Peroxisome Proliferator-Activated Receptors in HBV-Related Infection

Thirty years after its discovery, the hepatitis B virus (HBV) still remains a major global public health problem. Worldwide, two billion subjects have been infected, 350 million have a chronic infection and more than 600 000 die annually of HBV-related liver disease or hepatocellular carcinoma; new infections occur because of the presence of a large reservoir of chronic carriers of the virus. Since a decade several studies describe the interrelations between HBV and nuclear receptors and more particularly the peroxisome proliferator-activated receptors (PPARs). After a brief introduction, this review will make a rapid description of HBV incidence and biology. Then a report of the literature on the role of PPARs on viral transcription and replication will be developed. Finally, the role of HBV on PPARγ expression and activity will be discussed. Concluding remarks and perspectives will close this review

Clinical activity of CC-90011, an oral, potent, and reversible LSD1 inhibitor, in advanced malignancies

Lysine-specific demethylase 1 (LSD1) inhibitor; Neuroendocrine tumor; Non-Hodgkin lymphomaTumor neuroendocrino; Linfoma no Hodgkin; Inhibidores de desmetilasa-1 específica a lisinaTumor neuroendocrí; Limfoma no Hodgkin; Inhibidor de la desmetilasa-1 específica a la lisinaBackground CC-90011 is an oral, potent, selective, reversible inhibitor of lysine-specific demethylase 1 (LSD1) that was well tolerated, with encouraging activity in patients who had advanced solid tumors or relapsed/refractory marginal zone lymphoma. The authors present long-term safety and efficacy and novel pharmacodynamic and pharmacokinetic data from the first-in-human study of CC-90011. Methods CC-90011-ST-001 (ClincalTrials.gov identifier NCT02875223; Eudract number 2015–005243-13) is a phase 1, multicenter study in which patients received CC-90011 once per week in 28-day cycles. The objectives were to determine the safety, maximum tolerated dose, and/or recommended phase 2 dose (primary) and to evaluate preliminary efficacy and pharmacokinetics (secondary). Results Sixty-nine patients were enrolled, including 50 in the dose-escalation arm and 19 in the dose-expansion arm. Thrombocytopenia was the most common treatment-related adverse event and was successfully managed with dose modifications. Clinical activity with prolonged, durable responses were observed, particularly in patients who had neuroendocrine neoplasms. In the dose-escalation arm, one patient with relapsed/refractory marginal zone lymphoma achieved a complete response (ongoing in cycle 58). In the dose-expansion arm, three patients with neuroendocrine neoplasms had stable disease after nine or more cycles, including one patient who was in cycle 46 of ongoing treatment. CC-90011 decreased levels of secreted neuroendocrine peptides chromogranin A, progastrin-releasing peptide, and RNA expression of the blood pharmacodynamic marker monocyte-to-macrophage differentiation–associated. Conclusions The safety profile of CC-90011 suggested that its reversible mechanism of action may provide an advantage over other irreversible LSD1 inhibitors. The favorable tolerability profile, clinical activity, durable responses, and once-per-week dosing support further exploration of CC-90011 as monotherapy and in combination with other treatments for patients with advanced solid tumors and other malignancies.This study was supported by Bristol Myers Squibb, Princeton, New Jersey, USA. Writing and editorial assistance was provided by Bio Connections, LLC, funded by Bristol Myers Squibb

Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial

Nivolumab; Carcinoma cervical, vaginal o vulvar; Carcinoma metastàticNivolumab; Cervical, vaginal, or vulvar carcinoma; Metastatic carcinomaNivolumab; Carcinoma de cuello uterino, vaginal o vulvar; Carcinoma metastáticoPURPOSE Nivolumab was assessed in patients with virus-associated tumors in the phase I/II CheckMate 358 trial (ClinicalTrials.gov identifier: NCT02488759). We report on patients with recurrent/metastatic cervical, vaginal, or vulvar cancers. PATIENTS AND METHODS Patients received nivolumab 240 mg every 2 weeks. Although patients with unknown human papillomavirus status were enrolled, patients known to have human papillomavirus–negative tumors were ineligible. The primary end point was objective response rate. Duration of response (DOR), progression-free survival, and overall survival were secondary end points. Safety and patient-reported outcomes were exploratory end points. RESULTS Twenty-four patients (cervical, n = 19; vaginal/vulvar, n = 5) were enrolled. Most patients had received prior systemic therapy for metastatic disease (cervical, 78.9%; vaginal/vulvar, 80.0%). Objective response rates were 26.3% (95% CI, 9.1 to 51.2) for cervical cancer and 20.0% (95% CI, 0.5 to 71.6) for vaginal/vulvar cancers. At a median follow-up of 19.2 months, median DOR was not reached (range, 23.3 to 29.5+ months; + indicates a censored observation) in the five responding patients in the cervical cohort; the DOR was 5.0 months in the single responding patient in the vaginal/vulvar cohort. Median overall survival was 21.9 months (95% CI, 15.1 months to not reached) among patients with cervical cancer. Any-grade treatment-related adverse events were reported in 12 of 19 patients (63.2%) in the cervical cohort and all five patients in the vaginal/vulvar cohort; there were no treatment-related deaths. In the cervical cohort, nivolumab treatment generally resulted in stabilization of patient-reported outcomes associated with health status and health-related quality of life. CONCLUSION The efficacy of nivolumab in patients with recurrent/metastatic cervical and vaginal or vulvar cancers is promising and warrants additional investigation. No new safety signals were identified with nivolumab treatment in this population

