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Opinion statementEsophageal cancer is a leading cause of cancer deaths worldwide, with an increasing incidence in recent decades. The majority of esophageal cancers are squamous cell carcinoma. The 5-year survival rate of esophageal squamous cell carcinoma (ESCC) is poor, and there remains globally a pressing need for novel treatments that improve patient outcomes and quality of life. In this review, we discuss management of localized ESCC with an update on relevant newly published literature, including targeted therapy and novel biomarkers. The standard treatment approach for locally advanced, resectable ESCC is currently chemoradiation with or without surgery. Here we discuss different approaches to endoscopic resection, surgery, and radiation therapy. Although the typical chemotherapy regimen is a combination of a platinum with a fluoropyrimidine or paclitaxel, different regimens are being evaluated. With the landscape of immunotherapy rapidly evolving, at the forefront of new treatments for ESCC is immunotherapy and other targeted agents. Ultimately, the treatment approach should be individualized to each patient.

Supplementary Figure from Tadalafil Enhances Immune Signatures in Response to Neoadjuvant Nivolumab in Resectable Head and Neck Squamous Cell Carcinoma

Purpose:We hypothesize that the addition of the phosphodiesterase-5 inhibitor tadalafil to the PD-1 inhibitor nivolumab, is safe and will augment immune-mediated antitumor responses in previously untreated squamous cell carcinoma of the head and neck (HNSCC).Patients and Methods:We conducted a two-arm multi-institutional neoadjuvant randomized trial in any-stage resectable HNSCC (NCT03238365). Patients were stratified at randomization by human papillomavirus (HPV) status. Patients in both arms received nivolumab 240 mg intravenously on days 1 and 15 followed by surgery on day 28. Those in the combination therapy arm also received tadalafil 10 mg orally once daily for 4 weeks. Imaging, blood, and tumor were obtained pretreatment and posttreatment for correlative analysis.Results:Neoadjuvant therapy was well-tolerated with no grade 3 to 5 adverse events and no surgical delays. Twenty-five of 46 (54%) evaluable patients had a pathologic treatment response of ≥20%, including three (7%) patients with a complete pathologic response. Regardless of HPV status, tumor proliferation rate was a negative predictor of response. A strong pretreatment T-cell signature in the HPV-negative cohort was a predictor of response. Tadalafil altered the immune microenvironment, as evidenced by transcriptome data identifying enriched B- and natural killer cell gene sets in the tumor and augmented effector T cells in the periphery.Conclusions:Preoperative nivolumab ± tadalafil is safe in HNSCC and results in more than 50% of the patients having a pathologic treatment response of at least 20% after 4 weeks of treatment. Pretreatment specimens identified HPV status-dependent signatures that predicted response to immunotherapy while posttreatment specimens showed augmentation of the immune microenvironment with the addition of tadalafil.

Supplementary Date from Tadalafil Enhances Immune Signatures in Response to Neoadjuvant Nivolumab in Resectable Head and Neck Squamous Cell Carcinoma

Gastric cancer is the third leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability (MSI) status, and the expression of programmed death-ligand 1 (PD-L1), has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with localized gastric cancer. This selection from the NCCN Guidelines for Gastric Cancer focuses on the management of unresectable locally advanced, recurrent, or metastatic disease.

Purpose: We hypothesize that the addition of the phosphodiesterase-5 inhibitor tadalafil to the PD-1 inhibitor nivolumab, is safe and will augment immune-mediated antitumor responses in previously untreated squamous cell carcinoma of the head and neck (HNSCC). Patients and Methods: We conducted a two-arm multi-institutional neoadjuvant randomized trial in any-stage resectable HNSCC (NCT03238365). Patients were stratified at randomization by human papillomavirus (HPV) status. Patients in both arms received nivolumab 240 mg intravenously on days 1 and 15 followed by surgery on day 28. Those in the combination therapy arm also received tadalafil 10 mg orally once daily for 4 weeks. Imaging, blood, and tumor were obtained pretreatment and posttreatment for correlative analysis. Results: Neoadjuvant therapy was well-tolerated with no grade 3 to 5 adverse events and no surgical delays. Twenty-five of 46 (54%) evaluable patients had a pathologic treatment response of ≥20%, including three (7%) patients with a complete pathologic response. Regardless of HPV status, tumor proliferation rate was a negative predictor of response. A strong pretreatment T-cell signature in the HPV-negative cohort was a predictor of response. Tadalafil altered the immune microenvironment, as evidenced by transcriptome data identifying enriched B- and natural killer cell gene sets in the tumor and augmented effector T cells in the periphery. Conclusions: Preoperative nivolumab ± tadalafil is safe in HNSCC and results in more than 50% of the patients having a pathologic treatment response of at least 20% after 4 weeks of treatment. Pretreatment specimens identified HPV status-dependent signatures that predicted response to immunotherapy while posttreatment specimens showed augmentation of the immune microenvironment with the addition of tadalafil.

TPS480 Background: Locally advanced and metastatic gastric, esophageal, gastroesophageal junction, and pancreatic adenocarcinomas (GC, EC, GEJC, and PC) have poor overall survival, and more effective therapies are needed. Claudin 18.2 (CLDN18.2), a tight junction protein, is commonly expressed in these cancers. Monoclonal antibody and CAR-T cell therapies targeting CLDN18.2 have shown promising antitumor activity (Türeci O et al, 2019; Qi C et al, 2022). This study aims to assess the safety and preliminary efficacy of a CLDN18.2 targeted CAR-T, LB1908, in subjects with GC, EC, GEJC, and PC. Methods: This is a phase 1, open-label, multicenter, dose-escalation and expansion study of LB1908 that aims to identify the recommended phase 2 dose (NCT05539430; open to enrollment early 2023). During prescreening, that may occur as early as at initial diagnosis, we will screen subjects for tumor expression of CLDN18.2 by IHC of ≥ 1+ in ≥ 50% of tumor cells. Inclusion criteria include: must be ≥18 and ≤75 years old; histologically/cytologically confirmed unresectable, locally advanced, or metastatic adenocarcinoma of the GC, EC, GEJC, and PC; progressed on at least standard 1st line therapy; ECOG PS 0 or 1; life expectancy > 4 months per investigator judgment; and adequate organ function per protocol. The study has 2 parts. In Part A (dose escalation), 12 to 21 subjects with GC, EC, or GEJC will be enrolled in up to 3 planned dose level cohorts (0.5X106, 1.5X106, and 3.0X106 CAR+ viable T cells/kg), to determine the recommended dose for expansion (RDE). In Part B (dose expansion) the RDE will be administered to up to 35 subjects with GC, EC, and GEJC in one expansion cohort and PC in another cohort (n=11-17 for GC/EC/GEJ, to total 23 subjects when pooling with RDE-treated subjects from part A; n=18 for PC). LB1908 will be manufactured from autologous T cells collected via PMBC apheresis. Subjects may receive optional bridging therapy followed by lymphodepleting chemotherapy with fludarabine 30 mg/m2/day and cyclophosphamide 300 mg/m2/day for 3 days. One infusion of LB1908 will then be administered, and subjects will be followed post-infusion for safety, laboratory, and disease assessments. Primary endpoints are incidence, duration, and severity of AEs and laboratory abnormalities (Parts A and B); and frequency of DLTs at each dose level (Part A). Secondary and exploratory endpoints include: objective response rate, disease control rate, duration of response, progression-free survival, characterization of PK by CAR-positive T cell counts, CAR transgene level in blood, effusions, and target tissues, and evaluation of immunogenicity by presence of anti-LB1908 antibodies. Acknowledgments: This study is funded by Legend Biotech USA Inc. Clinical trial information: NCT05539430 .

