bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of immune-related adverse events and efficacy outcomes in phase II trial of consolidation nivolumab plus ipilimumab or nivolumab alone after chemoradiation in patients with unresectable stage III non–small-cell lung cancer (NSCLC).
Authors: Wei Cynthia , Althouse Sandra K. , Mamdani Hirva , Hanna Nasser H. , Durm Greg Andrew 
Published: June 2023

8565 Background: Immunotherapy has been widely incorporated into the treatment of patients with non-small-cell lung cancer. Many of these patients will experience immune-related adverse events (irAEs) that may lead to early discontinuation of therapy. Previous studies have reported that patients with Stage III and metastatic NSCLC who experienced irAEs receive fewer cycles of immunotherapy without decreased efficacy. Here we report a retrospective analysis of the association between irAEs and efficacy outcomes from the BTCRC LUN 16-081 randomized phase 2 trial of consolidation immunotherapy with nivolumab (N) plus ipilimumab (IPI) vs N alone following concurrent chemoradiotherapy in patients with unresectable Stage IIIA/IIIB NSCLC. Methods: A total of 105 eligible patients were enrolled from 9/2017 to 4/2021. Demographics, disease characteristics, and number of immunotherapy cycles received were reported in patients with and without irAEs in the two arms. Chi-square test was used for comparisons for categorical variables and Wilcoxon test for continuous variables. The Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS). A log-rank test was used to compare groups. Results: In treatment arm A (N alone), any grade irAEs occurred in 64.8% of patients. At a follow up of 48 months, there was no significant difference in number of N cycles started (6 vs 6, p = 0.238), progression free survival (29.4 vs 31.9 mo, p = 0.897), or overall survival (NE vs. 31.9 mo, p = 0.798) in patients with and without irAEs. Patients who discontinued N because of irAEs (n = 8 or 14.8% of patients) received significantly fewer cycles of N (2 vs 6, p = < .0001) and had a shorter PFS (8.2 vs. 31.9 months, p = < .0001) and OS (12.3 months vs. NE, p < .0001). In treatment arm B (IPI+N), any grade irAEs occurred in 84.3% of patients. At follow up of 48 months, there was no significant difference in number of IPI+N started (4 vs. 4, p = 0.260) or overall survival (NE vs. NE, p = 0.576), but there was a significantly longer PFS in those who experienced irAEs (30.9 months vs. 6.8 months, p = 0.0083). Patients who discontinued IPI+N because of irAEs (n = 18 or 35.3% of patients) received significantly fewer cycles of IPI+N (2 vs 4, p = < .0001) without a significant difference in PFS (28.1 vs. 25.3 mo, p = 0.830) or OS (NE vs NE, p = 0.755). Conclusions: The occurrence of irAEs alone in both arms, regardless of number, was not associated with decreased efficacy outcomes in this exploratory analysis. However, if irAEs resulted in the discontinuation of therapy, these patients did have a shorter PFS and OS in the N alone arm. This difference was not observed in the IPI+N arm and those who experienced any irAEs in the IPI+N arm had an improved PFS.
Optimal number of lymph node stations associated with improved survival among patients with non-small cell lung cancer (NSCLC).
Authors: Ray Meredith , Matthews Anberitha T , Akinbobola Olawale , Smeltzer Matthew , Fehnel Carrie , Faris Nicholas R , Saulsberry Andrea , Dortch Kourtney , Muhit Samuel , Osarogiagbon Raymond U. 
