bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stereotactic radiosurgery (SRS) versus whole brain radiation therapy (WBRT) in patients with small cell lung cancer (SCLC) and intracranial metastatic disease (IMD): A systematic review and meta-analysis.
Authors: Gaebe Karolina , Li Alyssa Y. , Park Amy , Parmar Ambika , Lok Benjamin H. , Sahgal Arjun , Chan Kelvin K. , Erickson Anders W. , Das Sunit 
Published: June 2022

8570 Background: Patients with SCLC are at high risk for the development of IMD and, subsequently, rapid intracranial progression. SRS has supplanted WBRT as first-line treatment for IMD in most solid cancers, but WBRT remains first-line treatment for IMD in SCLC patients. Data on SRS in SCLC are limited to small retrospective studies. Methods: Studies reporting on SRS in SCLC patients with IMD were collected from EMBASE, MEDLINE, CENTRAL, and grey literature sources (n = 3,732 studies). Random-effects meta-analysis pooled hazard ratios (HR) for overall survival (OS) between SRS and WBRT ± SRS boost, as well as medians for OS in months (mo) and risk rates for intracranial local (LC) and intracranial distant control (DC) in single-arm SRS studies. Results: OS following SRS was non-inferior compared with WBRT ± SRS boost (HR 0.90; 95% confidence interval (95CI), 0.73-1.10; n = 7 studies; n = 18,130 patients), and superior compared with WBRT alone (HR 0.80; 95CI, 0.66-0.96; n = 7 studies; n = 16,961 patients). Pooled median OS from single-arm studies following SRS was 8.99 mo (95CI, 7.86-10.15; n = 14 studies; n = 1,682 patients). Pooled LC and DC estimates following SRS were 81% (95CI, 67%-99%) and 66% (95CI, 50%- 86%), respectively, at 6 mo, and 78% (95CI, 61%-98%) and 58% (95CI, 46%-75%), respectively, at 12 mo. Conclusions: This systematic review and meta-analysis provides evidence that SRS may achieve analogous survival outcomes compared with WBRT in patients with SCLC and IMD, indicating that a subset of SCLC patients may benefit from first-line SRS treatment. Prospective trials should investigate the impact of metastatic burden as well as LC and DC differences between WBRT- and SRS-treated SCLC patients.
The predictive value of YAP-1 for efficacy of immunotherapy among patients with ES-SCLC.
Authors: Chen Yuqing , Guan Xu-Hui , Gao Ling-Ling , Kong Ling-Cong , Yang Huan , Lin Xiao-Cheng , Fang Mei-Mei , Li Yu-Fa , Zhang Xuchao , Liang Hui-Ying , Yang Jin-Ji 
Published: June 2022

8578 Background: IMpower133 showed benefits in both progression-free survival (PFS) and overall survival (OS) of etoposide/carboplatin plus atezolizumab (ECT) regimen in extensive-stage small-cell lung cancer (ES-SCLC), but the absolute benefit was limited. Previous studies have classified SCLC patients by RNA-seq clustering analysis to explore the dominant population for treatment, but was difficult for clinical application. We aimed to explore whether expressive status of Yes-Associated Protein 1 (YAP-1) can screen dominant population of immunotherapy among ES-SCLC patients. Methods: We selected ES-SCLC patients treated in our hospital from Jan, 2018 to Jul, 2021, and enrolled 21 patients with ES-SCLC received ECT regimen whose formaldehyde-fixed, paraffin-embedded sample was reachable. Assessments of complete remission (CR), partial remission (PR), disease stable (SD) and progressive disease (PD) were according to the efficacy evaluation criteria of solid tumor (RECIST) version 1.1. Immunohistochemistry (IHC) of YAP-1 (ET1608-30, 1/100) was conducted. The H-score was calculated by IHC Profiler. All statistical analyses were evaluated using SPSS 22.0, X-tile 3.6.1, and Excel. P values < 0.05 were considered statistically significant. Results: Baseline information was provided in table. The median H-score of responders (CR/PR patients) and non-responders were 13.97 (95%CI: 8.97-16.30) and 23.72 (95%CI: 8.13-75.40) that were significantly different (P＜0.05). H-score and PFS showed negative correlation by spearman (r = -0.603). Patients were divided into two groups as low expression group (H-score ≤25.00, n = 16) and high expression group (H-score ＞25.00, n = 5) according to the cut-off value of H-score. The median PFS of these two groups were 7.1m (95%CI: 2.6-11.6m) and 3.4m (95%CI: 0.9-5.9m), respectively. K-M curves of PFS were significantly different (P＜0.05). Conclusions: Our preliminary results have indicated a potential efficacy predictive value of YAP-1 protein. And the expression level of YAP-1 protein was negatively correlated with efficacy of ECT in ES-SCLC patients. [Table: see text]
Lenvatinib for the treatment of thymic epithelial tumors (TETs): A real-life multicenter experience.