452 Background: Following neoadjuvant therapy and definitive surgery, up to one-third of patients (pts) with esophageal (E), gastroesophageal junction (GEJ), and gastric (G) adenocarcinoma with a pathologic complete response (pCR) (tumor regression grade 0 [TRG0]) will experience disease recurrence, while up to one-half of pts with a near-pCR (TRG1) experience disease recurrence. Our study aims to provide real-world evidence that postoperative circulating tumor DNA (ctDNA) is prognostic of recurrence in pts with pCR or near-pCR after curative-intent neoadjuvant treatment and surgery. Methods: We identified pts from 11 institutions with stages I-III esophagogastric cancers who completed neoadjuvant therapy and had TRG0 or TRG1 scores at the time of curative-intent surgery. Postoperative plasma samples were collected for ctDNA analysis within a 16-week molecular residual disease (MRD) window after definitive surgery and serially during routine clinical follow-up from 9/19/19 to 2/21/22. MRD by ctDNA was assessed using a personalized, tumor-informed ctDNA assay (bespoke Signatera mPCR-NGS assay). The primary outcome was recurrence-free survival (RFS), measured from the date of surgery to the first documented sign of radiographic recurrence. Survival analysis was performed using the maximum likelihood bias reduction method for Cox regression in R (version 4.1) package survival. Results: We obtained 250 blood samples from 42 pts with E (n=18), GEJ (n=16), and G (n=8) adenocarcinomas who received either neoadjuvant chemoradiation or chemotherapy. 11 pts had a pCR (TRG0), and 31 pts had a near-pCR (TRG1). For pts analyzed in the post-operative, 16-week MRD window (n=21), the presence of ctDNA correlated with a higher recurrence rate (66.7%; 2/3) compared to the absence of ctDNA (11.1%; 2/18). Detectable ctDNA was associated with a significantly shorter RFS (HR 23.0, 95% CI 2.0 – 268.1; p = 0.012). 38 pts had ctDNA analyzed at any post-MRD time point (>16 weeks after surgery) over a median follow-up of 22.3 months. With additional routine ctDNA testing at any post-MRD time point, the recurrence rate was 90.0% (9/10) in ctDNA-positive pts compared to 10.7% (3/28) in ctDNA-negative pts, exhibiting a further reduction in RFS (HR 44.4; 95% CI 5.4-366.3; p

Background Radiation for patients with head and neck cancer (HNC) is associated with painful mucositis that impacts the delivery of treatment and contributes to high symptom burden. Methods This was a prospective, randomized pilot trial. Eligible patients received primary or adjuvant chemoradiation. Patients were randomized to usual care vs usual care plus gabapentin titrated to drug tolerance during radiation. Patients completed a symptom survey at baseline and weekly during therapy. Results Seventy-nine patients were enrolled in the study (38 control, 41 treatment). At interim analysis, gabapentin use resulted in a decrease in pain (P = .004), with the biggest decreases being in the latter weeks of therapy. By week 7, the median pain score in the treatment group was below the 0.25 quantile of the control group. Conclusion Prophylactic use of gabapentin during chemoradiation for HNC patients resulted in a decrease in pain, neurosensory symptoms, and general systemic symptoms.

Purpose: This randomized, multicenter, open-label, phase Ib/II study assessed durvalumab and tremelimumab in combination or as monotherapy for chemotherapy-refractory gastric cancer or gastroesophageal junction (GEJ) cancer. Patients and Methods: Second-line patients were randomized 2:2:1 to receive durvalumab plus tremelimumab (arm A), or durvalumab (arm B) or tremelimumab monotherapy (arm C), and third-line patients received durvalumab plus tremelimumab (arm D). A tumor-based IFNγ gene signature was prospectively evaluated as a potential predictive biomarker in second- and third-line patients receiving the combination (arm E). The coprimary endpoints were objective response rate and progression-free survival (PFS) rate at 6 months. Results: A total of 113 patients were treated: 6 in phase Ib and 107 (arm A, 27; arm B, 24; arm C, 12; arm D, 25; arm E, 19) in phase II. Overall response rates were 7.4%, 0%, 8.3%, 4.0%, and 15.8% in the five arms, respectively. PFS rates at 6 months were 6.1%, 0%, 20%, 15%, and 0%, and 12-month overall survival rates were 37.0%, 4.6%, 22.9%, 38.8%, and NA, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 4%, 42%, 16%, and 11% of patients, respectively. Conclusions: Response rates were low regardless of monotherapy or combination strategies. No new safety signals were identified. Including use of a tumor-based IFNγ signature and change in baseline and on-treatment circulating tumor DNA are clinically feasible and may be novel strategies to improve treatment response in this difficult-to-treat population.

During the past decade and a half, the most common cause of oropharyngeal squamous cell carcinoma (OPSCC) has shifted from tobacco and alcohol to the human papillomavirus (HPV). HPV-driven p16-positive OPSCC and tobacco-related OPSCC differ in their underlying molecular and genetic profiles, socioeconomic demographics, and response to treatment. HPV-related OPSCC tends to occur in younger patients and has a significantly better response to treatment and excellent prognosis. The stark contrast in prognosis-with around 90% overall 5-year survival for HPV-related p16-positive OPSCC and 40% for non-HPV-related p16-negative OPSCC-has prompted major changes in the eighth edition of the staging manual of the AJCC (American Joint Committee on Cancer). The past 10-15 years have also witnessed major advances in surgery, radiation therapy (RT), and systemic therapy. Minimally invasive surgery has come of age, with transoral robotic procedures and laser microsurgery. Intensity-modulated RT (IMRT) and more recently proton-beam RT have markedly improved the conformity of RT, with an ability to precisely target the cancer and cancer-bearing regions while sparing normal structures and significantly reducing long-term treatment-related morbidity. Progress in systemic therapy has come in the form of immunotherapy and targeted agents such as cetuximab. Owing to the better prognosis of HPV-driven OPSCC as well as the morbidity associated with treatment, de-escalation of therapy via multiple strategies is being explored. The article reviews the advances in diagnosis and multidisciplinary management of OPSCC in the HPV era.©RSNA, 2019.

ImportanceApproval by the US Food and Drug Administration of immune checkpoint inhibition (ICI) for advanced gastroesophageal cancer (aGEC) irrespective of PD-L1 status has generated controversy. Exploratory analyses from individual trials indicate a lack of meaningful benefit from ICI in patients with absent or low PD-L1 expression; however, analysis of a single variable while ignoring others may not consider the instability inherent in exploratory analyses.ObjectiveTo systematically examine the predictive value of tissue-based PD-L1 status compared with that of other variables for ICI benefit in aGEC to assess its stability.Data SourcesMEDLINE, Embase, Scopus, Web of Science, Cochrane Central Register (2000-2022).Study Selection, Data Extraction, and SynthesisRandomized clinical trials (RCTs) were included of adults with aGEC (adenocarcinoma [AC] or squamous cell carcinoma [SCC]) randomized to anti−PD-1 or PD-L1−containing treatment vs standard of care (SOC). Study screening, data abstraction, and bias assessment were completed independently by 2 reviewers. Of 5752 records screened, 26 were assessed for eligibility; 17 trials were included in the analysis.Main Outcomes and MeasuresThe prespecified primary end point was overall survival. The mean hazard ratio (HR) for ICI vs SOC was calculated (random-effects model). Predictive values were quantified by calculating the ratio of mean HRs between 2 levels of each variable.ResultsIn all, 17 RCTs (9 first line, 8 after first line) at low risk of bias and 14 predictive variables were included, totaling 11 166 participants (5067 with SCC, 6099 with ACC; 77.6% were male and 22.4% were female; 59.5% of patients were younger than 65 years, 40.5% were 65 years or older). Among patients with SCCs, PD-L1 tumor proportion score (TPS) was the strongest predictor of ICI benefit (HR, 0.60 [95% CI, 0.53-0.68] for high TPS; and HR, 0.84 [95% CI, 0.75-0.95] for low TPS), yielding a predictive value of 41.0% favoring high TPS (vs ≤16.0% for other variables). Among patients with AC, PD-L1 combined positive score (CPS) was the strongest predictor (after microsatellite instability high status) of ICI benefit (HR, 0.73 [95% CI, 0.66-0.81] for high CPS; and HR, 0.95 [95% CI, 0.84-1.07] for low CPS), yielding a predictive value of 29.4% favoring CPS-high (vs ≤12.9% for other variables). Head-to-head analyses of trials containing both levels of a variable and/or having similar design generally yielded consistent results.Conclusions and RelevanceTissue-based PD-L1 expression, more than any variable other than microsatellite instability-high, identified varying degrees of benefit from ICI-containing therapy vs SOC among patients with aGEC in 17 RCTs.