Trifluridine/tipiracil in combination with oxaliplatin and either bevacizumab or nivolumab in metastatic colorectal cancer: a dose-expansion, phase I study

Càncer colorectal metastàtic; Oxaliplatina; Trifluridina/TipiracilCáncer colorrectal metastásico; Oxaliplatino; Trifluridina/TipiracilMetastatic colorectal cancer; Oxaliplatin; Trifluridine/tipiracilBackground In preclinical studies trifluridine/tipiracil (FTD/TPI) plus oxaliplatin (Industriestrasse, Holzkirchen, Germany) sensitised microsatellite stable (MSS) metastatic colorectal cancer (mCRC) to anti-programmed cell death protein-1; the addition of oxaliplatin or bevacizumab (F Hoffmann- la ROCHE AG, Kaiseraugst, Switzerland) enhanced the antitumour effects of FTD/TPI. This study aimed to investigate the safety and efficacy of FTD/TPI plus oxaliplatin and either bevacizumab or nivolumab (Uxbridge business Park, Uxbridge, United Kingdom) in patients with mCRC who had progressed after at least one prior line of treatment. Patients and methods In 14-day cycles, patients received FTD/TPI 35 mg/m2 (twice daily, days 1-5) plus oxaliplatin 85 mg/m2 (day 1), and, on day 1, either bevacizumab 5 mg/kg (cohort A) or nivolumab 3 mg/kg (cohort B). Patients in Cohort B had confirmed MSS status. Results In total, 54 patients were enrolled: 37 in cohort A and 17 in cohort B. Recruitment in cohort B was stopped early due to the low response rate (RR) observed at interim analyses of efficacy. The most common adverse events (AEs) in cohort A were neutropenia/decreased neutrophils (75.7%), nausea (59.5%), vomiting (40.5%), diarrhoea (37.8%), peripheral sensory neuropathy (37.8%), fatigue (35.1%) and decreased appetite (35.1%). In cohort B, the most common AEs were neutropenia/decreased neutrophils (70.6%), diarrhoea (58.8%), nausea (47.1%), vomiting (47.1%), fatigue (47.1%), asthenia (41.2%), paraesthesia (41.2%), thrombocytopenia/decreased platelets (35.3%) and decreased appetite (35.3%). Confirmed objective RR was 17.1% in cohort A and 7.1% in cohort B; the corresponding values for median progression-free survival in the two cohorts were 6.3 and 6.0 months. Conclusion FTD/TPI plus oxaliplatin and bevacizumab or nivolumab had an acceptable safety profile and demonstrated antitumour activity in previously treated patients with mCRC.The study was funded jointly by Servier, France and Taiho Pharmaceutical, Japan

Evidence of pseudoprogression in patients treated with PD1/ PDL1 antibodies across tumor types

Background: PD(L)1 antibodies (anti-PD(L)-1) have been a major breakthrough in several types of cancer. Novel patterns of response and progression have been described with anti-PD(L)-1. We aimed at characterizing pseudoprogression (PSPD) among patients with various solid tumor types treated by anti-PD(L)-1. Methods: All consecutive patients (pts) enrolled in phase 1 trials with advanced solid tumors and lymphomas treated in phase I clinical trials evaluating monotherapy by anti-PD(L)-1 at Gustave Roussy were analyzed. We aimed to assess prevalence and outcome of PSPD across tumor types. We also intended to describe potential clinical and pathological factors associated with PSPD. Results: A total of 169 patients treated with anti-PD(L)-1 were included in the study. Most frequent tumor types included melanoma (n = 57) and non-small cell lung cancer (n = 19). At first tumor evaluation 77 patients (46%) presented with immune unconfirmed progressive disease. Six patients (8%) experienced PSPD: 2 patients with partial response; 4 patients with stable disease. Increase in target lesions in the first CT-scan was more frequently associated to PSPD (67% vs 33%; P = .04). Patients with a PSPD had a superior survival when compared to patients progressing (median OS: 10.7 months vs 8.7 months; P = .07). Conclusions: A small subset of PSPD patients may experience response after an initial progression. Assessment of the current strategy for immune-related response evaluations may require further attention

