT group, median follow up after RT was 801 days. In the RT+ anti-PD1 group, median follow up was 595 days from RT and 388 days from anti-PD1. The rate of hypothyroidism was significantly higher in the RT group 22.3% (23/103) versus 6% (3/50)after anti-PD1 therapy (p = 0.011). Multinomial logistical regression found no significant difference in hypothyroidism based on age, sex, or BMI. Larynx as primary tumor location was an independent risk factor for development of hypothyroidism (OR 4.74, p = 0.002). Conclusions: The addition of anti-PD1 therapy to standard HNSCC treatments does not significantly increase the risk of developing hypothyroidism. In fact, this study finds a lower incidence of hypothyroidism in HNSCC patient receiving RT + PD1 therapy which may be due to shorter duration of follow up and lower proportion of laryngeal cancer patients who are at relatively higher risk for surgical hypothyroidism.

6576 Background: Immune checkpoint inhibitors (ICIs) are FDA approved for use in head and neck squamous cell cancer (HNSCC), however, only ~20% patients achieve a response. Identification of biomarkers of response or toxicity remains a challenge. Polyfunctional T-cells, or T-cells producing multiple cytokines, have been recognized as contributors to durable immunity against various cancers. However, their role has not been studied prospectively in HNSCC patients receiving ICIs. To look for an early predictor of response, we used single-cell functional proteomic profiling (IsoPlexis) on blood samples pre- and post- first dose of nivolumab (nivo) in patients on our phase-II study of locally recurrent HNSCC (NCT03355560). Methods: HNSCC patients who failed definitive radiation +/-chemotherapy and were subsequently treated with curative intent salvage resection were enrolled to receive 6 months of nivo beginning 4 to 11 weeks after surgery. Blood samples were collected before and after the first dose of nivo. Peripheral blood mononuclear cells were isolated, enriched for CD8+ T cells and using the 32-plex IsoCode technology, single-cell cytokine signals were captured and polyfunctional strength of CD8+ T cells was evaluated across four groups (effector, stimulatory, regulatory, inflammatory). A comparison analysis was performed between pre- and post- nivo treatment and between patients who relapsed (non-responders) vs those who did not (responders). Results: Thirty-three of 39 planned patients have been enrolled, of which 28 are evaluable and 5/28 (18%) developed recurrence. Median age is 68 years (range 51-85), 9/28 (32%) patients are female, 26/28 (93%) are white, disease sites include oropharyngeal 6/28 (21%), oral cavity 11/28 (39%) and larynx 11/28 (39%). Samples were evaluated at a median follow up of 5.9 months from enrollment. Single-cell analysis demonstrated a strong upregulation of polyfunctional human CD8+ T cell subsets in responders. Polyfunctional Strength Index (PSI) was enhanced in CD8+ T cells across the responders’ samples, composed largely of effector cytokines (granzyme-β, IFN-γ, MIP-1α, perforin, TNF-α). Conclusions: Single-cell functional proteomic analysis revealed significantly upregulated polyfunctional profiles and an increase in effector cytokines in patients who responded to nivo. This data provides important insights into PD-1 inhibitor triggered T-cell activity and may be used to predict response to ICIs in HNSCC patients using a blood test. Clinical trial information: NCT03355560 .

e14273 Background: Cetuximab is a recombinant chimeric monoclonal IgG1 antibody which binds specifically to the epidermal growth factor receptor (EGFR) and stimulates an innate immune response by promoting natural killer (NK) cell mediated antibody-dependent cell-mediated cytotoxicity (ADCC). Cetuximab is approved as a single agent in relapsed/metastatic head and neck squamous cell carcinoma (R/M HNSCC). PD-1 check-point inhibitors which release the inhibition of the adaptive immune response, are also approved as single agents in this setting. However the response rates with these drugs, when used individually range from 10-20%. We hypothesized that adding a PD-L1 inhibitor, durvalumab to cetuximab would cause anti-tumor synergy by activating the innate as well as adaptive immune systems without compromising safety in this phase-2 trial in R/M HNSCC patients who have progressed on platinum based therapy. Methods: Blood samples were collected from the first six enrolled patients prior to starting treatment and 4 weeks after the first combined dose of cetuximab and durvalumab. PBMCs were isolated, stained with a live/dead stain as well as CD3, CD4, CD8, CD56, CD16 and NK2GD (natural killer group 2 member D activation receptor) antibodies and analyzed by flow cytometry. Cytokine levels in plasma were measured using standardized ELISA assay kits. Results: Compared to pre-treatment levels, post-treatment samples showed an increase in activated cytokine producing NK cells (CD56bright/CD16-) in all but one patient. Activated cytotoxic NK cell subpopulations (CD56dim/CD16+) showed variable results post-treatment. CD8+ T cells were similar pre and post-treatment in 5 patients. TGF-b levels increased in 5 patients and decreased in 1 patient post-treatment. Interestingly, the patient with decreased TGF-b levels post-treatment had an almost doubling of CD8+ T-cells and an increase in activated cytokine producing NK cells (CD56bright/CD16-). Conclusions: The clinical trial is ongoing and therefore, comparison to clinical response has not yet been analyzed. However, these findings support the combination of cetuximab and durvalumab in R/M HNSCC given the activation of an NK-cell mediated innate immune response in these patient samples. Clinical trial information: NCT03691714.