Context.— A standardized detailed surgical pathology report is the cornerstone of gastric cancer management. Objective.— To guide management and prognostication for patients with gastric carcinomas globally, the International Collaboration on Cancer Reporting aimed to produce an evidence-based international pathology reporting data set with a panel of globally recognized expert pathologists and clinicians. Design.— Based on published guidelines/data sets for gastric carcinomas, a working draft was developed by the chair of the expert panel of pathologists and clinicians. The draft was then circulated to the panel and discussed in a series of teleconferences and email communications until consensus was achieved. The draft data set was uploaded on the International Collaboration on Cancer Reporting Web site for public comment. The data set was reviewed in consideration of the feedback, and a final version was approved by the panel. Results.— This data set was developed for gastrectomy specimens for primary gastric carcinomas, including neuroendocrine carcinomas and mixed neuroendocrine-nonneuroendocrine neoplasms. Well-differentiated neuroendocrine tumors, nonepithelial malignancies, and secondary tumors were excluded from this data set. The final data set contains 15 core (required) elements and 8 noncore (recommended) elements. A commentary is provided for each element. Conclusions.— The International Collaboration on Cancer Reporting has published freely available, evidence-based data sets for gastric cancer reporting. Standardized reporting has been shown to improve patient care and facilitates data exchange and analysis for quality assurance, cancer epidemiology, and clinical and basic research.

TPS4162 Background: Advanced esophageal and gastric adenocarcinomas (EGA) have poor prognosis. Doublet chemotherapy with fluoropyrimidine and platinum agents in combination with nivolumab for PD-L1 positive tumors is now the standard first-line approach, but overall survival (OS) remains < 1.5 years. A subset of EGA patients have limited burden of metastatic disease. There is accumulating evidence that patients with oligometastatic states across disease types may benefit from locoregional ablative therapies during the course of their treatment. EA2183 is the first prospective study to evaluate the potential benefits of consolidative radiotherapy (XRT) in oligometastatic EGA. Methods: This is a prospective, randomized phase 3 study evaluating the role of consolidative XRT in oligometastatic EGA. Patients with ≤3 metastases at the time of diagnosis of advanced disease are eligible for enrollment. After completion of 4 months of systemic therapy, patients whose disease has not progressed are randomized to consolidation with XRT to all sites of disease followed by continuation of systemic therapy or continuation of systemic therapy alone. Patients are able to enroll in the study at the time of diagnosis of advanced disease or after completion of induction therapy. Systemic therapy is left to the discretion of the treating physician and can include FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine, oxaliplatin) in combination with nivolumab. Unless there are contraindications to immunotherapy or a history of prior treatment with immune checkpoint inhibitors, nivolumab use is mandatory if tumor has PD-L1 combined positive score (CPS) ≥5. The goal of radiation is to consolidate gains made by chemotherapy by delivering the highest dose that maintains the greatest tumor control probability that is also safe to deliver given the anatomic and normal tissue constraints. Specific radiation dose and fractionation are recommended in the protocol but is left to the discretion of the treating radiation oncologist to choose the course that is most suitable. Radiation must be administered over a maximum of 15 treatment days to minimize systemic therapy treatment breaks. Primary endpoint is OS from the time of randomization. Secondary endpoints include progression free survival from the time of randomization and safety and tolerability of consolidative XRT. We hypothesize that consolidative XRT will prolong OS from 10 to 15.6 months (an increase in median OS of 55.6%). The study is planning to enroll 314 patients with the goal of randomizing 204 patients in a 2:1 fashion. Stratification factors include number of metastatic sites, choice of immunotherapy with relation to PD-L1 CPS, as well as time of registration to the protocol (before or after systemic therapy initiation). Enrollment to the study is ongoing. Clinical trial information: NCT04248452.

e16078 Background: Globally, as of 2020, gastric cancer is the 5th most common cancer and the 4th common cause of cancer-related death. Our objective is to determine how gender/sex, race, treatment location, and socioeconomic factors contribute to the treatment of patients (pts) with gastric cancer. Methods: 233,479 pts were identified from the National Cancer Database (NCDB) between 2004 and 2018. Pts were divided into 3 age-based subgroups. The 70 y/o (N=100,242) group was termed late-onset gastric cancer (LOGC). Overall 114,117 (48.9%) received surgery; 112,953 (48.4%) received chemotherapy; and 55,024 (23.6%) received radiation therapy. Unfortunately, data were not available on the receipt of bimodal or trimodal therapy. We used chi-square tests and a logistic regression model to examine factors associated with treatment patterns. Factors considered in the model included: age, gender/sex, race/ethnicity, cancer stage, facility type, year of diagnosis, insurance status, and location of residence. Results: Females represented a higher proportion of EOGC pts (47%) compared to AOGC pts (34.5%) and LOGC pts (41%). A greater amount of EOGC pts were Hispanic (24.9%) compared to AOGC pts (10.4%) and LOGC pts (7.1%). EOGC pts were often treated at academic centers (65.8%) compared to AOGC pts (60.9%) and LOGC pts (54.4%). A larger percentage of EOGC pts were uninsured (11.7%) vs AOGC pts (5.4%) and LOGC pts (0.9%). The table outlines differences in treatment by age, sex, race/ethnicity, facility type, year of diagnosis, insurance, and location of residence (after adjusting for stage). Conclusions: EOGC pts display unique demographic characteristics. After adjusting for stage, significant differences exist in how pts with gastric cancer are treated. Further work is needed to delineate the impact of gastric cancer in young pts and determine which factors play a role in treatment for pts of all ages from both the patient and oncologist perspective.[Table: see text]

Metastatic or unresectable esophageal and gastroesophageal junction adenocarcinoma represent a devastating disease with 5-year survival rate of

Background Immuno-STATsTM are novel, modular fusion proteins designed to selectively activate tumor-antigen-specific CD8+ T cells. Human papillomavirus (HPV) associated cancers serve as a model system to assess the safety and efficacy of the Immuno-STAT platform. CUE-101 is comprised of human leukocyte antigen (HLA) complex, HLA A*0201, a peptide epitope derived from the HPV type 16 E7 protein, and 4 molecules of a reduced affinity human interleukin-2 (IL2) designed to bind and activate HPV-specific T cells for eradication of HPV16-driven cancers. In preclinical studies CUE-101 demonstrated selective binding, activation, and expansion of HPV16 E7-specific CD8+ T cells, which translated into anti-tumor activity.1 Methods CUE-101-01 is a first-in-human (FIH) phase 1 study in patients diagnosed with HPV16+ recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) refractory to one or more lines of therapy. Trial eligibility includes MHC class I type HLA-A*0201 and a diagnosis of an HPV16+ HNSCC, as assessed by p16 IHC and confirmed by HPV16 mRNA ISH. CUE-101 is administered intravenously over 60 minutes every 21 days. Objectives include determination of safety, pharmacodynamics (PD), pharmacokinetics (PK), recommended phase 2 dose (RP2D), and preliminary anti-tumor activity. The safety results from treated participants will be presented. Results 19 participants have received CUE-101 monotherapy as of August 7, 2020. Doses ranging from 0.06 to 1 mg/kg were determined to be safe and well-tolerated, enabling dose escalation to 2 mg/kg. Preliminary PK data demonstrate dose-dependent increases in drug exposure which are sustained upon repeat dosing, and low inter-subject variability. Preliminary data from systemic blood analyses show early signals of expansion of HPV-16 E711-20-specific CD8+ T cells. Stable disease (SD), as determined by RECIST 1.1, was observed in several participants in these early dose cohorts, with one subject maintaining SD up to 19 weeks. The maximum tolerated dose (MTD) has not yet been reached. As of May 14, 2020 (the development safety update report (DSUR) data-lock date), no dose limiting toxicities and the following adverse events were observed in the first 12 patients treated with CUE-101: fatigue (n=3), decreased appetite (n=1), arthralgia (n=1), muscular weakness (n=1), parasthesia (n=1), bullous pemphigoid (n=1), and infusion-related reactions (n=1). Conclusions CUE-101 is a novel agent that is demonstrating acceptable tolerability, favorable PK, and preliminary PD signals that support selective activation of tumor-specific T cells. Neither the MTD nor the monotherapy RP2D have been established. PD and PK analyses are ongoing as dose escalation continues. Acknowledgements The authors would like to thank all the patients who are participating in this study. The study is sponsored by Cue Biopharma. Trial Registration ClinicalTrials. gov NCT03978689 Ethics Approval This study was approved by Ethics and Institutional Review Boards (IRBs) at all study sites; IRB reference numbers: DF/HCC IRB# 19-374 (Massachusetts General Hospital), HRPO# 201905108 (Washington University School of Medicine), IRB 191714 (Vanderbilt University Medical Center Vanderbilt-Ingram Cancer Center), Advarra Pro00037736 (Moffitt Cancer Center), IRB(IRBMED) HUM00165746 (University of Michigan Comprehensive Cancer Center), 2019-087 (Karmanos Cancer Institute), WIRB IRB00112341(Winship Cancer Institute/Emory University), WIRB 2000026098 (Yale Cancer Center), WIRB STUDY00008948 (University of Washington, Seattle ), WIRB 1908869642 (University of Arizona Cancer Center, IRB 20-073 (Memorial Sloan Kettering Cancer Center), 2019-0578 (The University of Texas MD Anderson Cancer Center), IRB 52744 (Stanford University School of Medicine). Reference Quayle SN, Girgis N, Thapa DR, et al. CUE-101, a Novel HPV16 E7-pHLA-IL-2-Fc Fusion Protein, Enhances Tumor Antigen Specific T Cell Activation for the Treatment of HPV16-Driven Malignancies. Clin Cancer Res 2020;26:1953–64.

