Failure to predict response to immunotherapy (IO) limited its benefit in the treatment of head and neck squamous cell cancer (HNSCC) to 20% of patients or less. Biomarkers including tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) were evaluated as predictors of response to IO, but the results are inconsistent and with a lack of standardization of their methods. In this retrospective study, TMB and PD-L1 were measured by commercially available methodologies and were correlated to demographics, outcome, and response to PD-1 inhibitors. No correlation was found between TMB and PD-L1 levels. High TMB was associated with smoking and laryngeal primaries. PD-L1 was significantly higher in African Americans, patients with earlier stage tumors, nonsmokers, and nonethanol drinkers. Patients with high TMB fared better in univariate and multivariate survival analysis. No correlation was found between PD-L1 expression and prognosis. There was a statistically significant association between PFS and response to IO and TMB. There was no association between response to ICI and PD-L1 in this study, possibly affected by variations in the reporting method. Further studies are needed to characterize the biomarkers for IO in HNSCC, and this study supports further research into the advancement of TMB in prospective studies.

PARP inhibitors are currently approved for a limited number of cancers and targetable mutations in DNA damage repair (DDR) genes. In this single-institution retrospective study, the profiles of 170 patients with head and neck squamous cell cancer (HNSCC) and available tumor tissue DNA (tDNA) and circulating tumor DNA (ctDNA) results were analyzed for mutations in a set of 18 DDR genes as well as in gene subsets defined by technical and clinical significance. Mutations were correlated with demographic and outcome data. The addition of ctDNA to the standard tDNA analysis contributed to identification of a significantly increased incidence of patients with mutations in one or more genes in each of the study subsets of DDR genes in groups of patients older than 60 years, patients with laryngeal primaries, patients with advanced stage at diagnosis and patients previously treated with chemotherapy and/or radiotherapy. Patients with DDR gene mutations were found to be significantly less likely to have primary tumors within the in oropharynx or HPV-positive disease. Patients with ctDNA mutations in all subsets of DDR genes analyzed had significantly worse overall survival in univariate and adjusted multivariate analysis. This study underscores the utility of ctDNA analysis, alone, and in combination with tDNA, for defining the prevalence and the role of DDR gene mutations in HNSCC. Furthermore, this study fosters research promoting the utilization of PARP inhibitors in HNSCC precision oncology treatments.

e18016 Background: Next generation sequencing (NGS) has introduced the opportunity for targeted therapies and guidance regarding disease course and prognosis. The mutational landscape of squamous cell cancers of the head and neck (HNSCC) remains incompletely described. DNA repair gene (DRG) mutations are targeted by PARP inhibitors. This study presents the prevalence of DRG mutations in tumor and blood samples of patients with HNSCC and their outcome data. Methods: In this retrospective study, demographic and outcome data were collected and analyzed with regard to the presence or absence of mutated DRG (BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD51L, APC, ARID1A and MLL3). Mutated DRG were detected in tumor tissue (tDNA) by Foundation Medicine and/or in blood (ctDNA) by Guardant 360. All 18 genes were analyzed by FM, but only six are included in the G360 panel (BRCA1, BRCA2, ATM, APC, ARID1A and CDK12). Results: Our analysis included 170 HNSCC patients. Of these, 138 underwent NGS via ctDNA, 146 via tDNA and 114 via both methods. Sixty-five patients (47%) had at least one tDNA DRG mutation, 54 patients (37%) had at least one ctDNA DRG mutation and 96 patients (56%) had at least one DRG mutation detected by either method. No significant association was found between DRG mutations and age, gender, race, HPV status, tobacco/alcohol use or stage at diagnosis. Subsite analyses revealed that laryngeal primaries were associated with higher prevalence of DRG mutations detected via tDNA (p = 0.05), ctDNA (p = 0.03) or either method (p = 0.01). Oropharyngeal primaries correlated with a lower prevalence of DRG mutations detected via tDNA (p = 0.03) or via either method (p = 0.02) but were less significant when mutations were detected via ctDNA alone (p = 0.08). Mutated DRG detected via ctDNA correlated significantly with stage at time of ctDNA collection (p = 0.03), presence/absence of cancer at last visit (p = 0.05) and with stage at last visit (p = 0.05). Two-year survival and overall survival (OS) measured from the time of ctDNA collection correlated significantly with mutated ctDNA DRG. The relationship between ctDNA DRG mutations and OS remained statistically significant in a Cox proportional hazards regression model when adjusted for age, tobacco use, tumor site, nodal stage at diagnosis, and previous treatment with chemotherapy, radiation or combined chemoradiation therapy in a multivariate analysis model (p = 0.05). No similar correlation was found between tDNA mutations in DRG and prognosis. Conclusions: A significant proportion of patients with HNSCC were found to have mutations in DRG. Patients with laryngeal disease were most likely to have DRG mutations, whereas those with oropharyngeal disease were less likely. Patients with DRG mutations in ctDNA, but not tDNA, had significantly worse prognoses with a lower likelihood of overall survival and higher disease burden at last visit.

