bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of bevacizumab plus double dose icotinib on advanced non-small cell lung cancer with EGFR L858R mutation.
Authors: Jiang Zhansheng , Li Yong , Yan Zhuchen , Lan Lan , Zhang Xinwei , Ren Baozhu , Wang Fei , Zhang Wencheng , Pan Zhanyu
Published: June 2023

e21020

Background: Double-dose icotinib has been proven effective and well tolerated for advanced NSCLC patients with the Epidermal Growth Factor Receptor (EGFR) L858R mutation. For the same patients, the excellent efficacy of bevacizumab combined with erlotinib has been proven in previous studies. In this study, we would investigate the efficacy of the combined therapy bevacizumab and double-dose icotinib for advanced NSCLC patients with EGFR L858R mutation. Methods: 35 patients diagnosed from September 2, 2021 to September 28, 2022 were enrolled in this study and 5 patients were excluded for analysis due to missing efficacy evaluation data. All patients were treated with intravenous bevacizumab (15mg / kg) combined with oral double-dose icotinib (250mg, tid). The primary endpoint was progression-free survival (PFS), and the secondary endpoints were safety, efficacy, and overall survival (OS). Results: Among the 35 patients, 12 were male and 23 were female. The median age at diagnosis was 66. Eight patients were diagnosed with brain metastases. All of the patients have EGFR L858R mutation, and 14 patients were with other coexisting mutations. To the data of December 31, 2022, the median follow-up time was 10 months (range: 3 to 18 months). For 30 patients with complete efficacy evaluation data, 20 patients achieved partial responses (PR), 9 patients had stable disease (SD), and 1 patient developed progress disease (PD). The objective response rate (ORR) was 66.7%, the disease control rate (DCR) was 96.7%, and the median PFS was 14.8 months. For adverse reaction evaluation, the grade 3 adverse events were albuminuria (n = 1) and hepatotoxicity (n = 1). Other adverse events were grade 1-2, mainly oral mucositis, rash, diarrhea and hypertension. Conclusions: The combination of bevacizumab with double-dose icotinib is an effective and relatively safe treatment for advanced NSCLC patients with EGFR L858R mutation. Further exploration will provide more evidence for this type of treatment. Clinical trial information: NCT05263947 .
A series of nine newly developed techniques in CT-guided percutaneous lung biopsyPreliminary results from a prospective study.
Authors: Zhang Hanxi , Wang Xiaolu , Lv Xin , Zhou Xia , Liu Baorui , Wang Lifeng , Li Rutian
Published: June 2023

e21023

Background: CT-guided percutaneous lung biopsy is important for the diagnosis of lung cancer especially in the area of precision medicine. In ASCO 2015, we reported that "Liquid withdraw" technique (to inject small amount of liquid while withdraw of the needle) can prominently reduce incidence of pneumothorax when combined with co-axial technigue in 38 cases. In ASCO 2017, we retrospectively studied 90 patients undergoing CT-guided percutaneous lung biopsy to investigate the role of this technigue in reducing complications and promoting biopsy effectiveness. Based on the above studies, we conducted a prospective study to further evaluate the role of this technique in conjunction with the other eight techniques (Position compensation, Cushion for position adjustment, Skin expansion in advance, Secondary location outside the pleura, Needle core instantaneous replacement, Mutual fix, Simultaneous bleeding arrest, and Cortical displacement) in the precision diagnosis and treatment of lung cancer. Methods: From January 16th, 2018 to October 11th, 2021, a total of 150 CT-guided percutaneous transthoracic biopsy procedures performed in 146 patients were prospectively evaluated. The pathologies and complications secondary to biopsy procedure were analyzed. Pneumothorax and bleeding was graded as mild/very mild, moderate, and severe. All patients were divided into two groups: the lesion depth was < 30mm from the pleura and ≥30mm from pleura. Different complications between the two groups were analyzed using Pearson’s Chi-squared test for categorical values. Results: 148 cases was diagnosed out of 150 biopsies (98.67%), of which 118 cases were malignant (108 cases can be identified which type and source (91.53%), in which 68 cases were adenocarcinoma), 30 cases were benign. Pneumothorax occurred in 27 (18%) cases, among which, 12% were very mild pneumothorax and 6% were mild to moderate pneumothorax. 44 cases (29.33%) happened bleeding, among which, 21.33% could be classified as very mild, while 8% could be classified as mild to moderate. No infection, tumor implantation or aeroembolism observed. There were no statistically significant differences in the incidence of pneumothorax and bleeding at different distances from the pleura( < 30mm vs ≥30mm, P＞0.05). Conclusions: This series of new techniques in CT-guided percutaneous lung biopsy significantly reduced the incidence of pneumothorax and bleeding and were preliminarily proved that can facilitate acquiring more tumor tissue for molecular testing and re-biopsy of lung cancer. Clinical trial information: ChiCTR1800017958 .
Sex- and co-mutation-dependent prognosis of patients with SMARCA4-mutated malignancies.
Authors: Pan Minggui , Jiang Chen , Achacoso Ninah , Solorzano-Pinto Aleyda V , Tse Pamela , Suga Jennifer Marie , Thomas Sachdev P. , Habel Laurel A.
Published: June 2023

