bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical outcomes and genomic landscape of patients (pts) with EGFR-mutant lung cancer (EGFR+ LC) with central nervous system (CNS) metastases (mets).
Authors: Sui Jane Sze Yin , Wilcox Jessica , Tischfield Samuel , Choudhury Noura J. , Riely Gregory J. , Kris Mark G. , Boire Adrienne Ann , Yu Helena Alexandra 
Published: June 2023

e21146 Background: CNS mets are a major cause of morbidity and mortality in pts with LC. Up to 50% of pts with EGFR+ LC develop CNS mets over their disease course despite improvements in anti-EGFR therapies. The genomics alterations present in CNS mets in pts with EGFR+ LC and how these may compare to paired systemic samples has not been reported. Furthermore, it is unknown whether there are baseline clinicogenomic features that differ between EGFR+ LC pts with or without (w/wo) CNS mets. Methods: From an institutional database of LC pts with available next-generation sequencing (NGS) completed by MSK-IMPACT, we identified all EGFR+ LCs with molecularly characterized CNS tumor samples (CTS). We subsequently identified all pts with EGFR+ LCs with available paired CTS and systemic tumor samples (STS) profiled with MSK-IMPACT. All pts treated with 1L osimertinib with MSK-IMPACT available on their STS were also identified. We assessed clinicogenomic features of all selected EGFR+ LCs. Comparisons of frequencies of genes altered by somatic alterations were performed using Fisher’s exact test and logistic regression. Results: From 2014 to 2022, 90 EGFR+ LC pts with NGS performed on CTS were identified [brain metastasis (BrM), n = 38; leptomeningeal w/wo BrM (LM), n = 52]. 69 pts (77%) were female, median age 59 (IQR range:53-66 years), and 51 pts (57%) were never smokers. Patterns of EGFR+ were exon 19del (n = 43), L858R (n = 27) and atypical (n = 20). No genomic mutations were differentially altered in pts with LM vs BrM. Paired CTS and STS were available for 28 pts, where numerically higher rates of CDKN2A, CDKN2B loss and RAC1 amplification were seen in the CTS (respectively 43% vs 18%, 43% vs 18%, and 21% vs 0%, q > 0.05 for all). A total of 263 pts on 1L osi had NGS on their STS performed:136 pts (52%) had CNS mets during their disease course to date [94 pts (69%) de novo CNS mets; 42 pts with on-treatment CNS mets with median time to CNS mets of 25 mo (IQR: 13.5-35.3 mo)]. Between pts w/wo a lifetime history of CNS mets, there were no differences in sex, smoking history, EGFR alterations and co-alterations. CARD11 alterations were numerically higher in STS in pts with CNS mets (12% vs 2%, q > 0.05). Conclusions: In patients with EGFR+ LC, there were no genomic alterations that were significantly enriched in CNS mets compared to systemic disease, and no systemic genomic alterations that differentiate pts w/wo CNS mets.
Efficacy and safety study of osimertinib in advanced non-small cell lung cancer (NSCLC) with EGFR mutation.
