bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world experience of dacomitinib in EGFR mutated advanced NSCLC: A single center experience from India.
Authors: Biswas Bivas , Ganguly Sandip , Ghosh Joydeep , Roy Somnath , Bakshi Rupsa , Dabkara Deepak 
Published: June 2021

e21043 Background: Dacomitinib is an irreversible tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) approved in advanced non-small cell lung cancer (NSCLC) with mutated EGFR. Literature on real world experience of dacomitinib is lacking, especially in patients (pts) with brain metastasis and uncommon EGFR mutation. Methods: This is single center retrospective study of EGFR mutated advanced NSCLC patients treated with dacomitinib between July’19 and Dec’20. All patients received dacomitinib at 45 mg once oral dose except few with Eastern Cooperative Oncology Group performance status (ECOG PS) of 2-3 and elderly received 30 mg once daily. Clinicopathologic features, treatment details, toxicity and treatment outcome were recorded. Progression free survival was calculated from start date of dacomitinib till date of progression. All pts underwent re-biopsy with evaluation for EGFR T790M at progression. Results: Total 43 pts were treated with median age of 63 years (range:43-81) and M: F ratio of 22:21. 26 pts accessed the drug through early access program, 6 pts through clinical trial and rest through commercially available product. ECOG PS was 1 in 29 pts, 2 in 13 pts and 3 in 1 patient. Ten patients had brain metastasis (out of evaluated 38) and 9 received whole brain radiotherapy. Type of mutations was Del 19 in 27 pts, L858R in 12 pts, G719X in 2pts, and Del 19 + L858R, L861Q in one patient each. Histopathology types were – adenocarcinoma in 39 pts, adenosquamous in 2 pts, NSCLC-not otherwise specified and squamous histology in one patient each. Starting dose of dacomitinib was 45 mg in 34 pts and 30 mg in 9 pts. 39 pts had any grade of toxicity and 20 pts (47%) had any grade 2 & 3 toxicity- mostly diarrhea and acneiform skin rash. Total 18 pts (42%) required dose modification (all from 45 mg to 30 mg). 38 pts have evaluable response: complete response in 2, partial response in 34 and stable disease in 2 pts. 8 out of 10 pts with brain metastases had partial response. All three pts with uncommon EGFR mutation had partial response. Five pts underwent re-biopsy on subsequent progression (4 had Del 19 and one had L861Q) and two developed EGFR T790M mutation. Six patients died (5 died of infection and one died of acute myocardial infarction). After a median follow-up of 13.8 months (range: 1.2-20.1), the median PFS not reached (95% confidence interval [CI]: 17.9, not reached) and 2-yr PFS was 57.5%. Conclusions: This is the largest experience of dacomitinib in EGFR mutated advanced NSCLC from Indian subcontinent. This is first reported activity of dacomitinib in pts with brain metastasis and uncommon EGFR mutation. Response rate was high and durable. 42% pts on 45 mg oral daily dose required dose modification due to toxicity. 30 mg once daily may be an optimum dose of dacomitinib in Indian pts.
Efficacy of stereotactic body radiotherapy for oligoprogression on PD-1 axis inhibitors in advanced non-small cell lung cancer: A single-center retrospective study.
