bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multicenter pharmacokinetic study of pembrolizumab for non-small cell lung cancer in adults aged older than 75 years.
Authors: Yamanaka Yuta , Kurata Takayasu , Watanabe Kageaki , Hosomi Yukio , Horinouchi Hidehito , Ohe Yuichiro , Nakahara Yoshiro , Asao Tetsuhiko , Saeki Sho , Tsubata Yukari , Fujita Yu , Sakakibara-Konishi Jun , Mizugaki Hidenori , Ouchi Mayu , Yagishita Shigehiro , Hamada Akinobu 
Published: June 2023

e21098 Background: Pembrolizumab (Pemb) is a key drug for the treatment of advanced or recurrent non-small cell lung cancer (NSCLC). However, there are limited data on Pemb use in older adults aged > 75 years with NSCLC, especially in terms of pharmacokinetics (PK). Methods: This open-label multicenter observational study aimed to evaluate real-world data on the safety, efficacy, and blood concentrations of Pemb (both monotherapy and combination therapies) in older adults with NSCLC. Blood samples for PK analysis were collected immediately before Pemb administration. Quantitative Pemb concentrations were measured by liquid chromatography-mass spectrometry. Results: We enrolled 100 patients from July 2019 to September 2020; one patient was excluded due to stage migration. Patient characteristics were as follows: median age, 78 (75–87) years; male/female ratio, 70/29; performance status (PS) 0–1/2–3, 85/14; adenocarcinoma/squamous cell carcinoma/others, 62/25/12; stage I–III/IV/postoperative recurrence (TNM 7th edition), 9/60/30; PD-L1 TPS < 1%/1%–49%/≥50%, 12/31/48; and monotherapy/combination therapy, 65/34. The best overall efficacy was CR/PR/SD/PD (7/40/32/20), and the response rate was 47.5%. The median progression-free survival (PFS) and overall survival (OS) were 8.0 and 19.0 months, respectively. The adverse event profile was generally similar to that reported in previous studies. In total, 77 blood samples were collected immediately before the second cycle (C1 trough). Although no clear association between Pemb concentrations and patient background was found, PFS and OS were significantly shortened in the population with low C1 trough, a population characterized by lower PS, high number of metastatic organs at the beginning of treatment, and low blood albumin level. Conclusions: In older adults aged > 75 years with NSCLC and low albumin levels and PS and a high number of metastatic organs, C1 trough of Pemb is reduced and not expected to prolong PFS and OS. Clinical trial information: UMIN000036606 .
First-line HDACi plus tislelizumab combined with chemotherapy in advanced NSCLC.
Authors: Wang Lijie , Gao Ming , Yang Wenyu , Wang Chunyu , Wang Ting , Jing Fangfang , Ma Junxun , Zhang Fan , Tao Haitao , Hu Yi 
Published: June 2023

e21100 Background: Resistance to ICIs remains a challenge. HDAC inhibitors may synergize with PD-1 antibodies by inducing and activating NK cell and cytotoxic T cell (CTL) -mediated cellular immunity. Tislelizumab is an anti-PD-1 mAb approved for the treatment of NSCLC. Chidamide, a subtype-selective HDACi. This Phase 2 study assessed antitumor activity and tolerability of chidamide and tislelizumab combined with chemotherapy in advanced NSCLC. Methods: This was an open-label, prospective study. Patients with histologically or cytologically confirmed NSCLC (stage IIIB-IV) without prior systemic treatment was enrolled. EGFR/ALK mutation or fusion and symptomatic brain metastases were ineligible. Patients received chidamide 20 mg twice weekly orally, tislelizumab 200 mg Q3W intravenously, chemotherapy Q3W(≤4~6 cycles) until unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was ORR. Secondary endpoints include DCR、PFS、OS and safety. Tumor response was assessed using RECIST v1.1. Results: 20 patients were enrolled in the study. At the data cut-off February 10, 2023, the median age was 63.5 years (range: 49-75) and all patients were male 90% of who with smoking history. Most patients were stage IV(95%) .40% of the patients whose PD-L1 expression was positive (PD-L1 TPS≥1%) . The confirmed ORR was 75%(95%CI:56.0-94.0) and 1 patient was evaluated as CR. The DCR was 100%. The median follow-up was 13.1 months, median PFS was 11.7 months (95%CI:7.4m-16.0m) and 1-year PFS rate was 55.6% (95%CI:43.7%-67.5%). Median OS was not reached. 11 patients (55.0%) had ≥ Grade 3 TRAEs. The most common ≥Grade 3 TRAEs were leukopenia (25.0%), neutropenia (20.0%) and thrombocytopenia (15%). Conclusions: Adding HDACi(Chidamide) plus Tislelizumab combined with chemotherapy showed encouraging antitumor activity and a favorable safety profile as first-line therapy for advanced NSCLC. Clinical trial information: ChiCTR2000041542 . [Table: see text]
An individual patient-level meta-analysis of non–small-cell lung cancer leptomeningeal metastases treated with epidermal growth factor receptor inhibitors.
