Adverse Events Induced by PD-1/PD-L1 Inhibitors: A Real-World Single-Centre Experience with a Management-Based Approach.

AIM: To assess the efficacy and tolerance of programmed death-1 (PD-1) and PD-ligand 1 (PD-L1) inhibitors and the impact of a standardised management-based protocol in a real-world setting. PATIENTS AND METHODS: Data from patients who had received anti-PD-(L)1 were collected from our pharmacy database. Clinical response and toxicity were assessed using RECIST criteria and CTCAE version 5.0, respectively. Overall survival (OS) and progression-free survival (PFS) were estimated with the Kaplan-Meier method. Potential prognostic factors were identified using Cox's model. RESULTS: A total of 196 patients and 201 lines of treatment were included (median age: 66 (range: 38-89) years). Types of cancer included non-small cell lung cancer (73%), transitional cell carcinoma (10%), renal cell carcinoma (6%), small cell lung cancer (5%), head and neck squamous cell carcinoma (4%) and classical Hodgkin's lymphoma (1%). Twenty-five (12%) patients had pre-existing autoimmune conditions. Our standardised management-based protocol included 129 (64%) patients. Objective response rate was 29%, median OS was 10 months (IQR: 7-15) and median PFS was 5 months (IQR: 1-22). Patients with an abnormal baseline complete blood count had a worse OS (HR=2.48 [95% CI: 1.24-4.96]; p=0.0103). Thirty-three (16%) patients experienced severe (grade 3 or 4) immune-related adverse event (irAE). There were three (1%) irAE-related deaths. AEs resolved faster when patients were assessed by an internist before anti-PD-(L)1 initiation (p=0.0205). CONCLUSION: PD-1 and PD-L1 inhibitors are effective and safe in a real-world setting. Implementation of a standardised management-based protocol with internal medicine specialists is an effective way to optimise irAE management.

Original antileishmanial hits: Variations around amidoximes.

In continuation to our previous findings on amidoximes' antiparasitic activities, a new series of 23 original derivatives was designed and obtained by convergent synthesis. First, new terminal alkenes were synthesized by cross-coupling reaction. Then, cyclization was performed between terminal alkenes and ß-ketosulfones using manganese(III) acetate reactivity. Twenty-three amidoximes were tested for their in vitro activity against Leishmania amazonensis promastigotes and their toxicity on murine macrophages. Seven of the tested compounds exhibited an antileishmanial activity at lower than 10 µM with moderate to low toxicity. Six of these molecules showed activity at lower than 10 µM against promastigotes and toxicity at higher than 50 µM were selected and evaluated for their activity against intracellular Leishmania amazonensis amastigotes. Modulating chemical substituents in position 2 of dihydrofuran highly influenced their antileishmanial activities. The introduction of a methyl or trifluoromethyl group on the benzene ring of the benzyl group had a positive influence on activity without significantly increasing toxicity (52, 59, 60).