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Background: Immune checkpoint inhibitors (ICI) have changed the therapeutic landscape of many solid tumors. Modulation of the intestinal microbiota by antibiotics (Abx) has been suggested to impact on ICI outcomes., Methods: Retrospective analysis of 475 patients with advanced solid tumors treated with ICI from 2015 to 2022. For each patient, the use of Abx was recorded from 1 month before ICI initiation until disease progression or death. The impact of Abx on objective response rates (ORR), disease control rates (DCR), progression-free survival (PFS), and overall survival (OS) was analyzed. Kaplan-Meier and log-rank tests were used to compare survival outcomes., Results: In total 475 patients with advanced solid tumors were evaluated. Median age was 67.5 years and performance status (PS) was 0-1 in 84.6%. 66.5% of patients received Abx during treatment with ICI, mainly beta-lactams (53.8%) and quinolones (35.9%). The early exposure to Abx (from 60 days before to 42 days after the first cycle of ICI) was associated with a lower ORR (27.4% vs 39.4%; P < .01), a lower DCR (37.3% vs 57.4%; P < .001), lower PFS (16.8 m vs 27.8 m; HR 0.66; P < .001]) and lower OS (2.5 m vs 6.6 m; HR 0.68; P = .001]). The negative impact of Abx on OS and PFS was confirmed by a multivariable analysis. This effect was not observed among patients receiving Abx after 6 weeks from ICI initiation., Conclusions: Our results validate the hypothesis of a detrimental effect of an early exposure to Abxon the efficacy of ICI in a multi-tumor cohort of patients., (© The Author(s) 2024. Published by Oxford University Press.)

Previous studies have suggested a negative impact of steroids on the efficacy of immune checkpoint inhibitors (ICI), but how this effect is modulated by the dosage and time of administration is yet to be clarified. We have performed a retrospective analysis of 475 patients with advanced solid tumors treated with ICI as monotherapy from 2015 to 2022. Data regarding immune-related adverse events (irAEs) and clinical outcomes were collected. For each patient, the daily steroid dose (in mg/kg of prednisone) was registered until disease progression or death. The impact of cumulative doses on response rates and survival outcomes was analyzed within different periods. The objective response rate (ORR) was significantly lower among patients exposed to steroids within 30 days before the first cycle of ICI (C1) (20.3% vs. 36.7%, p < 0.01) and within the first 90 days of treatment (25.7% vs. 37.7%, p = 0.01). This negative association was confirmed by multivariable analysis. Higher mean steroid doses were observed among non-responders, and cumulative doses were inversely correlated with the disease control rate (DCR) around ICI initiation. Remarkably, poorer outcomes were observed even in patients belonging to the lowest dose quartile compared to the steroid-naïve population. The exposure to steroids after 6 months of ICI was not associated with worse survival outcomes. Our results suggest that the potential impact of steroids on ICI efficacy may be time-dependent, prevailing around ICI initiation, and dose-dependent, with modulation of neutrophil-to-lymphocyte ratio as a possible underlying mechanism., (© 2024. The Author(s).)

Metastatic colorectal cancer (mCRC) with mutated BRAF exhibits distinct biological and molecular features that set it apart from other subtypes of CRC. Current standard treatment for these tumors involves a combination of chemotherapy (CT) and VEGF inhibitors. Recently, targeted therapy against BRAF and immunotherapy (IT) for cases with microsatellite instability (MSI) have been integrated into clinical practice. While targeted therapy has shown promising results, resistance to treatment eventually develops in a significant portion of responsive patients. This article aims to review the available literature on mechanisms of resistance to BRAF inhibitors (BRAFis) and potential therapeutic strategies to overcome them.

Goals: We aim to describe the efficacy, safety profile, and variables associated with survival in patients with hepatocellular carcinoma (HCC) treated with sorafenib in South America., Background: Sorafenib has been shown to improve survival in patients with advanced HCC. There are few data on sorafenib use for HCC in South America., Study: We performed a retrospective analysis of HCC cases treated with sorafenib from 8 medical centers in 5 South American countries, between January 2010 and June 2017. The primary endpoint was overall survival (OS), which was defined as time from sorafenib initiation to death or last follow-up. Risk factors for decreased OS were assessed using Cox proportional hazard regression and log-rank tests., Results: Of 1336 evaluated patients, 127 were treated with sorafenib and were included in the study. The median age of individuals was 65 years (interquartile range, 55 to 71) and 70% were male individuals. Median OS in all patients was 8 months (interquartile range, 2 to 17). Variables associated with survival on multivariate analysis were platelets >/<250,000 mm (2 vs. 8 mo, P=0.01) and Barcelona Clinic Liver Cancer (BCLC) stage (A/B, 13 vs. C/D, 6 mo; P=0.04). In a subanalysis of patients with BCLC stage C, platelets >/<250,000 mm were also independently associated with survival (2 vs. 5.5 mo, P=0.03). Patients lived longer if they experienced any side effects from sorafenib use (11 vs. 2 mo, P=0.009). Patients who stopped sorafenib because of side effects had shorter survival compared with patients who were able to tolerate side effects and continue treatment (7.5 vs. 13 mo, P=0.01)., Conclusions: Pretreatment elevation of platelets and advanced BCLC stage were independently associated with poor survival on sorafenib in a South American cohort.