bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes of KRAS mutated, EGFR mutated, ALK mutated and wildtype patients in non-small cell lung cancer brain metastases.
Authors: Rauf Yasmeen , Tatineni Vineeth , Oshea Patrick joseph , Jia Xuefei , Peereboom David M. , Ahluwalia Manmeet Singh 
Published: June 2021

e21028 Background: Non-small cell lung cancer (NSCLC) is the most common primary tumor leading to brain metastases. Multiple genetic markers have been profiled in NSCLC patients for potential targeted therapies. EGFR is mutated in up 50% of NSCLCs, while ALK is mutated in around 4-7%. KRAS is the most commonly overexpressed marker, seen in up to 85% of all lung cancers. In this retrospective study, we evaluated the overall survival (OS) and progression-free survival (PFS) between NSCLCBM patients with KRAS mutations, ALK mutations, EGFR mutations, and wildtype. Methods: NSCLCBM patients diagnosed between 2010 and 2019 were analyzed. We collected information regarding molecular marker status, systemic therapies, and date of progression. We defined OS as the date of diagnosis of brain metastases to the date of last follow-up or death. OS and PFS were estimated by the Cox proportional model. Results: We found a total of 2989 NCSLCBM patients, 184 were KRAS mutated, 68 had an ALK gene rearrangement, 184 were EGFR mutated, and 1469 were wildtype. The respective median age was 64.3 years, 64.5 years, 58.2 years, and 64.2 years. Females made up 61.8% of KRAS-positive, 51.8% of ALK-positive, 63% of EGFR-positive, and 46.4% of wildtype patients. The median OS (mOS) in patients who were KRAS-positive, ALK-positive, EGFR-positive, and wildtype were 43.3 months, 119.2 months, 57.9 months, and 33.1 months, respectively. The median PFS (mPFS) for the same cohort was 38.0 months, 112.4 months, 55.3 months, and 30.5 months, respectively. ALK-positive patients showed statistically significant mOS (p-value (p) < 0.001) and mPFS (p = 0.002) when compared to EGFR-positive, KRAS-positive, and wildtype patients. Conclusions: Molecular mutations serve as both prognostic predictors and alternative targeted therapies for NSCLCBM treatment. Our retrospective study showed improved mOS and mPFS in NSCLCBM patients with ALK rearrangements when compared to patients with EGFR mutations, KRAS mutations, and the wildtype. While these results looked at patient outcomes with specific tumor markers, further investigation needs to be done regarding outcomes of specific therapies in each cohort, as well as, intracranial lesion response.
Anlotinib combined with pemetrexed and carboplatin as first-line treatment in advanced nonsquamous non-small cell lung cancer (NSCLC): ALTER L012.
Authors: Wang Qiming , Yang Xiuli , Ma Tianjiang , Yang Qiumin , Zhang Chenghui , Chen Yunfang 
Published: June 2021

e21040 Background: The anti-angiogenic drug bevacizumab combined with chemotherapy has achieved positive results in previous studies. In particular, the median progression-free survival (PFS) for EGFR-negative patients was increased to 8.3 months in the BEYOND study. Unlike bevacizumab, anlotinib is a novel multitarget tyrosine kinase inhibitor and can be conveniently orally administered. In the phase III trial ALTER 0303, anlotinib significantly improved overall survival (OS) and PFS in advanced NSCLC patients. This exploratory study aims to establish the efficacy and safety of anlotinib in combination with pemetrexed and carboplatin as first-line treatment in advanced non-squamous NSCLC. Methods: This is a multi-center, single-arm clinical trial. Adults with treatment-naive, histologically confirmed stage IIIB-IV non-squamous NSCLC, ECOG 0-1, and without known sensitizing EGFR/ALK alterations are included. Patients received anlotinib (12 mg p.o., QD, d1 to 14, 21 days per cycle) combined with pemetrexed (500 mg/m2, iv, d15-21, Q3W) + carboplatin (AUC = 5, iv, d15-21, Q3W) for 4 cycles followed by anlotinib and pemetrexed maintenance until disease progression (PD). The primary endpoint was PFS. Secondary endpoints were OS, objective response rate (ORR), disease control rate (DCR) and safety. Results: Between Mar 2019 and Dec 2020, 40 patients were enrolled in six centers and 31 of them have received at least one tumor assessment. Median age was 62 (33, 75); 66.7% male, 11.1% brain metastasis. At data cutoff (Dec 31, 2020), patients were followed up for a median of 8.26 months. Median PFS was 10.5 months (95% CI: NE, NE); ORR was 67.7% (0 CR, 21 PR), DCR was 96.8% (0 CR, 21 PR, 9 SD) and median OS was NE. The most common Grade ≥ 3 AEs were hypertension 22.2%, neutropenia 19.44%, myelosuppression 11.1%, thrombocytopenia 8.33%, leukopenia 5.56%, hand-foot syndrome 5.56% and there were no Grade 5 toxicities. Conclusions: This study finds that anlotinib plus pemetrexed and carboplatin can significantly improve PFS and ORR compared to standard chemotherapy for treatment-naive non-squamous NSCLC patients. The combination was well tolerated, and the AEs were manageable. The follow-up time is not sufficient, and the OS outcomes need further evaluation. Clinical trial information: NCT03790228.
Costs comparison of the immune check point inhibitors versus survival ratio in first-line non-small lung cancer.
Authors: Guirgis Helmy M. 
Published: June 2021

