Real-World Outcomes With Lurbinectedin in Second-Line Setting and Beyond for Extensive Stage Small Cell Lung Cancer.

BACKGROUND: Lurbinectedin has emerged as a potential treatment option for relapsed small cell lung cancer (SCLC). While clinical trials have demonstrated its efficacy and safety, real-world data are limited. This study aimed to evaluate the safety and efficacy of lurbinectedin in a real-world setting, focusing on its use as a second-line agent and beyond in SCLC patients. METHODS: A retrospective analysis was conducted on 90 patients who received lurbinectedin between June 2020 and June 2022 within the Mayo Clinic Health System. Of these, 50 patients received lurbinectedin as a second-line agent, and 14 patients received it as a third-line or later agent. The primary outcomes assessed were overall survival (OS), progression-free survival (PFS), and treatment-related adverse events. RESULTS: Lurbinectedin was generally well tolerated in this real-world cohort, with a median OS of 5.1 months in the second-line cohort and 5.6 months in the third-line or later cohort. Median PFS was 2.1 months in the second-line cohort and 3.4 months in the third-line or later cohort. Adverse events were manageable, with the most common being neutropenia, anemia, fatigue, and febrile neutropenia. No treatment-related deaths or grade 5 toxicities were reported. CONCLUSION: This real-world study provides valuable insights into the safety and efficacy of lurbinectedin in relapsed SCLC. Lurbinectedin demonstrated modest efficacy and a comparable safety profile to that observed in clinical trials. However, outcomes for relapsed SCLC remain suboptimal, particularly for patients with a shorter chemotherapy-free interval and central nervous system metastases.

Time from immune checkpoint inhibitor to sotorasib use correlates with risk of hepatotoxicity in non-small cell lung cancer: A brief report.

INTRODUCTION: We evaluated the risk factors and outcomes for patients who experienced hepatotoxicity after use of sotorasib in KRAS G12C mutated NSCLC. METHODS: Retrospective review of medical records of patients with KRAS G12C mutated NSCLC who received sotorasib between May 28th, 2021, and December 31st, 2021 across all Mayo Clinic sites, with follow up until December 31st, 2022. RESULTS: Thirty-one patients received sotorasib as standard of care treatment. Grade 3 or higher hepatoxicity was seen in 32% (10/31) patients presenting at a median of 51 days (range, 27-123) of sotorasib initiation. Baseline demographics were comparable between patients with and without ≥grade 3 hepatotoxicity, except for presence of CNS metastases and time from prior immune checkpoint inhibitor (ICI) treatment. Improvement in liver tests was observed in all patients after stopping sotorasib, and it was restarted at a lower dose in 8 patients. Despite dose reduction, hepatotoxicity requiring sotorasib discontinuation occurred in 2 patients. Twenty-eight of 31 patients had received prior ICI. Median time from prior ICI therapy was 69 days (range, 4-542). Rates of ≥grade 3 hepatoxicity were 75% (3/4), 64% (7/11) and 0% (0/13) for patients who received ICI within 30 days, 31-90 days and >90 days. None of the 3 patients without prior ICI exposure developed hepatoxicity. The median PFS and OS were 3.9 months and 9.9 months respectively. CONCLUSION: One-third of patients developed grade 3 or higher sotorasib induced hepatotoxicity. Risk of hepatotoxicity was higher in patients who received sotorasib within 90 days of ICI treatment.

EZH2 and POU2F3 Can Aid in the Distinction of Thymic Carcinoma from Thymoma.

