bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic role of preoperative chemosensitivity in patients with non–small cell lung cancer (NSCLC) treated with preoperative chemotherapy: A study of National Cancer Database (NCDB).
Authors: Deng Lei , Jiang Changchuan , Perimbeti Stuthi , Chen Hongbin
Published: June 2022

8538

Background: Response to preoperative systemic therapy may provide valuable information regarding tumor biology and prognosis. This is increasingly relevant nowadays considering the promising results from preoperative chemoimmunotherapy. This study aims to examine the prognostic role of preoperative chemosensitivity defined by TNM stage change in NSCLC. Methods: Patients with histologically confirmed clinical stage II-III NSCLC who have received preoperative chemotherapy followed by R0 curative surgery were identified in the NCDB between 2006 and 2017. Patients who have developed metastasis at the time of surgery, received any perioperative radiotherapy or single agent chemotherapy, or died within 90 days of surgery, were excluded. Preoperative chemosensitivity is categorized as ypT0N0, downstaged (pTNM < cTNM, excluding ypT0N0), and not downstaged (pTNM ≥ cTNM). Logistic regression was used to evaluate associations between chemosensitivity and demographic, clinical, and pathological factors. Log-rank was used for survival analysis and adjusted by cox regression for age, gender, race, year of diagnosis, academic center, insurance, comorbidity, histology, and clinical stage. Results: A total of 1266 patients were included, of whom 104 (8.2%) had ypT0N0, 575 (45.4%) were downstaged, while 587 (46.4%) were not. Female, diagnosis in recent years, treatment at academic centers, and squamous histology were significantly associated with better chemosensitivity, while clinical TNM stage, age, race, and comorbidity were not. Five-year overall survival rate is 81.2%, 57.7%, and 46.2%, respectively (log-rank p < 0.001). After Cox regression adjustment, compared with not downstaged, ypT0N0 (HR 0.28, 95% CI 0.17 – 0.45) and downstaged (HR 0.61, 95% CI 0.51 – 0.74) were independently associated with improved postoperative survival. Conclusions: Preoperative chemosensitivity defined by TNM stage change before and after chemotherapy may prognosticate NSCLC after curative surgery. It may be a useful clinical tool to identify patients with high risk of treatment failure after neoadjuvant chemoimmunotherapy in the future.[Table: see text]
Association of the KRAS genotype and clinicopathologic findings of resected non–small cell lung cancer.
Authors: Oya Yuko , Masago Katsuhiro , Matsushita Hirokazu , Kuroda Hiroaki
Published: June 2022

8545

Background: This study assessed the clinicopathological background of early-stage KRAS-mutated non-small-cell lung cancer and analyzed the biological process of KRAS-mutated tumor using an RNA sequencing procedure. Methods: We used a cohort of consecutive series of 179 surgically resected early-stage non-small-cell lung cancers harboring KRASmutations and analyzed the clinicopathological features, including the KRAS genotypes, affecting the recurrence-free survival and prognosis. Consequently, we performed RNA sequencing to determine the gene expression profiles of nineteen KRAS-mutated non-small-cell cancers. Results: The most common KRAS genotype was p.G12C (57; 31.8%). A high p-stage (hazard ratio [HR], 4.181; P < 0.0001) and solid predominant adenocarcinoma histology (HR, 2.343; P = 0.0076) were significant independent prognostic factors for the recurrence-free survival. A high p-stage (HR, 3.793; P < 0.0001), solid predominant adenocarcinoma histology (HR, 2.373; P = 0.0147), and KRAS p.G12V genotype (HR, 1.975; P = 0.0407) were significant independent prognostic factors for the overall survival. A gene expression analysis of the two factors revealed the p.G12V genotype to be closer to those of stem cells, and the traits of e an enhanced fatty acid and amino acid metabolism as well as a solid predominant phenotype were shown to an acquired a trait that can withstand hypoxia and the effect of prostaglandin-endoperoxide synthase Conclusions: The KRAS p.G12V genotype and solid predominant adenocarcinoma phenotype may be independent predictive factors of a poor clinical course in resected early-stage non-small-cell lung cancers, possibly due to the differentiation tendency observed in stem cells, the trait of an enhanced fatty acid and amino acid metabolism, and the effect of prostaglandin-endoperoxide synthase.
Treatment interruptions and discontinuations among patients with stage III unresectable non–small cell lung cancer treated with durvalumab at the Veterans Health Administration.
Authors: Alkadimi Munaf , Moore Amanda , Frei Christopher R , Reveles Kelly R , Brannman Lance , Cotarla Ion , Frankart Andrew , Mulrooney Tiernan , Datta Paromita , Whitehead Jennifer , Franklin Kathleen , Reichelderfer Renee , Williams Madison H. , Williams Ryan A. , Smith Sarah Allison , Jones Xavier , Nooruddin Zohra
Published: June 2022