e21050 Background: Five-year overall survival (OS) was reported in 20% of patients treated by Pembrolizumab (Pembro) in 1st-line advanced/metastatic (a/m)-non-small lung cancer (nsLC). Costs of the immune check point inhibitors (ICI) are relatively high and bound to increase with extended use. We purposed to weigh and compare costs of ICI vs outcome. Methods: OS, hazard ratio (HR) and survival ratio (SR) defined as (1.0-HR) were used. Chemo-drug excluded; costs were calculated in US$. Results: Adjuvant Durv one-year costs in unresectable stage III were $130,956, OS gain 363 days and SR 0.47. Pembro one-year costs were $134,778. OS were 474 and SR 0.37 in programmed death receptor-ligand-1 > 50%. At 5 years, costs were $673,890. Costs of 35-cycle Pembro combination were $336,945, OS 339 and SR 0.51. Costs increased with extended use. Atezolizumab/Bevacizumab-combination (Atezo/Bev) costs x 2-years were $492,114, OS 135 and SR 0.22. Using Biosimilar Bev costs dropped to $429,744. Ipilimumab/Nivolumab (Ipi/Nivo) costs x 2 were $544,696, OS 141 and SR 0.34. Costs of both Atezo/Bev and Ipi/Nivo increased by 50% with one year of extended use. Costs of Pembro-combination were 0.78 lower than Atezo/Bev and 0.62 than Ipi/Nivo. Pembro SR were 2.32 higher than Atezo/Bev and 1.65 than Ipi/Nivo. Absence of direct comparison, however, cast doubts on Pembro advantage. Conclusions: Costs of one-year adjuvant Durv, 3-year Pembro and 35-cycle Pembro-combination were considered fair and equitable with their corresponding SR. Pembro-combination costs were cheaper than Atezo/Bev and Nivo/Ipi. Costs of all drugs and combinations multiplied with extended use.
Comparison of fusions detection by next generation sequencing between malignant pleural effusion and tumor tissue in lung cancer.
Authors: Xu Yurong , Qi Yingxue , Luo Ningning , Zhang Qin , Wu Yaqing , Qi Chuang 
Published: June 2021