Authors: Benitez Jose Carlos , Florez-Arango Juan , Dansin Eric , Giaccone Giuseppe , Basse Clemence , Mazieres Julien , Pierret Thomas , Giaj Levra Matteo , Pons-Tostivint Elvire , Arrondeau Jennifer , Aldea Mihaela , Missy Pascale , Molina Thierry , Girard Nicolas , Besse Benjamin 
Published: June 2022

8585 Background: TETs are rare malignancies of the anterior mediastinum being thymoma (T) B3 and thymic carcinoma (TC) the most aggressive subtypes. There is no standard treatment after platinum-based chemotherapy in refractory or metastatic setting. A phase 2 trial has reported clinical benefit for lenvatinib 24mg (objective response rate [ORR] of 38%), a novel multi-targeted inhibitor of VEGFR, FGFR, RET, c-Kit, and other kinases; significant toxicity grade 3 hypertension was 64%. No real-life data exists. Methods: We selected patients (pts) under lenvatinib as a second-line or beyond for refractory TETs from 8 International centers from France (belonging to the nationwide network RYTHMIC) and United States. We analyzed epidemiologic, clinical and pathological characteristics of patients with TET’s. The toxicity was evaluated according to CTCAE v4, with a local evaluation of efficacy and we assessed toxicity profile and survival outcomes. Results: From March 2020 to December 2021, 29 pts were enrolled. Median age at diagnosis was 49 (24-71), 51.7% were women, 6/29 (20.7%) reported auto-immune disorders (AIDs). TC was the most frequent subtype (n=18, 62.1%), followed by B3 and B2. Lenvatinib was used as a second line for 52% of pts, mainly starting from 14 mg/daily (n=20, 69%) and one pts with concomitant pembrolizumab. The ORR was 17% (95%CI 3.0-32.0) with partial responses only seen in TC, and the disease control rate was 76% (95%CI 59.0-92.0). Response was observed with the dose of 24mg in 3 pts and 14mg in 2 pts, with a median follow-up period of 5 months (m) (95%CI 3.2-6.7), PFS at 6 and 12 m was 64% and 30%, respectively. Toxicity is summarized in table 1. Dose de-escalations were needed in 27.5% of pts. Conclusions: We confirm the activity of lenvatinib in pts with advanced or metastatic T and TC, despite the use of lower doses than the phase 2 study.[Table: see text]
CD47 expression patterns in thymic epithelial tumors.
Authors: Sun Thomas Yang , Nguyen Brandon , Chen Simon , Natkunam Yasodha , Padda Sukhmani Kaur , Van De Rijn Matt , Wakelee Heather A. , Riess Jonathan W. 
Published: June 2022

8586 Background: Blockade of CD47, an immunoglobulin overexpressed on solid tumor cells that inhibits macrophage phagocytosis, is a promising anti-cancer immunotherapy which has not yet been explored in thymic epithelial tumors (TETs). TETs, including thymomas and thymic carcinomas, are rare tumors with limited immunotherapy treatment options due to the high rates of immune-related adverse effects observed with PD-1/PD-L1 checkpoint inhibitors. This study aimed to examine CD47 protein expression in TETs. Methods: A clinically annotated tissue microarray of 67 TETs consisting of 64 thymomas and 3 thymic carcinomas, as well as 14 thymic controls were included. Each sample with an average of 3 cores was stained for CD47 epithelial expression (rabbit monoclonal antibody SP279, Abcam, USA). Samples were scored for intensity as follows: 0 = none, 1 = weak, 2 = moderate, and 3 = strong. An H-score, defined as intensity x percentage of tumor involved, was also assigned and ranged from 0 to 300. Samples with an intensity score of < 2 or an H-score of < 150 were categorized as CD47low, while the rest as CD47high. Multivariate linear regression analysis accounted for WHO subtype, stage, resection status and presence of paraneoplastic syndrome (Prism 9, Graphpad). Results: Compared to normal thymic tissue, TETs were more frequently CD47 positive and had significantly higher levels of CD47 expression. CD47 was present in 91% of TETs, compared to 64.3% of normal thymus. Importantly, the level of expression was significantly higher in TETs by 16-fold (mean H-score 75.0 vs 4.6, p = 0.003). Among tumors, univariate analyses showed that higher CD47 expression was correlated with a lower stage (p = 0.032) and more complete resection (p = 0.058). A multivariate analysis accounting for these factors showed that CD47 expression by both H-score and intensity were each highly correlated with WHO histology subtype (p = 0.0005; p = 0.0017 respectively) with lower grade subtypes more frequently found in CD47high tumors. The most frequent subtype in CD47high, when compared to CD47low tumors, was AB (61.5% vs 13.7%) and the least frequent was B2 (0% vs 37.3%). Tumors with the highest grade (subtype C, thymic carcinomas) were exclusively CD47low. CD47high tumors were associated with an increased incidence of paraneoplastic syndromes (52.4% vs 12.0%, p = 0.0014). Conclusions: CD47 expression was found in the vast majority of TETs, and in significantly higher levels than normal thymic tissue. Among tumors, those with higher CD47 expression tended to have lower grade and stage, as well as higher frequency of paraneoplastic syndromes. This study is the first to examine CD47 expression in TETs. Given the prevalent expression of CD47 found in TETs and current available CD47 targeted agents, this study lends support for further investigation of this novel therapeutic approach.