Thymic carcinoma is an aggressive malignancy that can be challenging to distinguish from thymoma using histomorphology. We assessed two emerging markers for these entities, EZH2 and POU2F3, and compared them with conventional immunostains. Whole slide sections of 37 thymic carcinomas, 23 type A thymomas, 13 type B3 thymomas, and 8 micronodular thymomas with lymphoid stroma (MNTLS) were immunostained for EZH2, POU2F3, CD117, CD5, TdT, BAP1, and MTAP. POU2F3 (≥10% hotspot staining), CD117, and CD5 showed 100% specificity for thymic carcinoma versus thymoma with 51%, 86%, and 35% sensitivity, respectively, for thymic carcinoma. All POU2F3 positive cases were also positive for CD117. All thymic carcinomas showed >10% EZH2 staining. EZH2 (≥80% staining) had a sensitivity of 81% for thymic carcinoma and a specificity of 100% for thymic carcinoma versus type A thymoma and MNTLS but had poor specificity (46%) for thymic carcinoma versus B3 thymoma. Adding EZH2 to a panel of CD117, TdT, BAP1, and MTAP increased cases with informative results from 67/81 (83%) to 77/81 (95%). Overall, absent EZH2 staining may be useful for excluding thymic carcinoma, diffuse EZH2 staining may help to exclude type A thymoma and MNTLS, and ≥10% POU2F3 staining has excellent specificity for thymic carcinoma versus thymoma.

Efficacy of immune checkpoint inhibitors in non-small cell lung cancer: A systematic review and meta-analysis.

Background: Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in non-small cell lung cancer (NSCLC). However, only a minority of NSCLC patients benefit from ICIs, and whether the magnitude of benefit is specific factor-dependent remains unclear. We performed a systematic review to improve our understanding of clinicopathologic and biomolecular features associated with improved survival upon treatment with ICIs for NSCLC. Methods: We searched PubMed, Web of Science, Embase, and Scopus from database inception to August 31, 2021, for randomized controlled trials (RCTs) comparing overall survival (OS) in NSCLC treated with ICIs vs control therapies. We calculated the pooled OS hazard ratio (HR) and 95% CI in subgroups using a random-effects model, and assessed the heterogeneity between the paired estimates using an interaction test. Results: A total of 23 RCTs involving 15,829 patients were included. We found that wild-type EGFR, high PD-L1 expression, and high bTMB were associated with a significant OS benefit from ICIs, but not mutant EGFR, low PD-L1 expression, and low bTMB. The differences of OS benefit between wild-type and mutant EGFR (HR=1.53, 95%CI 1.13-2.08), high and low PD-L1 (HR=1.35; 95%CI 1.14-1.61), high and low bTMB (HR=1.71; 95%CI 1.17-2.52) were statistically significant. OS benefit was found in all subgroups regardless of sex, age, ECOG PS, histology, smoking history, baseline brain metastasis, race, and region, and the interaction test demonstrated no significant difference of the OS benefit between these opposed subgroups (e.g. male vs female). Conclusions: Wild-type EGFR, high PD-L1 expression, and high bTMB are associated with a greater magnitude of efficacy from ICIs vs control therapies in NSCLC. However, the administration of ICIs should not be restricted to other clinicopathological factors (sex, smoking history, race, etc.).

Vulnerability and COVID-19 infection rates: A changing relationship during the first year of the pandemic.

In the first year of the COVID-19 pandemic, Spain was one of the worst-hit countries, although not all areas and social groups were affected equally. This study focuses on Malaga, a cosmopolitan tourist destination located on the southern Mediterranean coast that has the sixth largest population in Spain. Specifically, it examines the relationship between multidimensional vulnerability and COVID-19 infection rates across the city's census tracts for the period February 2020 to February 2021. The analysis uses high frequency (daily) data on the accumulated incidence of the disease at 14 days and shows that COVID-19 did not spread symmetrically across the census tracts of Malaga but had a greater impact on the most vulnerable neighbourhoods. However, the pattern of this relationship was not uniform in the period examined, with specific contextual factors driving the higher infection rates across time. Our findings show that pandemic containment regulations cannot overlook vulnerability considerations and universal restrictions to reduce the spread of disease should be supplemented by targeted regulations for specific areas.

Tempo-Spatial Modelling of the Spread of COVID-19 in Urban Spaces.

