Histone lysine acetylation is critical in regulating transcription. Dysregulation of this process results in aberrant gene expression in various diseases, including cancer. The bromodomain, present in several proteins, recognizes promotor lysine acetylation and recruits other transcription factors. The bromodomain extra-terminal (BET) family of proteins consists of four conserved mammalian members that regulate transcription of oncogenes such as MYC and the NUT fusion oncoprotein. Targeting the acetyl-lysine-binding property of BET proteins is a potential therapeutic approach of cancer. Consequently, following the demonstration that thienotriazolodiazepine small molecules effectively inhibit BET, clinical trials were initiated. We thus discuss the mechanisms of action of various BET inhibitors and the prospects for their clinical use as cancer therapeutics.

Background: Based on a potential synergistic effect of antiePD-L1 avelumab plus cetuximab and radiotherapy (RT), this combination was tested in a randomized phase III trial against 2 standards of care (SOC) in LA-SCCHN. Methods:The trial comprised 2 cohorts of patients (pts) fit for cisplatin (3 cycles of 100 mg/m 2 , Q3W) or unfit for cisplatin. The SOC was IMRT 70 Gy / 6.5 weeks with cisplatin in fit pts and with cetuximab in unfit pts (Bonner, 2006). In both cohorts, experimental arm (Exp) was 70 Gy / 6.5 weeks plus weekly cetuximab and avelumab 10 mg/kg at Day-7 and every 2 weeks during RT followed by avelumab for 12 months. The primary endpoint was progression-free survival (PFS). In Unfit pts, 115 events were needed / 277 pts to detect a HR of 0.62 (1-sided 0.05 type I error; power 80%). In Fit pts, 166 events were needed / 430 pts to detect a HR of 0.64 (2-sided 0.05 type I error; power 80%).Results: Between 2017 and 2020, 707 pts were randomized. For cisplatin unfit pts, out of 277 pts, the number of PFS events was reached. Median age 67 years, 88% smokers, 61% oropharyngeal tumors (35% p16+), 24% stage III, 76% stage IV. Grade >¼ 3 AEs were 80% in both arms (p¼0.91). Median follow-up was 21 months . PFS rate at 2 years (95%CI) was 44% (35%-53%) in Exp vs 31% (23%-40%) in Cetux-SOC (HR 0.85; p¼0.15). Loco-regional progression at 2 years (95%CI) was 34% (26%-43%) in Exp vs 44% (35%-53%) in Cetux-SOC (HR ¼ 0.83; p¼0.34). Distant metastasis rate was lower in Exp (HR ¼ 0.31, p¼0.007). The 2-year OS rate (95%CI) was 58% (48%-67%) in Exp vs 54% in SOC (44%-64%) (HR 1.08; p-¼0.69). For cisplatin fit pts, out of 430 pts, the number of PFS events was not reached. The interim analysis for futility based on 89 events in 317 first pts showed a 1-year PFS rate (95%CI) of 64% (54%-72%) in Exp vs 73% in SOC-cisplatin (65%-81%): HR 1.27 (95%CI 0.83-1.93), crossing the futility boundary. Conclusions:In cisplatin-Unfit pts, a favorable effect of adding avelumab to cetuximab was seen on PFS, local-regional control, distant metastases, but the primary endpoint on PFS was not met. In cisplatin-Fit pts, the futility boundary for efficacy was crossed, favoring SOC cisplatin.Clinical trial identification: NCT02999087.Legal entity responsible for the study: GORTEC.

PTU can cause ANCAassociated vasculitis resulting in multiorgan failure. Plasmapheresis should be held for 3 days after rituximab infusion in order to allow maximum exposure. The second dose of rituximab may be given before the recommended 7-day interval in cases in which plasmapheresis is being performed to maximize therapeutic benefit.

e21213 Background: Lung cancer is the leading cause of death in males and females in the United States. Approximately 85% of all cases are classified as non-small cell lung cancer (NSCLC) with majority diagnosed at an advanced stage. Unfortunately, response to traditional chemotherapy (ChT) has been poor with a five-year survival rate of 6% in metastatic NSCLC. Immune checkpoint inhibitors (ICI) have changed the therapeutic landscape for advanced NSCLC and are being utilized alone or in combination with ChT as the standard first-line therapy. With widespread use of ICIs, immune-related adverse events (irAE) are commonly seen and in some studies their occurrence correlates with improved outcomes. The aim of our study was to evaluate whether development of irAEs has an impact on survival in NSCLC. Methods: We performed a retrospective analysis on stage IV NSCLC patients treated with ChT, ChT plus ICI, or ICI monotherapy from December 2016 to December 2019. Univariable and multivariable analyses identified characteristics predictive of progression-free survival (PFS) and overall survival (OS). OS was calculated using Kaplan Meier curves. Log-rank statistics were used to assess statistical significance between groups. Multivariable logistic regression was performed to identify predictors of survival. Results: 193 patients were evaluated out of which 92 (47.2%) received ChT plus pembrolizumab, 69 (35.4%) received pembrolizumab alone and 32 (16.4%) received ChT alone. 130 patients were found to have no irAEs compared to 57 patients who were noted to have any grade of irAE. The median PFS was 17.4 months (irAE group) vs. 8.5 months (non-irAE group) with hazard ratio (HR) of 0.58 (95% CI: 0.41 to 0.80, p = 0.001). The median OS was 29.4 months (irAE group) vs. 14.4 months (non-irAE group) with HR of 0.56 (95% CI: 0.39 to 0.82, p = 0.0026). A multivariate analysis was performed for age, gender, ECOG performance status, insurance status, BMI, PDL1 status and smoking history, amongst other variables. Worse survival outcomes were noted with an ECOG performance status ≥ 2, no history of smoking, and involvement of palliative care. Multivariable logistic regression analysis showed that PDL-1 expression > 50% was the only predictor of developing an irAE. Of note, receipt of ChT in combination with pembrolizumab compared to pembrolizumab alone did not predict for development of irAE. Conclusions: Development of irAEs was associated with doubling of PFS and OS, regardless of whether the ICI was administered alone or in combination with ChT. The differences were statistically significant regardless of age, gender, race, BMI, insurance status or performance status. Our study highlights the correlation between development of irAEs and improved survival outcomes in advanced NSCLC patients treated with ICIs.

The Beckman LX20 and DxC analyzers use time-dependent photometric methods to measure serum PO4 which can be affected by hyperbilirubinemia. In contrast, the Roche Integra analyzer uses an endpoint photometric method with sample blanking, which helps to correct for the effect of hyperbilirubinemia. Clinicians managing patients with marked hyperbilirubinemia should consider spurious laboratory abnormalities.