BackgroundImmune-mediated diarrhea or colitis (IDC) is a potentially serious adverse event which can occur in up to 10% of patients receiving an immune checkpoint inhibitor (ICIs), but not all episodes of diarrhea among these patients are immune-mediated.1 There is a paucity of research regarding the diagnosis and management of this common symptom among patients receiving an ICI.MethodsWe collected retrospective clinical data for all patients who received at least one dose of an ICI for any cancer diagnosis (n=2,120) and subsequently underwent a diagnostic workup for acute diarrhea with stool testing for either C. difficile or a gastrointestinal pathogen panel (n=223) at any point between 1/1/13 to 3/17/21. We compared patients who had IDC “ruled out” to those who had confirmed IDC using Fisher's exact test for categorical variables and either independent samples t-test or Wilcoxon two-sample tests for interval variables. The Kaplan-Meier method was used to estimate progression-free and overall survival time. A two-sided alpha of 0.05 was utilized in determining which relationships might be significant.ResultsThirty-seven percent had ICIs deferred upon symptom onset, and 28% received systemic steroids. Patients receiving an ICI who developed diarrhea were 2.14x more likely to have a different etiology for their symptoms (n=152, 68%) than IDC. Patients who had IDC ruled out were more likely to be female (47%, p 0.029) and have at least one comorbidity (93%, p 0.028). Patients with confirmed IDC were more likely to have peptic ulcer disease (4%, p 0.031), to have received ipilimumab (24%, p<0.0001) or >1 ICI concurrently 23%, p<0.001), and to have a shorter time since last dose of immunotherapy to onset of symptoms (12 vs. 26 days, p <0.0001). There were no differences in age, race, ethnicity, prior cancer therapies, types of other comorbidities, symptoms, presence of other adverse events, number of ICI cycles prior to symptom onset, or performance status. Progression-free survival was longer among patients with confirmed IDC (p 0.003). Overall survival was longer among patients with confirmed IDC (p 0.021) (figure 1).ConclusionsDiarrhea is often due to another etiology besides IDC, especially among patients who have onset of symptoms over 2 weeks after receiving an ICI other than ipilimumab. If ipilimumab or two ICIs are used concurrently, it is warranted to have increased suspicion for IDC especially with rapid progression of symptoms. This dataset provides additional evidence that confirmed IDC may be associated with prolonged progression-free and overall survival.ReferenceWang Y, Zhou S, Yang F, et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: a systematic review and meta-analysis. JAMA Oncol 2019;5(7):1008–1019. doi:10.1001/jamaoncol.2019.0393Ethics ApprovalThe study was approved by Wake Forest Baptist Health Ethics Board, approval number #IRB00044126.Abstract 815 Figure 1Survival of confirmed IDC and ruled-out cases

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