The relationship between the social structure of urban spaces and the evolution of the COVID-19 pandemic is becoming increasingly evident. Analyzing the socio-spatial structure in relation to cases may be one of the keys to explaining the ways in which this contagious disease and its variants spread. The aim of this study is to propose a set of variables selected from the social context and the spatial structure and to evaluate the temporal spread of infections and their different degrees of intensity according to social areas. We define a model to represent the relationship between the socio-spatial structure of the urban space and the spatial distribution of pandemic cases. We draw on the theory of social area analysis and apply multivariate analysis techniques to check the results in the urban space of the city of Malaga (Spain). The proposed model should be considered capable of explaining the functioning of the relationships between societal structure, socio-spatial segregation, and the spread of the pandemic. In this paper, the study of the origins and consequences of COVID-19 from different scientific perspectives is considered a necessary approach to understanding this phenomenon. The personal and social consequences of the pandemic have been exceptional and have changed many aspects of social life in urban spaces, where it has also had a greater impact. We propose a geostatistical analysis model that can explain the functioning of the relationships between societal structure, socio-spatial segregation, and the temporal evolution of the pandemic. Rather than an aprioristic theory, this paper is a study by the authors to interpret the disparity in the spread of the pandemic as shown by the infection data.

PFKFB3 regulates cancer stemness through the hippo pathway in small cell lung carcinoma.

PFKFB3 (6-phosphofructo-2-kinase) is the rate-limiting enzyme of glycolysis and is overexpressed in several human cancers that are associated with poor prognosis. High PFKFB3 expression in cancer stem cells promotes glycolysis and survival in the tumor microenvironment. Inhibition of PFKFB3 by the glycolytic inhibitor PFK158 and by shRNA stable knockdown in small cell lung carcinoma (SCLC) cell lines inhibited glycolysis, proliferation, spheroid formation, and the expression of cancer stem cell markers CD133, Aldh1, CD44, Sox2, and ABCG2. These factors are also associated with chemotherapy resistance. We found that PFK158 treatment and PFKFB3 knockdown enhanced the ABCG2-interacting drugs doxorubicin, etoposide, and 5-fluorouracil in reducing cell viability under conditions of enriched cancer stem cells (CSC). Additionally, PFKFB3 inhibition attenuated the invasion/migration of SCLC cells by downregulating YAP/TAZ signaling while increasing pLATS1 via activation of pMST1 and NF2 and by reducing the mesenchymal protein expression. PFKFB3 knockdown and PFK158 treatment in a H1048 SCLC cancer stem cell-enriched mouse xenograft model showed significant reduction in tumor growth and weight with reduced expression of cancer stem cell markers, ABCG2, and YAP/TAZ. Our findings identify that PFKFB3 is a novel target to regulate cancer stem cells and its associated therapeutic resistance markers YAP/TAZ and ABCG2 in SCLC models.

PFKFB3 works on the FAK-STAT3-SOX2 axis to regulate the stemness in MPM.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm and often acquires chemoresistance by increasing stemness in tumour tissue, thereby generating cancer stem cells (CSCs). CSCs escape treatment by deploying metabolic pathways to trigger dormancy or proliferation, also gaining the ability to exit and re-enter the cell cycle to hide their cellular identity. METHODS: We employed various cellular and biochemical assays to identify the role of the glycolytic enzyme PFKFB3, by knocking it down and pharmacologically inhibiting it with PFK158, to determine its anticancer effects in vitro and in vivo by targeting the CSC population in MPM. RESULTS: Here, we have identified PFKFB3 as a strategic player to target the CSC population in MPM and demonstrated that both pharmacologic (PFK158) and genetic inhibition of PFKFB3 destroy the FAK-Stat3-SOX2 nexus resulting in a decline in conspicuous stem cell markers viz. ALDH, CD133, CD44, SOX2. Inhibition of PFKFB3 accumulates p21 and p27 in the nucleus by decreasing SKP2. Lastly, PFK158 diminishes tumour-initiating cells (TICs) mediated MPM xenograft in vivo. CONCLUSIONS: This study confers a comprehensive and mechanistic function of PFKFB3 in CSC maintenance that may foster exceptional opportunities for targeted small molecule blockade of the TICs in MPM.