344 Background: ICI with anti-PD-1 therapy was approved by the US FDA as 1st/2nd-line treatment of advanced GEC regardless of PD-L1 status. It is argued that patients (pts) with PD-L1-low GEC do not benefit from ICI. To avoid spurious exclusion of pts, we systematically reviewed phase 3 trials to assess the magnitude and consistency of PD-L1 to predict benefit from ICI. We also examined other potential predictive factors to understand their magnitude and consistency in comparison with PD-L1 status. Methods: MEDLINE, Embase, Scopus, Web of Science, and Cochrane Central Register were searched for all randomized clinical trials (RCT; 2000-2021) in advanced GEC comparing ICI, alone or with chemotherapy, vs standard of care (SOC). The primary endpoint was overall survival (OS). Study screening, data abstraction, and bias assessment were done independently by two reviewers per PRISMA guidelines. The mean HR for ICI vs SOC was calculated by random effects model. The predictive value of a factor was quantified using relative magnitude and consistency (table). Results: 14 RCTs at low risk of bias were included (N = 9,210 pts; KN62, CM649, CM648, ESCORT1st, KN590, ATT4, JAV100, KN181, KN61, ATT3, ESCORT, RATIONALE302, JAV300, ATT2). 6 trials were 1st-line, 8 were after 1st-line. Treatment comparisons were ICI + chemo vs chemo (6 trials), ICI vs chemo (9 trials), and ICI vs placebo (1 trial). ICI was always anti-PD-1/-L1 (1 trial also had anti-CTLA-4). Table shows primary results. To enable head to head comparisons, subgroup analyses of trials containing both levels of a factor or having similar design were done and generally yielded consistent results. Conclusions: PD-L1 CPS is the strongest predictive biomarker, after MSI, for OS benefit from ICI-containing therapy vs SOC. Additional research on gender is warranted.[Table: see text]

BackgroundClinical trials establish the standard of care for cancer and other diseases. While social network analysis has been applied to basic sciences, the social component of clinical trial research is not well characterized. We examined the social network of cancer clinical trialists and its dynamic development over more than 70 years, including the roles of subspecialization and gender in relation to traditional and network-based metrics of productivity.MethodsWe conducted a social network analysis of authors publishing chemotherapy-based prospective trials from 1946-2018, based on the curated knowledge base HemOnc.org, examining: 1) network density; 2) modularity; 3) assortativity; 4) betweenness centrality; 5) PageRank; and 6) the proportion of co-authors sharing the same primary cancer subspecialty designation. Individual author impact and productive period were analyzed as a function of gender and subspecialty.FindingsFrom 1946-2018, the network grew to 29,197 authors and 697,084 co-authors. While 99.4% of authors were directly or indirectly connected as of 2018, the network had very few connections and was very siloed by cancer subspecialty. Small numbers of individuals were highly connected and had disproportionate impact (scale-free effects). Women were under-represented and likelier to have lower impact, shorter productive periods (PInterpretationThe network of cancer clinical trialists is best characterized as a strategic or “mixed-motive” network, with cooperative and competitive elements influencing its appearance.Network effects e.g., low centrality, which may limit access to high-profile individuals, likely contribute to ongoing disparities.FundingVanderbilt Initiative for Interdisciplinary Research; National Institutes of Health; National Science FoundationResearch in contextEvidence before this studyWe reviewed the literature on social networks from the 1800’s to 2018. Additionally, MEDLINE was searched for (“Social Networking”[Mesh] OR “Social Network Analysis”) AND (“Clinical Trials as Topic”[Mesh] OR “Hematology”[Mesh] OR “Medical Oncology”[Mesh]) without date restriction. The MEDLINE search yielded 43 results, of which 8 were relevant; none considered gender nor temporality in their analyses. To our knowledge, there has not been any similar study of the dynamic social network of clinical trialists from the inception of the fields of medical oncology and hematology to the present.Added value of this studyThis is the first dynamic social network analysis of cancer clinical trialists. We found that the network was sparse and siloed with a small number of authors having disproportionate impact and influence as measured by network metrics such as PageRank; these metrics have become more disproportionate over time. Women were under-represented and likelier to have lower impact, shorter productive periods, less network centrality, and a greater proportion of co-authors in their same cancer subspecialty.Implications of all the available evidenceWhile gender disparities have been demonstrated in many fields including hematology/oncology, our analysis is the first to show that network factors themselves are significantly implicated in gender disparity. The increasing coalescence of the network by traditional cancer type and around a small number of high-impact individuals implies challenges when the field pivots from traditionally disease-oriented subspecialties to a precision oncology paradigm. New mechanisms are needed to ensure diversity of clinical trialists.

BackgroundUse of anti-PD-1 immune checkpoint inhibitors (ICI) is currently the first line therapy for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but critical work remains in identifying factors guiding resistance mechanisms.1 2 While recent studies have specifically implicated cancer-associated fibroblasts (CAFs) as potential mediators of immunotherapy response, the immunoregulatory role of CAFs in head and neck cancer has not been thoroughly explored.3–5MethodsTo determine if there are changes in cell populations associated with anti-PD-1 therapy in head and neck cancer patients, we performed high dimensional single-cell RNA sequencing (scRNA-SEQ) from a neoadjuvant trial of 50 advanced-stage head and neck squamous cell carcinoma (HNSCC) patients that were treated with the anti-PD-1 therapy, nivolumab, for the duration of one month. Tumor specimens were analyzed pre- and post-treatment with single-cell RNA sequencing performed on 4 patients as well as bulk RNA sequencing on 40 patients. Matched scRNA-SEQ data was analyzed using the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe) and Virtual Inference of Protein-activity by Enriched Regulon (VIPER) bioinformatic analysis platform to determine TME cells that correlated with response and resistance to nivolumab.6 For CAF functional studies, surgical tumor specimens were processed and enriched for CAF subtypes, and these were co-cultured with T cells from peripheral blood and tumor infiltrating lymphocytes.ResultsWe identified 14 distinct cell types present in HNSCC patients. Of these 14 cell types, the fibroblast subtype showed significant changes in abundance following nivolumab treatment. We identified 5 distinct clusters of cancer-associated fibroblast subsets (HNCAF-0, 1, 2, 3, and 4) of which, two clusters, HNCAF-0 and HNCAF-3 were predictive of patient response to anti-PD-1 therapy. To determine the significance of these CAF subsets’ function, we isolated HNCAF-0/3 cells from primary HNSCC tumor specimens and co-cultured with primary human T cells. Analysis by flow cytometry showed that HNCAF-0/3 reduced TGFβ-dependent PD-1+TIM-3+ exhaustion of T cells and increased CD103+NKG2A+ resident memory phenotype and cytotoxicity to enhance overall function.ConclusionsTo our knowledge, we are the first to characterize CAF heterogeneity within the head and neck TME and show direct immunostimulatory activity of CAFs. Our findings demonstrate the functional importance of CAF subsets in modulating the immunoregulatory milieu of the human HNSCC, and we have identified clinically actionable CAF subtypes that can be used as a biomarker of response and resistance in future clinical trials.Trial RegistrationNCT03238365ReferencesFerris RL, Blumenschein Jr G, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016;375:1856–1867.Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, Heath K, McClanahan T, Lunceford J, Gause C, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 2016;17:956–965.Dominguez CX, Muller S, Keerthivasan S, Koeppen H, Hung J, Gierke S, Breart B, Foreman O, Bainbridge TW, Castiglioni A, et al. Single-cell RNA sequencing reveals stromal evolution into LRRC15(+) myofibroblasts as a determinant of patient response to cancer immunotherapy. Cancer Discov 2020;10:232–253.Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, Connell CM, Roberts EW, Zhao Q, Caballero OL, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A 2013;110:20212–20217.Kieffer Y, Hocine HR, Gentric G, Pelon F, Bernard C, Bourachot B, Lameiras S, Albergante L, Bonneau C, Guyard A, et al. Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Cancer Discov 2020;10:1330–1351.Obradovic A, Chowdhury N, Haake SM, Ager C, Wang V, Vlahos L, Guo XV, Aggen DH, Rathmell WK, Jonasch E, et al. Single-cell protein activity analysis identifies recurrence-associated renal tumor macrophages. Cell 2021;184:2988–3005.Ethics ApprovalPatients provided informed consent for this work. All experimental procedures were approved by the Institutional Review Board of Vanderbilt University Medical Center (IRB: 171883).