Published: June 2023

8571 Background: Good quality pathologic nodal evaluation is associated with improved long-term survival in NSCLC after surgical resection. However, there is no universal definition of quality. We examined the association between number of lymph node stations (NLNS) sampled and overall survival. Methods: We examined the population-based Mid-South Quality of Surgical Resection (MS-QSR) cohort, excluding patients with neoadjuvant therapy, positive margins, and secondary resections. We summarized demographic and clinical characteristics with appropriate statistics. We employed four Cox regression models: 1) including NLNS as the only predictor; 2) model 1, adjusting for age, sex, histology, clinical stage, extent of resection, and surgical technique; 3) examined the impact of pathologic staging (pStage in 3 groups: IA/IB[<4cm tumor size]; IB[>4cm]/II/IIIA[pN2-]; pN2]) by modeling interaction with pStage and NLNS; 4) model 3 plus adjustments (no clinical stage). In a cut point analysis to identify the optimal NLNS for improved survival, we dichotomized the NLNS for cut points 0 to 12. Hazard ratios (HR) were calculated (as above) and plotted for each dichotomization. Results: The 3916 eligible patients were 21% Black, 54% male, 15% on Medicaid and 49% Medicare; 84% and 85% had clinical and pathologic stage I/II, respectively; 84% had no invasive staging; 84% had a PET-CT scan. For every additional lymph node station sampled, the HR decreased by 0.94 (95% confidence interval: 0.92, 0.96). After adjustments, the HR remained significant (Table). Our pStage cohorts comprised of 2474 (64%) IA/IB[<4cm]; 1080 (28%) IB[>4cm]/II/IIIA[pN2-]; and 290 (8%) pN2+. Once stratified, HRs remained significant among those with early stage but not for pN2+ (Table). When further adjusted, only pStage IA/IB[<4cm] patients had a significant HR, 0.94 (0.91, 0.97). The cut point analysis indicated sequential survival improvement up to ≥ 7 total stations sampled, consistently across all models/adjustments. Conclusions: The number of lymph node stations examined is directly associated with survival after lung cancer resection. Examination of a total of 7 intrapulmonary, hilar and mediastinal stations seems optimal. Hazard ratios (95% confidence intervals) for modeling hazards as a function of lymph node stations sampled (model 1), further adjusted for age, sex, histology, clinical stage, extent of resection, and surgical technique (model 2), including interaction with pathologic stage with no adjustments (model 3), and interaction with pathological stage with adjustments (no clinical stage) (model 4). [Table: see text]
Analysis of tumor- and circulating-free DNA methylation to identify clinically relevant small cell lung cancer subtypes.
Authors: Heeke Simon , Gay Carl Michael , Estecio Marcos Roberto , Tran Hai T. , Morris Benjamin B. , Zhang Bingnan , Tang XiMing , Raso Maria G , Rocha Pedro , Arriola Edurne , Hofman Paul , Kopparapu Prasad , Lovly Christine M. , Concannon Kyle , Xi Yuanxin , Diao Lixia , Wang Qi , Wang Jing , Byers Lauren Averett , Heymach John 
Published: June 2023

8577 Background: Small-cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, defined by the predominant expression of one of the three transcription factors ASCL1 (SCLC-A), NEUROD1 (SCLC-N) and POU2F3 (SCLC-P) as well as an inflamed subtype (SCLC-I; see Gay et al. Cancer Cell. 2021), each with potential therapeutic vulnerabilities. Implementing subtyping in the clinic has remained challenging due to limited tissue availability, particularly for longitudinal monitoring. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that there would be subtype-specific patterns of DNA methylation that could be detected in tumor or blood from SCLC patients. Methods: We included 179 patients with SCLC and performed RNA sequencing and genomic-wide reduced-representation bisulfite sequencing (RRBS). We further analyzed DNA methylation in 68 plasma samples including longitudinal samples to track SCLC subtype evolution over time. Results: Using machine learning approaches, we developed a highly accurate DNA methylation-based classifier (SCLC-DMC) that could distinguish SCLC subtypes using clinical tumor samples with 95.8% accuracy in the testing set compared to mRNA-based profiling. We further adjusted the classifier for circulating-free DNA (cfDNA) to subtype SCLC from plasma. Using the cfDNA classifier (cfDMC), we could demonstrate that SCLC subtypes evolve frequently during disease progression, highlighting the need for longitudinal tracking of SCLC during clinical treatment. Furthermore, methylation-based subtyping predicted response to a wide variety of drugs in preclinical models like CDK and AURK inhibitors, and clinical outcomes were indistinguishable in cohorts of patients subtyped using mRNA or SCLC-DMC (p = 0.95). Conclusions: These data establish that tumor and cfDNA methylation can be used to identify SCLC subtypes and guide precision SCLC therapy.