Evidence of the Relationship between Social Vulnerability and the Spread of COVID-19 in Urban Spaces.

Modeling the social-spatial structure of urban spaces can facilitate the development of guidelines aimed at curbing the spread of the COVID-19 pandemic while also acting as an instrument that helps decision-making concerning mitigation policies. The modeling process starts with categorization of urban spaces based on the concept of social vulnerability. A model is created based on this concept and the theory of analysis of social areas. Statistical techniques of factor analysis and geostatistics are applied. This generates a map of social differentiation that, when related to data on the evolution of the contagion, generates a multidimensional model of social vulnerability. The application of this model towards people (social structure) and the environment where they live (spatial structure) is specified. Our model assumes the uniqueness of cities, and it is intended to be a broadly applicable model that can be extrapolated to other urban areas if pertinent revisions are made. Our work demonstrates that aspects of the social and urban structures may be validly used to analyze and explain the spatial spread of COVID-19.

A Randomized, Open-Label Phase II Study Evaluating Emibetuzumab Plus Erlotinib and Emibetuzumab Monotherapy in MET Immunohistochemistry Positive NSCLC Patients with Acquired Resistance to Erlotinib.

INTRODUCTION: The hepatocyte growth factor receptor MET represents a resistance mechanism to epidermal growth factor receptor (EGFR) inhibition in EGFR mutant (mt) non-small cell lung cancer (NSCLC). This Phase 2 study tested whether acquired resistance to erlotinib in MET protein positive NSCLC patients enriched for EGFRmt can be overcome by emibetuzumab plus erlotinib. PATIENT AND METHODS: Patients with Stage IV NSCLC with acquired resistance to erlotinib and MET diagnostic (+) (≥ 10% of cells expressing MET at ≥ 2+ IHC staining intensity at any time) were randomized (3:1) to receive emibetuzumab 750 mg every 2 weeks with or without erlotinib 150 mg once daily. The primary objective was to evaluate the overall response rate (ORR) relative to historic control, with a co-primary objective of ORR in patients with MET expression in ≥ 60% of cells ≥ 2+ (MET ≥ 60%). RESULTS: One hundred and eleven MET+ patients received emibetuzumab plus erlotinib (N = 83) or emibetuzumab monotherapy (N = 28). 89 of 111 MET+ samples were post-erlotinib. ORR was 3.0% for emibetuzumab plus erlotinib (95% CI: 0.4, 10.5) and 4.3% for emibetuzumab (95% CI: 0.1, 21.9), in patients with post-erlotinib progression biopsies available (n = 89). Similar results were observed in patients with MET ≥ 60% expression (n = 74). Disease control rate and progression-free survival were higher for emibetuzumab plus erlotinib (50%/3.3 months) than for emibetuzumab (26%/1.6 months). No unexpected safety signals emerged. Partial responses were observed in patients with and without EGFRmt or MET amplification. EGFR sensitizing mutations were identified retrospectively in 84.2% of those with available tissue (85/101). CONCLUSION: Acquired resistance to erlotinib in MET diagnostic (+) patients was not reversed by emibetuzumab plus erlotinib or emibetuzumab monotherapy, although a subset of patients obtained clinical benefit.

Small Cell Lung Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Small Cell Lung Cancer (SCLC) provide recommended management for patients with SCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. This selection for the journal focuses on metastatic (known as extensive-stage) SCLC, which is more common than limited-stage SCLC. Systemic therapy alone can palliate symptoms and prolong survival in most patients with extensive-stage disease. Smoking cessation counseling and intervention should be strongly promoted in patients with SCLC and other high-grade neuroendocrine carcinomas. The "Summary of the Guidelines Updates" section in the SCLC algorithm outlines the most recent revisions for the 2022 update, which are described in greater detail in this revised Discussion text.

