bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of durvalumab plus olaparib as maintenance therapy in extensive-stage small-cell lung cancer (TRIDENT): Preliminary efficacy and safety results.
Authors: Huang Yan , Jia Jun , Wang Qiming , Liu Xianling , Zhang Li 
Published: June 2023

8518 Background: First-line durvalumab in extensive-stage small-cell lung cancer (ES-SCLC) demonstrated significant improvement of OS in phase Ⅲ CASPIAN trial. PARP inhibitors have the potential to confer antitumor activity, modify tumor immunogenicity, and sensitize tumors to anti-PD-1/PD-L1 therapy. Durvalumab in combination with Olaparib (a PARPi) had clinical activity in relapsed SCLC in a phase Ⅰ/Ⅱ study. This phase Ⅱ study aimed to assess the efficacy and safety of durvalumab plus olaparib as maintenance therapy in patients with ES-SCLC. Methods: TRIDENT is a single arm, multicenter, phase Ⅱ study. Treatment-naive ES-SCLC aged ≥18 with ECOG PS 0-2 were eligible. Durvalumab (1500 mg) was concurrently administered with platinum–etoposide every 3 weeks for 4 cycles, followed by durvalumab 1500 mg every 4 weeks plus olaparib 300 mg twice daily until disease progression or unacceptable toxicity. The primary endpoint was the rate of progression free survival (PFS) at 12 months, the secondary endpoints included progression free survival, objective response rate (ORR) according to RECIST 1.1, duration of response (DoR), overall survival (OS) and safety profile. All patients should provide tumor sample for biomarker analysis (exploratory endpoint). Results: Between August 2021 and August 2022, 60 eligible patients were enrolled from 4 sites in China. At data cut-off (Jan 16th, 2023), 18 (30%) patients were still on treatment. The median age was 63 years (range 57-68). The median cycle of durvalumab was 7 (range 1-17), and durvalumab plus olaparib as maintenance therapy was 3.5 (range 1-13). The PFS rate at 6-, 9-, 12-month were 49.7% [95%CI 37.8%-65.4%], 26.3% [95%CI 13.8%-40.3%] and 18% [95%CI 9.3%-34.7%], respectively. ORR was 75% (45/60), the median DoR was 5.0 months [95%CI 3.8-6.5]. With a median follow-up of 10.5 months, the median PFS was 5.8 months [95%CI 4.9-7.7] as calculated from the first cycle of durvalumab plus chemotherapy. The median OS was not reached [95%CI 10-NA]. Of all, treatment emergent adverse event (AE) occurred in 93.3% (56/60) patients, and AEs ≥ grade 3 occurred in 36.7% (22/60) patients. There were no unexpected adverse events identified in this study. There were 5 patients (8.3%) discontinued treatment and 1 death (1.6%) due to AE. Biomarker analysis is still on-going and will be presented in the meeting. Conclusions: TRIDENT is the first study to evaluate the efficacy and safety of durvalumab plus olaparib as maintenance therapy in Chinese ES-SCLC patients to date. The preliminary result warrant further investigation of this treatment modality in ES-SCLC. Clinical trial information: NCT05245994 .
Pembrolizumab vs placebo for early-stage non‒small-cell lung cancer after resection and adjuvant therapy: Subgroup analysis of patients who received adjuvant chemotherapy in the phase 3 PEARLS/KEYNOTE-091 study.