Authors: Bian David Jiahua , Lazaratos Anna-Maria , Maritan Sarah M. , Quaiattini Andrea , Zeng Zhimin , Zhu Zhengfei , Sener Ugur , Malani Rachna , Kim Yu Jung , Ichihara Eiki , Bouganim Nathaniel , Dankner Matthew 
Published: June 2023

e21118 Background: Leptomeningeal metastasis (LM) is a debilitating condition associated with advanced non-small cell lung cancer (NSCLC). When driver mutations in the epidermal growth factor receptor (EGFR) are identified, targeted therapies (TT) represent an appealing therapeutic strategy. However, the efficacy of TT for LM is unknown as LM patients are routinely omitted from clinical trials. Methods: We conducted a systematic review and meta-analysis of individual patient data to evaluate the efficacy of EGFR TT in EGFR-mutant NSCLC LM in accordance with PRISMA guidelines. EGFR-TTs evaluated were erlotinib, gefitinib, icotinib, afatinib, dacomitinib, osimertinib, zorifertinib, and furmonertinib. The co-primary endpoints were progression-free survival (PFS) and overall survival (OS). To assess differences between groups, shared frailty Cox regression models were used to estimate the hazard ratio (HR), 95% confidence interval (CI) and p-value. Results: 7780 abstracts were screened, identifying 126 publications with 232 patients, corresponding to 272 lines of EGFR-TT for NSCLC LM which met inclusion criteria. The overall median PFS (mPFS) in patients receiving any EGFR-TT was 9.15 months and the median overall survival was 14.5 months. In univariable analyses, osimertinib was associated prolonged PFS compared to other EGFR-TT, (mPFS of 11 versus 8 months, HR = 0.64; 95% CI: 0.44-0.93; P = 0.02). Osimertinib was numerically associated with prolonged OS compared to other EGFR-TT (mOS 16.8 months versus 13.6 months, HR = 0.72; 95% CI 0.44-1.17, P = 0.188). In multivariable analyses, ECOG performance status > 2 was independently associated with shortened PFS (mPFS 10 versus 8 months, HR = 1.54, 95% CI: 1.26-3.04; P < 0.05) and OS (mOS 16.5 versus 10 months, HR = 3.33, 95% CI: 1.80-6.18; P < 0.05). Conclusions: In the largest cohort of NSCLC LM treated with EGFR TT compiled to date, osimertinib is associated with marginally improved outcomes compared to other EGFR TTs. ECOG performance status is an independent predictor of prognosis in these patients. These results highlight the need for prospective studies for this difficult to treat patient population.
Molecular characterization of nectin-4 in non-small cell lung cancer subtypes.