BackgroundImmuno-STATsTM are novel, modular fusion proteins designed to selectively activate tumor-antigen-specific CD8+ T cells. CUE-101 is comprised of a human leukocyte antigen (HLA) complex, HLA-A*0201, a peptide epitope derived from the HPV16 E7 protein, and 4 molecules of a reduced affinity human interleukin-2 (IL-2) and is designed to bind and activate HPV16-specific T cells for treatment of HPV16-driven cancers. In preclinical studies CUE-101 demonstrated selective binding, activation, and expansion of HPV16 E7-specific CD8+ T cells, and a murine surrogate activated anti-tumor immunity.1MethodsCUE-101-01 is a first-in-human study in HLA-A*0201 positive patients with HPV16+ recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Safety of escalating monotherapy and combination doses was evaluated to establish the recommended phase 2 dose (RP2D) for expanded enrollment. Patients with R/M HNSCC refractory to 1 or more prior platinum or pembrolizumab based systemic treatments received CUE-101 monotherapy, and patients with R/M HNSCC and PD-L1 tumor expression received combination CUE-101 and 200 mg pembrolizumab as first line treatment. Study treatment was administered intravenously every 3 weeks until progression or toxicity. Objectives included evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.ResultsAs of June 30, 2021, 39 patients have received CUE-101 monotherapy ranging from 0.06 to 8 mg/kg. The maximum tolerated dose (MTD) was not identified. Based on PK, PD and clinical data, a monotherapy RP2D of 4 mg/kg was selected. The combination cohort of 1 mg/kg CUE-101 and pembrolizumab has been tested and dose escalation is ongoing. Adverse events have included CTCAE grade 2 or less fatigue (41%), anemia (31%), lymphopenia (24%), chills (21%), decreased appetite (19%) and dyspnea (17%). CUE-101 PK data demonstrate dose-dependent increases in drug exposure that are sustained upon repeat dosing. PD data demonstrate dose-dependent expansion of HPV-16 E711-20-specific CD8+ T cells, sustained increase in natural killer cells and transient increase in Treg cells. An increase in CD3+ GZMB+ tumor infiltrating T cells was observed in tissue following treatment with CUE-101 in one patient with available pre- and post-treatment biopsies. One patient at the CUE-101 monotherapy RP2D has an ongoing partial response and 8 of 33 patients have experienced stable disease ≥ 12 weeks based on RECIST 1.1 criteria.ConclusionsCUE-101 is a novel immunotherapeutic demonstrating acceptable safety and tolerability with encouraging PD signals, supporting selective activation of tumor-specific T cells, and promising antitumor activity. Enrollment continues in both monotherapy and combination cohorts.AcknowledgementsThe authors would like to thank all the patients who are participating in this study. The study is sponsored by Cue Biopharma.Trial RegistrationClinicalTrials.gov NCT03978689ReferencesQuayle SN, Girgis N, Thapa DR, et al. CUE-101, a Novel HPV16 E7-pHLA-IL-2-Fc fusion protein, enhances tumor antigen specific T cell activation for the treatment of HPV16-driven malignancies. Clin Cancer Res 2020;26:1953–64.Ethics ApprovalThis study was approved by Ethics and Institutional Review Boards (IRBs) at all study sites. IRB reference numbers: Advarra Pro00037736 (Moffitt Cancer Center), IRB 52744 (Stanford University School of Medicine), IRB 191714 (Vanderbilt University Medical Center Vanderbilt-Ingram Cancer Center), HRPO# 201905108 (Washington University School of Medicine), 2019–087 Karmanos Cancer Institute, DF/HCC IRB# 19-374 (Massachusetts General Hospital), WIRB 2000026098 (Yale Cancer Center), WIRB 1908869642 (University of Arizona Cancer Center), WIRB STUDY00008948 (University of Washington, Seattle), IRB(IRBMED) HUM00165746 (University of Michigan Comprehensive Cancer Center), WIRB IRB00112341(Winship Cancer Institute/Emory University), 2019–0578 (The University of Texas MD Anderson Cancer Center), IRB 20-073 (Memorial Sloan Kettering Cancer Center), IRB00255391 (Johns Hopkins University School of Medicine).

Author(s): Geiger, Jessica L; Bauman, Julie E; Gibson, Michael K; Gooding, William E; Varadarajan, Prakash; Kotsakis, Athanasios; Martin, Daniel; Gutkind, Jorge Silvio; Hedberg, Matthew L; Grandis, Jennifer R; Argiris, Athanassios | Abstract: BackgroundPatients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) demonstrate aberrant activation of the phosphotidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. We examined the efficacy of everolimus, an mTOR inhibitor, in patients with recurrent or metastatic HNSCC.MethodsThis single-arm phase II study enrolled biomarker-unselected patients with recurrent or metastatic HNSCC who failed at least 1 prior therapy. Everolimus was administered until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit rate (CBR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and evaluation of tissue and serum biomarkers related to the PIK3CA pathway.ResultsSeven of 9 patients treated in the first stage were evaluable. No objective responses were seen; CBR was 28%. Three patients discontinued everolimus because of toxicity. Median PFS and OS were 1.5 and 4.5 months, respectively. No activating PI3K mutations were identified in available tumor tissue.ConclusionEverolimus was not active as monotherapy in unselected patients with recurrent/metastatic HNSCC. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1759-1764, 2016.

Background The purpose of this study was to establish the efficacy and toxicities of concurrent erlotinib and docetaxel with intensity-modulated radiotherapy (IMRT) for locally advanced head and neck squamous cell carcinoma (HNSCC). Methods Patients received daily erlotinib for 2 weeks, followed by daily IMRT with concurrent weekly docetaxel and daily erlotinib, followed by daily erlotinib for up to 2 years. The primary objective was disease-free survival (DFS). Secondary objectives included overall survival (OS), patterns of failure, and toxicities. Forty-three patients were recruited for this study. Results With a median follow-up of 48.7 months, the 3-year DFS, OS, locoregional failure-free survival, and distant metastasis-free survival was 69.5%, 81%, 82.4%, and 83.7%, respectively. The most common grade III/IV local toxicities were dysphagia, dermatitis, and mucositis. Patients with p16-positive tumors had significantly better outcomes. Conclusion The regimen is tolerable and effective. It is worthy of further investigation in selected patients and may be useful in patients who cannot tolerate cisplatin. © 2016 Wiley Periodicals, Inc. Head Neck, 2016

Background We present a case of myositis and possible overlapping neuromuscular junction disorder following treatment with nivolumab for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Methods We report a 75-year-old man with recurrent stage IVA, T1N2cM0 oral cavity HNSCC treated with weight-dosed nivolumab who presented three weeks later with severe fatigue, generalized weakness, and bilateral ptosis. Evaluation demonstrated elevated creatine kinase and myopathic motor units on electromyography, supporting a diagnosis of an underlying muscle disease. Elevated serum acetylcholine receptor binding antibodies raised the possibility of concurrent myasthenia gravis. Results He received corticosteroids and plasmapheresis without improvement in muscle weakness. His course was complicated by bacteremia, cardiac arrest, and concerns for recurrent malignancy. Following a two-month hospital stay, he was made comfort care and died. Conclusions With increasing usage of checkpoint inhibitors in HNSCC, clinicians must be aware of and vigilant for associated rare but serious adverse events.