Quinacrine Has Preferential Anticancer Effects on Mesothelioma Cells With Inactivating NF2 Mutations.

Mesothelioma is a rare cancer with disproportionately higher death rates for shipping and mining populations. These patients have few treatment options, which can be partially attributed to limited chemotherapy responses for tumors. We initially hypothesized that quinacrine could be combined with cisplatin or pemetrexed to synergistically eliminate mesothelioma cells. The combination with cisplatin resulted in synergistic cell death and the combination with pemetrexed was not synergistic, although novel artificially-generated pemetrexed-resistant cells were more sensitive to quinacrine. Unexpectedly, we discovered cells with NF2 mutations were very sensitive to quinacrine. This change of quinacrine sensitivity was confirmed by NF2 ectopic expression and knockdown in NF2 mutant and wildtype cell lines, respectively. There are few common mutations in mesothelioma and inactivating NF2 mutations are present in up to 60% of these tumors. We found quinacrine alters the expression of over 3000 genes in NF2-mutated cells that were significantly different than quinacrine-induced changes in NF2 wildtype cells. Changes to NF2/hippo pathway biomarkers were validated at the mRNA and protein levels. Additionally, quinacrine induces a G1 phase cell cycle arrest in NF2-mutated cells versus the S phase arrest in NF2-wildtype cells. This study suggests quinacrine may have repurposing potential for a large subset of mesothelioma patients.

SATB2 Is Expressed in a Subset of Pulmonary and Thymic Neuroendocrine Tumors.

OBJECTIVES: To evaluate SATB2 expression and prognostic implications in a large cohort of thoracic neuroendocrine tumors. METHODS: Surgical pathology files (1995-2017) and an institutional thymic epithelial tumor database (2010-2020) were searched for resected neuroendocrine tumors. Cases were stained with SATB2 (clone EP281). Percent SATB2-positive tumor cells and expression intensity were scored. RESULTS: In the lung, SATB2 was expressed in 5% or more of tumor cells in 29 (74.4%) of 39 small cell carcinomas and 9 (22.5%) of 40 atypical and 26 (40.6%) of 64 typical carcinoid tumors. SATB2 percent tumor cell expression and intensity were higher in small cell carcinomas than in carcinoid tumors (both P < .001, respectively). After adjusting for tumor subtype, SATB2 expression did not correlate with outcome. In the thymus, four (100%) of four atypical carcinoid tumors and one large cell neuroendocrine carcinoma but no small cell carcinoma (n = 2) expressed SATB2 in 5% or more of tumor cells. CONCLUSIONS: SATB2 (clone EP281) is expressed in a large subset of pulmonary and thymic neuroendocrine tumors and therefore does not appear to be a useful marker to identify the origin of neuroendocrine tumors. Validation studies are needed, specifically including thymic neuroendocrine tumors, as the expression pattern might be different in those tumors.

Identifying the prognostic significance of B3GNT3 with PD-L1 expression in lung adenocarcinoma.