Updated safety and efficacy results of SHR-1316 combined with chemotherapy and sequential chest radiotherapy as first-line therapy for extensive-stage small cell lung cancer (ES-SCLC) from a phase II trial.
Authors: Chen Dawei , Gao Aiqin , Huang Wei , Shao Qian , Meng Xiangjiao , Tang Xiaoyong , Zhang Pinliang , Hu Xudong , Zhang Yan , Guo Jun , Fu Lei , Zhao Wei , Zhao Changhong , Yuan Jiajia , Yu Jinming , Wang Linlin 
Published: June 2023

8580 Background: CAPSTONE-1 study showed that SHR-1316 (PD-L1 antibody) combined with first-line chemotherapy could prolong overall survival in patients (pts) with ES-SCLC. Previous studies have shown that radiotherapy could potentially promote tumor antigen presentation and reverse immunosuppressive microenvironment in tumor. The purpose of this study was to explore the efficacy and safety of SHR-1316 combined with chemotherapy and sequential chest radiotherapy as first-line therapy for ES-SCLC. Methods: Key inclusion factors were 18-75 years old, histologically or cytologically confirmed ES-SCLC, ECOG performance status 0-1, no previous systematic treatment. Pts included in this study received 4~6 cycles of SHR-1316 (20mg/kg, D1, q3w) combined with EP/EC (cisplatin, 75mg/m², D1-3, q3w or carboplatin, AUC = 5, D1, q3w and etoposide, 100mg/m2, D1-5, q3w), sequentially SHR-1316 combined with chest radiotherapy (≥3Gy*10f or ≥2Gy*25f, involved-field irradiation), and then entered the maintenance treatment stage until disease progression or intolerable side effects. The main endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety. Results: From October 2020 to January 2023, 63 pts with ES-SCLC were enrolled and received at least one dose of SHR-1316, 33 of them have received chest radiotherapy. The median age was 63 (range: 38-75), and most pts were male (53, 84.1%), former smokers (42, 66.7%) with an ECOG performance status 1 (60, 95.2%). At baseline, 24 (38.1%) pts were diagnosed with brain metastasis and 19 (30.2%) pts had liver metastasis. At the data cutoff date, the average number of treatment cycles was 6.9, 17 pts remained on treatment. 55 pts had at least one post-treatment tumor assessment. 41 pts achieved a confirmed partial response, and 12 pts had stable disease. The confirmed ORR and DCR were 74.5% and 96.4%, respectively. The median PFS was 7(CI: 4.3~9.7) months. Adverse events (AEs) occurred in 47 (74.6%) pts. Grade 3 or 4 AEs occurred in 35 (55.6%) pts. The most common grade 3 or 4 AEs included neutropenia (27, 42.9%), leukopenia (13, 20.6%), lymphocytopenia (5, 7.9%), pneumonia (4, 6.3%), anemia (3, 4.8%), and thrombocytopenia (2, 3.2%). Conclusions: SHR-1316 combined with chemotherapy and sequential chest radiotherapy as first-line therapy for ES-SCLC showed promising efficacy and acceptable safety. It is worthy of further clinical exploration. Clinical trial information: NCT04562337 .
Efficacy and safety of lurbinectedin in elderly patients with relapsed SCLC.