Purpose Salvage options for unresectable locally recurrent, previously irradiated squamous cell carcinoma of the head and neck (rSCCHN) are limited. Although the addition of reirradiation may improve outcomes compared to chemotherapy alone, significant toxicities limit salvage reirradiation strategies, leading to suboptimal outcomes. We therefore designed a phase 2 protocol to evaluate the efficacy of stereotactic body radiation therapy (SBRT) plus cetuximab for rSCCHN. Methods and Materials From July 2007 to March 2013, 50 patients >18 years of age with inoperable locoregionally confined rSCCHN within a previously irradiated field receiving ≥60 Gy, with a Zubrod performance status of 0 to 2, and normal hepatic and renal function were enrolled. Patients received concurrent cetuximab (400 mg/m 2 on day −7 and then 250 mg/m 2 on days 0 and +8) plus SBRT (40-44 Gy in 5 fractions on alternating days over 1-2 weeks). Primary endpoints were 1-year locoregional progression-free survival and National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 graded toxicity. Results Median follow-up for surviving patients was 18 months (range: 10-70). The 1-year local PFS rate was 60% (95% confidence interval [CI]: 44%-75%), locoregional PFS was 37% (95% CI: 23%-53%), distant PFS was 71% (95% CI: 54%-85%), and PFS was 33% (95% CI: 20%-49%). The median overall survival was 10 months (95% CI: 7-16), with a 1-year overall survival of 40% (95% CI: 26%-54%). At last follow-up, 69% died of disease, 4% died with disease, 15% died without progression, 10% were alive without progression, and 2% were alive with progression. Acute and late grade 3 toxicity was observed in 6% of patients respectively. Conclusions SBRT with concurrent cetuximab appears to be a safe salvage treatment for rSCCHN of short overall treatment time.

Objectives Prognosis for patients with locally advanced esophagogastric adenocarcinoma (EAC) is poor with surgery alone, and adjuvant therapy after open esophagectomy is frequently not tolerated. After minimally invasive esophagectomy (MIE); however, earlier return to normal function may render patients better able to receive adjuvant therapy. We examined whether primary MIE followed by adjuvant chemotherapy influenced survival compared with propensity-matched patients treated with neoadjuvant therapy. Methods Patients with stage II or higher EAC treated with MIE (N = 375) were identified. Using 30 pretreatment covariates, propensity for assignment to either neoadjuvant followed by MIE (n = 183; 54%) or MIE as primary therapy (n = 156; 46%) was calculated, generating 97 closely matched pairs. Hazard ratios were adjusted for age, sex, body mass index, smoking, comorbidity, and final pathologic stage. Results In propensity-matched pairs, adjusted hazard ratio for death did not differ significantly for primary MIE compared with neoadjuvant (hazard ratio, 0.83; 95% confidence interval, 0.60-1.16). Recurrence patterns were similar between groups and 65% of patients with IIb or greater pathologic stage received adjuvant therapy. Clinical staging was inaccurate in 37 out of 105 patients (35%) who underwent primary MIE (n = 18 upstaged and n = 19 downstaged). Conclusions Primary MIE followed by adjuvant chemotherapy guided by pathologic findings did not negatively influence survival and allowed for accurate staging compared with clinical staging. Our data suggest that primary MIE in patients with resectable EAC may be a reasonable approach, improving stage-based prognostication and potentially minimizing overtreatment in patients with early stage disease through accurate stage assignments. A randomized controlled trial testing this hypothesis is needed.

Background The purpose of this study was to establish the efficacy and toxicities of concurrent bevacizumab and docetaxel with radiation for locally advanced head and neck squamous cell carcinoma (HNSCC). Methods Patients with previously untreated HNSCC received standard daily radiotherapy (RT) with concurrent weekly docetaxel (20 mg/m2) and biweekly bevacizumab (5 mg/kg). Biweekly bevacizumab was then continued for up to 1 year after RT. The primary objective was progression-free survival (PFS). Secondary objectives included overall survival (OS), patterns of failure, and toxicities of treatment. Results Thirty patients were recruited. With median follow-up of 38 months, the 3-year PFS, OS, locoregional recurrence-free survival, and distant metastasis-free survival was 61.7%, 68.2%, 84.5%, and 80.5%, respectively. The most common local toxicities were mucositis and dermatitis. Two patients developed hemorrhage. There was no grade 5 toxicity. Conclusion The combination of bevacizumab, docetaxel, and RT is tolerable and effective in HNSCC. This regimen is worthy of further study in appropriate subset of patients receiving chemoradiation therapy. © 2014 Wiley Periodicals, Inc. Head Neck 37: 1665–1671, 2015

Objective Src family kinase (SFK) activation circumvents epidermal growth factor receptor (EGFR) targeting in head and neck squamous cell carcinoma (HNSCC); dual SFK-EGFR targeting could overcome cetuximab resistance. Patients and methods We conducted a Simon two-stage, phase II trial of the SFK inhibitor, dasatinib, and cetuximab in biomarker-unselected patients with cetuximab-resistant, recurrent/metastatic HNSCC. Pre- and post-treatment serum levels of interleukin-6 (IL6) were measured by ELISA. HNSCC cell lines were assessed for viability and effects of IL6 modulation following dasatinib-cetuximab treatment. Results In the first stage, 13 patients were evaluable for response: 7 had progressive and 6 had stable disease (SD). Enrollment was halted for futility, and biomarker analysis initiated. Low serum IL6 levels were associated with SD (raw p = 0.028, adjusted p = 0.14) and improved overall survival (p = 0.010). The IL6 classifier was validated in a separate trial of the same combination, but was unable to segregate survival risk in a clinical trial of cetuximab and bevacizumab suggesting serum IL6 may be specific for the dasatinib-cetuximab combination. Enhanced in vitro HNSCC cell death was observed with dasatinib-cetuximab versus single agent treatment; addition of IL6-containing media abrogated this effect. Conclusion Clinical benefit and overall survival from the dasatinib-cetuximab combination were improved among patients with low serum IL6. Preclinical studies support IL6 as a modifier of dasatinib-cetuximab response. In the setting of clinical cetuximab resistance, serum IL6 is a candidate predictive marker specific for combined dasatinib-cetuximab. The trial was modified and redesigned as a biomarker-enriched Phase II study enrolling patients with undetectable IL6.

Purpose There are no approved treatments for recurrent/metastatic head and neck squamous cell carcinoma refractory to platinum and cetuximab. In the single-arm, phase II KEYNOTE-055 study, we evaluated pembrolizumab, an anti–programmed death 1 receptor antibody, in this platinum- and cetuximab-pretreated population with poor prognosis. Methods Eligibility stipulated disease progression within 6 months of platinum and cetuximab treatment. Patients received pembrolizumab 200 mg every 3 weeks. Imaging was performed every 6 to 9 weeks. Primary end points: overall response rate (Response Evaluation Criteria in Solid Tumors v1.1, central review) and safety. Efficacy was assessed in all dosed patients and in subgroups on the basis of programmed death ligand 1 (PD-L1) expression and human papillomavirus (HPV) status. Results Among 171 patients treated, 75% received two or more prior lines of therapy for metastatic disease, 82% were PD-L1 positive, and 22% were HPV positive. At the time of analysis, 109 patients (64%) experienced a treatment-related adverse event; 26 patients (15%) experienced a grade ≥ 3 event. Seven patients (4%) discontinued treatment, and one died of treatment-related adverse events. Overall response rate was 16% (95% CI, 11% to 23%), with a median duration of response of 8 months (range, 2+ to 12+ months); 75% of responses were ongoing at the time of analysis. Response rates were similar in all HPV and PD-L1 subgroups. Median progression-free survival was 2.1 months, and median overall survival was 8 months. Conclusion Pembrolizumab exhibited clinically meaningful antitumor activity and an acceptable safety profile in recurrent/metastatic head and neck squamous cell carcinoma previously treated with platinum and cetuximab.