Cabozantinib (C) plus atezolizumab (A) or C alone in patients (pts) with advanced non–small cell lung cancer (aNSCLC) previously treated with an immune checkpoint inhibitor (ICI): Results from Cohorts 7 and 20 of the COSMIC-021 study.
Authors: Neal Joel W. , Santoro Armando , Viteri Santiago , Ponce Aix Santiago , Fang Bruno , Lim Farah Louise , Gentzler Ryan D. , Goldschmidt Jerome H. , Khrizman Polina , Massarelli Erminia , Patel Shiven B. , Puri Sonam , Sudhagoni Ramu , Scheffold Christian , Curran Dominic , Felip Enriqueta 
Published: June 2022

9005 Background: C, a multitargeted receptor tyrosine kinase inhibitor (TKI), promotes an immune-permissive environment that may enhance ICI activity. COSMIC-021 (NCT03170960) is a multicenter phase 1b study evaluating C + A in advanced solid tumors. In COSMIC-021, C + A demonstrated encouraging clinical activity in the cohort of pts with aNSCLC previously treated with ICIs (cohort 7 [C7]) (Neal. ASCO 2020. Abstr 9610). Updated outcomes of C + A in expanded C7 and outcomes for C alone in exploratory cohort 20 (C20) are presented. Methods: Pts with stage IV nonsquamous NSCLC without mutations in EGFR, ALK, ROS1, or BRAF V600E who progressed on one prior ICI and ≤2 prior lines of systemic anticancer therapy but no prior VEGFR TKI were eligible. Cohorts were not accrued contemporaneously. Pts received C 40 mg PO QD plus A 1200 mg IV Q3W (C7) or C alone 60 mg PO QD (C20). Primary endpoint was objective response rate (ORR) per RECIST v1.1 by investigator. Other endpoints included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). CT/MRI scans were performed Q6W for the first year and Q12W thereafter. Results: A total of 81 and 31 pts received C + A and C, respectively; baseline characteristics were as follows: median age, 67 y, 70 y; male, 57%, 58%; ECOG PS 1, 64%, 71%; liver metastasis, 21%, 23%; refractory to prior ICI (progressive disease [PD] as best response), 32%, 45%; median number of prior systemic therapies, 3 and 3. As of Nov 30, 2021, median follow-up (range) (mo) was 24.7 (10.7, 42.8) and 21.5 (17.3, 27.6) for C + A and C, respectively, with 6 (7%) and 1 (3%) on study treatment. Clinical activity was observed for C + A and C alone (Table). Most common treatment-related adverse events (TRAEs) of any grade for C + A and C, respectively, included diarrhea (40%, 42%), nausea (22%, 45%), decreased appetite (25%, 26%), vomiting (14%, 23%), and fatigue (28%, 19%); grade 3/4 TRAEs occurred in 44% and 52% and one grade 5 TRAE occurred in each cohort (pneumonitis [C + A] and gastric ulcer hemorrhage [C]). Conclusions: C + A and C demonstrated encouraging clinical activity with manageable toxicity in pts with aNSCLC previously treated with ICIs. A phase 3 trial (CONTACT-01; NCT04471428) of C + A vs docetaxel is ongoing in NSCLC previously treated with an ICI and platinum-containing chemotherapy. Clinical trial information: NCT03170960. [Table: see text]
Association of progression-free survival and overall response rate with overall survival in first-line randomized trials of immune checkpoint inhibitor–based regimens for metastatic non–small cell lung cancer (NSCLC): An FDA pooled analysis.