Authors: Oselin Kersti , Shim Byoung Yong , Okada Morihito , Bryl Maciej , Bonanno Laura , Demirag Guzin , Colantonio Ida , Kimmich Martin , Janzic Urska , Vansteenkiste Johan F. , Bernabe Caro Reyes , Scherz Amina , Curioni-Fontecedro Alessandra , Früh Martin , Wollner Mira , Yang Jing , Shariati Nazly , Marreaud Sandrine , Peters Solange , O'Brien Mary ER 
Published: June 2023

8520 Background: In the randomized, triple-blind, phase 3 PEARLS/KEYNOTE-091 study (NCT02504372), at the second interim analysis, pembrolizumab (pembro) significantly prolonged DFS vs placebo (pbo) in the overall population of patients (pts) with completely resected stage IB–IIIA NSCLC per AJCC v7 who may or may not have received adjuvant chemotherapy (chemo; up to 4 cycles) as recommended per local guidelines (n = 1177; HR, 0.76 [95% CI, 0.63–0.91]; P = 0.0014). Here we present outcomes for those pts who received 1–4 cycles of prior adjuvant chemo, per protocol. Methods: Eligible adults had pathologically confirmed, completely resected stage IB (T ≥4 cm), II, or IIIA NSCLC (AJCC v7) of any PD-L1 expression, ECOG performance status of 0 or 1, and had not received neoadjuvant radiotherapy or chemo. Pts were randomized 1:1 to pembro 200 mg or pbo Q3W for 18 doses (~1 year); receipt of adjuvant chemo (yes vs no) was one of the stratification factors. Dual primary endpoints were DFS in the ITT and PD-L1 TPS ≥50% populations. No alpha was assigned to this subgroup analysis of pts who received adjuvant chemo for 1–4 cycles per local guidelines. Results: Of 1177 pts in the ITT population, 1010 (85.8%) received adjuvant chemo and were included in this analysis (pembro, n = 506; pbo, n = 504). Pts received a median of 17 and 18 study doses, respectively. As of data cutoff (Sep 20, 2021), 52.6% in the pembro arm vs 64.9% in the pbo arm had completed treatment. Median time from randomization to data cutoff was 37.4 mo. Median (95% CI) DFS was 58.7 mo (39.2 mo–not reached [NR]) in the pembro arm vs 34.9 mo (28.6 mo–NR) in the pbo arm (HR, 0.73 [95% CI, 0.60–0.89]). Estimated 18-mo DFS rates were 73.8% and 63.1%, respectively. In pts with PD-L1 TPS ≥50% (pembro, n = 143; pbo, n = 141), median DFS was NR in both treatment arms (HR, 0.80 [95% CI, 0.54–1.20]). Grade 3–5 adverse events (AEs) occurred in 170 pts (34.3%) in the pembro arm and 128 (25.7%) in the pbo arm (grade 5, 2.2% vs 1.0%). Immune-mediated AEs and infusion reactions occurred in 195 pts (39.3%) in the pembro arm and 69 (13.8%) in the pbo arm. Conclusions: Consistent with the ITT population, pembro substantially improved DFS vs pbo in the subgroup of pts with stage IB (T2a ≥4 cm), II, or IIIA NSCLC who received adjuvant platinum-based chemo following complete resection. Based on these results, pembro was approved for adjuvant treatment in this pt population by the US FDA. Clinical trial information: NCT02504372 .
Clinical outcomes with neoadjuvant nivolumab (N) + chemotherapy (C) vs C by definitive surgery in patients (pts) with resectable NSCLC: 3-y results from the phase 3 CheckMate 816 trial.