6037 Background: Metformin is a biguanide, widely used oral hypoglycemic agent. Metformin has also shown to inhibit tumor growth and progression in a wide variety of cancers including Head and Neck Squamous Cell Carcinoma (HNSCC). Metformin activates AMP protein kinase (AMPK) related pathways leading to inactivation of mammalian target of rapamycin (mTOR) and suppression of its downstream effectors. In addition, metformin is postulated to alter immune regulation in the tumor microenvironment leading to increased tumor cell killing. Here, we report our findings on the impact of metformin on T cells, NK cells and cytokines from patient peripheral blood mononuclear cells (PBMCs) from a phase I open-label single site dose escalation study combining metformin and chemoradiation (CRT) in HNSCC (NCT02325401). Methods: In this study, we evaluated the immune cell phenotypes and cytokine profiles of peripheral blood in patients before and after metformin treatment on trial by using flow cytometry and cytokine magnetic bead assays (Luminex). Cytokine profiles were further studied in co-culture experiments combining PBMCs, HNSCC cell lines, and metformin. Results: Patients who received metformin developed expanded NK cell populations, increased NKG2D expression, and a shift in their CD8+ T-cell memory phenotypes. Patient serum ELISA examination revealed increased anti-tumorigenic cytokine profiles. Metformin treatment of HNSCC cell lines in vitro as well as HNSCC PBMCs ex vivo resulted in downregulation of STAT3 compared to healthy controls. Downregulation of STAT3 may be a potential mechanism in which metformin stimulates NK cells. Conclusions: Here we show evidence that metformin treatment has a direct effect on the innate immune system in patients with HNSCC, inducing an anti-tumorigenic immune response suggesting that metformin continues to be a good candidate to yield improved clinical outcomes in patients with advanced stage HNSCC. Clinical trial information: NCT02325401.

6017Background: 2Despite aggressive adjuvant treatment, locally advanced HNSCC patients undergoing primary surgical resection with high risk [HR] features (extracapsular extension of lymph nodes (L...

6074Background: Up to 60% of HNSCC present as locally advanced disease (LAHNSCC). Although prognosis has improved significantly, 3 year PFS and OS remain at 62%, and 73% respectively (RTOG 0522) de...

6059Background: Immune checkpoint inhibitors have been shown to induce durable tumor response in a subset of recurrent and/or metastatic HNSCC. Higher expression of PD-L1, INF-γ, and composite sign...

e17572 Background: Salvage surgical resection is often offered in HNSCC patients who develop locally recurrent disease after definitive therapy. However, survival outcomes are often poor and subsequent recurrence is frequently fatal. Patients with adverse pathological features (extracapsular extension (ECE) of lymph nodes (LN), positive margins, peri-neural spread, lympovascular invasion, multiple LN metastases) after primary surgical resection have been shown to have poor outcomes. It is unclear if these same features affect outcomes in surgical salvage patients. Therefore we conducted a retrospective analysis to analyze outcomes and potential risk factors in these patients. Methods: We analyzed forty-five patients at the University of Cincinnati from 2008-2014 that underwent salvage surgery after definitive radiation with or without chemotherapy. Independent categorical variables analyzed were age, gender, alcohol, smoking, time to relapse after definitive therapy and adverse pathological features. Dependent variables were relapse free survival (RFS) and overall survival (OS) censored at time of event or last follow-up visit. Kaplan-Meier curves were used to estimate RFS and OS and Cox Proportional Hazard models were used to assess hazard ratios between groups. Results: Median age was 57 (range 41 to 86). 75.6% of patients were male. 68.9% patients had adverse pathological features. Median OS was 59 months and median RFS was 38 months from surgery. Demographics and adverse pathological features did not affect survival. However, patients who relapsed after definitive therapy within 6 months vs. after 6 months had worse OS (See Table 1). Conclusions: Although adverse pathological features correlate with poor outcome in primary surgery, these features did not impact outcomes after salvage surgery in our population. However, patients who relapsed within 6 months of definitive therapy and underwent salvage resection had significantly worse outcomes than those who developed recurrence after 6 months. [Table: see text]

e17500 Background: Metformin is hypothesized to suppress tumor cell growth by mTOR pathway inhibition, which mediates the phosphoinositide 3-kinase/Akt signaling pathway (frequently deregulated in human cancers). This effect is mediated by activation of the AMP protein kinase (AMPK). Despite knowledge of the mechanism, various retrospective studies show conflicting results about effect of metformin on survival in head and neck squamous cell carcinoma (HNSCC) patients (pts). Methods: We analyzed a retrospective cohort of 1500 consecutive pts (between 2009-2015) with HNSCC. We added about 1000 pts to previously presented data (e17514-ASCO 2016). These pts included those with diabetes (DM) on metformin (MET) or other anti-diabetic agents. Descriptive statistics were used for demographic and pt data. Kaplan-Meier method was used to calculate median overall survival (OS) and progression free survival (PFS), 95% CI. Cox model was used to test association between MET (or DM) and OS (or PFS) (using SPSS-24 (IBM)). Results: Of the 1500 pts with HNSCC, 329 had advanced cancer (stage III/ IV), and received definitive chemo-radiation (CRT). Of these, majority were Caucasian (90%), males (90%) and smokers (70%). Mean age at diagnosis was 57 years (SD 10). 53 pts had DM, of which 37 were on MET. Statistical results are shown in Table 1. Conclusions: This retrospective study showed no statistically significant difference between various subgroups described in the table. Given the low number of diabetics, and pts on MET, data is limiting. However, further subset analyses are ongoing to determine whether a difference in treatment (RT vs. cetuximab vs. cisplatin) had an impact on outcomes. Future experiments will utilize tissue microarrays to evaluate for association with mTOR pathway aberrations. [Table: see text][Table: see text]

TPS6109Background: Diabetic patients with head and neck squamous cell carcinoma (HNSCC) receiving the oral hypoglycemic, metformin, demonstrated improved survival compared to those not on metformin...

6065 Background: The benefits of adding chemotherapy to radiation, combined with the ability to spare more normal tissue with conformal radiation techniques have led to an increased interest in rei...