Authors: Wang Zhen , Li Jing , Zhou Han , Li Si , Zhu Xi-xu 
Published: June 2021

e21065 Background: Immunotherapy has brought considerable benefit for patients with advanced non-small cell lung cancer (NSCLC), while acquired resistance could occur, of which most were oligoprogression. Adding locoregional therapy into the current systematic treatment could significantly improve the survival of oligoprogressed group. One of the conventional locoregional therapy for oligoprogression is stereotactic body radiotherapy (SBRT), however efficacy of combing SBRT to the ongoing PD-1 axis inhibitors was unclear in oligoprogressive NSCLC. Methods: In this study, we retrospectively reviewed data of patients with advanced NSCLC, who received SBRT on oligoprogressive lesions after acquired resistance to PD-1 axis inhibitor (First line or more) in our hospital, between June 2015 and June 2019. Acquired resistance was defined as initial CR/PR (by RECIST) followed by progression/death. Oligo patterns of acquired resistance were defined as progression in ≤ 3 sites of disease. We summarized the locoregional control rate (LR), progression-free survival (PFS) and overall survival (OS) after SBRT. Results: A total of 18 patients were included, 5 females and 13 males. The median age was 63 years (range: 37-82). 10 (55.6%) patients had a PD-L1 expression > 1%, 13 (72.2%) received combination therapy (anti-PD-1+chemo/antivascular), duration of immunotherapy was longer than 24 months in 9 (50%) patients. After acquired resistance, 25 sites of oligoprogressive lesions were identified (11 in brain, 5 in lung, 3 in lymph node, 3 in bone, 2 in adrenal, 1 in liver), the median maximum dimension was 14.8 cm (range, 10 to 79 cm). The SBRT dose were 30-55 Gy/2-6 fx, with the median biological effective dose at 60 Gy (range: 45-124.8). At a median follow-up of 28.5 months (range: 15-60), 12 (48%) lesions achieved complete response, 7 (28%) had a partial response, 4 (16%) remains stable and 2 (8%) developed progressive disease. The 1 and 2 years’ LR were 100% and 77.8% respectively. The median PFS was 10 months (range: 7-18). Among them, 44.4% and 14.8% had a 1 and 2 years of PFS, and 87.5% and 60% achieved 1-year and 2-year survival respectively. Conclusions: We observed that SBRT for oligoprogression can improve disease control and bring survival benefit, suggesting that SBRT could be considered in patients with oligoprogression after required resistance on immunotherapy in NSCLC. Meanwhile, prospective evaluation or stratified analysis with larger sample size was needed to verify its efficacy and safety in specific group.
Retrospective analysis of efficacy of immune checkpoint inhibitors in BRCA-mutant non-small cell lung cancer.
Authors: Chen Shaomu , Li Si , Chen Dongsheng , Xiao Mingzhe 
Published: June 2021

e21067 Background: Efficacy of BRCA1/2 inhibitor in non-small cell lung cancer (NSCLC) is under investigation in serval clinical trials. Meanwhile immune checkpoint inhibitor (ICI) has become one of the standard therapies for advanced NSCLC, while its efficacy in BRCA mutant NSCLC is not clear. This study assessed the efficacy of anti-PD-(L)1/CTLA-4 in advanced BRCA-mutant NSCLC. Methods: Data of cohort OAK, POPLAR and Rizvi et al.,2018 was downloaded. Efficacy including objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were reviewed for BRCA1/2 mutant and wild-type group. The impact of mutant gene ( BRCA1, BRCA2), histological types (adenocarcinoma, squamous) and tumor mutation burden ranges (TMB, > 10 SNVs/Mb, < 10 SNVs/Mb) was analyzed if information was available. Results: A total of 809 ICI-treated advanced NSCLC patients, including 53 (6.6%) with BRCA1/2 mutation, were identified. In OAK/POPLAR cohort (atezolizumab monotherapy, 2nd line or more), TMB in BRCA1/2 mutant group was significant higher (19.2 vs. 10.24, P=0.008) than group of wild-type. The ORR of mutant group was 21.9% (Table), median PFS was 2.5 months, median OS was 9.5 months. The ORR and PFS were comparable between mutant and wild-type groups, while OS of the mutant group was significantly shorter than that in wild-type group (mOS, 9.5 months vs. 14.1 months, P= 0.02). Within mutant group, no significant difference of ORR, PFS and OS were found between mutant gene ( BRCA1 vs. BRCA2), histological type (adenocarcinoma vs. squamous) and TMB range (>10 vs. <10). In Rizvi’s cohort (anti-PD-(L)1 /CTLA-4 mono- or combination therapy, 1st line or more), TMB in mutant group was also significant higher (22.2 vs. 9.1, P=0.04) than wild-type group. ORR, PFS for mutant and wild-type groups were 25.0% vs. 20.1%, 3.2 months vs. 3.4 months, without significant difference. Within mutant group, superior PFS was found in adenocarcinoma subgroup (mPFS, 5.5 months vs. 1.2 months (squamous subgroup), P = 0.008) and BRCA2-mutant subgroup tend to have superior PFS (mPFS 5.5 months vs. 1.8 months, P=0.08) than BRCA1-mutant subgroup. Conclusions: This retrospective multicohort analysis showed a trend of worse survival in BRAC-mutant NSCLC patients after ICI treatment compared to those in wild-type group, in spite of higher TMB level. Analysis with more samples are needed to provide more precise treatment reference. [Table: see text]
MRI-based radiomics signature for the prediction of response of lung cancer brain metastases after whole-brain radiotherapy.