Authors: Spicer Jonathan , Forde Patrick M. , Provencio Mariano , Lu Shun , Wang Changli , Mitsudomi Tetsuya , Broderick Stephen , Swanson Scott , Awad Mark M. , Felip Enriqueta , Brahmer Julie R. , Kerr Keith , Saylors Gene Brian , Chen Ke-Neng , Tanaka Fumihiro , Cai Junliang , Mahmood Javed , Hu Nan , Tran Phuong , Girard Nicolas 
Published: June 2023

8521 Background: In CheckMate 816, neoadjuvant N + C demonstrated statistically significant and clinically meaningful improvements in event-free survival (EFS) and pathologic complete response (pCR) vs C in pts with resectable NSCLC. Here, we report clinical outcomes in pts with or without definitive surgery following neoadjuvant treatment (tx). Methods: Adults with stage IB (tumors ≥ 4 cm) to IIIA (per AJCC 7th ed) resectable NSCLC, ECOG PS ≤ 1, and no known EGFR/ ALK mutations were randomized 1:1 to 3 cycles of N 360 mg + C Q3W or C Q3W, followed by definitive surgery within 6 wk of tx. Primary endpoints were EFS and pCR, both per blinded independent review. Exploratory analyses included EFS (secondary definition; no censoring for subsequent tx), time to death or distant metastasis (TTDM), and EFS2 (EFS on next-line tx) in pts with or without surgery. Results: Among 358 randomized pts, 149 (83%; N + C) and 135 (75%; C) had definitive surgery. Baseline characteristics were similar in pts with or without surgery (N + C, 30; C, 44) and between tx arms, except that a higher proportion of pts who did not have surgery had ECOG PS 1 (both arms) or were from Europe (N + C arm). Surgery was canceled due to progressive disease (PD) in 11 (N + C) and 17 (C) pts; PD was locoregional in 4 and 15 pts and distant in 3 and 2 pts, while 4 pts in the N + C arm had both locoregional and distant PD. At database lock (October 14, 2022; median f/u: 41.4 mo), EFS, TTDM, and EFS2 were numerically improved in pts with vs without surgery, regardless of tx arm. In pts with surgery, median TTDM was not reached (NR) vs 46.8 mo (HR, 0.55) with N + C vs C, respectively; 3-y TTDM rates were 77% vs 59%. In pts without surgery, median TTDM was 24.8 vs 15.6 mo (HR, 0.63) with N + C vs C; 3-y rates were 36% vs 13%. Among pts without surgery, 17 (57%) vs 28 (64%) pts in the N + C vs C arms, respectively, received subsequent tx: radiotherapy 37% vs 41%; surgery 3% vs 2%; systemic tx 50% vs 52%. Grade 3/4 tx-related AEs occurred in 38% (N + C) and 36% (C) in pts with surgery, and 26% and 46% in pts without surgery. Conclusions: In CheckMate 816, neoadjuvant N + C demonstrated long-term clinical benefit vs C in pts with resectable NSCLC who received definitive surgery. In pts who did not receive definitive surgery, these exploratory analyses showed that neoadjuvant N + C was associated with numerically improved TTDM. Clinical trial information: NCT02998528 . [Table: see text]
IMpower010: Exploratory analysis of disease-free survival by KRAS status in patients with stage II-IIIA NSCLC treated with adjuvant atezolizumab vs best supportive care.
Authors: Reck Martin , Srivastava Minu K , Wakelee Heather A. , Felip Enriqueta , Altorki Nasser K. , Csoszi Tibor , Moiseyenko Vladimir , Akopov Andrey , Smolin Alexey , Chella Antonio , Vallieres Eric , Martinez-Marti Alex , Zou Wei , McNally V. , Bennett Elizabeth , Prizant Hen , Nabet Barzin , Ballinger Marcus , Gitlitz Barbara J. , Zhou Caicun 
Published: June 2023

8522 Background: The Phase III IMpower010 trial (NCT02486718) met its primary disease-free survival (DFS) endpoint leading to approval of atezolizumab after adjuvant platinum-based chemotherapy for completely resected PD-L1 TC ≥1% or ≥50% stage II-IIIA NSCLC in the US, EU and other regions. Mutant KRAS (mKRAS) is the most prevalent oncogenic driver in metastatic NSCLC (27% mKRAS [KRAS G12C,11%]; Osta et al, J Thorac Oncol 2019). Here, we report exploratory DFS outcomes by KRAS mutational status in patients from IMpower010. Methods: The study design and primary results of IMpower010 have been reported (Felip et al, Lancet 2021). After complete resection, patients received cisplatin-based doublet chemotherapy (1-4 21-day cycles) and were subsequently randomized to receive atezolizumab 1200 mg q3w (16 cycles) or best supportive care (BSC). This post hoc analysis evaluated DFS in subgroups of patients by KRAS mutational status. KRAS mutational status was assessed retrospectively using whole-exome sequencing (WES) on resected tumor tissue. Analyses were conducted in patients whose tumors harbored any mKRAS type, including G12C. A separate analysis of the KRAS G12C subgroup was not conducted due to limited patient numbers. Results: Of the 1005 patients in the intention-to-treat population (all randomized patients with stage IB-IIIA NSCLC), 603 comprised the WES biomarker-evaluable population (WES-BEP), and of these, 536 had stage II-IIIA NSCLC. Within the stage II-IIIA WES-BEP, the prevalence of mKRAS and KRAS G12C was 22% (n=118) and 10% (n=52), respectively. mKRAS was enriched in White, non-squamous and smoker populations. Atezolizumab showed DFS improvement vs BSC regardless of KRAS status in the stage II-IIIA WES-BEP (Table). In the mKRAS stage II-IIIA WES-BEP, atezolizumab showed DFS improvement vs BSC regardless of PD-L1 status. Conclusions: In IMpower010, the prevalence of mKRAS and KRAS G12C was similar to that seen in metastatic NSCLC. Despite limited patient numbers in this exploratory analysis, DFS appeared to be consistent and in favor of atezolizumab across subgroups regardless of KRAS status. Clinical trial information: NCT02486718 . [Table: see text]
Predictive value of co-existing genetic alterations and tumor mutation burden for patients with completely resected non-small cell lung cancer harboring EGFR mutation: Biomarker analysis of phase III IMPACT study.