Authors: Hsu Robert , Gandhi Nishant , Kim Chul , Mamdani Hirva , Halmos Balazs , Vanderwalde Ari M. , Oberley Matthew James , Ma Patrick C. , Liu Stephen V. , Nieva Jorge J. 
Published: June 2023

e21119 Background: Nectin-4 (Nectin cell adhesion molecule-4) is a tumor associated antigen overexpressed in multiple solid tumor types. Studies show that over 60% of NSCLC are nectin-4 overexpressed. As enfortumab vedotin, an antibody-drug conjugate directed against nectin-4, has been FDA approved for advanced urothelial carcinoma, this holds treatment implications. Here, we investigated nectin-4 expression in NSCLC subtypes. Methods: 27,607 NSCLC tumors were tested for whole transcriptome sequencing (WTS, NovaSeq) and NextGen DNA sequencing (592 gene panel or whole exome sequencing, WES) at Caris Life Sciences (Phoenix, AZ). Tumors were analyzed overall in quartiles by nectin-4 expression (Q4-greatest, Q1-least) and further analyzed in the adenocarcinoma (AD) and squamous carcinoma (SQ) cohorts. PD-L1 expression was tested by IHC (Dako 22C3). Immune cell populations were estimated by QuanTISeq. Statistical significance was determined using Chi-square/Fisher-Exact/Mann-Whitney U tests and adjusted for multiple comparisons (q < 0.05). Results: We saw significantly greater expression of nectin-4 in SQ (median TPM- 15.68) versus AD tumors (median TPM - 9.88) (p < 0.05). We saw a greater prevalence of NFE2L2, STK11, ERBB2 mutations and genomic loss of heterozygosity (LOH) but a lower percentage of PD-L1+ tumors in Q4 vs Q1 tumors (all q-value < 0.05, Table 1). mRNA expression of immune checkpoints PDL1, CTLA4, CD80, CD86, HAVCR2, and IDO1 was increased in Q4 tumors (1.1-1.3-fold, all q < 0.05). Q4 tumors had reduced estimates of M1 macrophages, regulatory T cells (Tregs), and CD8+ T cells and increased estimates of neutrophils and NK cells. The association of nectin-4 expression with the immune landscapes of AD and SQ was similar. Q4 tumors in AD and SQ displayed increased expression of the above-mentioned immune checkpoints (q < 0.05). In AD and SQ, estimates of M1 macrophages, Tregs, and CD8+ T cells were reduced, but neutrophils and NK cells were increased in Q4 tumors (q < 0.05). The pattern of molecular alterations was different in AD and SQ. While KEAP1, STK11 and ERBB2 mutations were significantly enriched in AD Q4 tumors, NFE2L2 mutations were significantly enriched in SQ Q4 tumors (Table 1). Prevalence of LOH was higher and PD-L1+ tumors was lower in Q4 tumors in both AD and SQ (Table 1). Conclusions: NFE2L2 alterations in SQ and STK11, KEAP1 mutations in AD, which are associated with poor immunotherapy (IO) response, were enriched in Q4 tumors. This suggests that the immune landscape associated with high nectin-4 expression in NSCLC may be driven by the dysregulated KEAP1-NFE2L2 pathway. Targeted therapy towards nectin-4 may benefit these NSCLC subtypes that do not respond well to IO. [Table: see text]
Yttrium-90 radioembolization for lung cancer metastases: Small institutional experience.