To retrospectively review post-treatment (post-tx) FDG-PET/CT scans in patients with advanced head and neck squamous cell carcinoma (HNSCC) and known p16 status, treated with definitive (chemo)radiation (RT).A total of 108 eligible patients had N2A or greater HNSCC treated with chemoRT from August 1, 2008, to February 28, 2015, with post-tx PET/CT within 6 months after RT. Kaplan-Meier curves, log-rank statistics, and Cox proportional hazards regression were used for statistical analysis.Median follow-up was 2.38 years. Sixty-eight (63.0%) patients had p16+ and 40 (37.0%) had p16- status. Two-year overall survival and recurrence-free survival were 93.4% and 77.8%, respectively. The negative predictive value (NPV) of PET/CT for local recurrence (LR) was 100%. The NPV for regional recurrence (RR) was 96.5% for all patients, 100% for p16+ patients, and 88.5% for p16- patients. The positive predictive value (PPV) of PET/CT for recurrence was 77.3% for all patients, 50.0% for p16+, and 78.6% for p16-. The PPV for LR was 72.7% for all patients, 50.0% for p16+ patients, and 72.7% for p16- patients. The PPV for RR was 50.0% for all patients, 33% for p16+, and 66.6% for p16-. Post-tx PET/CT and p16 status were independent predictors of recurrence-free survival (p 0.01).Post-tx PET/CT predicts treatment outcomes in both p16 + and p16- patients, and does so independently of p16 status. P16- patients with negative PET have a 10% risk of nodal recurrence, and closer follow-up in these patients is warranted.

Background: Anti-PD-L1 and anti-CTLA-4 agents have demonstrated clinical activity in gastric and gastroesophageal junction cancer (GC/GEJC) tumors. However, response rates are low suggesting clinical benefit in only a subset of the population. This study prospectively evaluated the ability of a tumor-based interferon (IFN)-γ gene signature to identify a subset of GC/GEJC patients more likely to respond to checkpoint inhibitor therapy. Methods: Second and third-line patients were prescreened using archival formalin-fixed paraffin-embedded tissue to assess IFN-γ gene signature (comprising IFNy, CD274, LAG3, and CXCL9) status with a custom, targeted RNA sequencing assay using Ion AmpliSeq (Thermo Fisher Scientific) sequencing technologies. The cutoff for positive was established at the upper tertile of expression from an existing data set. Patients who were positive during prescreening were eligible to screen. Enrolled patients received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV every 4 weeks (Q4W) for 4 cycles, followed by durvalumab 10 mg/kg Q2W for ≤12 months. Disease assessments were performed every 8 weeks according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. Results: As of August 24, 2018, 176 patients were prescreened. In these patients, the IFN-γ gene signature assay had a 70% rate for providing actionable data; 37.5% of prescreened patients had high expression. The primary failure reason was insufficient tissue, resulting in insufficient nucleic acid. 19 patients were enrolled, with a median follow-up of 5.8 months. Drug-related adverse events (AEs) occurred in 8 patients (42%); 4 (21%) had grade 3/4 AEs (fatigue, elevated lipase, decreased appetite, and interstitial lung disease, the latter of which led to treatment discontinuation). There were no drug-related deaths. Objective response rate (ORR) was 15.8% (95% CI, 3.4%-39.6%), including 1 complete response and 2 partial responses; 1 patient had stable disease. Duration of response was 13.3 weeks (range, 8.1-16.3 w). Median progression-free survival (PFS) was 1.8 months (95% CI, 1.6-1.9 mo), and median overall survival (OS) was 7 months (95% CI, 2.4-7.5 mo). Conclusions: Prospective screening of patients using a novel RNA-based IFN-γ gene expression signature was feasible for patient selection with predictable assay performance. Clinical activity of durvalumab + tremelimumab was increased, with a higher ORR in enrolled patients, compared with unselected populations receiving durvalumab and/or tremelimumab (presented at ASCO 2018); however, PFS and OS remained similar. Given the added complexity of patient preselection and lack of substantial improvement in clinical outcomes, these results, while encouraging, do not support further implementation of the IFN-γ gene signature for patient selection in this indication and treatment regimen. Citation Format: Geoffrey Ku, Jeeyun Lee, Heinz-Josef Lenz, Cheng Ean Chee, Takeshi Omori, Keun-Wook Lee, Yee Chao, Daniel Catenacci, Michael Gibson, Deirdre Cohen, Zev Wainberg, Philip Z. Brohawn, Peng He, Siddharth Sheth, Judson Englert, Ronan Kelly, Yung-Jue Bang. Safety and efficacy of durvalumab in combination with tremelimumab in patients with advanced gastric cancer with elevated tumor interferon-γ gene signature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT057.

6059 Background: Preliminary data suggest that gabapentin (G) administered during HNC radiation may decrease treatment associated pain. To confirm this, we undertook a prospective, randomized trial in HNC patients undergoing CCR. Primary outcomes: pain severity (scale of 0-10) and opioid use. Exploratory outcomes: local and systemic symptoms measured by the Vanderbilt Head and Neck Symptom Survey version 2 plus the general symptom survey (VHNSSv2/GSS). We report results of the exploratory endpoints from the interim analysis. Methods: Measures: VHNSSv2 - 50 items, demonstrated reliability/validated, captures acute/chronic local HNC specific symptoms; GSS – 11 item checklist, demonstrated content validity, captures acute/chronic systemic symptoms. Population: HNC patients (≥ stage 2) undergoing primary or adjuvant CCR. Procedures: Randomized to standard pain management (SPM) or SPM + G dose escalated to 900mg tid. VHNSSv2/GSS completed weekly during treatment beginning week 1 and ending the last week of radiation therapy. Results were analyzed using a mixed-effects regression analysis adjusting for baseline levels of each symptom. Results: 71 patients completed a mean of 5.5 surveys. Patients on G experienced a reduction in overall systemic symptoms as measured by the GSS (11-items, p = 0.0073), fatigue (two-items, p = 0.013 ) sleep disturbance (five items, p < 0.0001) , neurosensory eating (3 items, p = 0.026), phlegm-related symptoms (4 items, p = 0.004), and trend to better smell (2 items, p = 0.055). No impact on swallow, xerostomia, voice, dental or musculoskeletal symptoms was noted. Conclusions: This exploratory analysis suggests that G may moderate neurological and neuropsychiatric toxicities in HNC patients undergoing CCR. Further studies are warranted.

Treatment of esophageal adenocarcinoma often involves surgical resection. Newer technologies in interventional endoscopy have led to a substantial paradigm shift in the management of early-stage neoplasia in Barrett’s esophagus comprising high-grade dysplasia (HGD), intramucosal carcinoma, and, in some cases, submucosal carcinoma. However, there has been no consensus regarding the indications for esophageal preservation in these cases. In this work, consensus guidelines were established for the management of early-stage esophageal neoplasia considering clinically relevant aspects (age, comorbidities, and social environment) in each scenario. Seventeen experts were invited to participate based on their background and clinical expertise at high-volume centers. A questionnaire was created that included four clinical scenarios covering a wide range of situations within HGD and/or early esophageal neoplasia, particularly where controversies are likely to exist. Each of the clinical scenarios was open to discussion subdivided by patient age (20, 50, and 80 s). For each clinical scenario an expert was chosen to defend that position. Each defense triggered a subsequent discussion during a consensus meeting. Conclusions of that discussion together with an accompanying literature analysis allowed experts to confirm or change their original choices and served as the basis for the recommendations stated in this article. There was 100 % consensus supporting esophageal preservation in patients with HGD, independent of patient age or Barrett’s length. In patients with T1a adenocarcinoma, consensus for preservation was not reached (65 %) for young and middle-aged individuals but was supported for elderly patients (100 %). For T1b adenocarcinoma, consensus was reached for surgical resection (90 %), leaving organ preservation for patients with very low risk of nodal invasion or poor surgical candidates. Advances in endoscopic imaging and therapy allow for organ preservation in most settings of early-stage neoplasia of the esophagus, provided that the patient understands the implications of this decision.