Authors: Ikeda Satoshi , Tsuboi Masahiro , Sakai Kazuko , Misumi Toshihiro , Akamatsu Hiroaki , Iwamoto Yasuo , Sakakura Noriaki , Nakamura Atsushi , Ohde Yasuhisa , Hayashi Hidetoshi , Okishio Kyoichi , Okada Morihito , Yoshino Ichiro , Okami Jiro , Takahashi Kazuhisa , Ikeda Norihiko , Mitsudomi Tetsuya , Tada Hirohito , Nakagawa Kazuhiko , Nishio Kazuto 
Published: June 2023

8524 Background: Although osimertinib has recently become an option for adjuvant therapy in many countries, biomarkers predicting the efficacy of adjuvant EGFR-TKI and the risk of postoperative recurrence in completely resected NSCLC harboring EGFR mutations have not been fully investigated. Methods: This IMPACT-TR study is an exploratory biomarker study for completely resected, EGFR-mutated NSCLC patients who received gefitinib or cisplatin plus vinorelbine (cis/vin) in a phase III IMPACT study (Trial registration number: UMIN000044738. Funding: AstraZeneca K.K.). Surgically resected lung cancer tissue specimens were analyzed for co-existing somatic mutations and tumor mutation burden (TMB) determined by Oncomine Tumor Mutation Load, and these data were matched with disease free survival (DFS) and overall survival (OS) data. Results: Of the 234 patients in the IMPACT study, 211 patients were enrolled, and 202 patients in the Per Protocol Set were analyzed. The most frequent co-existing somatic mutation was TP53 (58.4%), followed by CSMD3 (11.8%), NOTCH1 (9.9%) and SYNE1 (9.9%). The median TMB was 6.67 mutations/Mb, and only 15.2% had ≥10 mutations/Mb. EGFR mutation subtypes, TP53 co-mutation and TMB were not associated with DFS or OS in either the gefitinib or cis/vin groups. In the gefitinib group, patients with NOTCH1 mutation had significantly shorter OS (hazard ratio [HR] 4.18, 95%CI 1.65-10.61, p=0.003) and tended to have shorter DFS (HR 1.44, 95%CI 0.62-3.37, p=0.399) than those without NOTCH1 mutation. In the cis/vin group, patients with CREBBP mutation had significantly shorter DFS (HR 2.70, 95%CI 1.05-6.97, p=0.040) and tended to have shorter OS (HR 3.05, 95%CI 0.90-10.37, p=0.074) than those without CREBBP mutation. Conclusions: This study suggested that NOTCH1 mutation may be a biomarker to predict poor response to adjuvant gefitinib and CREBBP mutation to predict poor response to cis/vin in patients with completely resected, EGFR-mutated NSCLC. Clinical trial information: UMIN000044738 .
Dynamic ctDNA to inform the precise management of resected NSCLC: LUNGCA-2 study.