8554

Background: The PD-1/PD-L1 pathway is a mechanism of immune evasion and disruption of this pathway with immune checkpoint inhibitors (ICIs) has shown clinical benefit in multiple malignancies. Based on results from the PACIFIC trial, durvalumab is approved as consolidation therapy in patients (pts) with stage III unresectable non-small cell lung cancer (UR-NSCLC) without progression following concurrent chemoradiotherapy (cCRT). Durvalumab has been used extensively in Veterans Health Administration (VHA) facilities, providing an opportunity to evaluate durvalumab treatment interruptions (TI), treatment discontinuations (TD), and the reasons for these on a national scale. Methods: Patients with stage III UR-NSCLC receiving durvalumab consolidation immunotherapy at the VHA between January 1, 2017 and June 30, 2020 with a minimum follow up for 12 months were included using ICD-10, HCPCS, and J codes and followed from their durvalumab start date through the earliest of last VHA visit, loss to follow up, death, or end of study (excluded if durvalumab therapy was ongoing at the end of the study, because the full treatment course could not be determined). TI were defined as durvalumab infusions separated by >28 days. Reasons for TI and TD are presented descriptively. Durations are reported using medians and interquartile ranges (IQR). Results: 935 pts were included (median age = 69 years; 95% males; 96% current or former smokers; 70% with COPD; histologies [squamous (50%), non-squamous (43%), other/missing (7%)]; and 77% with carboplatin-paclitaxel as their platinum-based CRT). Durvalumab TI were experienced by 19% of pts (median [IQR] number of TI = 1 [1-1], median [IQR] TI duration = 53 days [39-90]). The main reasons for TI were toxicity (8%) and social reasons (3%) (Table). The median duration of treatment (DoT) with durvalumab (TI included) was 9.0 months (IQR 2.9-11.8). Durvalumab TD occurred in 59% of pts. Top reasons for discontinuation across all 935 pts included disease progression (24%) and toxicity (18%) (Table). Conclusions: In this real world analysis of national VHA data, durvalumab DoT was similar to PACIFIC despite having a patient population with worse prognostic factors (e.g. more males, squamous, COPD) with 8% of VHA pts experiencing TI and 18% TD due to toxicity. Patients could benefit from additional efforts to prevent, identify, and manage toxicities in the UR-NSCLC population [Table: see text]
Durvalumab treatment initiation delays in patients with unresectable stage III non–small cell lung cancer treated at Veterans Health Administration facilities.
Authors: Datta Paromita , Moore Amanda , Frei Christopher R , Reveles Kelly R , Brannman Lance , Cotarla Ion , Frankart Andrew , Mulrooney Tiernan , Alkadimi Munaf , Whitehead Jennifer , Franklin Kathleen , Reichelderfer Renee , Williams Madison H. , Williams Ryan A. , Smith Sarah Allison , Jones Xavier , Nooruddin Zohra
Published: June 2022