The following paper on the molecular biology of Barrett's esophagus (BE) includes commentaries on signaling pathways central to the development of BE including Hh, NF-κB, and IL-6/STAT3; surgical approaches for esophagectomy and classification of lesions by appropriate therapy; the debate over the merits of minimally invasive esophagectomy versus open surgery; outcomes for patients with pharyngolaryngoesophagectomy; the applications of neoadjuvant chemotherapy and chemoradiotherapy; animal models examining the surgical models of BE and esophageal adenocarcinoma; the roles of various morphogens and Cdx2 in BE; and the use of in vitro BE models for chemoprevention studies.

Background Trials examining FOLFIRINOX in metastatic pancreatic cancer demonstrate higher response rates compared to gemcitabine-based regimens. There is currently limited experience with neoadjuvant FOLFIRINOX in pancreatic cancer.

BACKGROUND Activated hedgehog (Hh) pathway is associated with development of both Barrett esophagus (BE) and esophageal adenocarcinoma (EAC). We hypothesize that blockade of the Hh pathway with smoothened (Smo) inhibitor can prevent the development of BE/EAC in the Levrat model, in which induced gastroduodenoesophageal reflux (GDER) leads to esophageal carcinogenesis. METHODS GDER was induced in 6- to 8-week-old male Sprague-Dawley rats. The Smo inhibitor (10 mg/kg/d) was given orally on postoperative weeks 10 to 16, 18 to 22, and 24 to 28, and rats were killed on week 28. The primary outcome measure was the incidence of BE and EAC. To examine potential therapeutic effects of Smo inhibition on tumor tissue, semiquantitative immunohistochemistry for Ki-67 and caspase 3 was performed. In treated animals that developed cancer, gene expression was analyzed. RESULTS Thirty-eight of 48 controls and 32 of 46 treated animals survived to 28 weeks. messenger ribonucleic acid (mRNA) expression of Indian Hh, a ligand of transmembrane receptor patched 1, was 184× higher in BE and 99× higher in EAC compared with normal esophageal tissue (P = 0.0239 and P = 0.0004, respectively). Compared with controls, the incidence of BE and EAC was decreased in treated animals by 35.7% (relative risk reduction, 36%; P = 0.0015) and 36% (relative risk reduction, 62%; P = 0.0033), respectively. Compared with untreated EAC, Ki-67 was downregulated (P = 0.04) and cleaved caspase 3 was no different in treated EAC (P = 0.398). Of the 84 well-known genes involved in cancer drug resistance, 50 were dysregulated in treated EAC (P < 0.05 for each gene). CONCLUSIONS Smo inhibitor prevents the development of BE and EAC in an in vivo model of GDER.

Background We evaluated combined targeting with cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, and bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in squamous cell carcinoma of the head and neck (SCCHN). Patients and methods The combination was studied in human endothelial cells and head and neck and lung cancer xenograft model systems. Patients with recurrent or metastatic SCCHN were treated with weekly cetuximab and bevacizumab, 15 mg/kg on day 1 given intravenously every 21 days, until disease progression. Analysis of tumor biomarkers and related serum cytokines was performed. Results Cetuximab plus bevacizumab enhanced growth inhibition both in vitro and in vivo, and resulted in potent reduction in tumor vascularization. In the clinical trial, 46 eligible patients were enrolled. The objective response rate was 16% and the disease control rate 73%. The median progression-free survival and overall survival were 2.8 and 7.5 months, respectively. Grade 3–4 adverse events were expected and occurred in less than 10% of patients. transforming growth factor alpha, placenta-derived growth factor, EGFR, VEGFR2 increased and VEGF decreased after treatment but did not correlate with treatment efficacy. Conclusions Cetuximab and bevacizumab are supported by preclinical observations and are well tolerated and active in previously treated patients with SCCHN.

Background The underlying contributors to cardiovascular disease (CVD) in patients with head and neck squamous cell carcinoma (HNSCC) are poorly characterized. Methods Patients with HNSCC who underwent definitive or adjuvant (chemo)radiation between 2011 and 2013 were retrospectively reviewed. The 10-year risk estimates for a CVD event were calculated according to the Framingham Risk Score (FRS). Results One hundred fifteen patients with predominantly stage III/IV HNSCC had a median follow-up of 2 years. At diagnosis, 23% of patients had CVD. The FRS was higher among patients with laryngeal cancer versus other sites (20.5% vs 14.4%). Twenty-four percent of all patients had uncontrolled blood pressure at diagnosis. Among the patients with CVD, 41% were not taking antiplatelet therapy and 30% were not taking statin therapy. Thirty-four percent of patients without CVD had indications for initiating statin therapy. Conclusion Patients with HNSCC have a high baseline CVD risk and many do not receive optimal preventive care. © 2016 Wiley Periodicals, Inc. Head Neck 39: 527–532, 2017

BACKGROUND. Patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) demonstrate aberrant activation of the phosphotidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. We examined the efficacy of everolimus, an mTOR inhibitor, in patients with recurrent or metastatic HNSCC. METHODS. This single-arm phase II study enrolled biomarker-unselected patients with recurrent or metastatic HNSCC who failed at least 1 prior therapy. Everolimus was administered until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit rate (CBR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and evaluation of tissue and serum biomarkers related to the PIK3CA pathway. RESULTS. Seven of 9 patients treated in the first stage were evaluable. No objective responses were seen; CBR was 28%. Three patients discontinued everolimus because of toxicity. Median PFS and OS were 1.5 and 4.5 months, respectively. No activating PI3K mutations were identified in available tumor tissue. CONCLUSION. Everolimus was not active as monotherapy in unselected patients with recurrent/metastatic HNSCC. VC 2016 Wiley Periodicals, Inc. Head Neck 38: 1759–1764, 2016

The standard of care for patients with locally-advanced head and neck cancer is chemoradiation or surgical resection followed by radiation treatment with or without chemotherapy and despite aggressive, multimodality therapies with their associated toxicities, attempts are being made to improve efficacy while reducing toxicity. Cetuximab is a chimeric mAb directed against the EGFR that showed clinical activity in squamous cell carcinoma of head and neck (SCCHN).Cetuximab is beneficial in recurrent and metastatic setting, as well as in the definitive setting. In a landmark study by Bonner et al., cetuximab was found to be effective in prolonging survival in conjunction with radiation treatment in locally-advanced tumors versus radiation therapy alone. The Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer (EXTREME) trial also showed an improvement in conjunction with chemotherapy in recurrent and metastatic tumors.Cetuximab is an important therapeutic option in SSCHN, and will continue to be used in metastatic and definitive settings. While cetuximab is a valuable tool in the treatment of SCCHN, more studies are needed to maximize the efficacy of this mAb in clinical settings and to identify the subpopulation of patients that truly benefit from its use.

© 2015 Elsevier Ltd. All rights reserved. Background High risk head and neck mucosal premalignancy has a malignant conversion rate of up to 40%, despite adequate surgical therapy. Epidermal Growth Factor Receptor (EGFR) blocking agents, including cetuximab, have shown activity in head and neck squamous cell carcinoma (HNSCC) and have potential for therapy in high risk premalignancy. Methods We conducted a randomized, prospective, phase II clinical trial to determine the effects of cetuximab on patients with high risk premalignancy. Patients were randomized to treatment with cetuximab 400 mg/m2on week one followed by 250 mg/m2on week 2-8 or observation, with the option for crossover to cetuximab therapy for patients originally randomized to the observation arm. Results Two of 19 enrolled patients did not complete therapy due to treatment toxicity. Analysis of 17 patients who completed the trial regimen show a trend toward a larger mean decrease in grade of dysplasia in the cetuximab treated group (-1.0) vs. the observation group (-0.2) (P = 0.082, one-sided exact Wilcoxon rank sum test). However, in the observation group, none of the 5 patients (0%) achieved complete resolution of dysplasia; while 4 of 12 (33.3%) cetuximab treated patients had no remaining dysplasia after therapy. Conclusions Treatment of high risk premalignancy of the upper aerodigestive tract with cetuximab alone may result in significant, durable, and complete clinical and histological resolution of moderate to severe dysplasia in at least a subset of high risk patients. These results warrant further investigation in larger studies with increased statistical power.