Authors: Xu Ruizhe , Tian Ye , Zhang Bo 
Published: June 2021

e21096 MRI-based Radiomics signature for the Prediction of Response of Lung Cancer Brain Metastases After Whole-Brain Radiotherapy Background: Local response prediction for brain metastases (BMs) from lung cancer after Whole-Brain Radiotherapy (WBRT) is challenging, as existing criteria are based solely on unidimensional measurements. This study sought to determine whether radiomic features of lung cancer BMs derived from pre-treatment magnetic resonance imaging (MRI) could be used to predict local response following WBRT. Methods: A total of 88 Lung Cancer patients with BMs treated with WBRT were analyzed. After volumes of interest were drawn, 944 radiomic features including first-order, shape, Gray Level Co-occurrence Matrix (GLCM), Gray Level Dependence Matrix (GLDM), Gray Level Run Length Matrix (GLRLM), Gray Level Size Zone Matrix (GLSZM), Neighborhood Gray Tone Difference Matrix (NGTDM), and Laplacian of Gaussian (LoG) features were extracted, using the baseline pre-treatment post-contrast T1 (T1c) and T2 fluid-attenuated inversion recovery (FLAIR) MRI sequences, respectively. Local response status was determined by contrasting the baseline and follow-up MRI according to the RANO-BM criteria. The independent samples t test or Mann-Whitney U test, and then least absolute shrinkage and selection operator (LASSO) were used for dimensionality reduction and feature selection. An adaboost classifier was trained using the selected radiomic features and evaluated using the area under the receiver operating characteristic curve (AUC) in both the training and testing sets. Other discrimination metrics, including classification accuracy, positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity, were also calculated. Results: The optimal radiomics signature was developed based on a multivariable logistic regression with 4, 5, 6 radiomic features on T1c, T2 FLAIR and T1c+T2 FLAIR, respectively. The radiomics model based on T1c features presented the AUC of (0.920 vs. 0.805, respectively) for both the training and testing sets, followed by T2 FLAIR features (0.893 vs. 0.701, respectively), and T1c+T2 FLAIR features (0.971 vs. 0.857, respectively). The classification accuracy of the radiomics model also well predicted the local response of BMs for both the the training and testing sets (T1c: 82.9% vs. 77.8%, T2 FLAIR: 82.9% vs. 77.8%, T1c+T2 FLAIR: 90.0% vs. 77.8%, respectively). Conclusions: Radiomics holds promise for predicting local tumor response following WBRT in patients with lung cancer and brain metastases. A predictive model built on radiomic features from an institutional cohort performed well on cross-validation testing. These results warrant further validation in independent datasets. Such work could prove invaluable for guiding management of individual patients and assessing outcomes of novel interventions.
KEAP1 mutations in squamous cell lung cancer.