8556

Background: Durvalumab is an FDA-approved immunotherapy for the treatment of adults with UnResectable stage III non-small cell lung cancer (UR-NSCLC) without disease progression following concurrent chemoradiotherapy (CRT). There are limited real-world data regarding Durvalumab treatment initiation delays (TIDs) and reasons for them in the UR-NSCLC population. Methods: Patients with stage III UR-NSCLC receiving consolidation Durvalumab at the Veterans Health Administration (VHA) between January 1, 2017 and June 30, 2020 were selected from the VHA database using ICD-10, HCPCS, and J codes. All had the opportunity to be treated for 12 months and were followed from Durvalumab initiation through the earliest of their last VHA visit, loss to follow up, death, or the study’s end (and excluded if Durvalumab therapy was ongoing at the study’s end). Trained data abstractors determined the occurrence and reasons for TIDs (> 6 weeks from end of CRT to initiation of Durvalumab as in the PACIFIC trial) by chart review. Results: 935 patients were eligible for analysis (median age = 69 years; 95% males; 16% with ECOG performance status >1). TIDs occurred in 39% of the patients (Table). Durvalumab was initiated 61 days (median) from the end of CRT in TID patients vs. 31 days for those without TIDs. There were no significant (α<0.05) differences in age, race, smoking status, histology, or ECOG performance status and no comorbidity differences (except in patients with a history of cerebrovascular accident, for whom TIDs were more likely) between the TID/No-TID patients. Patients without timely post-CRT scans were more likely to have a TID. Of the 367 patients who experienced TIDs, 200 had documented reasons for the delay, consisting of other (not categorized) (28.5%), physician preference (20%), toxicity (11%), patient preference (10.5%), decline in performance status (10%), system issues (9.5%), social reasons (9%), and progression (0.5%). Conclusions: This is one of the largest retrospective cohort studies reporting real-world data in patients with UR-NSCLC receiving Durvalumab. TIDs were associated with increased time to post-CRT scans. This potential issue can be improved with care coordination and involvement of cancer navigators. Additional studies are needed to assess the impact of TIDs on survival outcomes.[Table: see text]
Atezolizumab and bevacizumab in patients with relapsed mesothelioma: MIST4—a phase IIa trial with cellular and molecular correlates of efficacy.
Authors: Fennell Dean Anthony , King Amy , Branson Amy , Barber Shaun , Greystoke Alastair , Dulloo Sean , Poile Charlotte , Harber James , Scotland Molly , Darlison Liz , Bajaj Amrita , Morgan Bruno , Brookes Cassandra , Wells-Jordan Peter , Richards Catherine Jane , Thomas Anne
Published: June 2022

8560

Background: Targeting the PD1-PDL1 axis has demonstrated significant efficacy in patients with relapsed malignant mesothelioma (MM) however the factors that determine sensitivity are unknown. Combined inhibition of vascular endothelial growth factor (VEGF) may potentiate efficacy through remodelling of the tumour microenvironment and inhibition of angiogenesis. We therefore developed a multi-centre molecularly stratified phase IIa trial to test this hypothesis and to uncover cellular and molecular determinants of efficacy as arm 4 of the Mesothelioma Stratified Therapy umbrella trial (NCT03654833, MiST4). Methods: Patients with any histological subtype or site of MM (pleural or peritoneal) were enrolled. Key inclusion factors: histological confirmation of MM with an available archival tissue block, ECOG performance status 0-1, prior platinum-based 1st line chemotherapy (any line allowed), evidence of disease progression with measurable disease by CT (RECIST 1.1), and adequate haematological/organ function. Patients received Atezolizumab 1200mg iv q3w with bevacizumab 15mg/kg iv q3w (AtzBev). Primary endpoint was disease control rate at 12 weeks (DCR12w). The null hypothesis was rejected if ≥ 11 patients had disease control (A’Hern design). Secondary endpoints: DCR at 24 weeks (DCR24w), best objective response rate and toxicity (NCI CTCAE 4.03). Patients could undergo an optional re-biopsy upon disease progression. Baseline BAP1, p16ink4a, PD-L1 (DAKO22C3), gut microbiome 16s RNA metagenomics, multiplex immunofluorescence, and whole exome and RNA transcriptome sequencing was conducted to explore cellular and molecular correlates of sensitivity. Results: Between January 2020 and February 2021, 26 patients with MM started treatment and received at least one dose of AtzBev. The median age of pts was 68 (range, 44-80) years, 69% were male, 77% epithelioid, 85% ECOG PS1, > 1 prior systemic therapy 54%. The median cycles of Atz dosing was 4.5 (IQR, 2-8) and Bev dosing was 4.5 (IQR, 2-7). DCR12w: 53.8% (95% confidence limit (CI), 33.4% – 73.4%), DCR24w: 23.1% (95%CI, 9.0% – 43.6%). Best responses (evaluable within 24w): partial – 3.8% (95%CI, 0.1- 19.6%); stable disease – 69.2% (48.2 – 85.7%); progression – 15.4% (4.4 – 34.9%). Adverse events (any cause): ≥ grade 3 toxicities affected 35% of pts. Conclusions: MiST4 met its primary endpoint however responses were heterogeneous. Analysis of cellular and molecular correlates are ongoing and will be presented. Clinical trial information: NCT03654833.
Exploratory analysis using cfDNA-based fragmentomics to predict disease recurrence in limited disease small cell lung cancer.
Authors: Park Sehhoon , Kang Jun-Kyu , Kim Hwang-Phill , Kim Su Yeon , Lee Naeun , Jung Hyun Ae , Sun Jong-Mu , Ahn Jin Seok , Ahn Myung-Ju , Lee Se-Hoon
Published: June 2022