e21059 Background: Anaplastic lymphoma kinase ( ALK), c-ros oncogene 1 receptor tyrosine kinase ( ROS1), ret proto-oncogene ( RET) and neurotrophic receptor kinase ( NTRK) are important driver genes in lung cancer. Each of these four genes fusions as therapeutic targets have been recommended by the national comprehensive cancer network (NCCN) guidelines for non-small cell lung cancer (NSCLC). Malignant pleural effusion (MPE) is observed in multy types of malignancies, especially in lung cancer. Studies have indicated that next generation sequencing (NGS) detection of somatic mutations by MPE is reliable. Nevertheless, the distribution and comparison of fusions in lung cancer between malignant pleural effusion and tumor tissue specimen have not been well characterized yet. Methods: In this study, 9-gene, 69-gene and 539-gene panel NGS profiling were performed by MPE and tumor tissue in 640 and 10013 patients with lung cancer respectively. The variation analysis between patients with or without gene fusion in different sample groups were calculated by fisher exact test via SPSS v26.0. Results: In lung cancer patients using MPE detection, 59 of 640 (9.22%) were found harboring at least one of the four gene fusions, and the ratio of ALK, ROS1, RET and NTRK fusion was 6.25% (40/640), 1.41% (9/640), 0.63% (4/640) and 0.47% (3/640) respectively. Meanwhile, we found gene fusions in 6.25% (626/10013) lung cancer patients using tumor tissue detection, including 3.66% (366/10013) ALK fusion, 1.07% (107/10013) ROS1 fusion, 1.09% (108/10013) RET fusion and 0.22% (626/10013) NTRK fusion. Significant differences of gene fusion frequency between different sample groups were found via fisher exact test ( p = 0.005), especially ALK fusion ( p = 0.001). Conclusions: The frequency of fusion in MPE was significantly higher than in tumor tissue, especially ALK fusion. However, as a retrospective study, the conclusions and the specific mechanisms are needed to be verified.
The efficacy and safety of EGFR-TKI combined with chemotherapy in NSCLC patients with EGFR co-mutation with other oncogenic alterations.
Authors: Zhao Wenhua , Jiang Wei , Qiu Hongtu , Zeng Aiping , Song Xiangqun , Zhou Shaozhang , Ning Ruiling , Su Cuiyun , Wang Huilin , He Jianbo , Zhao Yun , Tan Liping , Yu Qitao 
Published: June 2021

e21077 Background: Previous studies indicated primary resistance to EGFR-TKIs might occur in EGFR co-mutation with other oncogenic alterations. However, the optimal therapeutic regimen for advanced NSCLC with EGFR co-mutation was still unknown. This respective observation study aimed to assess the efficacy and safety of the combination therapy with EGFR-TKI and chemotherapy in this sub-population. Methods: In this retrospectively study, from March 2017 to November 2019 advanced NSCLC patients with EGFR mutation detected using next-generation sequencing targeting 59 genes were screened for eligibility. We included patients of EGFR co-mutation with other oncogenic alterations receiving EGFR-TKI monotherapy or TKI plus chemotherapy as first-line therapy. The primary outcome was objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Disease control rate (DCR) and safety profile were considered to be the secondary endpoints. Results: Total 48 patients were enrolled. Among patients with concomitant mutation, the combination of chemotherapy with TKI was found to prolong mPFS (12.5 vs 7.3 months; HR, 0.38; 95%CI: 0.17-0.81; P = 0.012) compared with TKI monotherapy, with a trend of longer mOS (27.0 vs 22.4 months; HR, 0.40; 95%CI: 0.15-1.05; P = 0.062) and higher ORR (68.4% vs 44.8%, P = 0.113). The DCR were 100% in combination group and 93.1% in monotherapy group (P = 0.99). A proportion of 13.8% patients reported grade≥3 treatment-related adverse events in monotherapy group and 36.8% in combination group. Conclusions: EGFR co-mutation with other oncogenic alterations associated with poor treatment outcome with EGFR-TKI monotherapy. The combination of EGFR-TKI and chemotherapy was effective in this sub-population and side-effects were tolerable. The outcomes of this study should be confirmed by prospective clinical trials in future.
Adverse events in non-small cell lung cancer patients receiving immune checkpoint inhibitors: A single center, real-world study in China.
Authors: Xu Chongrui , Tu Hai-Yan , Sun Yueli , Li Yang-Si , Xu Bingfei , Wang Binchao , Chen Hua-Jun , Wang Zhen , Zhou Qing , Yang Jinji , Yang Qi , Wu Yi-Long 
Published: June 2021