Authors: Koleczko Sophia , Hillmer Axel , Bayarassou Abdel Hakim , Grohé Christian , Buchenroth Martin , Kaminsky Britta , Schulte Clemens , Michels Sebastian Yves Friedrich , Schaufler Diana , Kron Anna , Riedel Richard , Westphal Theresa , Weber Jan-Phillip , Fischer Rieke Nila , Merkelbach-Bruse Sabine , Nogova Lucia , Buettner Reinhard , Wolf Juergen , Scheffler Matthias 
Published: June 2021

e21098 Background: KEAP1 mutations have been shown to decrease the efficacy of both chemotherapy (CTX) and immune-checkpoint inhibition (ICI) in lung adenocarcinoma. However, few is known about their impact on systemic treatment of squamous cell lung cancer (SqCC). The aim of this study was to assess the impact of KEAP1 mutations on systemic treatment outcome in SqCC. Methods: Tumor biopsies of SqCC patients were analyzed within the German Network Genomic Medicine (NGM) using a next-generation DNA sequencing (NGS) panel comprising 17 genes. In subsets, PD-L1 expression was tested with immunohistochemistry (IHC). MET amplification and FGFR1 amplification was tested with fluorescence in situ hybridization (FISH). Overall survival was estimated using Kaplan Meier statistics. For comparisons, we used log rank. A cohort with KEAP1 wild-type patients from the same panel served as control group. Results: Out of 1399 SqCC patients analyzed, 151 had a KEAP1 mutation (11%). The most common co-occurring mutations besides TP53 were PTEN, KRAS and NFE2L2. The median overall survival (OS) of stage IV KEAP1 mutated patients (n = 82) compared to stage IV control group patients (n = 82) was 7.3 vs. 11.4 months (hazard ratio (HR) 0.87 [95% confidence interval (CI) 0.62-1.23], p = 0.43). The addition of a second treatment line with ICI led to marked OS improvements in both KEAP1 mutant patient group (18.7 vs. 6.6 months, HR 0.11, [95% CI 0.04-0.25], p < 0.0001) and control group (20.3 vs. 5.0 months, HR 0.12 [95% CI 0.06-0.24], p < 0.0001). PD-L1 expression did not differ significantly in both groups. Conclusions: KEAP1 mutations occur commonly in SqCC patients and do not impact the efficacy of ICI in terms of OS. To identify prognostic markers for response to ICI further research is needed.
Efficacy and safety of afatinib in advanced non-small cell lung cancer with EGFR mutations: A real-world study based meta-analysis.
Authors: Zhang Lemeng 
Published: June 2021

e21134 Background: This study aimed to explore the efficacy and safety of Afatinib in advanced EGFR mutation NSCLC patients based on real-world evidence. We also explore the effectiveness of tolerability-guided dose reduction on outcomes in the real-world setting. Methods: Eligible real-world studies from Pubmed, Emabse and Cochrane Library were included in this study. The quality assessment of the included studies was based on the guidelines of Cochrane. Then heterogeneity analysis was performed based on Cochran’s Q test and I2 statistics. Results: A total of twenty-five studies were enrolled for this meta-analysis. Meanwhile, nine studies were included in qualitative descriptive analysis. The efficacy of DCR and ORR were 87.6 % (81.5, 92.7) and 58.9 % (48.8, 68.7). The pooled medium PFS was 12.45 months (10.36, 14.54), medium TTF was 15.42 months (13.62, 17.22) and medium OS was 31.67 (26.78, 36.56) months. The efficacy of afatinib in first-line only group was superior than those in second-line. The total incidence of adverse events for diarrhea, mucositis and skin rashes were 70.4 (60.1, 79.8)%, 36.5 (29.5, 43.8)% and 71.4 (64.4, 77.9)%, respectively. Meanwhile, the serious adverse reactions (Grade ≥3) for diarrhea, mucositis and skin rashes were 9.7 (6.8, 13.1)%, 2.1 (1.0, 3.6)% and 5.8 (4.5, 7.2)%, respectively. Furthermore, the different for PFS and OS between afatinib non-full dose group ( < 40mg) and full dose group ( > 40mg) was not significant (P < 0.05). however, the ORR in full dose group was 78.5 % (66.7, 88.4), which was significantly higher in the non-full dose group 67.8 % (56.8, 77.9). Conclusions: Afatinib was a safe and effective TKI for real-world EGFR-mutated NSCLC patients, which was consistent with the results of RCT. Tolerability-guided dose adjustment might affect the efficacy of afatinib in real-world setting.