8569

Background: The current standard of care (SOC) for limited disease (LD) small cell lung cancer (SCLC) is definitive concurrent chemoradiotherapy (CCRT). Despite the high response rate to SOC, up to 70% of the patients potentially experience disease recurrence and fail to show the prolonged clinical benefit. We investigated the feasibility of cell-free DNA (cfDNA) based genomic alteration and fragmentomic analysis using pre-and post-treatment samples to investigate the predictive value of disease recurrence in LD-SCLC. Methods: The blood sample from fifty LD-SCLC who were treated with definitive CCRT were collected before and after the treatment. Target sequencing, AlphaLiquid scan (IMBdx, Korea), composed of 106 target genes, was conducted using cfDNA and peripheral blood mononuclear cells. Based on the recurrence-free survival (RFS) interval of 12 months, patients were categorized into group with persistent response (PeR, n = 29) and non-PeR (n = 21). Fragmentomics analyses were collected using the proportion of cfDNA fragments sized in P1 (100 – 155 bp) and P2 (160 – 180 bp) ranges. Results: Initial analysis was conducted based on the gene of interest. Patients with RB1 mutation (n = 11) detected in follow-up sample demonstrated significant shorter RFS compared to the RB1 wild type (WT) patients (n = 39) (7.9 mon. vs. NR, P = 0.002). Among the patients who were available for our fragmentomics analysis in follow up samples (n = 19), non-PeR (n = 9) group were significantly high in P1 range ( P = 0.003) and low in P2 range ( P = 0.002) compared to PeR group (n = 10). AUCs using the fragment proportion in P1, proportion in P2, and the fragmentation ratio (proportion in P1 / proportion in P2), were 0.889, 0.911, and 0.889, respectively. The survival analysis using fragmentation ratio showed significantly longer RFS in fragmentation ratio low group compared to the high group (7.6 mon. vs. NR, P = 0.002). Integrating RB1 mutation status with fragmentation ratio, patients with both RB1 WT and fragmentation ratio low (n = 9) showed the most favorable outcomes ( P = 0.006). On the contrary, patients with either RB1 mutated or high in fragmentation ratio (n = 10) showed median RFS of rest than 12 months. Conclusions: In this study, we investigated the clinical feasibility of cfDNA detected mutation and size of the fragment in disease recurrence of LD-SCLC using the sample collected before and after definitive CCRT. It is observed that patients with either RB1 mutation or high fragmentation ratio detected from cfDNA after the completion of CCRT are likely to experience early disease recurrence. Our findings suggest that cfDNA could provide supplementary information in predicting early treatment failure and support the clinical decision in selecting high-risk patients who might need intense monitoring and additional consolidative treatment.
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.
Association between lung immune prognostic index, microbiome, and immunotherapy outcomes in non–small cell lung cancer.
Authors: Auclin Edouard , Nolin-Lapalme Alexis , Richard Corentin , Malo Julie , Tonneau Marion , Benlaifaoui Myriam , Ponce Mayra , Messaoudene Meriem , Okuma Yusuke , Hakozaki Taiki , Routy Bertrand
Published: June 2022