Authors: Kovalenko Iuliia , Ng Wern Lynn , Nasrollahi Elham , Sangha Lillian , Proskuriakova Ekaterina , Wert Yijin , Reninger Charles , Hoffman Todd 
Published: June 2023

e21122 Background: Yttrium-90 radioembolization (Y-90) is a local cancer therapy which can provide quality of life improvement with minimal systemic toxicity. Yet, it remains underused in nonconventional cancers malignancies including lung cancer liver metastases. We present institutional experience in Central PA of treating metastatic liver disease in lung cancer patients. Methods: We performed retrospective analysis of patients with lung cancer liver metastasis who underwent Y90 in a 5-year period at the UPMC Harrisburg. Modified RESIST criteria were used to assess response rates. Common terminology criteria for adverse events v3.0 was used to grade adverse events (AEs). Descriptive statistics were reported including median and range. Results: A total of 7 patients were included in the study with median age of 67. Median time from diagnosis was 13.7 months (5-41), median number of metastases was 3 (1-4), and median number of previous systemic therapies was 1 (1-4). Five patients have received two Y-90 procedures while two patients have received one Y90 procedure. All patients achieved liver partial response with median sustained response of 9.4 months (2-36). A total of 3 patients (42%) developed Grade 1 AEs including rash, abdominal pain, and liver enzymes elevation. Only two patients (28%) developed Grade 3 AEs (liver enzymes elevation). Patient’s characteristics and treatment outcomes are listed in the Table 1. Conclusions: Our institutional experience supports growing body of literature demonstrating safety of Y-90 radioembolization for the treatment of metastatic lung cancer to the liver. Heterogeneity in the individual patient response is multifactorial with further investigation required to understand which patients and at what point in their treatment would benefit from treatment the most. [Table: see text]
Circulating tumour DNA (ctDNA) as a predictor of clinical outcome in non-small cell lung cancer undergoing targeted therapies: A systematic review and meta-analysis.
Authors: Zaman Farzana Yasmin , Subramaniam Ashwin , Afroz Afsana , Samoon Zarka , Zwieky Walid , Arulananda Surein , Alamgeer Muhammad 
Published: June 2023

e21124 Background: Liquid biopsy (LB) analysis using circulating-tumour DNA (ctDNA)/cell-free DNA (cfDNA) is an emerging alternative to tissue profiling in non-small cell lung cancer (NSCLC). LB is used to guide treatment decisions, detect resistance mechanisms, and predicts responses, and therefore outcomes. This systematic review and meta-analysis evaluated the impact of LB quantification on clinical outcomes in molecularly altered advanced NSCLC undergoing targeted therapies. Methods: We searched Embase, MEDLINE, PubMed and Cochrane Database, between 01/01/2000 and 01/08/2022. The primary outcome was progression-free survival (PFS) and overall survival (OS). Secondary outcomes included objective response rate (ORR), sensitivity and specificity of the test. Age stratification was performed based on the mean age of the individual study population. The quality of studies was assessed using the Newcastle-Ottawa Scale (NOS). Results: Twenty-seven studies reporting 2424 patients were included. Eleven studies (n = 1359) reported an association of baseline ctDNA levels, while 16 studies (n = 1649) reported an association of dynamic ctDNA changes to treatment, with clinical outcomes of PFS and/or OS. Baseline ctDNA-negative patients had higher PFS (pooled hazard ratio [pHR] = 2.97; (95%CI: 1.92-4.85; I2= 97.4%), and OS (pHR = 3.49; (95%CI: 1.73-6.95; I2= 84.2%), than ctDNA-positive patients. Egger’s test suggested publication bias (p < 0.001). Early reduction/clearance of ctDNA levels after treatment improved PFS (pHR = 3.78; 95%CI: 1.91-7.38; I2= 98.4%) and OS (pHR = 2.20; 95%CI: 1.49-3.28; I2= 90.6%), compared to those with no reduction/persistence of ctDNA levels. The PFS was comparable for patients stratified by age (age ≤60 years [pHR = 2.92; 95%CI: 1.43-5.93; I2= 98.3 %] vs. age > 60 years [pHR = 3.94; 95%CI: 1.54-10.07; I2= 83.6 %]). The sensitivity analysis based on study quality (NOS) demonstrated improved PFS only for good quality studies (pHR = 3.67; 95%CI: 1.79-7.54; I2= 91.6 %), but not for poor or fair quality studies. Conclusions: This large systematic review, despite heterogeneity, found that baseline negative ctDNA levels, and early reduction in ctDNA following treatment are strong prognostic markers for PFS and OS in patients undergoing targeted therapies for advanced NSCLC. Future randomised clinical trials should incorporate serial ctDNA monitoring to further establish the clinical utility in advanced NSCLC management. Systematic review registration: PROSPERO registration No. CRD42022347791 Keywords: non-small cell lung cancer; NSCLC; liquid biopsy; circulating tumour DNA; ctDNA; progression-free survival; targeted therapies.