BACKGROUND: As a novel treatment, programmed cell death protein 1 (PD-1) inhibitor appears to be less effective in tumors of lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation. Beta-1,3-N-acetylglucosaminyltransferase 3 (B3GNT3) has reported to be associated with programmed death ligand 1 (PD-L1)/PD-1 interaction. However, the relationship between B3GNT3 and PD-L1 and its prognostic significance in. EGFR: mutant status are still unknown. METHODS: B3GNT3 was identified through transcriptome sequencing and The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) database. Flow cytometry and real-time polymerase chain reaction were performed to investigate the association between B3GNT3, PD-L1, and EGFR. Then, B3GNT3 and PD-L1 expression were evaluated by immunohistochemical analysis in 145 surgically resected primary lung adenocarcinomas. The relationships between survival and B3GNT3, PD-L1, and EGFR status were assessed, and the potential prognostic factors in patients with B3GNT3 expression were identified. RESULTS: We found that EGFR activation induced PD-L1 expression, and EGFR tyrosine kinase inhibitor (TKI) could reduce PD-L1 protein in EGFR-TKI-sensitive HCC827 and PC9 cell lines. Subsequent analysis showed that EGFR inhibitor could also lead to both decreased PD-L1 and B3GNT3 mRNA expression. A total of 145 lung adenocarcinoma patients were included. PD-L1 >1% and B3GNT3-positive expression in patients might contribute to worse prognosis in both overall survival (OS) [hazard ratio (HR), 2.63; 95% confidence interval (CI), 0.98-7.06; P=0.048] and disease-free survival (DFS) (HR, 3.04; 95% CI, 1.13-8.14; P=0.019), especially in the PD-L1 ≥50% group. However, when patients were negative for B3GNT3, PD-L1, and EGFR (or "triple negative"), there were significant decreases in OS (HR, 5.44; 95% CI, 0.99-29.83; P=0.029) and DFS (HR, 7.24; 95% CI, 1.32-39.73; P=0.008). Positive B3GNT3 expression was a significant risk factor associated with lower DFS (HR, 3.30; P=0.043). CONCLUSIONS: Our results indicate that the B3GNT3 expression is tightly correlated with PD-L1 expression and EGFR mutation status. B3GNT3 is associated with poor prognosis in lung adenocarcinoma patients. Collectively, these findings may offer new insight into enhancing immune therapy efficacy for lung adenocarcinoma patients.

Salicylates enhance CRM1 inhibitor antitumor activity by induction of S-phase arrest and impairment of DNA-damage repair.

Chromosome region maintenance protein 1 (CRM1) mediates protein export from the nucleus and is a new target for anticancer therapeutics. Broader application of KPT-330 (selinexor), a first-in-class CRM1 inhibitor recently approved for relapsed multiple myeloma and diffuse large B-cell lymphoma, have been limited by substantial toxicity. We discovered that salicylates markedly enhance the antitumor activity of CRM1 inhibitors by extending the mechanisms of action beyond CRM1 inhibition. Using salicylates in combination enables targeting of a range of blood cancers with a much lower dose of selinexor, thereby potentially mitigating prohibitive clinical adverse effects. Choline salicylate (CS) with low-dose KPT-330 (K+CS) had potent, broad activity across high-risk hematological malignancies and solid-organ cancers ex vivo and in vivo. The K+CS combination was not toxic to nonmalignant cells as compared with malignant cells and was safe without inducing toxicity to normal organs in mice. Mechanistically, compared with KPT-330 alone, K+CS suppresses the expression of CRM1, Rad51, and thymidylate synthase proteins, leading to more efficient inhibition of CRM1-mediated nuclear export, impairment of DNA-damage repair, reduced pyrimidine synthesis, cell-cycle arrest in S-phase, and cell apoptosis. Moreover, the addition of poly (ADP-ribose) polymerase inhibitors further potentiates the K+CS antitumor effect. K+CS represents a new class of therapy for multiple types of blood cancers and will stimulate future investigations to exploit DNA-damage repair and nucleocytoplasmic transport for cancer therapy in general.

Comparative Analysis of Predictive Biomarkers for PD-1/PD-L1 Inhibitors in Cancers: Developments and Challenges.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) have dramatically changed the landscape of cancer therapy. Both remarkable and durable responses have been observed in patients with melanoma, non-small-cell lung cancer (NSCLC), and other malignancies. However, the PD-1/PD-L1 blockade has demonstrated meaningful clinical responses and benefits in only a subset of patients. In addition, several severe and life-threatening adverse events were observed in these patients. Therefore, the identification of predictive biomarkers is urgently needed to select patients who are more likely to benefit from ICI therapy. PD-L1 expression level is the most commonly used biomarker in clinical practice for PD-1/PD-L1 inhibitors. However, negative PD-L1 expression cannot reliably exclude a response to a PD-1/PD-L1 blockade. Other factors, such as tumor microenvironment and other tumor genomic signatures, appear to impact the response to ICIs. In this review, we examine emerging data for novel biomarkers that may have a predictive value for optimizing the benefit from anti-PD-1/PD-L1 immunotherapy.