9050

Background: Host-related inflammatory biomarkers and gut microbiome are two major prognostic factors for non-small cell lung cancer (NSCLC) patients (pts) treated with immune checkpoint inhibitors (ICI). In this study, we aimed to assess an association between the Lung Immune Prognostic Index (LIPI) and the microbiome composition on ICI outcomes in two independent cohorts of NSCLC pts. Methods: We included 205 patients with advanced NSCLC treated with ICI (monotherapy or in combination with chemotherapy) from two independent cohorts. Metagenomics microbiome profiling was performed on the Canadian discovery cohort of 72 pts while 16S rRNA microbiome sequencing was used in the Japanese validation cohort of 133 pts. The LIPI score was calculated using the dNLR (neutrophils/[leucocytes-neutrophils]) and lactate deshydrogenase (LDH). Pts were classified as Good (G: 0 high factor), Intermediate (I: 1 high factor) and Poor (P: 2 high factors). Median overall survival (OS) was estimated using the Kaplan-Meier method. Microbiome diversity indexes and bacterial relative abundances were compared according to LIPI groups. Results: Among the 72 pts included in the discovery cohort, the median follow-up of 20.6 months (mos). The LIPI was distributed as follows: G (n = 31, 43.1%), I (31, 43.1%), P (10, 13.8%) and baseline characteristics were well balanced between the 3 groups. When segregating pts according to LIPI, the OS was 25.6 mo, 19.8 mo, and 5.7 mo in the G, I (HR: 1.71, 95%CI: 0.80-3.65) and P (HR: 3.97, 95%CI: 1.60-9.82) groups, respectively (p = 0.003). The microbiome alpha diversity was lower in the P group compared with the G group (p = 0.03), and there was a trend towards different microbiome composition in beta diversity (p = 0.055) between both groups. Pts in the G group had a favorable microbiome (enriched in Ruminococcus and Anaerostipes), while pts from the P group had an unfavorable microbiome (enriched in Enterobacteriaceae and Clostridium symbiosum and lavalense). Next, in the validation cohort of 133 pts, LIPI was distributed as follows: G (n = 62, 46.6%), I (51, 38.3%), P (20, 15%). Pts with G LIPI had not reached their median OS compared to pts in the I [15.7 mo HR: 1.60 (0.88-2.94)] and P [8.8 mo groups, HR: 2.02 (0.98-4.19)], p = 0.03. Similar to the discovery cohort, at the genus level, G LIPI group had enrichment of Ruminococcus as well as Anaerostipes compared with pts in the P and I groups with an overrepresentation of Hungatella. Conclusions: Host-related inflammatory biomarkers, represented by the LIPI, seemed to be associated with microbiome and ICI outcomes in pts treated with NSCLC. This observation was validated in an external validation cohort. This link could be in relation to the presence of proinflammatory bacteria in pts with poor LIPI.
A phase II trial of ALK/ROS1 tyrosine kinase inhibitor WX-0593 (iruplinalkib) in ALK-positive and crizotinib-resistant advanced non–small cell lung cancer.
Authors: Shi Yuankai , Chen Jianhua , Zhang Helong , Zhang Zhihong , Zhang Yiping , Wang Zhehai , Zhang Shucai , Zhao Jian , Liu Chunling , Wang Xiuwen , Zhao Yanqiu , Hu Changlu , Yang Lei , Hao Xuezhi , Wang Lin , Si Meimei , Ge Mingjing , Geng Huaize
Published: June 2022