Authors: Samblás Victoria García , Fernández Madrigal Laura , Rodriguez Garcés Maria Yeray , Inoriza Angel 
Published: June 2023

e21150 Background: The frequency of transmission on EGFR is more frequent in women and non-smokers. It is characteristic of the Asian population (10% in the Caucasian race). EGFR tyrosine kinase domain inhibitors (EGFR-TKIs) are the standard first-line therapy in non-small cell lung cancer (NSCLC) with EGFR mutations. The efficacy and safety of osimertinib (third generation TKI-EGFR) were evaluated in the FLAURA phase III clinical trial, comparing it against first and second generation TKI-EGFR (erlotinib and gefitinib) in patients with advanced NSCLC. The objective is to evaluate the efficacy and safety of osimertinib in routine clinical practice at the Juan Ramon Jimenez Hospital. Methods: Descriptive observational, and retrospective study of patients with advanced NSCLC and EGFR + treated TKI-EGFR in the period 2015-2022. We analyzed (IBM SPSS Statistics 22) sociodemographic and clinical variables, toxicity profile, objective response rate (ORR), treatment response and progression-free survival (PFS) with Kappan-Meier curves. Results: We included 41 patients (p). 24 women (58.5%). The median age 66 years. 61% had a smoking habit (39% active smokers and 22% ex-smokers). 1p South American race, rest Caucasians. Present histologies: adenocarcinoma (87.8%), squamous cell (4.9%) and signet ring cells (2.4%). EGFR mutations: 53.7% exon 19 deletion and 36.6% exon 20 mutation and 9.8% were not specified. In 10 p the T790 mutation was analyzed, positive in 14.6%. Stage at diagnosis: IV (87.8%); III (12.2%). Symptoms at diagnosis: persistent cough (22%), pain (22%), dyspnea (19.5%) and constitutional syndrome (12.2%). Status Performance: 0-1 (85.4%). Pulmonary (48.8%), bone (36.6%), lymph node (29.3%), liver (22%), brain (22%), and adrenal (14.6%) metastases. 58.5% received osimertinib in the first line, 17.1% in the second. ORR: 77.4% partial response, 9.7% complete response and 12.9% disease progression. Toxicity (T) 90.9%. Digestive T: Diarrhea: grade G1 36.7%, G2 13.3%, G3 6.7%; nausea: G1 3.3%; hyporexia: G1 25.8%; hypertransaminasaemia: G1 3.2%. Dermal T: skin dryness: G1 20.7%, G2 10.3%, G3 3.4%; onycholysis: G1 19.4%. Asthenia: G1 25.8%, G2 12.9%, G3 12.9%. Pneumonitis: G1 3.2%, G2 3.2%, G3 6.5%. Hematological T: anemia: G1 6.5%, G2 16.1%, G3 3.2%. Dose reduction to 40 mg (37.5%). 12.5% discontinued osimertinib. mPFS in 1st line (L): 14 m (m). mPFS in 2nd L: 8 m. 95% CI (0-31.5). 95% CI (9.8- 18.1. mOS: 21 m (95% CI: 17.73-24.26). Conclusions: Osimertinib presents an adequate safety profile for patients with G1, G2 toxicities, generally easy to manage in clinical practice. A very low percentage of patients had to discontinue treatment. No fatal adverse event was reported. Our results in OS and PFS, although favorable, are somewhat lower than those of the FLAURA clinical trial, possibly due to dealing with real-life patients and/or the size of the sample, which is not entirely sufficiently representative.
How comparable are outcomes for approved PD-1/PD-L1 checkpoint inhibitors (CPI)? A model-informed drug development approach to answer the question.
Authors: Zhao Molly , Mangal Naveen , Witjes Han , Zierhut Matthew L , Chen Ting , Dang Thao , Girish Sandhya , Kasichayanula Sreeneeranj 
Published: June 2023

e21152 Background: Treatment strategies in metastatic non-small cell lung cancer (mNSCLC) have been implemented by anti-PD-(L)1 based therapies. This work aimed to develop a model-based meta-analysis (MBMA) to compare ORR, median PFS (mPFS), median OS (mOS), and treatment-related adverse events Grade 3-5 (TRAEs Gr3+) among anti-PD-(L)1 therapies in mNSCLC. Methods: A curated database of phase 1, 2, and 3 study results in mNSCLC patients treated with at least one FDA-approved PD-(L)1 CPI was used for these analyses. The ORR, mPFS, mOS, and TRAEs Gr3+ analysis datasets included results from 40, 39, 35 and 45 studies, and represented 13324, 13220, 13029, and 21077 patients, respectively. Treatments included: platinum doublet (Pt), pembrolizumab (+/- Pt), nivolumab (+/- Pt and +/- ipilimumab), atezolizumab (+/- Pt), and cemiplimab. Models were developed to quantify drivers of variability on outcomes across trials (i.e., treatment, covariates, random effects). The following covariates were evaluated: PD-L1 expression, line of therapy, ECOG PS, histology, geography/race, sex, age, and smoking status. Results: Treatment naïve patients showed better efficacy than treatment experienced patients, while higher PD-L1 expression was associated with improvement for CPI-containing therapies. Asian-majority trials and patients with PS 0 achieved higher mOS. After adjusting for covariates, similar efficacy was observed across PD-(L)1 within both mono- and combination therapy groups (Table 1). No clinically meaningful covariates were identified for TRAEs Gr3+. Rates were comparable between chemotherapy +/- PD-(L)1, but lower for PD-(L)1 monotherapy. Conclusions: MBMA enables an appropriate comparison of CPI-containing therapy using published study results. To our knowledge, this is the first such analysis in mNSCLC comparing efficacy and safety across PD-(L)1 based therapies. Results suggest PD-(L)1 CPI have similar treatment outcomes in mNSCLC, and PD-L1 expression may be more impactful on clinical benefit of monotherapy compared to CPI combination with chemotherapy. [Table: see text]
Efficacy and safety study with alectinib in advanced ALK-positive non-small-cell lung cancer.
