The Value of PD-L1 Expression as Predictive Biomarker in Metastatic Renal Cell Carcinoma Patients: A Meta-Analysis of Randomized Clinical Trials

Immune checkpoint inhibitors (ICIs) are soluble antibodies that have dramatically changed the outcomes including overall survival in a subset of kidney tumors, specifically in renal cell carcinoma (RCC). To date, there is no a single predictive biomarker approved to be used to select the patients that achieve benefit from ICIs targeting. It seems reasonable to analyze whether the programmed death-ligand 1 (PD-L1) expression could be useful. To assess the role of PD-L1 expression as a potential predictive biomarker for benefit of ICIs in RCC patients, we performed a search of randomized clinical trials (RCTs) comparing ICIs (monotherapy or in combination with other therapies) to standard of care in metastatic RCC patients according to PRISMA guidelines. Trials must have included subgroup analyses evaluating the selected outcomes (progression-free survival (PFS) and overall survival (OS)) in different subsets of patients according to PD-L1 expression on tumor samples. Hazard ratios with confidence intervals were used as the measure of efficacy between groups. A total of 4635 patients (six studies) were included (ICIs arm: 2367 patients; standard of care arm: 2268 patients). Globally, PFS and OS results favored ICIs. Differential expression of PD-L1 on tumor samples could select a subset of patients who could benefit more in terms of PFS (those with higher levels; p-value for difference between subgroups: <0.0001) but it did not seem to impact in OS results (p-value for difference: 0.63). As different methods to assess PD-L1 positivity were used among trials, this heterogeneity could have an influence on the results. PD-L1 could represent a biomarker to test PFS in clinical trials but its value for OS is less clear. In this meta-analysis, the usefulness of PD-L1 expression as a predictive biomarker to select treatment in metastatic RCC patients was not clearly shown

The Value of PD-L1 Expression as Predictive Biomarker in Metastatic Renal Cell Carcinoma Patients: A Meta-Analysis of Randomized Clinical Trials

Immune checkpoint inhibitors (ICIs) are soluble antibodies that have dramatically changed the outcomes including overall survival in a subset of kidney tumors, specifically in renal cell carcinoma (RCC). To date, there is no a single predictive biomarker approved to be used to select the patients that achieve benefit from ICIs targeting. It seems reasonable to analyze whether the programmed death-ligand 1 (PD-L1) expression could be useful. To assess the role of PD-L1 expression as a potential predictive biomarker for benefit of ICIs in RCC patients, we performed a search of randomized clinical trials (RCTs) comparing ICIs (monotherapy or in combination with other therapies) to standard of care in metastatic RCC patients according to PRISMA guidelines. Trials must have included subgroup analyses evaluating the selected outcomes (progression-free survival (PFS) and overall survival (OS)) in different subsets of patients according to PD-L1 expression on tumor samples. Hazard ratios with confidence intervals were used as the measure of efficacy between groups. A total of 4635 patients (six studies) were included (ICIs arm: 2367 patients; standard of care arm: 2268 patients). Globally, PFS and OS results favored ICIs. Differential expression of PD-L1 on tumor samples could select a subset of patients who could benefit more in terms of PFS (those with higher levels; p-value for difference between subgroups: &lt;0.0001) but it did not seem to impact in OS results (p-value for difference: 0.63). As different methods to assess PD-L1 positivity were used among trials, this heterogeneity could have an influence on the results. PD-L1 could represent a biomarker to test PFS in clinical trials but its value for OS is less clear. In this meta-analysis, the usefulness of PD-L1 expression as a predictive biomarker to select treatment in metastatic RCC patients was not clearly shown

531. Practical and Evidence-Based Considerations for Implementation of Bacterial Whole-Genome Sequencing Within Longitudinal Infection Control Practice