e21031

Background: Whether sex and co-mutations impact prognosis of patients with SMARCA4-mutated (mutSMARCA4) malignancies is not clear. Methods: This cohort included patients from Northern California Kaiser Permanente with next-generation sequencing (NGS) performed from August 2020 to October 2022. We used Cox regression modeling to examine the association between sex and overall survival (OS), adjusting for demographics, performance status, Charlson comorbidity index, receipt of treatment, tumor mutation burden (TMB), and TP53, KRAS, CDKN2A and STK11 co-mutations. Results: Out of 9221 cases with NGS performed, 125 cases (1.3%) had a mut SMARCA4. The most common malignancies with a mutSMARCA4 were non-small cell lung cancer (NSCLC, 35.2%), esophageal and stomach adenocarcinoma (12.8%), and cancer of unknown primary (11.2%). The most common co-mutations were p53 (mutp53, 59.2%), KRAS (mutKRAS, 28.8%), CDKN2A (mutCDKN2A, 31.2%) and STK11 (12.8%) mutations. Male patients had substantially worse OS than female patients both among the entire cohort (HR = 1.76, [95% CI .94-3.30]) with a median OS of 3.0 versus 43.3 months ( P < .001), and among NSCLC cohort (HR = 9.72, [95% CI 2.19-43.19]) with a median OS of 2.75 months versus un-estimable ( P = .02). Among the entire cohort, mutp53 versus wtp53 (HR = 2.16, [95% CI 1.06-4.41]) and mutSTJ11 versus wtSTK11 (HR = 3.09, [95% CI 1.10-8.68]) were associated with worse OS. Among NSCLC cohort, mutp53 versus wtp53 (HR = .20, [.03-1.31]) and mutKRAS versus wtKRAS (HR = .13, [.01-1.03]) were associated with better OS, while mutCDKN2A versus wtCDKN2A (HR = 4.38, [1.13-16.9]) and mutSTK11 versus wtSTK11 (HR = 18.1, [95% CI 1.30-251]) were associated with worse OS. Conclusions: Male patients had substantially worse prognosis than female patients, while MutTP53, mutKRAS, mutCDKN2A and mutSTK11 were differentially associated with prognosis among the entire cohort and among NSCLC cohort. Our results, if confirmed, could suggest potentially unidentified mechanisms that underly this sex and co-mutation-dependent prognostic disparity among patients whose tumor bears a mutSMARCA4.
Cerebrospinal fluid circulating tumor DNA for the detection and characterization of leptomeningeal metastasis in non-small cell lung cancer.
Authors: Miao Qian , Zheng Xinlong , Zheng Xiaobin , Jiang Kan , Lin Gen , Zhang Longfeng
Published: June 2023

e21039

Background: Cerebrospinal fluid (CSF) has revealed the unique genetic characteristics of leptomeningeal metastasis (LM) from non-small cell lung cancer (NSCLC). However, the research in this area is still very limited. Methods: Patients with LM from NSCLC were retrospectively analyzed. Circulating tumor DNA (ctDNA) of CSFand pairedextracranial tissue or plasma were tested by ARMS or next-generation sequencing(NGS).Clinical outcomes were compared with Kaplan-Meier log-rank test and Coxproportional hazards methodologies. Results: We reviewed charts of 80 patients with LM treated atFujian Cancer Hospital. A total of 57 CSF and of which 30 contemporaneouslypaired extracranial samples tested by NGS were analyzed. Most interestingly, CSF ctDNA revealed EGFR mutations in 4 patients previously diagnosed as wild-type by extracranial specimens, and survival was extended by targeted therapy. In the gene map of paired samples, CSF showed more abundant cell-cycle regulatory genes and complex independent evolutionary. CDKN2A/2B CNVs-del was enriched threefold in CSF (~26.3%) with LM compared to extracranial specimens (~8.9%)in lung adenocarcinoma without LM. The median overall survival (OS) was 14.1 months [95% confidence interval (CI): 10.7–17.5 months]. Univariate analyses and multivariate Cox analyses demonstrated that patients with CDKN2A/CDKN2Bco-mutation had poor prognosis. Conclusions: CSF-based ctDNA testing contributes to the phenotypic detection and unique characterization of resistance mechanisms of LM in NSCLC. CDKN2A/2B mutation maybe a poor prognostic factor in LM patients.
Outcome analysis of immunotherapy and possible prognostic role of pretreatment neutrophil-lymphocyte ratio in lung cancer: An Appalachian study.
Authors: Yadala Vivek , Kachynski Yury , Tahboub Ihab , Titus Abraham , Khatri Jai Kumar , Vemula Bhavana , Urella Madhulika , Marshall Kelsey , Shenouda Mina , Jamil Muhammad Omer , Tirona Maria Tria
Published: June 2023

e21053

Background: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of lung cancer resulting in better survival benefits. We are reporting outcome analysis of lung cancer patients treated with ICI in our institution. Methods: We performed retrospective chart review of lung cancer patients treated with ICI at our institution between June 2016 and March 2022. Results: A total of 289 patients were identified- 241 had non-small cell lung cancer (NSCLC) and 48 had small cell lung cancer (SCLC). A total of 109 patients (37.7%) developed immunotherapy related adverse events (IRAE): 92 (38.1%) with NSCLC and 17 (35.4%) with SCLC. Average time to develop IRAE was 3 months in both NSCLC and SCLC. IRAE grades 1,2,3,4 were noted in 33%, 20%, 15%, 31% patients respectively. 34 of 63 (53%) patients who received Ipilimumab-Nivolumab developed more IRAE than any other ICI with fatigue and dermatitis being the most common IRAE associated with this ICI. 79 of 183 (43%) patients who received RT developed IRAE (p = 0.012). Median overall survival (OS) for NSCLC was 35 months, 41 months, 27 months, 15 months for stages 1,2,3,4, respectively (p = 0.03). Median OS for extensive stage SCLC was 14.6 months. Median OS for NSCLC with and without IRAE was 30 and 23 months, respectively (p = 0.02). Median OS for SCLC with and without IRAE was 16.7 and 16.2 months, respectively (p = 0.5). Median OS for NSCLC when steroids were used to treat IRAE was 25 months, and 63 months if no steroids were used (p = 0.027). Better median overall survival rate was noted in patients with low Neutrophil-Lymphocyte ratio (defined as NLR < 5) 29.23 months vs 20.59 months (high NLR) (p = 0.019). Although demographics like male sex, smoking history, higher BMI and poor ECOG performance status had numerically increased the risk of developing IRAE, no statistical significance was noted. Conclusions: Overall results of our analysis are mostly consistent with the current literature on survival rates in Lung Cancer. IRAE may have a predictive role in survival, as we observed that patients with NSCLC developing IRAE had better survival rates. Ipilimumab-Nivolumab combination resulted in more IRAE than any other ICI. Pneumonitis was the most common IRAE among all patients receiving ICI. Also, Radiation-therapy increased the risk of developing IRAE. Our observation that steroid use in treating IRAE was associated with lower survival is concerning. This may be due to higher grade IRAE/toxicities and possible decreased ICI effectiveness. Regardless of IRAE, low pretreatment NLR resulted in better survival rates. The role of pretreatment NLR as a potential prognostic tool to assess survival outcomes requires validation in a randomized clinical trial.
Treatment outcomes in patients (pts) with advanced/metastatic non-small cell lung cancer (NSCLC) harboring MET amplification as a secondary oncogenic driver.
Authors: Ryder Alex , Oksen Dina , Boutmy Emmanuelle , Ellers-Lenz Barbara , Stroh Christopher , Karachaliou Niki
Published: June 2023