Authors: Fernández Madrigal Laura , Samblás Victoria García , Amor Urbano María , Inoriza Angel 
Published: June 2023

e21153 Background: 5% of patients with non-small-cell lung cancer (NSCLC) have a translocation of the ALK (anaplastic lymphoma kinase) gene on chromosome 2. The phase III clinical trial (ALEX study) analyzed the efficacy and safety in patients with a diagnosis of NSCLC and ALK mutation -positive (ALK+) randomized to alectinib versus crizotinib. The objective of our study is to describe our results with alectinib. Methods: Observational and descriptive study of patients with advanced NSCLC and ALK+ treated with alectinib in the period 2019-2022. Sociodemographic and clinical variables, toxicity profile, objective response rate (ORR), treatment response and progression free survival (PFS) were extracted and entered into IBM SPSS Statistics 22 for statistical analysis. Results: 7 patients received treatment. The median age was 46 years. Baseline characteristics: male (57%); non- Asian race (100%); non-smoker (57%), ECOG 0-1 (100%). All had adenocarcinoma histology. 57% had liver metastasis and 37% central nervous system metastasis at the time of diagnosis. The most frequent symptom was dyspnea (43%). Only one patient was previously terated with 2 lines of chemotherapy and a 3rd line with crizotinib prior to alectinib. Adjuvant chemotherapy was administered in one patient. The rest of the participants received alectinib as first line. The most frequent toxicities were: grade 1-2 increased alanine and aspartate aminotransferase (70%); grade 1 anemia (28.6%); grade 1 increased blood bilirubin (28.6%), skin toxicities (71.5%), myalgia (57%), visual disorders (28.6%); constipation (28.6%) and sinus bradycardia (14.5%). A 28.6% incidence of dose reductions due to adverse events (AEs) with alectinib. One patient had to discontinue treatment with alectinib due to grade 4 AEs consisting of toxic pneumonitis.Hospital admission was required. The ORR was 57.2%. Complete response ocurred in 28.6% of patients. The median response to treatment was 16 months and the median PFS was 16 months. Conclusions: The sociodemographic characteristics of our patients were similar to those described in the ALEX trial. However, the AEs were higher in our study. The ORR was lower in our study, despite obtaining a high percentage of complete responses. We have a reduced number of patients who have been treated with alectinib to obtain final conclusions efficacy.
Prevalence of KRAS p.G12C mutation in patients with metastatic non-small cell lung cancer in Argentina.