Retrospective validation of a pretreatment serum protein profile in metastatic non-small cell lung cancer patients treated with a pembrolizumab containing regime as first line of treatment.
Authors: Mellema Wouter W. , Basak Edwin A. , Roder Heinrich , Roder Joanna , Georgantas Robert W. , Smit Egbert F. , Aerts Joachim 
Published: June 2021

e21135 Background: There is an unmet need for reliable biomarkers predictive of treatment outcome with immunotherapy in patients with non-small cell lung cancer (NSCLC). The aim of our study is to examine, in front-line patients, the potential utility of a proteomic signature, PIR (primary immune response), developed and validated in 2nd line patients (M. Muller Clin Cancer Res. 2020 Oct 1;26(19):5188-5197. doi: 10.1158/1078-0432.CCR-20-0538. Epub 2020 Jul 6) as a predictive biomarker of response to treatment with pembrolizumab in a first-line setting. Methods: Pretreatment serum samples were collected from stage IV NSCLC patients treated with a pembrolizumab-containing regimen in first-line at the Netherlands Cancer Institute and Erasmus Medical Center between 2016 and 2020. Data on demographics, ECOG performance status (PS), PD-L1 expression, treatment, progression free survival (PFS) and overall survival (OS) were collected. The PIR test was performed and classified in two groups: resistant vs. intermediate/sensitive (not-resistant). Results: Serum samples of 119 patients were available for analysis. Median age was 65 (36-82) years; 49% female; PS 0-1 80%. 45 samples failed QC and were excluded allowing for the analysis of 74 patients: 24 receiving pembrolizumab monotherapy, and 50 receiving a combination of chemotherapy and pembrolizumab. Overall, median PFS was 5.3 months in the resistant group vs. 9.0 months in the not-resistant group (HR 0.60 (95%CI 0.33-1.08; p = 0.09). In patients receiving pembrolizumab monotherapy, the resistant group had a trend toward shorter PFS (median PFS 3.4 months vs. 10.3 months) then the non-resistant group, (HR 0.42 (95% CI 0.15-1.21; p = 0.11))). No difference was observed in patients treated with a combination of chemotherapy and pembrolizumab (median PFS 5.8 months vs. 9.0 months, respectively; HR = 0.65 (95% CI 0.31-1.36; p = 0.25). Median OS was not reached vs 17.0 months, respectively (HR 0.90 (95% CI 0.34-2.36; p = 0.83)). We did not observe any significant association between performance score and PD-L1 expression, and the PIR test. Conclusions: These data encourage further study of PIR as a predictive biomarker for first-line treatment with pembrolizumab in NSCLC patients.
Identification of predictive biomarker for immunotherapy by associating with CD8+T cell Infiltration in lung adenocarcinoma.
