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Nearly half of patients diagnosed with head and neck cancers are 65 years or older at the time of diagnosis. Older adults with cancer are at increased risk of treatment related toxicities and recent studies have suggested that geriatric assessment can be used to predict those at risk of excess toxicities. The objective of the current study was to study the prevalence of frailty and geriatric assessment impairments among older adults diagnosed with head and neck cancers. Using data from the Cancer and Aging Resilience Evaluation (CARE) registry, a prospective cohort study of older adults (≥60y) diagnosed with cancer, we identified patients with biopsy proven head and neck cancers with an initial medical oncology visit at our institution between 3/2018 and 5/2021. All patients underwent a pragmatic multidimensional GA prior to their initial oncologist visit, as previously described (Williams et al J Geriatr Oncol 2019). Using deficit accumulation method, we constructed a 44-item frailty index (CARE-FI), categorizing patients as robust, pre-frail, and frail. Domain specific impairments were characterized using published cut points. Subsequently, we examined the prevalence of frailty and GA domain impairments and the association between pre-treatment frailty and overall survival in multivariable time to event (Cox) models adjusted for age, sex, race/ethnicity, cancer stage and time from diagnosis. All statistical tests were two sided and the level of significance was chosen as 0.05. A total of 94 patients were identified with a mean age of 70±7y, 79% males and 87% non-Hispanic Whites. Majority of patients had stage III (20%) or IV cancers (52%; 27% with distant metastasis) treated with radiation therapy (76%), chemotherapy (64%) and/or surgery (46%). Overall, 23% and 30% respectively were identified as pre-frail or frail respectively. GA impairments were prevalent: 19% reported ≥1 falls in past 6 months, 17% reported dependence in activities of daily living (ADL), 53% reported dependence in Instrumental ADL, 43% had malnutrition, 72% reported polypharmacy (≥4 medications) and 40% had ≥3 comorbidities. As compared to robust patients, frailty was associated with significantly increased risk of all-cause mortality in unadjusted (HR 2.74; 95% CI 1.19-6.35; p=0.02) and adjusted (HR 2.37; 1.03-6.08; p=0.04) models. Frailty and GA impairments are common among older adults with head and neck cancers and appear to have prognostic relevance. Future studies should explore how GA can inform treatment decision making and guide interventions to improve treatment outcomes in this population. [ABSTRACT FROM AUTHOR]

Prexasertib is a checkpoint kinase 1 (Chk-1) inhibitor that induces tumor cell apoptosis through bypassing DNA repair checkpoints. We and others have shown that prexasertib in combination with chemotherapy with or without radiation (RT) has significant antitumor effects in both in vitro and in vivo models of head and neck squamous cell carcinoma (HNSCC). Recently, we reported the results of a phase 1b trial assessing the safety and efficacy of prexasertib in combination with cetuximab-RT or cisplatin-RT (Yang et al. Radiotherapy and Oncology 2021). In this study, we report tumor and immune biomarker analyses from this trial. Gene expression profiling using multiplex analysis platform and panels was performed on archival tumor tissue obtained prior to administration of prexasertib in combination with RT and either cisplatin or cetuximab from 17/25 patients with locally advanced HNSCC enrolled in a Phase 1b study (NCT02555644). Differentially expressed genes were compared between patients with complete response (CR) and not complete response (NCR; includes partial response, progressive and stable disease), as defined by RECIST criteria. Immune gene signatures that correlated with prexasertib clinical response involved Th1 T cell and M1 macrophage phenotypes. While exhausted CD8+ T and Treg cell gene scores, as well as PD-L1 mRNA levels, were higher in tumors from CR patients, we found significantly higher immune tolerogenic M2 macrophage-associated gene expression and increased CSF1 tumor cell signaling in NCR patients. Gene expression of functional markers of T and NK cells, including IL-2, IFN-γ, granzyme and perforin, were similarly elevated in CR patients with correspondingly increased tumor mRNA levels of JAK/STAT signaling elements such as JAK2, STAT1/3, and IFNG. Conversely, Wnt/β-catenin pathway mediators CTNNB1 and AXIN2, as well as IL-6 mRNA levels, which may mediate immune exclusion, were upregulated in NCR patients. Consistent with our prior preclinical observations, Notch signaling activators JAG1/2, which are implicated in maintaining cancer stem cells, apoptosis inhibition and tumor growth, were found to be elevated in NCR patients. Gene expression analysis found that baseline immune and tumor gene signatures correlated with Chk-1 inhibitor sensitivity in patients receiving chemo-RT. Findings suggest that oncogenic pathway activity and intact immune surveillance may be important in response to combination of prexasertib with RT, and that baseline immunosuppressive tumor microenvironments may impede maximal Chk-1 inhibitor efficacy. Future studies aimed to validate tumor and immune signatures as biomarkers of efficacy of Chk-1 inhibition and to identify targetable mediators to enhance responsiveness are warranted. [ABSTRACT FROM AUTHOR]

Background: The use of Escherichia coli purine nucleoside phosphorylase (PNP) to activate fludarabine has demonstrated safety and antitumor activity during preclinical analysis and has been approved for clinical investigation. Patients and methods: A first-in-human phase I clinical trial (NCT 01310179; IND 14271) was initiated to evaluate safety and efficacy of an intratumoral injection of adenoviral vector expressing E. coli PNP in combination with intravenous fludarabine for the treatment of solid tumors. The study was designed with escalating doses of fludarabine in the first three cohorts (15, 45, and 75 mg/m>2) and escalating virus in the fourth (1011-1012 viral particles, VP). Results: All 12 study subjects completed therapy without dose-limiting toxicity. Tumor size change from baseline to final measurement demonstrated a dose-dependent response, with 5 of 6 patients in cohorts 3 and 4 achieving significant tumor regression compared with 0 responsive subjects in cohorts 1 and 2. The overall adverse event rate was not dosedependent. Most common adverse events included pain at the viral injection site (92%), drainage/itching/burning (50%), fatigue (50%), and fever/chills/influenza-like symptoms (42%). Analysis of serum confirmed the lack of systemic exposure to fluoroadenine. Antibody response to adenovirus was detected in two patients, suggesting that neutralizing immune response is not a barrier to efficacy. Conclusions: This first-in-human clinical trial found that localized generation of fluoroadenine within tumor tissues using E. coli PNP and fludarabine is safe and effective. The pronounced effect on tumor volume after a single treatment cycle suggests that phase II studies are warranted. ClinicalTrials.gov Identifier: NCT01310179. [ABSTRACT FROM AUTHOR]