Authors: Cousin Sophie , Paz-Ares Luis G. , Fülöp Andrea , Horvath Ildiko , Trigo Perez Jose Manuel Manuel , Zugazagoitia Jon , Bonanno Laura , Lopez-Vilariño Jose Antonio , Kahatt Carmen Maria , Fernandez Cristian Marcelo , Gomez Javier , Zeaiter Ali Hassan , Navarro Alejandro , Syrigos Kostas N. , Smit Egbert , Ciuleanu Tudor-Eliade , Chiappori Alberto , Lopez-Lopez Rafael , Besse Benjamin 
Published: June 2023

8591 Background: Relapsed SCLC is a difficult-to-treat disease. A considerable number of SCLC patients are elderly with associated fragility and numerous comorbidities. Accelerated approval from the US FDA of lurbinectedin (Zepzelca) 3.2 mg/m2 q3wk as second-line therapy in metastatic small cell lung cancer (SCLC) was based on results from a phase 2 basket trial (NCT02454972) showing overall response rate of 35.2% and duration of response of 5.3 months. The ATLANTIS trial (NCT02566993) assessed the combination of lurbinectedin 2mg/m2/ doxorubicin (DOX) 40 mg/m2 as second-line treatment for SCLC vs. a control arm of topotecan/CAV. Methods: This post hoc analysis explores the efficacy and safety of lurbinectedin in relapsed SCLC patients ≥65 years included in both phase 2 basket (26 patients treated with lurbinectedin) and ATLANTIS (121 patients treated with lurbinectedin/DOX and 118 patients treated in the control arm) trials. This analysis did not include patients from the phase 2 basket trial with chemotherapy-free interval (CTFI) < 30 days, as these patients were excluded in the ATLANTIS trial. Results: Median age was similar (72.5 in lurbinectedin basket vs. 69 in ATLANTIS lurbinectedin/DOX vs. 69 in ATLANTIS control arm), most were males (65.4% vs. 57.9% vs. 60.2%), with ECOG PS 1 (65.4% vs. 68.6% vs. 68.6%) and CNS involvement (7.7% vs. 10.7% vs. 15.3%). Median CTFI (days) was also similar (105.5 vs. 123 vs. 120). Median number of cycles was 4 vs. 6 vs. 4. Main efficacy and safety results are shown in the table. Treatment-related adverse events (AEs) were reported in 92.3%, 92.6% and 94.1% of patients, respectively (grade ≥3 in 50.0%, 59.5% and 81.4%). Conclusions: In elderly patients, lurbinectedin seems to be superior to the standard of care in terms of both efficacy (higher response rate and longer duration of response and overall survival) and safety (less associated hematological AEs), which reinforces its role as a treatment option in relapsed SCLC patients ≥65 years. Clinical trial information: NCT02454972 , NCT02566993 . [Table: see text]
Randomized phase 3 study of first-line AZD3759 (zorifertinib) versus gefitinib or erlotinib in EGFR-mutant (EGFRm+) non–small-cell lung cancer (NSCLC) with central nervous system (CNS) metastasis.