e21081 Background: Immune checkpoint inhibitors (ICIs) have improved clinical outcomes in non-small cell lung cancer (NSCLC), whereas they also can cause various adverse events (AEs). We reported the incidences, spectrum and severity of AEs in real-life practice after the approval of ICIs in Chinese NSCLC patients. Methods: In this single center, retrospective study, anonymized electronic medical record data were collected from the dedicated lung cancer immunotherapy outpatient clinic of Guangdong Provincial People’s Hospital through the LinkDoc database. The patients (≥18 years old) with pathologically diagnosed metastatic NSCLC who receiving ICIs between 1 June 2019 and 31 December 2020 were included. The immune-related adverse events (irAEs) were diagnosed and assessed by oncologists. All AEs were classified and graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE V5.0). Results: A total of 203 patients with a median age of 60.5 years were included in this study. Most patients were male (81.8%), smokers (49.8%), non-squamous histological type (51.7%). 61.1% of patients visited the outpatient clinic more than once. Pembrolizumab and Nivolumab were given to the majority of patients (80.8%). 114 patients (56.2%) received single-agent and 89 patients (43.8%) received combination therapy. The median duration of ICIs therapy was 271.2 days. In our study, 68.0% of patients experienced any-grade AEs, and 19.7% experienced grade≥3 AEs. The most commonly AEs were abnormal laboratory findings (57.1%), blood and lymphatic system disorders (25.1%), and respiratory disorders (19.7%). All of 93 patients (45.8%) experienced irAEs and 6 patients (8.4%) developed grade≥3 irAEs. The most frequent irAEs included blood and lymphatic system disorders (25.1%), hepatobiliary disorders (17.7%), and cardiac disorders (9.9%). Cough (3.4%), sputum (2.5%), and pain (2.0%) were the most frequent AEs which received treatment. Conclusions: Our results showed 68.0% and 45.8% patients experienced AEs and irAEs, respectively. The AEs and irAEs were primarily low grade. This study also demonstrated the information of AEs could be well collected and managed through our dedicated lung cancer immunotherapy outpatient clinic. [Table: see text]
Analysis of first-line treatment (tx) patterns in advanced non-small cell lung cancer (NSCLC) patients (pts) with compromised performance status (PS), organ dysfunction (dfxn) or other significant comorbidities.
Authors: Judd Julia , Handorf Elizabeth A. , Gupta Brinda , Edelman Martin 
Published: June 2021

e21093 Background: NSCLC is a disease of the elderly and most cases are related to tobacco. Therefore, concomitant organ dfxn, which increases the risk of toxicity with cancer directed therapy, is prevalent. Patterns of care studies have shown that the elderly, those with organ dfxn or compromised PS are frequently not treated, despite prospective studies demonstrating survival benefit with active tx. We hypothesized that the advent of new, more active therapies has resulted in practice changes in these populations. Methods: We conducted a retrospective, observational cohort study using the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database to compare first line tx patterns from 2011 to 2020 in pts with advanced NSCLC meeting at least 1 of the following criteria: age > 70 years, organ dfxn (serum creatinine > 1.5 times the upper limit of normal [ULN] and/or total bilirubin > 2 times ULN), ECOG PS > 2 or documented HIV. Pts were excluded if there was a > 90-day post-diagnosis gap in EHR data. Tx patterns were categorized as having received standard, non-standard or no frontline tx. Tx groups included PD-1/PD-L1 inhibitor single agent, chemoimmunotherapy, platinum-based (Plat) doublet +/- VEGF inhibitors (VEGFi), single agent chemotherapy (chemo) and tyrosine kinase inhibitors (TKIs). Descriptive statistics were used to analyze tx patterns, and the relationship between txs and variables of interest were tested using Chi-squared tests or t-tests. Results: Of the 58,145 pts with advanced NSCLC in the database, 33,701 met at least 1 criterion for inclusion. There was a small but significant increase in the number of pts treated with standard therapy from 2011 to 2020 (p < 0.001). There was rapid uptake of PD-1/PD-L1 inhibitors as well as chemoimmunotherapy upon FDA approvals in 2016 and 2018, respectively. This correlated with a rapid decrease in the use of Plat-doublet chemo +/- VEGFi as well as a decrease in the number of pts receiving single agent chemo or not treated at all (Table). Conclusions: Real world data from 2011 to 2020 demonstrates an increase in the use of standard therapies as well as the rapid incorporation of immunotherapy into first line tx in advanced NSCLC pts who are elderly, have a poor PS, or organ dfxn. However, a substantial proportion of pts (28.9%) still do not receive any documented tx, within the Flatiron Health network.[Table: see text]
Fibroblast growth factor receptor (FGFR) inhibitor rogaratinib in patients with advanced pretreated squamous-cell non-small cell lung cancer over-expressing FGFR mRNA: The SAKK 19/18 phase II study.
Authors: Addeo Alfredo , Joerger Markus , Rothschild Sacha , Eboulet Eric I. , Godar Gilles , Waibel-Pachinger Christine , Haefliger Simon , Mark Michael Thomas , Fernandez Eugenio , Mach Nicolas , Mauti Laetitia A. , Frueh Martin 
Published: June 2021