e21056

Background: There is limited published evidence on the treatment outcomes of pts with oncogene driven NSCLC who have developed resistance to targeted therapies or novel therapies such as immune checkpoint inhibitors (ICIs) and have MET amplification ( METamp). METamp has been identified as a secondary driver of EGFR TKI resistance. We report here on real-world (rw) outcomes for these pts. Methods: A non-interventional, descriptive cohort study design was applied using ConcertAI electronic medical record data derived from US community oncology centers and linked with ASCO/CancerLinQ data. Eligible pts had stage IIIB–IV NSCLC, and METamp. Study period: Jan 1, 2004 – Oct 31, 2021. Subgroup analyses included 1: pts with oncogene driven NSCLC who received targeted therapy or ICIs after diagnosis of advanced NSCLC, then progressed and had a positive test for METamp, and 2: pts from subgroup 1 who received an EGFR TKI after diagnosis of advanced NSCLC, then progressed and had a positive test for METamp. The presence of METamp after progression on a therapy was hypothesized to indicate METamp as a secondary driver of resistance. Outcomes were analyzed for pts who received a subsequent line of systemic therapy after progression. Results: Of 8,454 pts with lung cancer and minimum 1 molecular test including MET alterations, 164 had METamp (1.9%) and were included in the study cohort. In subgroup 1, 35 pts had METamp detected (21.3%) after disease progression on a targeted therapy or ICIs (EGFR TKI n = 17, ICIs n = 11, other n = 7). Of those pts, 27 received a subsequent systemic therapy after disease progression. The rw overall response rate (ORR) was 18.5% (95% CI: 6.3, 38.1), the median rw progression-free survival (PFS) was 2.2 months (95% CI: 1.6, 4.2) and the median overall survival (OS) from start of the subsequent therapy was 11.3 months (95% CI: 3.4, 21.3). In subgroup 2, 17 pts had METamp detected after disease progression on an EGFR TKI (erlotinib or afatinib n = 13, osimertinib n = 4). Of those pts, 15 received a subsequent systemic therapy after disease progression. The rw-ORR was 13.3% (95% CI: 1.7, 40.5), median rw-PFS was 2.1 months (95% CI: 1.1, 4.6), and median OS from start of the subsequent therapy was 8.5 months (95% CI: 1.7, 15.2). Conclusions: METamp as a secondary driver of resistance is a new target for systemic therapy in pts with EGFR-mutant NSCLC who have developed resistance to EGFR TKIs. Overcoming this resistance using combinations with MET inhibitors is currently under investigation in several clinical trials. The analyses reported here suggests that the treatments available and current standard of care result in poor outcome for pts with METamp, highlighting the high medical unmet need in this population.
Biomarker testing and treatment patterns in US patients (pts) with advanced/metastatic non-small cell lung cancer (NSCLC) harboring MET amplification.
Authors: Ryder Alex , Oksen Dina , Boutmy Emmanuelle , Wang Yuexi , Nisbett Alnecia R. , Stroh Christopher , Johne Andreas
Published: June 2023

e21057

Background: Limited published evidence exists on pts with advanced stage NSCLC harboring MET amplification ( METamp), a rare oncogenic driver. We report here real-world biomarker testing and treatment patterns for these patients. Methods: This was a non-interventional, descriptive cohort study using ConcertAI electronic medical record data derived from US community oncology centers and linked with ASCO/CancerLinQ data. Eligible pts had stage IIIB–IV NSCLC and METamp. Study period: Jan 1, 2004 – Oct 31, 2021. Results: Of 8,454 lung cancer pts with minimum 1 molecular test including MET, 164 had METamp (1.9%). Pts were mainly identified from 2015 onwards and primarily in oncology in the Southern and Midwest regions (86.6%). Majority of pts were tested by tissue biopsy (67.1%), 20.7% by liquid biopsy and 12.2% not specified. At least 64.5% of pts were highly MET amplified (either gene copy number ≥8 or by liquid biopsy ++, +++). Other mutations screened for were ALK, ROS1 and EGFR (99.4%, 98.2% and 97.6%), with oncogenic ALK, ROS1 fusions and activating EGFR mutations in 0.6% and 13.1%, respectively. BRAF and KRAS were less frequently screened for (90.2% and 87.2%), with potential oncogenic alterations in 2.0% and 12.6%. Of 127 pts tested for PD-L1 (by immunohistochemistry), 63.0% were positive, and 72.5% had tumor proportion score ≥50. Eighteen pts had METamp detected after receiving an EGFR tyrosine kinase inhibitor (TKI), indicating METamp as a secondary oncogenic driver. RB1 loss and MYC amplification, as potential mechanisms of MET inhibition resistance, were not frequently screened for (30.5% and 46.3%). RB1 loss was identified in 2.0% and MYC amplification in 15.8%. Next generation sequencing was the most frequent diagnostic used overall. A total of 144 pts (87.8% of 164 pts) received first-line (1L) anticancer therapy; platinum-based chemotherapy 57/144 (39.6%), immune-checkpoint inhibitors 50/144 (34.7%) or EGFR TKI monotherapy 24/144 (16.7%), other 2/144 (1.4%) and MET TKIs (mainly crizotinib) were used in 11/144 pts (7.6%) in 1L, 14/78 (17.9) in second line and 7/42 (16.7%) in third line. Conclusions: In this cohort of pts identified in a US community oncology setting, biomarker screening even for rarer genetic alterations occurred. Concomitant genetic alterations to METamp were infrequent except for alterations of EGFR and KRAS. The frequency of pts with high level of METamp in the cohort may explain the lower frequency of other biomarkers, as high level of amplification indicates a cleaner MET profile. Overall MET inhibitor treatment was not common. Screening for novel and rare biomarkers such as METamp as a primary or secondary oncogenic driver is becoming increasingly important to enable efficacious targeted treatment.
Therapeutic effects of combination with EGFR-TKIs and radiotherapy on the prognosis of stage IV lung adenocarcinomas harboring 19-Del or 21-L858R: A retrospective study.
Authors: Liang Shuai , Li Chengming , Zhang Yingyun , Hua Dong
Published: June 2023