Authors: Haddock Lobo Goulart Bernardo , Mushti Sirisha , Chatterjee Somak , Larkins Erin A. , Donoghue Martha Boeri , Tang Shenghui , Pazdur Richard , Mishra-Kalyani Pallavi Shruti , Beaver Julia A. , Singh Harpreet 
Published: June 2022

9029 Background: Overall Survival (OS) has represented the endpoint of choice to support approvals of Immune Checkpoint Inhibitors (ICIs) in first-line metastatic NSCLC. Despite continued interest in the use of earlier clinical endpoints as true surrogates for OS in this setting, the correlation of Progression-Free Survival (PFS) and Overall Response Rate (ORR) with OS remain an area of active investigation. We conducted a patient-level and trial-level pooled analysis of first-line randomized trials of ICI-based regimens to assess correlations of early clinical endpoints of PFS and ORR with OS in first-line metastatic NSCLC. Methods: The analysis included randomized trials comparing ICI-based regimens (anti-PD-(L)1 with or without anti-CTLA4 antibodies, with or without platinum-based chemotherapy) to platinum-based chemotherapy alone for the first-line treatment of patients with metastatic NSCLC that were submitted to the U.S. Food and Drug Administration between July 2016 to March 2021 to support a marketing application. Patient-level associations were estimated using Spearman (rs) correlation coefficients for PFS and OS, and Cox Proportional Hazards models in RECIST response-based subgroups for ORR and OS. At the trial level, associations were estimated using R2 coefficients from weighted linear regression models, using the log of hazard-ratio (HRs) for PFS and OS and log-odds ratio for ORR. Results: The pooled analysis included 13 trials enrolling 9,285 patients total. Seven trials compared ICIs combined with chemotherapy vs chemotherapy; 6 trials compared ICIs alone vs chemotherapy. Among all patients, the distribution of PD-L1 expression was 31%, 66%, and 32% for PD-L1 <1%, ≥1%, and ≥50%, respectively. The table shows the correlation coefficients for PFS and OS, and ORR and OS at the patient and trial levels. At the patient level, the OS HR comparing ICI-based regimens to chemotherapy was 0.54 (95% CI: 0.48, 0.61) for RECIST responders and 0.96 (95% CI: 0.90, 1.02) for non-responders. Conclusions: This pooled analysis did not indicate a strong correlation between endpoints of PFS and ORR with OS at the patient and trial levels in first-line randomized trials of ICI-based regimens for metastatic NSCLC, potentially because of use of subsequent therapies, cross-over to ICIs, and continuation of ICIs beyond progression. Future research will explore the correlation of alternative endpoints with OS, such as time to treatment discontinuation. Our analysis supports the continued importance of OS as an endpoint for first-line NSCLC trials of ICI-based regimens.[Table: see text]
Immunogenicity and disease control induced by a multineoantigen vaccine (ADXS-503) in patients with metastatic non–small cell lung cancer who have progressed on pembrolizumab.
Authors: Lisberg Aaron E. , Goldman Jonathan W. , Halmos Balazs , Gerstner Gregory James , Morganstein Neil , Farber Charles Michael , Lee Kyoung A Viola , Holtgrewe Lydia ML , Codd Casey , Bisconte Angelina , Foss Theodore , Vangala Surya , Parsi Megan , Gutierrez Andres A. , Ramalingam Suresh S. 