Authors: Xing Puyuan , Li Teng , Wang Han , Yang Lin , Wang Guoqiang , Cai Shangli , Junling Li 
Published: June 2021

e21177 Background: Tumor immune microenvironment (TIME) has been proved associated with response to immunotherapy(I/O). We hypothesized that screening potential mutation pattern which could significantly impact the tumor infiltrating lymphocytes(TILs) can help us to identify predictive biomarkers for I/O in Lung adenocarcinoma(LUAD). Methods: Multiple-dimensional data from The Cancer Genome Atlas LUAD cohort (n = 514) was used for building a mathematical model beween mutation signature and CD8+TIL score (based on MCP-counter). An independent public validation cohort (cohort 1: LUAD, n = 598) were used to assess the immunotherapeutic predictive performance of the potential mutation patterns. Results: Top 100 gene associated with CD8+TIL score were selected based on MC+ model which can provides the minimum non-convexity of the penalized loss given the level of bias. Seven TIME genes (SPTA1 coef 0.09; MET coef 0.02; HSD3B1 coef -0.00; STAT4 coef -0.01; EGFR coef -0.08; PIK3CB coef -0.08; KEAP1 coef -0.24) were generated by taking the intersection of the top 100 mutant genes and FoundationOne (F1) CDx NGS 315 genes panel and verified in cohort 1. Survival analysis showed that SPTA1mt was the only one that associated with both significantly longer PFS (median PFS 3.15 vs 2.89 months; HR 0.65; 95% CI 0.45 to 0.93; p = 0.02) and OS (median PFS 15.08 vs 7.36 months; HR 0.59; 95% CI 0.40 to 0.88; p = 0.01) for patients who received I/O compared with chemotherapy(CT) among seven TIME genes. In order to test our hypothesis fully, a pooled analysis of SPTA1mt (a core positive predictors of CD8+TILs) and KEAP1mt (a core negative predictors for CD8+TILs ) were conducted and yielded that co occurrence of SPTA1mt and KEAP1mt had a compound effects for TIME. The validation showed that co mutation with SPTA1mt was accompanied by an decrease HR for I/O vs. CT in both PFS (HR S+K vs. K only 0.59 vs 1.56) and OS (HR S+K vs. K only 0.39 vs 0.80) for KEAP1mt patients. Conclusions: Our data show that it is feasible to identify individuals or groups of individual with specific mutations to immunotherapy responses from TIME view. SPTA1mt was a core predictors for higher CD8+ TILs and can be identified as a predictive biomarker for benefit from I/O compared with CT. Prospective studies are warranted for further investigation.
Real-world data of osimertinib in the management of leptomeningeal metastases in EGFR mutant NSCLC: Light at the end of the tunnel?
Authors: Sharma Mansi , Nathany Shrinidhi , Narayan Satya , Redhu Pallavi , Jain Parveen , Batra Ullas 
Published: June 2021

e21197 Background: Presence of leptomeningeal metastases (LM) in NSCLC is indicative of aggressive disease and the incidence is as high as 9%-16% in the EGFR mutant subgroup. Traditionally, these patients had a dismal outcome with WBRT and intrathecal chemotherapy. Osimertinib crosses the blood brain barrier and is efficacious in the second line setting, as seen in BLOOM trial (LM ORR of 62%) and AURA program (LM ORR 55%). Osimertinib has also demonstrated CNS efficacy in the first line (FLAURA trial). This study is a retrospective review of cases with LM treated with osimertinib, and their response outcomes. Methods: 16 patients of EGFR mutant NSCLC developed LM at some point in their disease course and were treated with osimertinib. Clinical features and response outcomes were retrieved from medical record archives. Descriptive statistics were done using SPSS v23 software. LM PFS was defined as the time between 1st dose of osimertinib and date of progression in LM. LM OS was defined as the time between the first dose of osimertinib to the date of last follow up/death. ORR was defined as the percentage of cases showing CR/PR to osimertinib. Results: Median age was 61 years (range: 33-79) with 9 males and 7 females. Del19 mutations were seen in 9 patients and L858R in 7 patients. Only one patient was given WBRT prior to TKI. 6 patients with LM at diagnosis were given 1st line osimertinib. 3 (50%) progressed in LM and 3 (50%) showed partial response. Median LM PFS and median LM OS was not reached. ORR for osimertinib in the first line was 83.3%. 10 patients developed LM later in the course of the disease and median time to onset of LM was 12.47 months. Median LM PFS for osimertinib was 7.9 months (95% CI:3.2-8.3). Median LM OS was 8.2 months (95% CI: 2.6-19.8 months). ORR for osimertinib in the later line was 60%. Conclusions: This early experience reveals superior efficacy of osimertinib in LM with an excellent LM ORR in the first line setting and concordant results with second line BLOOM Study. Despite the small numbers in this study, this report becomes clinically relevant owing to the rarity of LM occurrence and paucity of available data. Efficacy of osimertinib in EGFR treatment-naive patients with LM requires further investigation and a larger prospective trial with a longer follow up may help confirm our preliminary findings.