e21067

Background: To evaluate the therapeutic effects of combining epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) with radiotherapy on the prognosis of patients with stage IV lung adenocarcinomas (LUAD) that harbor either exon 19 deletion (19-Del) or exon 21 L858R mutation (21-L858R). Methods: Clinical data in the real-world study were retrospectively collected and analyzed from 177 stage IV LUAD patients who received the combination of EGFR-TKIs and radiotherapy at Shandong Cancer Hospital between June 2012 and August 2017. And the primary endpoint of the study was overall survival (OS). Results: The results revealed that the stage IV LUAD patients harboring 19-Del showed similar clinical characteristics as those harboring 21-L858R (all P > 0.05). The median OS (mOS) of all patients was 32.0 (95%CI, 28.6-35.5) months. Multivariate analysis identified EFGR mutations and thoracic radiotherapy as the independent factors in predicting OS ( P = 0.001, 0.013, respectively). Moreover, subgroup analysis showed that patients who received EGFR-TKIs plus bone metastasis radiotherapy or thoracic radiotherapy showed a longer OS in 19-Del group than those in 21-L858R group (mOS, 34.7 vs. 25.1 months, 51.0 vs. 29.6 months; P = 0.0056, 0.0013, respectively), while not observed for patients with brain metastasis radiotherapy (mOS, 34.7 vs. 25.1 months; P = 0.088). Conclusions: Although there were no significant differences in clinical characteristics of stage IV LUAD patients between 19-Del group and 21-L858R group, patients harboring 19-Del could still achieve longer OS than those harboring 21-L858R after receiving EGFR-TKIs in combination with radiotherapy.
Predicting non-small cell lung cancer response to immune checkpoint inhibitors with machine learning based on heterogeneous biomarkers.
Authors: Schmutz Hugo , Mattei Pierre-Alexandre , Tricarico Pierre , Contu Sara , Hugonnet Florent , Guisier Florian , Decazes Pierre , Chardin David , Humbert Olivier
Published: June 2023

e21068

Background: In patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICPI), individual clinical, biological, and imaging prognostic biomarkers have recently been identified. However, the combination of these biomarkers has not yet been studied. This study aims to analyse various clinical, biological and 18FDG PET/CT parameters using machine-learning algorithms to build more accurate prognostic models of NSCLC response to ICPI. Methods: The exploratory cohort consisted of patients with metastatic NSCLC, treated with either pembrolizumab or nivolumab in monotherapy, included in two prospective cohort studies of our institution. For all patients, a total of 28 baseline quantitative features were collected just before the initiation of ICPI (12 clinical, 6 biological and 10 PET/CT parameters), such as the patient’s ECOG performance status, PD-L1 tumour expression level (PD-L1%), neutrophil to lymphocyte blood ratio, number and metabolism of lesions, metabolic tumour volume (MTV). The two endpoints were the progression-free survival at 6 months (6M-PFS) and the overall survival at 12 months (12M-OS). The 28 features were sorted according to their selection frequency by a LASSO logistic regression on extensive cross-validation to predict 6M-PFS and 12M-OS. The top eight features were selected using the intersection of the most frequently selected features of both outcomes and used to build a logistic regression to predict 6M-PFS and 12M-OS. An independent validation cohort was collected to assess the performance of the 8-features model. This cohort consisted of metastatic NSCLC patients treated with monotherapy ICPI and retrospectively included in three different hospitals: Nice (N =16), Monaco (N =10) and Rouen (N =19). We reported the area under the receiver operating characteristic (AUROC). Results: 117 patients were included in the exploratory cohort (N = 93 for training and features selection and N = 24 for the test set). Without any feature selection, the AUROC of the logistic regression was 73.6% and 77.6% on the test set. Using LASSO, the top eight selected features were: age, MTV, number of lesions, PD-L1%, smoking status, ECOG, SUVmax of the most intense lesion and blood sugar level. The AUROC of the 8-features model was 74.3% for 6M-PFS and 85.5% for 12M-OS on the test set. 45 patients were retrospectively included in the validation cohort. The AUROC of the model were 81.9% for the 6M-FPS and 88.2% for the 12M-OS. Conclusions: The combination of heterogeneous biomarkers provides a powerful model for predicting the outcomes of NSCLC patients treated with ICPI. Rigorous feature selection is a critical point in ML approaches to avoid overfitting. [Table: see text]
Safety and efficacy of stereotactic body radiotherapy (SBRT) to oligoresidual sites combine with osimertinib in stage IV EGFR mutant NSCLC patients: A prospective pilot study.
Authors: Chen Cheng , Wang Ying , Liao Siqin , Zheng Bin , Chen Chen , Zeng Bangwei , Liao Lianming , Xu Benhua , Chen Chun
Published: June 2023