T cell-inflamed gene expression profile and PD-L1 expression and pembrolizumab efficacy in advanced esophageal cancer

Aim: Investigate the relationship between response to pembrolizumab and expression of the 18-gene T cell-inflamed gene expression profile (TcellinfGEP) or PD-L1 combined positive score (CPS) in esophageal cancer. Materials & methods: This analysis included heavily pretreated patients with advanced/metastatic esophageal/gastroesophageal junction adenocarcinoma or squamous cell carcinoma who received pembrolizumab in the single-arm, phase II study KEYNOTE-180. PD-L1 CPS was evaluated with PD-L1 IHC 22C3 pharmDx. Results: In patients with squamous cell carcinoma, trends toward enrichment for responders were observed for patients with PD-L1 CPS ≥10 tumors. In patients with adenocarcinoma, a trend was observed for TcellinfGEP but not for PD-L1. Conclusion: TcellinfGEP and PD-L1 CPS may enrich for responders to pembrolizumab in patients with esophageal cancer. Clinical Trial Registration: NCT02559687 (ClinicalTrials.gov

Development and Validation of a Bedside Score to Predict Early Death in Cancer of Unknown Primary Patients

BACKGROUND: We have investigated predictors of 90-day-mortality in a large cohort of non-specific cancer of unknown primary patients. METHODS: Predictors have been identified by univariate and then logistic regression analysis in a single-center cohort comprising 429 patients (development cohort). We identified four predictors that produced a predictive score that has been applied to an independent multi-institutional cohort of 409 patients (validation cohort). The score was the sum of predictors for each patient (0 to 4). RESULTS: The 90-day-mortality-rate was 33 and 26% in both cohorts. Multivariate analysis has identified 4 predictors for 90-day-mortality: performance status>1 (OR = 3.03, p = 0.001), at least one co-morbidity requiring treatment (OR = 2.68, p = 0.004), LDH>1.5 x the upper limit of normal (OR = 2.88, p = 0.007) and low albumin or protein levels (OR = 3.05, p = 0.007). In the development cohort, 90-day-mortality-rates were 12.5%, 32% and 64% when the score was [0-1], 2 and [3]-[4], respectively. In the validation cohort, risks were 13%, 25% and 62% according to the same score values. CONCLUSIONS: We have validated a score that is easily calculated at the beside that estimates the 90-days mortality rate in non-specific CUP patients. This could be helpful to identify patients who would be better served with palliative care rather than aggressive chemotherapy

Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial

Purpose: Nivolumab was assessed in patients with virus-associated tumors in the phase I/II CheckMate 358 trial (ClinicalTrials.gov identifier: NCT02488759). We report on patients with recurrent/metastatic cervical, vaginal, or vulvar cancers. Patients and methods: Patients received nivolumab 240 mg every 2 weeks. Although patients with unknown human papillomavirus status were enrolled, patients known to have human papillomavirus-negative tumors were ineligible. The primary end point was objective response rate. Duration of response (DOR), progression-free survival, and overall survival were secondary end points. Safety and patient-reported outcomes were exploratory end points. Results: Twenty-four patients (cervical, n = 19; vaginal/vulvar, n = 5) were enrolled. Most patients had received prior systemic therapy for metastatic disease (cervical, 78.9%; vaginal/vulvar, 80.0%). Objective response rates were 26.3% (95% CI, 9.1 to 51.2) for cervical cancer and 20.0% (95% CI, 0.5 to 71.6) for vaginal/vulvar cancers. At a median follow-up of 19.2 months, median DOR was not reached (range, 23.3 to 29.5+ months; + indicates a censored observation) in the five responding patients in the cervical cohort; the DOR was 5.0 months in the single responding patient in the vaginal/vulvar cohort. Median overall survival was 21.9 months (95% CI, 15.1 months to not reached) among patients with cervical cancer. Any-grade treatment-related adverse events were reported in 12 of 19 patients (63.2%) in the cervical cohort and all five patients in the vaginal/vulvar cohort; there were no treatment-related deaths. In the cervical cohort, nivolumab treatment generally resulted in stabilization of patient-reported outcomes associated with health status and health-related quality of life. Conclusion: The efficacy of nivolumab in patients with recurrent/metastatic cervical and vaginal or vulvar cancers is promising and warrants additional investigation. No new safety signals were identified with nivolumab treatment in this population