Authors: Xia Liang , Pu Qiang , Kang Ran , Mei Jiandong , Li Lu , Yang Ying , Deng Senyi , Feng Gang , Ma Lin , Lin Feng , Liao Hu , Liu Chengwu , Zhu Yunke , Li Qingyun , Zhang Xiaolong , Liu Lunxu 
Published: June 2023

8528 Background: Circulating tumor DNA (ctDNA) has been reported to be valuable for minimal residual disease (MRD) detection, but there is a lack of studies comprehensively assessing whether dynamic ctDNA monitoring can inform whole-course precise postoperative cancer management. In the present study (LUNGCA-2), we analyzed data obtained from longitudinal ctDNA monitoring of stage I-III NSCLC patients in the LUNGCA cohort, and sought to assess the use of dynamic ctDNA monitoring for precise whole-course postoperative management of NSCLC patients. Methods: All eligible NSCLC patients underwent curative-intent surgery and subsequently received adjuvant therapies when indicated by clinical practice guidelines for NSCLC. The clinical follow-up was scheduled to be every 3-6 months mainly involving CT and/or MRI. Fresh frozen or paraffin-embedded tissues of primary tumors were collected intraoperatively for baseline somatic mutation profiling. Blood samples were collected before surgery, at 3 days and 1 month after surgery, and then every 3-6 months at clinical visits up to 3 years postoperatively. 233 patients with a total of 2123 plasma samples were ultimately included in the longitudinal ctDNA analysis in the current study. NGS assays were performed with a custom-designed panel that covered 769 cancer-related genes via the MinerVA platform (Genecast Biotechnology Co., Ltd). Results: Among the cohort, 166 patients harboring targetable mutations in the primary tumor tissue, 15 were preadjuvant ctDNA positive, and among them, only 25% patients treated with adjuvant TKI therapy experienced relapse during follow-up, and patients received ACT or no adjuvant therapy had a relapse rate of 100%. TKI treatment tended to improve RFS compared with no treatment (HR 0.1, P = 0.025), but ACT failed to improve RFS (HR 1.1, P = 0.834). Among all 82 patients receiving adjuvant therapy, the pre- and post-adjuvant therapy postoperative ctDNA status with a negative-negative or positive-negative pattern had similar and favorable RFS ( P = 0.545) but that patients with a positive-positive or negative-positive pattern had significantly inferior RFS than those with a negative-negative pattern (both P < 0.001). For recurrence monitoring, posttreatment ctDNA MRD status had a positive predictive value of 100% and a negative predictive value of 91.8%, and the sensitivity of MRD detection was affected by the organ of relapse. Among positive ctDNA MRD patients, faster increase of ctDNA concentration correlated with more imminent clinical relapse. The median lead time from ctDNA detection to radiological relapse was 273 days. Moreover, ctDNA negativity after relapse was associated with favorable survival. Conclusions: These findings highlight the clinical significance of ctDNA dynamics for the precise whole-course postsurgical management of NSCLC patients.
Differential expression analysis of circRUNX1 in patients with early resected EGFR-mutant NSCLC.