e21069

Background: Presently osimertinib is used as first-line therapy in stage IV EGFR mutation NSCLC patients. Unfortunately, acquired resistance gradually develops, resulting in disease progression in most patients after 1 to 2 years. A retrospective study demonstrates that similar to the first- and second-generation EGFR-TKIs, half of the patients experienced failure within the residual disease. Consolidative local therapy had been evaluated as a promising strategy to improve PFS and delayed the appearance of new metastatic lesions in the pre-osimertinib era. It is intriguing to hypothesize that new distant metastases may arise from drug-resistant tumor cells at the residual tumor lesions. Therefore, compared to the salvage SBRT, preemptive consolidative SBRT to all oligo-residual tumor sites could potentially prevent recurrence and improve survival. Of note, this proposal is challenging because both EGFR-TKI and thoracic radiation have a detrimental effect on pulmonary interstitial tissue. Two retrospective studies had reported severe pneumonitis with radiotherapy plus osimertinib. Therefore, the potential toxicity profile needs to evaluate prospectively. Therefore, we performed this preliminary trial (ChiCTR2100053807) to evaluate the safety of consolidation SBRT at maximal osimertinib response. Methods: Patients were enrolled if residual metastasis was limited to five sites. Consolidative SBRT was initiated to all residual sites with different doses (30–50Gy) and fractions (3-10) when maximal tumor shrinkage was achieved with osimertinib. The primary endpoint was an adverse reaction defined by the Common Terminology Criteria for Adverse Events, version 4.0. Results: 5 consecutive patients were enrolled between December 2021 and December 2022. 80% of their residual disease was located in the lungs and lymph nodes, which constituted targets for thoracic SBRT. The median time to maximal response was 3 months (range, 2-6). The median follow-up time from consolidative SBRT was 6 months（range,6-12）. The most common grade 1-2 adverse events included leukopenia (60%, n = 3), anorexia (40%, n = 2), lymphopenia (40%, n = 2), paronychia (40%, n = 2), rash (40%, n = 2), which were thought to be likely related to osimertinib. One patient suffered from grade 1 pulmonary fibrosis at 16 months after SBRT. There was no Grade 3/4 acute and late radiation toxicity. So far, no disease progression occur with a median follow-up time of 18 months（range, 13-19）. Conclusions: This pilot studydemonstrated concurrent treatment with osimertinib and SBRT for the oligo-residue disease at TKI maximum response was well tolerated. Future prospective, randomized studies are desirable to confirm these preliminary findings. Clinical trial information: ChiCTR2100053807 .
Anaplastic lymphoma kinase (ALK) and ROS 1– positive advanced NSCLC: A real-world institutional experience.
Authors: Bala Stalin Chowdary , G Sindhu , Chennamaneni Rachana , Konatam Meher Lakshmi , Gundeti Sadashivudu
Published: June 2023

e21074

Background: A novel fusion gene of EML4-ALK and ROS 1 has been identified in a subset of non-small-cell lung cancers (NSCLCs). Patients with the ALK-EML4 and ROS1 fusion gene demonstrate unique clinicopathological characteristics and treatment with targeted therapy led to improved survivals. Various clinical trials had shown the efficacy of ALK inhibitors, and they had become the standard of care. The real-world data of ALK inhibitors from a developing country like India is sparse and the present study was designed to analyze the incidence and outcomes of ALK positive NSCLC. Methods: Data of advanced NSCLC patients diagnosed between 2016 and 2022 with ALK and ROS1 positivity was analyzed. Detection of ALK was done by IHC or fluorescent in situ hybridization (FISH) and ROS1 was done by FISH. Results: A total of 776 advanced NSCLC patients between 2016 and 2022 were tested for ALK of which 63(8.1%) were positive. The median age at presentation was 50 years (range, 19-80 years). Of 63 patients, 34(54%) and 29(46%) were males and females. Cough (83%) was the most common symptom at presentation followed by breathlessness (73%), anorexia (59%) weight loss (59%) and chest pain (43%). The median duration of symptoms was 3 months (range, 1-18). 44(86%) patients were never smokers and 9(14%) patients had history of smoking or tobacco usage. The most common site of metastases was opposite lung (59%) followed by bone (50%), pleural effusion (41%) and brain metastasis were seen in 13(21%) patients. Adenocarcinoma was the most common histology (95%). Detection of ALK positivity was done by IHC and FISH in 45(72%) and 18(28%) patients. Of 63 patients, 52 patients received at least 4 months of treatment and were assessed for survival. First line therapy was crizotinib, chemotherapy followed by maintenance crizotinib, ceritinib, Alectinib in 40(77%), 4(7.7%), 6(11.5%) and 2(3.8%) patients respectively. At a median follow up of 14 months, the one-year progression free and overall survival was 71% and 75% respectively. The 2 year and 3-year OS were 54% and 30% respectively. Of 322 patients tested for ROS1, 9(2.8%) were positive for ROS1 translocation and received first line therapy with crizotinib. The one-year PFS and OS of ROS 1 positive patients were 75% and 89% respectively. Conclusions: ALK and ROS1 positivity was seen in 8.1% and 2.8% of advanced NSCLC patients. Majority of patients were never smokers. Opposite lung and bone were the most common site of metastases. Approximately more than half of the patients had two-year survival rate and survivals are almost similar to clinical trials. Crizotinib is well tolerated in majority of patients.
Clinical efficacy analysis of furmonertinib and structural insights into sensitivity to diverse TKIs for NSCLC with EGFR exon 20 insertion.
Authors: Zhang Xiao , Feng Guoxing , Liu Baoxing , Han Huan , Dong Bosheng , Yang Yanfang , Zhu Hui , Wang Huijuan , Fan Saijun , Tang Hong
Published: June 2023