Authors: Mendoza Bertelli Andrea , Otero Pizarro Maria Mercedes , Fernandez Maria Paz , Dibarbora Delfina , Cantarella Maria Florencia , Mahmoud Yamil Damian , Girotti Romina , Guttlein Leandro , Chico Isagani , Brandalise Patrícia , Dutra Carolina , Salanova Ruben 
Published: June 2023

e21155 Background: KRAS is mutated in ∼30% of non-small-cell lung cancer (NSCLC). Most of the mutations involve codon 12 of exon 2, with G12C mutation being the most frequent (~12%). Differences in mutational frequency have been demonstrated in patients of different ethnicities and smoking status. However, the effects of ancestry and environmental factors have not been exhaustively described for the Argentine population. Methods: An observational study was conducted in a cohort of 1810 patients. Specifically, 1510 retrospective tissue samples and 300 prospective tissue samples were analyzed by quantitative PCR(qPCR) using AmoyDx KRAS Mutation Detection Kit. A validation was also performed on 181 tissue samples by digital droplet PCR (ddPCR) with the commercial kit PrimePCR ddPCR Mutation Detection Assay Kit: KRAS p.G12C (Biorad). Statistical analyses were performed to address the association of KRAS p.G12C across demographics characteristics such as smoker-ex smoker / no smoker condition, sex, age, geographical distribution, histological subtype, metastasis or primary tumor and organ site of metastasis. Results: A prevalence of 14.48% in KRAS p.G12C was observed comparable with those observed in other populations. A significant association was observed between clinical variables and KRAS p.G12C prevalence: the proportion of KRAS p.G12C is increased in stage IV samples compared to stage III (p = 0.012) and in active smokers/ex-smokers compared to non-smokers (p < 0.0001). The proportion of KRAS p.G12C decreases in samples from the pleura as a biopsy site. Our results suggest that there is a 92.05% concordance between qPCR KRAS p.G12C kit and ddPCR. Conclusions: This study represents a deep understanding of KRAS p.G12C mutational landscape in the Argentine population and its association with demographic and clinical characteristics and demonstrates that qPCR is a feasible methodology for routine testing.
Restaging scans frequency heterogeneity in patients being treated for stage IV non-small cell lung cancer (NSCLC).
Authors: Sacchi de Camargo Correia Guilherme , Mooradian Ariana , Zhao Yujie , Lou Yanyan , Manochakian Rami 
Published: June 2023

e21161 Background: Patients with stage IV NSCLC undergo frequent restaging scans (RS). While vital to assess treatment response, RS add anxiety and financial burdens to patients. The ideal frequency of RS is unclear. The numerous treatment options available, such as targeted therapy (TT) and immunotherapy (IO), and the variability in frequency of RS in the trials that led to their approval reflect this uncertainty. Due to the lack of clear guidelines about their ideal interval in daily practice, we reviewed the heterogeneity in frequency of RS in those trials, comparing it to the reported progression-free survival (PFS). Methods: In this study, we reviewed the FDA-approved drugs for stage IV NSCLC since 10/18/2016 and selected the TT and IO. Each trial that led to approval was reviewed, collecting the frequency of RS and the median PFS for the intervention (IA) and control arms (CA). Results: 18 TT drugs and 12 IO regimens, with and without chemotherapy (chemo), were found. Among them, the frequency of RS varied from every 4 to 9 weeks (w) upfront, later modified to every 6 to 12 w until disease progression. The median PFS for both groups in the IA ranged from 2.8 to 19.4 months (m), and from 3.0 to 12.4 m in the CA. The TT group had drugs directed at 7 different mutations, and it presented more discrepancy in terms of restaging frequency. The period between RS varied from every 4 to 8 w initially, later modified to every 6 to 12 w. However, 11 of 18 trials had an interval of every 6 w. The shortest median PFS in the IA arm was 5.4 m, and 5.6 m in the CA. While the longest median PFS was 19.4 m in the IA and 12.4 m in the CA. The IO group included 5 regimens with chemo and 7 without. The interval between RS varied from 6 to 9 w originally, to every 8 to 12 w later. Yet, 8 of 12 regimens’ trials scanned patients every 6 w initially. The median PFS in the IA ranged from 2.8 to 10.3 m, and between 3.0 to 6.5 m in the CA. Conclusions: We observed notable heterogeneity among trials regarding the frequency of RS in patients treated for stage IV NSCLC. When comparing these intervals to the median PFS, we noted the shortest PFS reported is longer than most adopted intervals. This may indicate RS were obtained more frequently than needed. The increased frequency of RS raises a burden for patients and the medical system, while contributing to disparities. This finding, coupled with further comparisons between the frequency of RS in trials and in daily practice, may pave the way for prospective studies analyzing the ideal interval for RS. This can lead to a more efficacious and less burdensome strategy for patients. [Table: see text]
UCLA l-08: A phase ib/II study of combined HER inhibition adding necitumumab and trastuzumab to osimertinib in patients with refractory EGFR-mutated lung cancer.