Published: June 2022

9042 Background: The administration of a lung cancer-specific immunotherapy with 22 tumor-associated antigens (ADXS-503, A503), has been evaluated as an add-on therapy for patients (pts) with metastatic non-small-cell lung cancer (NSCLC) who have progressed on pembrolizumab (pembro) as last therapy [Haigentz M et al. ASCO 2021]. The present study explores the immunogenicity and potential reversal of immune resistance with A503 when added-on to pembro at the time of progressive disease (PD). Methods: A phase 2 study of A503 + pembro is being conducted in pts with metastatic squamous or non-squamous NSCLC. In Part B of the study, A503 was added-on to pembro within 12 weeks after the first scan showing disease progression following pembro therapy (per RECIST criteria v1.1). Both A503 (1x108 CFU) and pembro (200 mg) were infused by IV every 3 weeks until disease progression or dose-limiting toxicity. Immunogenicity assays included serum cytokine and chemokine levels; flow cytometry; and in-vitro stimulation FluoroSpot assay with 4 different antigen-pools represented in A503 [i.e., hot spot mutations, heteroclitic/wild-type tumor-associated antigens and other antigens not included in the A503 construct (antigen spreading)]. Results: A total of 14 pts have been treated in Part B, of which 13 are clinically evaluable and up to 11 have immune assessments. Combination therapy was well tolerated with transient increased secretion of cytokines for several hours after infusion of A503 consistent with the expected immune activation and transient ‘flu-like’ syndrome. The objective response rate (16%) and disease control rate (46%) were encouraging with 2 partial responses (PR), 4 stable diseases (SD) and 7 pts with PD. Pts with disease control, in particular, generated CD8+ T cells reactive to neoantigens in 1 or more of the 4 antigen pools tested in FluoroSpot. Also, activation of NK cells and of cytotoxic- and memory-CD8+ T cells was mainly observed in pts with PR or SD, but not in those with PD, as shown in the table. Conclusions: Adding A503 to pembro after PD appears to induce innate and adaptive immune responses that may restore or enhance sensitivity to checkpoint inhibitors in pts with clinical benefit. Clinical trial information: NCT03847519. [Table: see text]
Dynamic changes in serum analyte levels associated with clinical outcome in squamous cell lung cancer trial SWOG Lung-MAP S1400I of nivolumab ± ipilimumab.
Authors: Gonzalez-Kozlova Edgar , Huang Hsin-Hui , Redman Mary Weber , Herbst Roy S. , Gettinger Scott N. , Bazhenova Lyudmila , Xie Hui , Patel Manishkumar , Nie Kai , Harris Jocelyn , Argueta Kimberly , Cerami Ethan , Hong Joyce , Biswas Roshni , Van Nostrand Stephen , Kelly Karen , Moravec Radim , Del Valle Diane , Kim-Schulze Seunghee , Gnjatic Sacha 
Published: June 2022

9044 Background: While Immune checkpoint blockade (ICB) is standard treatment for lung cancer there are limited biomarkers that predict benefit, pharmacokinetic on-treatment activity or explain progression. S1400I was a randomized Phase III trial of nivolumab(N)+ipilimumab(I) versus N (NCT02154490, PMID 34264316) for ICB naïve, previously treated stage IV or recurrent squamous cell lung cancer. We performed circulating serum protein analysis of serial blood specimens from patients enrolled in S1400I to evaluate if serum proteins levels changed over time, changes differed by treatment arm, and if they were associated with overall survival. Methods: 561 serial blood specimens (baseline, weeks (wk) 3, 7, 9, and progression [PD]) from 160 of 252 eligible patients enrolled to S1400I were analyzed for 92 immuno-oncology analytes with the Olink proximity extension assay. Protein levels were normalized with use of internal controls and quantified as log2 protein expression (denoted as NPX). Linear mixed models evaluated change in expression from baseline at each time point (wks 3,7,9 and PD), and NPX differences at baseline, wk3, and PD depending on best objective response. A Cox model was used to evaluate the association between baseline NPX and survival. Overall survival and longitudinal cytokine expression were jointly modeled using a linear mixed model to estimate dynamic biomarker changes in NPX and a Cox model for survival. The joint models for time-varying NPX values included a random intercept and modeled time using a natural spline with three knots. Significance was defined as P < 0.05. Results: Serum proteins PCDC1, CXCL9, and CXCL10 were increased from baseline at wks 3,7,9 and at PD. CCL19 was increased at wks 3 and 7 but not at wk 9 and PD. IL10 and IFNγ were increased at wk 3 but subsequently returned to baseline. Change in CXCL13 from baseline to PD was larger for N+I versus N. Baseline CCL23, CSF-1, IL6, and MUC-16 were associated with shorter survival (HR > 1). Joint modeling of survival with cytokines showed an increased risk of death (HR > 1) with higher longitudinal serum levels of CXCL13, MMP12, CSF-1, and IL8. Patients achieving objective response had higher IL4 and LAMP3 and lower IL6 and IL8 at baseline and wk 3 compared to non-responders. Conclusions: Measurements of blood circulating soluble proteins represent easily accessible biomarkers that may be useful as indicators of outcome, and that will need to be prospectively confirmed. Clinical trial information: NCT02154490.