Immunotherapy in patients with autoimmune disease.

Immune checkpoint inhibitors (ICIs) such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1) inhibitors are widely used for the treatment of multiple cancers. Seven of these agents are currently FDA approved in the US as first or second line options for solid tumors and hematologic malignancies. These agents work by downregulating pathways that suppress T-cell activation and thereby mounting an immune response to the tumor. In general, ICI are well tolerated with only mild to moderate toxicity. However, in some patients severe immune-related adverse events (irAEs) that mimic the presentation of autoimmune diseases (AID) may occur. It is believed that irAEs occur due to disruption of immunologic self-tolerance, a mechanism that also seems to explain AID. Patients with pre-existing AID are usually excluded from prospective clinical trials due to concerns for flares of the underline AID. There is limited retrospective evidence supporting the use of ICI in patients with some pre-existing AID. These patients have an increased risk of malignancy and there is an unmet need to study ICIs in this population. This manuscript intends to review the current available evidence for the safety and activity of ICIs in patients with pre-existing AID. We summarize the reported use of ICI in patients with pre-existing AID according to the primary tumor site and type of ICI used.

Association of Sex, Age, and Eastern Cooperative Oncology Group Performance Status With Survival Benefit of Cancer Immunotherapy in Randomized Clinical Trials: A Systematic Review and Meta-analysis.

Importance: Sex, age, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) may affect immune response. However, the association of these factors with the survival benefit of cancer immunotherapy with immune checkpoint inhibitors (ICIs) remains unclear. Objective: To assess the potential sex, age, and ECOG PS differences of immunotherapy survival benefit in patients with advanced cancer. Data Sources: PubMed, Web of Science, Embase, and Scopus were searched from inception to August 31, 2019. Study Selection: Published randomized clinical trials comparing overall survival (OS) in patients with advanced cancer treated with ICI immunotherapy vs non-ICI control therapy were included. Data Extraction and Synthesis: Pooled OS hazard ratio (HR) and 95% CI for patients of different sex, age (<65 and ≥65 years) or ECOG PS (0 and ≥1) were calculated separately using a random-effects model, and the heterogeneity between paired estimates was assessed using an interaction test by pooling study-specific interaction HRs. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. Main Outcomes and Measures: The difference in survival benefit of ICIs between sex, age (<65 vs ≥65 years), and ECOG PS (0 vs ≥1), as well as the difference stratified by cancer type, line of therapy, agent of immunotherapy, and immunotherapy strategy in the intervention arm. Results: Thirty-seven phase 2 or 3 randomized clinical trials involving 23 760 patients were included. An OS benefit of immunotherapy was found for both men (HR, 0.75; 95% CI, 0.71-0.81) and women (HR, 0.79; 95% CI, 0.72-0.88); for both younger (<65 years: HR, 0.77; 95% CI, 0.71-0.83) and older (≥65 years: HR, 0.78; 95% CI, 0.72-0.84) patients; and for both patients with ECOG PS 0 (HR, 0.81; 95% CI, 0.73-0.90) and PS greater than or equal to 1 (HR, 0.79; 95% CI, 0.74-0.84). No significant difference of relative benefit from immunotherapy over control therapy was found in patients of different sex (P = .25, I2 = 19.02%), age (P = .94, I2 = 15.57%), or ECOG PS (P = .74, I2 = 0%). No significant difference was found in subgroup analyses by cancer type, line of therapy, agent of immunotherapy, and immunotherapy strategy in the intervention arm. Conclusions and Relevance: This meta-analysis found no evidence of an association of sex, age (<65 vs ≥65 years), or ECOG PS (0 vs ≥1) with cancer immunotherapy survival benefit. This finding suggests that the use of ICIs in advanced cancer should not be restricted to certain patients in sex, age, or ECOG PS categories.