Predictors of benefit to radiation for oligoprogressive disease in EGFR-mutant metastatic non-small cell lung cancer patients treated with osimertinib.
Authors: Chen Monica F , Ma Jennifer , Kris Mark G. , Gomez Daniel Richard , Yu Helena Alexandra 
Published: June 2023

e21127 Background: While osimertinib has transformed the treatment paradigm of EGFR-mutant lung cancers (EGFR+ LC), all patients inevitably progress. Oligoprogression is a common pattern of progression for which radiation therapy (RT) can be utilized to prolong the time on osimertinib. However, data supporting the benefit of osimertinib in prolonging progression is limited. Furthermore, predictors of response to RT in the setting of oligoprogression are unknown. We aim to identify clinical and genomic factors associated with robust progression-free survival (PFS) after RT for oligoprogression in EGFR+ LC in patients treated with osimertinib. Methods: Patients with metastatic EGFR+ LC on osimertinib who underwent radiation from 2010 to 2022 for oligoprogression (i.e. progression in 5 or less lesions) were identified. Patients received RT to all active sites of intra- and extra- thoracic disease. Patients who progressed within 3 months of radiation therapy were classified as “rapid progressors,” and those that had longer PFS were “late progressors.” All cases underwent clinical and genomic annotation. Comparisons of categorical variables were performed by Fisher’s exact test. Results: 84 patients were identified who underwent RT for oligoprogression on osimertinib, of which 25% (n = 21) were rapid progressors. Median time from radiation to subsequent progression was 6 months (range 1-26mo) and upon progression most patients had growth of more than one lesion (71%). Median time to death or last follow-up was 13.5 months (range 1-48mo). There was no significant difference in gender, ethnicity, and baseline KPS between rapid and late progressors. Patients with baseline exon 19 deletion (63% vs 76%, p = 0.3) and atypical mutations (14% vs 3%, p = 0.1) were more likely to be rapid progressors while those with exon 21 L858R (10% vs 33%, p = 0.03) were more likely to be late progressors. Among the rapid progressors, 50% underwent radiation to the lung, 10% to the brain, 35% to the bone, and 5% to lymph nodes. Median size of the largest lesion and number of lesions was similar between the two groups (rapid 2.5 cm and 1.5 lesions vs late 2.7 cm and 1 lesion). In-field recurrence rate was 18% and did not differ between rapid and late progressors (14% vs 19%). Conclusions: Radiation therapy for oligoprogression results in clinically meaningful time on osimertinib beyond progression for many patients. However, 25% of patients rapidly progress after radiation therapy and should be directed to switch systemic therapy. Further study is needed to better elucidate benefit at the time of radiation, so that the systemic treatment approach for these patients can be optimized.
Differential therapeutic benefit of platinum-doublet chemotherapies with ICIs based on the classification by combined with smoking status and PD-L1 expression in patients with advanced NSCLC.