e21119 Background: A substantial proportion of patients with squamous lung cell carcinoma (SQCLC) (46%) exhibit tumor overexpression of fibroblast growth factor receptor (FGFR) messenger ribonucleic acid (mRNA). Rogaratinib is a novel pan-FGFR inhibitor with anti-tumor activity in pre-clinical models as a single agent in FGFR pathway-addicted tumor models. Phase I data showed promising activity and good safety profile. The objective of the SAKK 19-18 trial was to determine clinical activity and safety of rogaratinib in patients with advanced SQCLC overexpressing tumor FGFR1-3 mRNA. Methods: Patients with metastatic SQCLC, previously treated with systemic treatment, overexpressing tumour FGFR mRNA were treated with rogaratinib 600 mg BID until progression of disease or drug intolerance. A rate ≤15% of PFS at 6 months was considered uninteresting, whereas a PFS rate at 6 months ≥38% was considered promising. Ten patients were needed in the first stage with at least 2 achieving 6 months PFS in order to continue the accrual. Results: Between May and November 2020, 49 patients were screened and 20 were classified FGFR positive. Among them15 patients were registered in the trial and the first 10 were assessed for the first stage analysis. Most commons treatment related adverse events (TRAEs) were hyperphosphatemia (60%), diarrhoea (20%), and dry mouth (20%). Grade ≥3 TRAEs occurred in 50% of the patents with Hypercalcemia being the most frequent one (20%). Among 10 first patients only 1 achieved 6 months PFS while 2 was the boundary required for continuing this trial. Conclusions: Despite preliminary signal of activity, rogaratinib failed to improve PFS in patients overexpressing tumor FGFR mRNA. Further studies on a more reliable biomarker are needed, the development of rogaratinib in SQCLC has been put on hold by Bayer and the SAKK 19/18 study was terminated early due to lack of efficacy. Clinical trial information: NCT03762122.
Association between germline DNA damage repair-related genes mutation and tumor mutational burden in lung cancer patients.
Authors: Nie Wei , Zhong Hua , Zhang Ding , Chen Shiqing , Han Baohui 
Published: June 2021

e21163 Background: Deleterious somatic DNA damage repair (DDR) gene mutations are frequent in non-small cell lung cancer (NSCLC) and are associated with improved clinical outcomes of immunotherapy. DDR gene mutations are associated with higher tumor mutational burden (TMB) in cancer. However, the effect of germline DDR-related genes mutation with different functional annotations on TMB in NSCLC patients is still unclear. Methods: 1671 Chinese patients with NSCLC were enrolled in this study. Genomic profiling was performed on formalin-fixed paraffin-embedded tumor samples or peripheral blood by next generation sequencing (NGS) with 733 cancer-related genes panel. The germline mutation data were obtained. All annotations in clinical significance were according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines. Results: 1076 patients (64.39%) had germline DDR-related gene mutations and 595 (35.61%) had no germline DDR-related gene mutations. Among patients with DDR-related gene mutations, 78 (7.25%) patients had the pathogenic (P) mutations or likely pathogenic (LP) mutations and 1056 (98.14%) had variants of unknown significance (VOUS) mutations. In total, the median TMB was 3.91 mutations/MB (range, 0-68.16) and 4.47 mutations/MB (range, 0-51.40) in patients with P, LP or VOUS mutations and no germline DDR-related gene mutations, respectively. To the further analysis, we divided patients with germline DDR-related gene mutations into three groups: only P or LP mutations (Group 1), only VOUS mutations (Group 2) and concurrence with P/LP/VOUS mutations (Group 3). Compare to the DDR-negative group, TMB was significantly lower in Group 2 (P < 0.001). No significant differences in Group 1 and Group 3 were observed. In addition, we found that mutations in different DDR pathway could not affect TMB value significantly. Conclusions: Germline DNA damage repair-related genes mutation may be not associated with TMB.