e21084

Background: Currently approved EGFR TKIs have dissatisfactory efficacy in most advanced NSCLC with EGFR exon 20 insertion mutations (EGFRex20ins). Whereas，preclinical studies have shown that furmonertinib demonstrated significantly antitumor activity in NSCLC with EGFRex20ins in vitro and in vivo. Here, we analyzed the clinical efficacy of furmonertinib in patients(pts) who harboring EGFRex20ins and explored mechanism. Methods: A retrospective single-arm analysis was performed to evaluate the efficacy of 20 NSCLC pts harboring EGFRex20ins receiving furmonertinib treatment who were determined at three institutions between Feb 2021 to Jul 2022. ORR, DCR, PFS, DOR and OS were analysed. The last follow-up time was February 1, 2023. Meanwhile, we investigated the clinical efficacy of furmonertinib (8 pts) versus osimertinib (8 pts) as second-line treatment, because pts about furmonertinib as first-line treatment were immature. In addition, the binding activity of different EGFR TKIs to EGFRex20ins were computationally constructed based on the crystal structure of EGFR_D770_N771insNPG/V948R (PDB ID: 7LGS) by the Schrödinger software (2021-2 Release, Schrödinger Inc., Portland, Oregon). Results: There are 10 (50.0%) females and the median age was 51 (32-77) years old. Of the 20 pts selected, we found that EGFRex20ins p.S768_D770dup (n = 5) variants were more common. We observed 14 pts with PR and six pts with SD as best response to furmonertinib (ORR: 70.0%, DCR: 100%). All pts showed tumor shrinkage in target lesions (median best percent change, -36.43% [-74.78%, -5.56%]). Median PFS was 10.2 (95 % CI, 7.00-13.40) months(mo). Median DOR was 8.5 (95 % CI, 5.08-11.92) mo. 13 pts were still alive by the last follow-up date. Comparative analysis of the efficacy of different groups showed that median PFS was significantly longer in furmonertinib group than in osimertinib (10.2 vs 3.8 mo, p = 0.008). Median OS was numerically longer in furmonertinib group than in osimertinib (18.9 vs 11.7 mo, p = 0.148). No grade 3 or above adverse events were observed. Furthermore, rather than erlotinib (GlideScore: -5.564; MM/GBSA: -52.8044), gefitinib (-7.68; -47.317), and afatinib (-5.075; -44.64), furmonertinib (-11.085; -68.1575) and osimertinib (-10.031; -63.87) revealed favorable binding activity to EGFRex20ins, with furmonertinib being the most significant. Conclusions: Furmonertinib might have positive clinical efficacy to advanced NSCLC pts with EGFRex20ins on account of its favorable binding activity to EGFRex20ins. It may be the optimal choice for these pts in the future.
Clinical outcomes with frontline immunotherapy (IO) in BRAF-mutant NSCLC.
Authors: Marin-Acevedo Julian A. , Thapa Ram , Puri Sonam , Hicks James Kevin , Gray Jhanelle Elaine
Published: June 2023

e21089

Background: Oncogenic BRAF mutations are present in approximately 4% of non-small cell lung cancers (NSCLC). They are categorized as class I, II, or III according to their effect on the MAPK pathway. Little is known about how oncogenic BRAF mutations influence tumor PD-L1 expression and response to IO. We evaluated the clinical outcomes of frontline IO among BRAF classes. Methods: We performed a retrospective analysis of patients with BR AF-mutant NSCLC from January 1, 2012 through March 30, 2020. BRAF mutations were detected using next-generation sequencing or genotyping methods. PD-L1 expression was assessed using 22C3 or SP263 assays. Patient demographics were collected through electronic medical records review. In those with advanced/metastatic disease, we captured response to anticancer therapies using standardized real-world (rw) criteria and calculated rwOS using Kaplan-Meier method with log-rank test. Results: Of all 9,004 lung cancer patients (all histologies) with genotyping testing, 79 had NSCLC and an oncogenic BRAF mutation. 52% were females, 95% had adenocarcinoma, 81% were active/former smokers, and 76% had PD-L1 ≥1%. 39 patients had class I, 24 had class II, and 16 had class III mutations. Of these, 43 patients had advanced/metastatic disease evaluable for response. Patients with class I mutations who received first-line IO trended towards improved rwOS (42.6 months) vs. frontline anti-BRAF therapy (22.7 months; p= 0.51) and chemotherapy (19.6 months; p= 0.63). Patients with non-class I mutations, also trended towards improved rwOS with frontline IO (18.8 months) compared to frontline chemotherapy (9.9 months; p= 0.25). Outcomes were better in all patients with PD-L1 levels ≥1% and ≥50% who received IO. Patients with non-class I variants tended to have shorter rwOS with IO or chemotherapy compared to those with class I mutations (Table 1). Despite an overall trend towards improved outcomes with first-line IO, results did not reach significance likely due to the limited number of evaluable patients. Conclusions: The use of frontline IO may be associated with better outcomes than frontline chemotherapy or targeted therapies in patients with BRAF-mutant NSCLC. Patients with class I mutations and/or higher tumor PD-L1 expression seem to derive the most benefit. [Table: see text]
Evaluation of the prevalence of MET and protein tyrosine kinase 7 expression in non-small cell lung cancer to evaluate overlap of ADC antigens.
Authors: Ansell Peter J. , Camidge D. Ross , Baijal Shobhit , Xia Xiaoyu , Vasilopoulos Athanasios , Li Martha , Seshadri Ramya , Arvanitis Leonidas , Lindsey Sidney S. , Cai Mona H. , Choi Yookyung Christy , Ratajczak Christine , Jeng Edwin E. , Gruber Stephen B. , Lu Shun
Published: June 2023