Evolution à 5 ans de la stéatose et de la fibrose hépatique chez les obèses morbides traités par chirurgie bariatrique

LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

731 A first-in-human trial of an integrin beta-6 targeted antibody-drug conjugate (ADC), SGN-B6A, in patients with advanced solid tumors: interim results of a phase 1 study (SGNB6A-001)

Background Integrin beta-6 plays a role in tumor pathogenesis and invasiveness, and is correlated with poor outcomes in several cancers, making it a therapeutic target of interest.1,2 SGN-B6A is an investigational vedotin ADC comprised of an integrin beta-6-directed monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable linker. SGN-B6A elicits antitumor activity through MMAE-mediated cytotoxicity, bystander effect, and immunogenic cell death.3 Herein, we present the first clinical data in Part A (dose escalation) of a Phase 1 clinical trial evaluating SGN-B6A. Methods SGNB6A-001 (NCT04389632) is a Phase 1, open-label, multicenter dose-escalation/expansion study evaluating the safety, pharmacokinetics, and antitumor activity of SGN-B6A (confirmed objective response per Response Evaluation Criteria in Solid Tumors v1.1) in adults with advanced solid tumors. Part A is enrolling patients with histologically or cytologically confirmed metastatic or unresectable solid tumors, relapsed or refractory disease or intolerance to standard-of-care therapies. Data for continuous weekly dosing (Days 1, 8, and 15 in a 21-day cycle [Q1W]) and intermittent dosing (Days 1 and 8 in a 21-day cycle [2Q3W]) are presented in this abstract. Results As of 10 May 2022, 30 patients in Q1W (0.8, 1.0, and 1.2 mg/kg) and 18 patients in 2Q3W (1.2 or 1.25 mg/kg) received SGN-B6A. Baseline demographics are outlined in Table 1. In Q1W, 1 dose limiting toxicity (DLT) of stomatitis (5.9%) was reported at the 1.2 mg/kg dose level (n=17; Table 2). The most common treatment-related adverse events (TRAEs) in Q1W across all doses (n=30) were fatigue (26.7%), peripheral sensory neuropathy (23.3%), alopecia (20%) and decreased appetite (20%). The most common Grade ≥ 3 TRAE reported across all dose groups was neutropenia (10%). In 2Q3W (n=18), two patients experienced DLTs (diarrhea, neutropenia, and rash maculo-papular [5.6%]). The most common TRAEs were alopecia, diarrhea, and peripheral sensory neuropathy (16.7% each), and the most common Grade ≥ 3 TRAEs were diarrhea, hyperglycemia, and neutropenia (11.1%). Objective responses were observed in Q1W and 2Q3W in several tumor types including non-small cell lung, head and neck squamous cell, esophageal, and cutaneous squamous cell cancer, starting at 1.2 mg/kg. Detailed efficacy results will be presented. Conclusions SGN-B6A at both dosing schedules demonstrated an acceptable safety profile, with more favorable tolerability at 2Q3W (table 2). Preliminary antitumor activity has been observed starting at 1.2 mg/kg. Enrollment in Part B (dose expansion) is ongoing. Trial Registration NCT04389632 References Li F, Shang Y, Shi F, Zhang L, Yan J, Sun Q, She J. Expression of Integrin β6 and HAX-I Correlates with Aggressive Features and Poor Prognosis in Esophageal Squamous Cell Carcinoma. Cancer Management and Research. 2020;12:9599-9608 Elayadi A, Samli K-N, Prudkin L, Liu Y-H, Bian A, Xie X-J, Wistuba I.I, Roth J.A, McGuire M.J, Brown K.C. A Peptide Selected by Biopanning Identified the Integrin αvβ6 as a Prognostic Biomarker for Nonsmall Cell Lung Cancer. Cancer Res. 2007;67:(12) Klussman K, Tenn E-M, Higgins S, Mazahreh R, Snead K, Hamilton J, Grogan B, Sigurjonsson J, Cao A, Gardai S, Liu B. Vedotin ADCs Induce ER Stress and Elicit Hallmarks of ICD Across Multiple Cancer Indications. J Immunother Cancer. 2020;8(Suppl 3):A1–A559 Ethics Approval The trial is being conducted in compliance with the Declaration of Helsinki and International Conference on Harmonization Guidelines for Good Clinical Practice. All patients, or their legal representatives, provided informed consent. All participating sites have been approved by a corresponding institutional review board or independent ethical committee per the participating institution