Authors: Wu Yi-Long , Zhou Qing , Wang Jie , Yu Yan , Xing Ligang , Wang Ying , Cheng Ying , Pan Yueyin , Fan Yun , Shi Jianhua , Zhang Guojun , Cui Jiuwei , Zhou Jianying , Song Yong , Zhuang Wu , Ma Zhiyong , Hu Yanping , Li Gaofeng , Dong Xiaorong , Ahn Myung-Ju 
Published: June 2023

9001 Background: Patients (pts) with EGFRm+ NSCLC have high rates of CNS metastasis, few treatment options, and a poor prognosis. So far there are no solid evidence from head to head phase 3 trials in this setting. The potent EGFR TKI AZD3759 has high blood–brain barrier penetration, preliminary data has shown promising intracranial (IC) and systemic antitumor activity, and a tolerable safety profile. Methods: This was the first phase 3, open-label, multicenter, randomized controlled trial to compare the efficacy and safety of first-line AZD3759 with first generation EGFR TKIs specifically in pts with EGFRm+ (L858R and/or exon 19Del) NSCLC and CNS metastasis. Adult pts were randomized 1:1 to receive AZD3759 (200 mg twice daily) or first generation EGFR TKIs (the control group, gefitinib 250 mg or erlotinib 150 mg once daily). The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1. Results: Between Feb 1, 2019, and Jan 12, 2021, 439 pts were randomized: 220 to AZD3759 and 219 to the control group. As of July 12, 2022, median follow-up was 20.4 months (mo) for both. Median PFS (95% CI) was significantly superior with AZD3759 vs the control group (9.6 [8.2–9.7] vs 6.9 [6.3–8.0] mo; HR 0.719, 95% CI 0.580–0.893; p=0.0024). The objective response rate (ORR; BICR/RECIST 1.1) was 68.6% for AZD3759 vs 58.4% for the control group ( p=0.027), with a trend toward longer median duration of response (DoR) with AZD3759 (8.2 vs 6.8 mo; p=0.0997). IC PFS, ORR, and DoR with AZD3759 were all superior vs the control group regardless of the assessor or evaluation criteria. The overall survival was immature. The incidence of any-grade treatment-related adverse events (TRAEs) was similar between the two groups (97.7% vs 94.0%). Grade ≥3 TRAEs occurred in 65.9% (AZD3759) and 18.3% (the control group) of pts. The main TRAEs were skin and subcutaneous tissue events, gastrointestinal system events and abnormal liver function. No new safety signals arose. Conclusions: First-line AZD3759 demonstrated superior systemic and IC antitumor efficacy compared with first generation EGFR TKIs in pts with EGFRm+ NSCLC and CNS metastasis. Adverse events were as expected and manageable. IC antitumor activity. Clinical trial information: NCT03653546 . [Table: see text]
Final overall survival and biomarker analyses of CHOICE-01: A double-blind randomized phase 3 study of toripalimab versus placebo in combination chemotherapy for advanced NSCLC without EGFR/ALK mutations.
Authors: Wang Jie , Wang Zhijie , Wu Lin , Li Baolan , Cheng Ying , Li Xiaoling , Wang Xicheng , Han Liang , Wu Xiaohong , Fan Yun , Yu Yan , Lv Dongqing , Shi Jianhua , Huang Jianjin , Zhou Shaozhang , Han Baohui , Sun Guogui , Guo Qisen , Ji Youxin , Zhu Xiaoli ,   Shanghai Junshi Biosciences
Published: June 2023

9003 Background: Toripalimab in combination with chemotherapy showed significant improvement over chemotherapy alone in progression-free survival (PFS) and overall survival (OS) as first-line treatment of advanced NSCLC at the final PFS analysis of the CHOICE-01 study (NCT03856411). Here we report the final OS analysis. Methods: Patients (n=465) with treatment-naïve, advanced NSCLC without EGFR/ALK mutations were randomized 2:1 to receive toripalimab 240 mg (n=309) or placebo (n=156) in combination with chemotherapy for 4-6 cycles, followed by maintenance toripalimab or placebo plus standard care until disease progression, intolerable toxicity, or completion of 2 years of treatment. Patients from the placebo arm were actively crossed-over to receive toripalimab upon disease progression. The primary endpoint was PFS. The secondary endpoints included OS and safety. Results: By the cutoff date of August 31, 2022, when 283 events triggered the final OS analysis, the median survival follow up was 19.4 months. A significant improvement in OS was observed for the toripalimab arm over the placebo arm: HR=0.73 (95% CI: 0.57-0.93), two-sided p=0.0108, median OS 23.8 vs 17.0 months. A consistent effect on OS, favoring the toripalimab arm, was observed all PD-L1 expression subgroups. The OS benefit is greater in non-squamous NSCLC, HR=0.50 (95% CI: 0.36-0.70), median OS 27.8 vs 15.9 months, whereas no significant difference was found in the squamous subgroup (mOS 19.6 vs 18.1 months) despite a significant PFS improvement. The squamous subgroup had a high 70% crossover rate. No new safety signal was identified since the interim report. The incidence of Grade ≥3 adverse events (AEs) (78.9% vs 82.1%) was similar between the two arms. AEs leading to discontinuation of toripalimab/placebo (14.3% vs 3.2%), fatal AEs (5.5% vs 2.6%), and immune-related (irAEs) (50.6% vs. 21.2%) were more frequent in the toripalimab arm. Whole exome sequencing results indicated patients with mutations in the FAK-PI3K-Akt pathway achieved significantly better OS from the toripalimab arm. Conclusions: The addition of toripalimab to chemotherapy in patients with advanced NSCLC provided significant OS benefit than chemotherapy alone with a manageable safety profile. These results support the use of toripalimab with chemotherapy as 1st line therapy for advanced NSCLC patients without EGFR/ALK mutations. Clinical trial information: NCT03856411 .