e21105

Background: Biomarker-targeted antibody-drug conjugates (ADCs) have shown promise in treating lung cancer. Telisotuzumab vedotin (Teliso-V; ABBV-399) is a first-in-class MET (also known as c-Met)-directed ADC comprising the monoclonal antibody telisotuzumab (ABT-700) conjugated to a cytotoxic microtubule inhibitor, monomethyl auristatin E (MMAE), via a cleavable dipeptide linker. In the phase 2 LUMINOSITY study (NCT03539536), Teliso-V demonstrated promising anticancer activity in previously treated patients with MET-overexpressing (OE), non-squamous epidermal growth factor receptor wild type ( EGFR WT) non-small cell lung cancer (NSCLC; 52.2% overall response rate in MET OE high group, 36.5% in all MET OE cohort [intermediate and high]) and an acceptable safety profile (Camidge et al. J Clin Oncol. 2022;40:16 suppl, 9016). These data provide proof of concept that biomarker-selected MMAE-based ADCs could be beneficial to patients with NSCLC. Cofetuzumab pelidotin (ABBV-647), an ADC with a similar composition to Teliso-V, contains an anti-protein tyrosine kinase 7 (PTK7) monoclonal antibody (hu6MO24) conjugated to a microtubule-inhibiting cytotoxin, Aur0101 auristatin, via a cleavable cysteine-reactive linker. PTK7 expression and oncogenic functions have been reported in several cancers. We sought to establish the co-prevalence of MET OE and PTK7 in NSCLC to understand if both these antigens targeted by ADCs are co-expressed or present in distinct tumors. Methods: Antigen prevalence was analyzed in tumor samples from patients at the City of Hope National Medical Center with non-squamous NSCLC and EGFR WT or unknown status. Immunohistochemistry (IHC) assays used were MET (SP44) Assay for MET OE (Roche Tissue Diagnostics; positive if ≥25% cells at 3+ intensity) and an AbbVie-developed assay for PTK7 expression (positive if ≥90% cells at ≥2+ intensity). Results: A total of 148 patients (median age 67 years, 52% stage ≥III at diagnosis, 68% ECOG 0–2) were screened (data shown in table). About 24% of the patients were MET IHC positive, whereas 11% were PTK7 IHC positive. Further, MET OE and PTK7 had complementary prevalence with only 3% of the patients co-expressing both antigens. Conclusions: MET OE and PTK7 expression by IHC were found to be complementary in patients with non-squamous EGFR WT/unknown NSCLC. About 32% of patients were positive for MET OE or PTK7 expression or both. Data represent patients from a single center and more pre-treatment tissue samples that were viable and available. These IHC findings suggest that MET OE and PTK7 are indeed complementary NSCLC biomarkers. [Table: see text]
Clinical trial versus standard of care in EGFR-wild type and ALK- negative lung adenocarcinoma: A propensity-matched analysis.
Authors: Jung Hyun Ae , Park Boram , Park Sehhoon , Sun Jong-Mu , Lee Se-Hoon , Ahn Jin Seok , Ahn Myung-Ju
Published: June 2023

e21116

Background: Clinical trials have been a vital role for survival improvement in recurrent or metastatic lung cancer. Recent advances in targeted therapy for EGFR-mutant or ALK-positive lung adenocarcinoma dramatically increased survival. However, EGFR-wild type and ALK negative lung adenocarcinoma still had relatively poor survival outcome. Clinical trial of targeted therapy for rare driver mutation or immunotherapy was introduced in 2015. Moreover, next-generation sequencing was reimbursed in 2017 in Korea. This study evaluated the benefit of clinical trials for EGFR-wild type and ALK negative lung adenocarcinoma in recent 5 years. Methods: This study included patients with recurrent or metastatic lung adenocarcinoma who received systemic treatment between March 2017 and June 2022 at Samsung Medical Center. We compared overall survival in group with clinical trial and the standard of care (SOC) by using propensity score matching (PSM) (1:1). We used cox proportional hazard models to calculate the hazard ratio (HR) and 95% confidence interval while accounting for clustering among matched pairs. Results: Of total, 1,686 EGFR-wild type and ALK negative lung adenocarcinoma were included for final analysis. Among them, 1,380 received SOC only and 306 patients enrolled at least one clinical trial. In a group of clinical trial, 41.5%, 29.1%, and 23,2% of patients were enrolled for first-, second-, and third-line treatment, respectively. To achieve the balance between the SOC group and the clinical trial group, 8 baseline characteristics (age, sex, smoking history, ECOG performance status, brain metastasis, liver metastasis, bone metastasis, and rare driver mutation) were included. After PSM, 612 patients were matched to group of the SOC (n = 306) and the group of clinical trial (n = 306). Among the clinical trial, 27.8% was a clinical trial of targeted therapy and 72.2% was a clinical trial of immunotherapy or others. Median follow-up duration was 32.8 months (range, 5.0–64.4). Median overall survival was 17.1 months (95% CI, 13.2–21.4) for SOC and 27.3 months (95% CI, 22.1–32.4) for group of clinical trial (HR = 0.71 (95% CI, 0.58–0.88, P = 0.002). Conclusions: This study showed the performance of clinical trials for patients with EGFR-wild type and ALK-negative lung adenocarcinoma at tertiary hospital. After PSM, clinical trials showed survival benefits that reduced the risk of death by 29% in patients with EGFR-wild type and ALK-negative lung adenocarcinoma.
Correlation of homologous recombination deficiency (HRD) score with response to the first-line treatment of immune checkpoint inhibitors plus chemotherapy in non-small cell lung cancer.
Authors: Li Guo , Zeng Lili , Wang Lingling , Cai Yuhang , Xuan Chenghao , Zhong Dian-Sheng , Zhang Linlin
Published: June 2023