Authors: Pedraz Carlos , Ito Masaoki , Giménez-Capitán Ana , Giannoukakos Stavros , Molina Vila Miguel Angel , Rosell Rafael 
Published: June 2023

8529 Background: In the ADAURA study, patients with stage IB-IIIA of resected EGFR mutated lung adenocarcinoma receiving adjuvant osimertinib had a 2-year survival of 89% versus 52% in the placebo group (p<0.001), however, predictive markers of response and recurrence are still needed. Circular RNA (circRNA) is a type of RNA which forms a covalently closed continuous loop. Some circRNAs have been reported as essential for tumor cell proliferation through functions distinct from the canonical linear RNA. In this project, we studied circRNA expression levels in formalin-fixed paraffin-embedded (FFPE) lung tumor samples in order to explore potential biomarkers that could predict the benefit of adjuvant EGFR TKIs in EGFR-mutant NSCLC patients. Methods: FFPE tumor samples from patients with EGFR-mutant, stage I-IIIB NSCLC (n=79) were collected. RNA was purified using the High Pure FFPET RNA Isolation Kit (Qiagen) and quantified by Nanodrop 2000 (Thermo Scientific). A total of 250 ng of RNA were subjected to overnight hybridization and downstream nCounter processing (NanoString) following manufacturer’s instructions for our circRNA custom panel. Differential expression analysis was performed using Excel (Microsoft) and Prism GraphPad (Dotmatics) software. Results: Analysis of the 79 samples included in the study shown a cluster of 3 circRNAs significantly upregulated (p<0.05 and >2 fold-change) in EGFR mutation-positive NSCLC relapsing withing the 36 months after resection, including circRUNX1, circFUT8 and circAASDH. Disease-free survival (DFS) was significantly shorter for the subgroup of patients with high versus low circRUNX1 expression. Additional multivariate analysis identified circRUNX1 expression and tumor stage as the only statically significant prognostic factors (circRUNX1 hazard ratio = 4.480, confidence interval = 2.172-9.239, P < 0.001; pathological stage hazard ratio = 2.237, confidence interval = 1.183- 4.231, P = 0.008). Conclusions: CircRUNX1 could be a novel biomarker to predict the benefit of adjuvant EGFR TKIs with regards to DFS in EGFR-mutant resected NSCLC patients.
Examining ultrafine particle pollution and lung cancer risk in a large, diverse cohort.
Authors: Bookstein Arthur , Po Justine , Cheng Iona , Wu Anna H. , Larson Timothy V. , Park Lani , Wu Jun , Shariff-Marco Salma , Inamdar Pushkar , Setiawan Veronica Wendy , DeRouen Mindy , Gomez Scarlett L. , Le Marchand Loic , Stram Daniel , Samet Jonathan , Ritz Beate , Fruin Scott A. 
Published: June 2023

8532 Background: Health effects associated with particles less than 2.5 μm in diameter (PM2.5) have been well studied, leading to the establishment of air quality standards and routine monitoring. Additionally, there is growing experimental evidence that ultrafine particles (UFPs), defined as particles less than 0.1µm in diameter, may adversely affect lung health, eliciting greater injury than larger particles due to deeper penetration into airways and longer retention in the lung parenchyma. Only two epidemiological studies have investigated this topic, finding no associations between ambient UFPs and respiratory mortality or overall lung cancer incidence respectively. Given the limited epidemiologic investigation of UFPs and lung cancer, we examined the association between airport-related UFPs and lung cancer incidence in a large, racially and ethnically diverse cohort. Methods: We estimated airport-related UFP exposure for 71,387 participants of the Multiethnic Cohort, who lived within a 53 km×43 km grid area around the Los Angeles International Airport (LAX) from date of cohort entry (1993-1996) through December 31, 2013. Cox proportional hazards regression was used, with calendar month/year as the time variable, to examine associations between UFP exposure and lung cancer risk adjusting for demographics, lifetime smoking, neighborhood socioeconomic status, occupation and lifestyle factors. Subgroup analyses were conducted by racial and ethnic groups, lung cancer histology, and smoking status. Co-pollutant models were run to mutually adjust for other traffic-related air pollutants. Results: A per unit increase in the interquartile range (IQR) of airport-related UFP exposure was not associated with lung cancer risk overall [HR = 1.01, 95% CI: 0.97-1.05] or by race and ethnicity. UFP exposure was suggestive of a positive association with risk of lung squamous cell carcinoma (SCC) [HR per IQR = 1.08, 95% CI: 1.00-1.17]. No associations were observed for other histologies [Phet for histology = .05]. UFP exposure was associated with an increased SCC risk among current smokers [HR = 1.11, 95% CI: 1.01-1.22] but not among never or past smokers [Phet for smoking = 0.51]. Conclusions: This study suggests a possible association between airport-related UFP exposure and risk of SCC. These results may be explained by previous studies finding that UFPs activate genes involved in oxidative damage, TNF-α signaling via NF-κB, and secretion of inflammatory and cardiopulmonary disease biomarkers. These findings warrant further investigation in large epidemiologic cohorts.