Abstract Background Whole-genome sequencing (WGS) of bacteria is becoming a routine tool within microbiology, yet its utility to help guide infection control (IC) practice longitudinally is underexplored. As with any technology adopted in the hospital, the integration of WGS into IC practice must be carefully managed and considered. We qualitatively report an evidence-based implementation workflow that considers WGS to help proactively guide IC professionals during investigation of infectious outbreaks. Methods We built upon lessons learned in an ongoing surveillance effort at a tertiary care hospital—utilizing retrospective WGS data within the Philips IntelliSpace Epidemiology system—to understand facilitators and barriers to the use of bacterial WGS longitudinally to inform IC workflow. Our team established a 9-month workgroup to study the practical aspects of implementing WGS in routine IC practice. From expert opinion collected via the workgroup, in addition to evidence from the literature, a workflow guidance document and checklist were codified. New ideas included incorporating education to promote the establishment of an IC triage process. Results Facilitators to implementation included ability to display genomic relatedness alongside relevant patient data to enable clinical actionability, ability to pivot time and resources rapidly when infections are a pseudo outbreak (false positive) or missed outbreak (false negative), opportunities for nuanced staff education, and willingness to be a first-of-kind adopter. Barriers were communication of genomic concepts to IC professionals and relevant institutional stakeholders, maintaining sharable notes of active investigations to promote data-sharing practices, and timing and review of relevant interventions into the facility workflow. Strategies to address these issues are considered. Conclusion This study provides a novel framework for adaptation of existing IC workflow strategies to leverage the utility of bacterial WGS, and it presents a schema to effectively engage relevant stakeholders, based on an analysis of the unique challenges inherent within IC practice. It also offers an innovative model for the development and implementation of IC workflows to account for, and adapt to, site-specific conditions. Disclosures All authors: No reported disclosures. </jats:sec

Safety and efficacy of immune checkpoint inhibitors in advanced urological cancers with pre-existing autoimmune disorders: a retrospective international multicenter study

BackgroundThere is limited experience regarding the safety and efficacy of checkpoint inhibitors (CPI) in patients with autoimmune disorders (AD) and advanced urological cancers as they are generally excluded from clinical trials due to risk of exacerbations.MethodsThis multicenter retrospective cohort analysis of patients with advanced renal cell cancer (RCC) and urothelial cancer (UC) with pre-existing AD treated with CPI catalogued the incidence of AD exacerbations, new immune-related adverse events (irAEs) and clinical outcomes. Competing risk models estimated cumulative incidences of exacerbations and new irAEs at 3 and 6 months.ResultsOf 106 patients with AD (58 RCC, 48 UC) from 10 centers, 35 (33%) had grade 1/2 clinically active AD of whom 10 (9%) required corticosteroids or immunomodulators at baseline. Exacerbations of pre-existing AD occurred in 38 (36%) patients with 17 (45%) requiring corticosteroids and 6 (16%) discontinuing CPI. New onset irAEs occurred in 40 (38%) patients with 22 (55%) requiring corticosteroids and 8 (20%) discontinuing CPI. Grade 3/4 events occurred in 6 (16%) of exacerbations and 13 (33%) of new irAEs. No treatment-related deaths occurred. Median follow-up was 15 months. For RCC, objective response rate (ORR) was 31% (95% CI 20% to 45%), median time to treatment failure (TTF) was 7 months (95% CI 4 to 10) and 12-month overall survival (OS) was 78% (95% CI 63% to 87%). For UC, ORR was 40% (95% CI 26% to 55%), median TTF was 5.0 months (95% CI 2.3 to 9.0) and 12-month OS was 63% (95% CI 47% to 76%).ConclusionsPatients with RCC and UC with well-controlled AD can benefit from CPI with manageable toxicities that are consistent with what is expected of a non-AD population. Prospective study is warranted to comprehensively evaluate the benefits and safety of CPI in patients with AD.</jats:sec

Safety and efficacy of restarting immune checkpoint inhibitors after clinically significant immune-related adverse events in metastatic renal cell carcinoma