e21121

Background: Homologous recombination (HR) gene mutations were reported to be associated with efficiency of immune checkpoint inhibitors (ICIs). However, up to date, no recognized standard has been set up for definition of HR mutation (+), which limited its clinical application. Homologous recombination deficiency (HRD) score reflects genomic scar induced by HR genes alteration and disfunction. Thus, it may be worth to explore whether HRD score could predict the efficacy of ICIs-based therapy. Methods: We collected tumor tissues from metastatic non-small cell lung cancer (NSCLC) patients who received first-line treatment of ICIs combined with platinum-based chemotherapy. HRD score testing were carried by BGI genomic scar analysis kit, which calculates the sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), large-scale state transitions (LST) scores, and corrected by ploidy of tumor samples, through next generation sequencing(NGS) data. The association of HRD score and response to ICIs plus chemotherapy were analyzed. Results: 22 EGFR/ALK wild-type metastatic NSCLC patients were included. The average HRD score was 24.57, varying from -26.37 to 92.34. Threshold traversal was performed based on analysis of the progression free survival (PFS) data from the included NSCLC patients. HRD score 31 or more were define as HRD (+). Kaplan-Meier PFS Survival analysis showed prolonged median PFS (mPFS) in HRD (+) versus HRD (-) NSCLC patients (N/A vs. 7.0 ms, Log-rank P = 0.029; HR 0.20, 95%CI 0.04-0.96, likelihood-ratio P = 0.03). The objective response rate (ORR) was 45.5% (5/11) in HRD(+) versus 27.2% (3/11) in HRD(-) patients. In patients with PD-L1 TPS≥1% (22C3), the mPFS was N/A vs. N/A, and the ORR was 75.0% (3/4) vs. 37.5% (3/8), in HRD (+) vs. HRD(-) patients. In patients with PD-L1 TPS < 1% (22C3), the mPFS was 8.5 ms vs.2.0 ms (Log-rank P = 0.0085; HR 0.08, 95%CI 0.01-0.82, likelihood-ratio P = 0.02), and the ORR were 28.6% (2/7) vs. 0%(0/3), in HRD (+) vs. HRD(-) patients. Conclusions: In addition to PD-L1 expression level, HRD score would be a potential promising biomarker for predicting the efficiency of ICIs plus platinum-based chemotherapy in NSCLC patients.
Effect and safety of combining bevacizumab and fractionated stereotactic radiotherapy for brain metastases in patients with non-small cell lung cancer: A phase II trial.
Authors: Zhou Rui , Zheng ShiYang , Huo LanQing , Luo QiaoTing , Wang DaQuan , Guo JinYu , Liu BiaoShui , Zhang Jun , Wang Bin , Qiu Bo , Liu Hui
Published: June 2023

e21132

Background: W e aimed to assess the efficacy and safety of c ombining b evacizumab and fractionated stereotactic radiotherapy ( FSRT ) for brain metastases (BMs) in non-small cell lung cancer ( NSCLC ) patients with stable extracranial disease status in this study. Methods: NSCLC patients with BMs were recruited between J anuary 20 20 and J anuary 202 2 . P atients were assigned to receive FSRT of 40Gy in 10 fractions (BED 56eGy) or 30Gy in 5 fractions (BED 48eGy). Meanwhile, bevacizumab was administered before FSRT (d1) and after FSRT (d21) with a dosage of 7.5mg/Kg. The primary endpoint of the study is intra-cranial progression-free survival (IPFS) . The secondary endpoints contained overall survival (OS), progression-free survival (PFS) , quality of life (QOL) score and toxicities. All time-to-event endpoints (IPFS, OS and PFS) were measured from the end of radiotherapy. Results: From J anuary 2020 and J anuary 202 2, 108 patients were recruited with a median follow-up duration was 15.2 months . The 1-year IPFS and OS rate were 82.9% ( 95% confidence interval (CI), 79.6%-86.2% ) and 80.4% ( 95% CI, 76.8%-84.0% ), respectively . The median PFS was 15.0 months ( 95% CI, 9.50-20.50 months ). The median IPFS and OS had not been reached at the time of the last follow-up. The treatment-related toxicities were mild with low incidence. Reversible mild hypertension and cerebral radio-necrosis were observed in 2 and 1 patients, respectively. No signs of ex tra-lesional haemorrhage and progression of peri-lesional oedema was found during the assessment period of treatment response. More importantly, significant improvent of QOL was observed in symptomatic patients. Conclusions: The combination of FSRT with bevacizumab in patients with NSCLC was well tolerated and achieved promising intracranial disease control. Patients maintained satisfactory QOL after receiving the combined regimen with low incidence of cerebral radio-necrosis. Clinical trial information: NCT04345146 .
Association between body mass index and survival outcomes for patients with advanced non–small-cell lung cancer treated with immune checkpoint inhibitors: A systematic review and meta-analysis.
Authors: Sun Yanxin , Sun Yuping , Li Juan , Gao Aiqin
Published: June 2023

e21136

Background: Growing researches have focused on obesity as an useful prognostic factor for pan-cancer patients with immmnotherapy. The role of body-mass index (BMI) in predicting response to ICIs is not consistent in different tumors. This meta-analysis was conducted to evaluate the relationship between BMI and outcome in patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors, which is not clear as studies have demonstrated inconsistent results and significant interpretation biases. Methods: We searched PubMed and Embase, for relevant studies published up to December 2022. Title/abstract screening, full-text review, data extraction, and quality assessment were performed independently. Results: The correlation between BMI and prognosis in patients with advanced non-small cell lung cancer treated with ICIs was compared in ten trials encompassing 5000 individuals with the disease. The findings showedthat immunotherapy was significantly more effective for non-small cell lung cancer patients with a higher BMI compared to those with a lower BMI (OS: HR: 0.832, 95% CI: 0.725-0.955, p = 0.009; PFS: HR: 0.860, 95% CI: 0.771-0.960, p = 0.007). While，in the investigation of the obese group, no statistically significant differences were found. Conclusions: In patients with advanced non-small cell lung cancer treated with ICIs, appropriate higher BMI was significantly linked to better outcomes. However, discrepant findings from different cutoff subgroup analyses urgently call for further analysis.