9073

Background: This single-arm, multicenter phase II trial aimed to evaluate the efficacy and safety of second generation ALK/ROS1 TKI WX-0593 (iruplinalkib) in advanced ALK/ ROS1-positive non-small cell lung cancer (NSCLC). We reported the results from the crizotinib-resistant ALK-positive cohort. Methods: Patients aged ≥18 years, with histologically or cytologically confirmed ALK-positive NSCLC, progression on ≥12-week crizotinib treatment, ≥one measurable lesion according to RECIST v1.1, and ECOG PS of 0 to 2 were eligible. Patients received oral WX-0593 180 mg once daily (with a 7-day lead-in period at 60 mg once daily). The primary endpoint was confirmed overall response rate (ORR) by independent review committee (IRC) per RECIST v1.1. Secondary endpoints included confirmed disease control rate (DCR) by IRC, ORR, DCR, duration of response (DoR), progression-free survival (PFS), time to progression (TTP), intracranial ORR (iORR) per RANO-brain metastases criteria by investigator (INV), overall survival (OS), safety, and Cmax,ss. Results: Between August 7, 2019 and October 30, 2020, totally 146 patients were enrolled. The data cutoff date was March 10, 2021. The median follow-up was 9.3 months (IQR 6.3-14.1). 90 (61.6%) patients had brain metastases, of which 41 (46%) had measurable intracranial lesions and 20 (22%) received prior radiotherapy to brain. 56 (38.4%) patients received prior chemotherapy. The IRC-assessed ORR was 67.8% (95% CI 59.6%-75.3%). Efficacy data were detailed in the Table. Additionally, subgroup analyses indicated IRC-assessed ORR were slightly higher in the patients without brain metastases (79% vs 61%) or prior radiotherapy to brain (66% vs 45%). Patients with prior chemotherapy or not had similar results (71% vs 66%). The iORR was 63% (95% CI 47%-78%) in pts with measurable intracranial lesions. OS data were immature. 134 (91.8%) of 146 experienced treatment-related adverse events (TRAEs). The most common TRAEs were AST increased (60 [41.1%]), ALT increased (52 [35.6%]), and blood creatine phosphokinase increased (49 [33.6%]). Dose reduction and discontinuation due to TRAE, and serious TRAEs occurred in 15 (10.3%), three (2.1%), and six (4.1%), respectively. No treatment-related death was reported. Drug concentration reaches steady state at Day 21 (Cmax,ss =255.4 ng/mL). Conclusions: WX-0593 showed promising activity against ALK-positive NSCLC after crizotinib resistance and favorable safety profile, demonstrating WX-0593 could be a new treatment option for this patient population. Clinical trial information: NCT04641754. [Table: see text]
Quality of life (QoL) of OSE2101 in patients with HLA-A2+ non–small cell lung cancer (NSCLC) after failure to immune checkpoint inhibitors (IO): Final data of phase 3 Atalante-1 randomized trial.
Authors: Besse Benjamin , Campelo Rosario Garcia , Cobo-Dols Manuel , Quoix Elisabeth Anne , Madroszyk Anne , Felip Enriqueta , Cappuzzo Federico , Denis Fabrice , Hilgers Werner , Romano Giampiero , Debieuvre Didier , Galetta Domenico , Baldini Editta , Viteri Ramirez Santiago , Phan Minh Duc , Schuette Wolfgang , Zer Alona , Vasseur Berangere , Dziadziuszko Rafal , Giaccone Giuseppe
Published: June 2022

9094

Background: OSE2101 (Tedopi) is an anticancer vaccine increasing overall survival (OS) versus Standard of Care (SoC docetaxel or pemetrexed) in HLA-A2+ NSCLC patients with secondary resistance after sequential Chemo (CT)-IO (ESMO 2021 #47LBA). Here we present the QoL analysis. Methods: EGFR and ALK negative NSCLC patients who failed prior IO, ECOG PS 0-1 were randomized 2:1 to receive either OSE2101 or SoC (docetaxel or pemetrexed). Primary endpoint was OS; secondary endpoints included time to ECOG PS deterioration and QoL by EORTC QLQ-C30/LC13 questionnaires at baseline and before each treatment administration until the end of treatment (EOT). Changes in QLQ-C30/LC13 scores from baseline to EoT were assessed using mixed-effects model for repeated measures (MMRM). Overall treatment effect and associated p value were estimated using MMRM. Results: 95 out of 118 (81%) patients with secondary resistance to IO completed baseline and ≥ one follow-up questionnaire. Median OS was 11.1 mo for OSE2101 vs 7.5 mo for SoC [HR 0.59; p = 0.02]. Median time to ECOG PS deterioration was 9.0 mo for OSE2101 vs 3.3 mo for SoC [HR: 0.43; p = 0.004]. Global Health Status remained stable with OSE2101 whereas it deteriorated from the 1st cycle with SoC (p = 0.045). Most pronounced effects were observed in the physical (ability to perform activities that require physical effort; p = 0.07) and the role (ability to work and carry out daily activities; p = 0.03) functioning scores (refer table below). Patients had less mouth soreness (p = 0.01), dysphagia (p = 0.01), peripheral neuropathy (p = 0.03), alopecia (p < 0.001) and fatigue (p = 0.06) with OSE2101 than with SoC. The change from baseline of dyspnea, coughing, hemoptysis, and pain were not significantly different between the 2 groups. Conclusions: In advanced HLA-A2+ NSCLC patients with secondary resistance to IO after sequential CT-IO, OSE2101 improves OS and maintains QoL vs. SoC, especially global health status, physical and role functioning scores. Patients presented fewer symptoms typically related to adverse effects of chemotherapy as compared to SoC. Clinical trial information: NCT02654587. [Table: see text]