The primary endpoint analysis of SCARLET study: A single-arm, phase II study of sotorasib plus carboplatin-pemetrexed in patients with advanced non-squamous, non-small cell lung cancer with KRAS G12C mutation (WJOG14821L).
Authors: Sakata Shinya , Akamatsu Hiroaki , Azuma Koichi , Uemura Takehiro , Tsuchiya-Kawano Yuko , Yoshioka Hiroshige , Osuga Mitsuo , Koh Yasuhiro , Morita Satoshi , Yamamoto Nobuyuki 
Published: June 2023

9006 Background: Efficacy and safety of sotorasib in combination with platinum-doublet chemotherapy in KRAS G12C-mutated non-squamous, non-small cell lung cancer (non-Sq, NSCLC) has not been investigated. Methods: In this single-arm, phase 2 study, chemotherapy-naïve, advanced non-Sq, NSCLC patients with KRAS G12C mutation were enrolled. Participants were treated with sotorasib 960mg, QD plus carboplatin (AUC 5)/pemetrexed 500mg/m2 for four cycles, followed by sotorasib plus pemetrexed until disease progression. The primary endpoint was overall response rate (ORR) by independent review. The secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Using plasma samples, next-generation sequencing analysis was done at baseline, 3 weeks and disease progression. Regarding statistical consideration, the threshold and the expected ORR were set as 40% and 65%, respectively with one-sided α = 0.1, and β = 0.1, the required sample size was 28 cases (Simon’s two-stage design). A total of 30 cases was planned to take into account the possibility of a few dropped or ineligible cases. This study was funded by AMGEN Inc. and Trial identification no. is jRCT2051210086. Results: Between Oct 2021 and Jul 2022, 30 patients were enrolled. Twenty-nine and 27 were analyzed for safety and efficacy, respectively. Of those, median age was 70, male/female: 25/5, never-/smoker: 1/29, ECOG performance status: 0/1 11/19 and PD-L1 expression level: ≥50%/1-49%/<1% 15/10/5. The primary endpoint, ORR by independent review was 88.9% (80%CI 78.5-94.8%). Median PFS was not reached mainly due to shorter follow-up period (median 4.2 months) and PFS rate at 6 months was 61.2%. OS rate at 6 months was 87.0%. Subgroup analysis revealed that ORR did not differ by PD-L1 expression level (≥50%/1-49%/<1%: 76.9%/77.8%/80.0%, respectively). Common adverse events were anemia, neutrophil count decreased, nausea and platelet count decreased. Grade≥3 AEs were mostly hematological toxicities, but one treatment-related death (pneumonia) occurred. At baseline, 70% of plasma samples were positive for KRAS G12C and most common co-occurring mutation was TP53 (50%). At 3 weeks, plasma KRAS G12C disappeared among 60% of patients. Conclusions: Sotorasib in combination with CBDCA/PEM demonstrated favorable ORR and tolerability in advanced non-Sq, NSCLC patients with KRAS G12C mutation. Clinical trial information: jRCT2051210086 .