Authors: Fukuda Akito , Yoshida Tatsuya , Masuda Ken , Shinno Yuki , Okuma Yusuke , Goto Yasushi , Horinouchi Hidehito , Yamamoto Noboru , Ohe Yuichiro 
Published: June 2023

e21131 Background: Chemotherapy combined with immune checkpoint inhibitors (Chemo-ICIs) has been the standard of care for advanced NSCLC patients. Smoking status is associated with PD-L1 expression and the TILs within tumor microenvironment, which leads to the efficacy of ICIs. It remains unclear how the combined with PD-L1 expression and smoking status affect the efficacy of Chemo-ICIs. Methods: We retrospectively reviewed advanced NSCLC patients without driver mutation (EGFR, ALK, ROS-1, BRAF) who received Chemo-ICIs from January 2019 to June 2021, and Chemo from January 2014 to December 2016 as a first-line therapy at the National Cancer Center Hospital, Tokyo, Japan. The additional benefit of ICIs to chemotherapy were evaluated by comparing the Chemo-ICIs group with Chemo group. Results: During study period, 225 patients received Chemo-ICIs and 133 received Chemo as a first line therapy. Overall response rate (ORR) and progression free survival (PFS) was significantly better in the Chemo-ICIs group than the Chemo group (ORR: 44.9% vs. 40.2%, p=0.01, and median PFS: 8.2 months vs. 6.2 months, P<0.001). The median overall survival was 27.9 months in Chemo-ICIs and 20.4 months in chemo (P=0.14). In the subgroup analysis of PFS, the benefit of Chemo-ICIs compared to Chemo was not observed in never-smoker patients (8.9months vs 8.8months, P=0.27). In contrast, among smoker patients, Chemo-ICIs showed significant longer PFS compared to Chemo (7.5 months vs 5.7 months, P<0.001). Next, patients received Chemo-ICIs were classified into six groups, based on the smoking status (never smoker or smoker) and PD-L1 expression (TPS: 0%, 1-49%, or 50%). Chemo-ICIs showed better PFS rate at 12 months in the smoker/ TPS ≥50% group (42.2% vs 25.0%, p=0.03), and the never smoker/TPS ≥50% group (75.0% vs 27.3%, p=0.05) compared with Chemo (Table). In patients with 1-49% TPS, compared to the Chemo group, significant PFS benefit of ICIs was observed only in smoker patients (42.2% vs 25.0%, p=0.003), not in never smoker patients (46.2% vs 27.3%, p=0.13). In patients with 0% TPS, although the additional benefit of ICIs to Chemo was not observed both in never and smoker patients, PFS rate at 12 months in never smoker (13.3%) was lowest among all six groups. Conclusions: Our study suggested that additional benefit of ICIs to chemotherapy could be predicted by combined with smoking status and PD-L1 expression.[Table: see text]
Immunotherapy combined with rh-endostatin improved clinical outcomes over ICIs plus chemotherapy for second-line treatment of advanced NSCLC.
Authors: Huang Hongxiang , Zhong Peiyuan 
Published: June 2023

e21133 Background: Despite the fact that numerous clinical and preclinical studies have demonstrated the synergistic effects of combining antiangiogenic or chemotherapy with immunotherapy, no data have been found to indicate that combination therapy is more effective and safer as second-line therapy. Methods: We retrospectively compared the effectiveness and safety of ICIs plus rh-endostatin to ICIs plus chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). The evaluation indicators were progression-free survival (PFS), safety profile, overall response rate (ORR), disease control rate (DCR) and 1-year survival rate. Results: The median PFS with immunotherapy plus rh-endostatin (IE) was 7.10 months (95% CI, 4.64 to 9.56) versus 5.13 months (95% CI, 4.29 to 5.97) with immunotherapy plus chemotherapy (IC) (HR, 0.56; 95%CI, 0.33 to 0.95). Treatment-related adverse events of grade 3 or 4 occurred in 7.5% of the IE group versus 25.0% of the IC group. The ORR in the IE group was 35.0% versus 20.8% in the IC group ( P = 0.137), and the DCR in the IE group was 92.5% versus 77.1% in the IC group ( P = 0.049). The 1-year survival rate for the IE group was 69.4%, which was higher than the IC group's rate of 61.4%. Conclusions: Our study demonstrates that ICIs in conjunction with endostatin therapy, demonstrate high efficacy and safety, suggesting that such a combination of therapy may be a viable treatment option for pretreated NSCLC patients in the future.