BackgroundImmune checkpoint inhibitors (ICI) induce a range of immune-related adverse events (irAEs) with various degrees of severity. While clinical experience with ICI retreatment following clinically significant irAEs is growing, the safety and efficacy are not yet well characterized.MethodsThis multicenter retrospective study identified patients with metastatic renal cell carcinoma treated with ICI who had &gt;1 week therapy interruption for irAEs. Patients were classified into retreatment and discontinuation cohorts based on whether or not they resumed an ICI. Toxicity and clinical outcomes were assessed descriptively.ResultsOf 499 patients treated with ICIs, 80 developed irAEs warranting treatment interruption; 36 (45%) of whom were restarted on an ICI and 44 (55%) who permanently discontinued. Median time to initial irAE was similar between the retreatment and discontinuation cohorts (2.8 vs 2.7 months, p=0.59). The type and grade of irAEs were balanced across the cohorts; however, fewer retreatment patients required corticosteroids (55.6% vs 84.1%, p=0.007) and hospitalizations (33.3% vs 65.9%, p=0.007) for irAE management compared with discontinuation patients. Median treatment holiday before reinitiation was 0.9 months (0.2–31.6). After retreatment, 50% (n=18/36) experienced subsequent irAEs (12 new, 6 recurrent) with 7 (19%) grade 3 events and 13 drug interruptions. Median time to irAE recurrence after retreatment was 2.8 months (range: 0.3–13.8). Retreatment resulted in 6 (23.1%) additional responses in 26 patients whose disease had not previously responded. From first ICI initiation, median time to next therapy was 14.2 months (95% CI 8.2 to 18.9) and 9.0 months (5.3 to 25.8), and 2-year overall survival was 76% (95%CI 55% to 88%) and 66% (48% to 79%) in the retreatment and discontinuation groups, respectively.ConclusionsDespite a considerable rate of irAE recurrence with retreatment after a prior clinically significant irAE, most irAEs were low grade and controllable. Prospective studies are warranted to confirm that retreatment enhances survival outcomes that justify the safety risks

Safety and efficacy of restarting immune checkpoint inhibitors after clinically significant immune-related adverse events in metastatic renal cell carcinoma

BackgroundImmune checkpoint inhibitors (ICI) induce a range of immune-related adverse events (irAEs) with various degrees of severity. While clinical experience with ICI retreatment following clinically significant irAEs is growing, the safety and efficacy are not yet well characterized.MethodsThis multicenter retrospective study identified patients with metastatic renal cell carcinoma treated with ICI who had &gt;1 week therapy interruption for irAEs. Patients were classified into retreatment and discontinuation cohorts based on whether or not they resumed an ICI. Toxicity and clinical outcomes were assessed descriptively.ResultsOf 499 patients treated with ICIs, 80 developed irAEs warranting treatment interruption; 36 (45%) of whom were restarted on an ICI and 44 (55%) who permanently discontinued. Median time to initial irAE was similar between the retreatment and discontinuation cohorts (2.8 vs 2.7 months, p=0.59). The type and grade of irAEs were balanced across the cohorts; however, fewer retreatment patients required corticosteroids (55.6% vs 84.1%, p=0.007) and hospitalizations (33.3% vs 65.9%, p=0.007) for irAE management compared with discontinuation patients. Median treatment holiday before reinitiation was 0.9 months (0.2–31.6). After retreatment, 50% (n=18/36) experienced subsequent irAEs (12 new, 6 recurrent) with 7 (19%) grade 3 events and 13 drug interruptions. Median time to irAE recurrence after retreatment was 2.8 months (range: 0.3–13.8). Retreatment resulted in 6 (23.1%) additional responses in 26 patients whose disease had not previously responded. From first ICI initiation, median time to next therapy was 14.2 months (95% CI 8.2 to 18.9) and 9.0 months (5.3 to 25.8), and 2-year overall survival was 76% (95%CI 55% to 88%) and 66% (48% to 79%) in the retreatment and discontinuation groups, respectively.ConclusionsDespite a considerable rate of irAE recurrence with retreatment after a prior clinically significant irAE, most irAEs were low grade and controllable. Prospective studies are warranted to confirm that retreatment enhances survival outcomes that justify the safety risks.</jats:sec