Authors: Goldman Jonathan W. , Cummings Amy Lauren , Arzoo Karo K. , Hu Eddie Hong-Lung , Garon Edward B. , Kirimis Evangelia K. , Olevsky Olga , DiCarlo Brian Anthony , Davidson Sheldon J. , Kaul Anita , Noor Zorawar Singh , Mendenhall Melody A. , Wong Deborah J.L. , Huang Holly K.T. , Velez Maria A , Chauv James , Yarden Yosef , Slamon Dennis J. 
Published: June 2023

e21165 Background: Patients (pts) with metastatic EGFR-mutated NSCLC who have progressed on osimertinib have limited treatment options. Dual EGFR with HER2 blockade results in complete and long-term reversal of osimertinib resistance in preclinical models. Methods: This is an investigator-initiated, single arm, open label phase 1b/2 study to identify the recommended phase 2 dose (RP2D), safety, tolerability, and preliminary efficacy of the combination of osimertinib, necitumumab, and trastuzumab (ONT) in adults with histologically confirmed, metastatic NSCLC with an activating and sensitizing EGFR mutation who have progressed on osimertinib as their most recent treatment. Study pts receive daily oral osimertinib in conjunction with necitumumab and trastuzumab intravenously every other week. In phase 1b, a 3+3 dose-escalation design is used to determine the RP2D (Table 1). In phase 2, if ≥ 2 responses are seen out of 10 pts treated at the RP2D, an additional 10 pts will be accrued. Patient reported outcomes (PRO-CTCAE) and quality of life (FACT-L) data are collected prospectively. Efficacy is assessed as objective response rate (ORR) based on RECIST 1.1 criteria. Results: 22 pts (median age = 63; range = 40-82) have been enrolled and treated. The most commonly observed treatment-related AEs seen at any DL included acneiform rash (63.6%), headache (45.5%), nausea (40.9%), dry skin (36.4%), diarrhea (31.8%), paronychia (27.3%), oral mucositis (27.3%), vomiting (22.7%), fatigue (18.2%), chills (18.2%), and anorexia (18.2%). Grade 3 treatment-related toxicities were acneiform rash (22.7%), diarrhea (4.5%), decreased lymphocyte count (4.5%) and hypertension (4.5%). There were no treatment-related Grade ≥ 4 AEs. 12 evaluable pts were enrolled in phase 1b [3 at Dose Level (DL) 1, 3 at DL 2, and 6 at DL 3]; 3 non-evaluable pts were replaced. Pts treated at DL 1 and DL 2 had no dose-limiting toxicities (DLTs) and 1/6 pts at DL 3 had a DLT (persistent grade 3 rash). Due to grade 2 and 3 rash and paronychiae occurring after cycle 1 at DL 3, DL2 was determined to be the RP2D.The proportion of evaluable phase 1b pts achieving partial response or stable disease was 58.3% (7/12). Seven pts have been enrolled at DL2. Conclusions: ONT toxicities are manageable, and the combination has promising preliminary efficacy in refractory EGFR-mutated metastatic NSCLC. Evaluation of phase 2, stage 1 is expected to be completed by April 2023 and will be reported at the meeting. Clinical trial information: NCT04285671 . [Table: see text]
Sintilimab, SBRT and GM-CSF for metastatic NSCLC: A prospective, multicenter, phase II trial.
Authors: Ni JianJiao , Wu Lin , Chu Qian , Han Chengbo , Ai Xinghao , Dong Xiaorong , Zhu Zhengfei 
Published: June 2023

e21172 Background: PD-1/PD-L1 inhibitors have transformed the therapeutic landscape in metastatic non-small cell lung cancer (NSCLC). However, the objective response rate (ORR) remains limited in unselected population. Incorporating SBRT to PD-1/PD-L1 inhibitors may improve treatment efficacy and the anti-tumor immunity induced by SBRT may be enhanced by GM-CSF, which plays a pivotal role in dendritic cell differentiation and maturation. The current trial (NCT04106180) is the first prospective, multicenter, phase II study assessing the safety and efficacy of a PD-1 inhibitor (Sintilimab), SBRT and GM-CSF in metastatic NSCLC patients without sensitizing driver mutations. Methods: Metastatic EGFR/ALK negative NSCLC pts who had failed first-line standard chemotherapy were eligible. Pts received SBRT (8 Gy*3) to one lesion, followed by Sintilimab (200 mg d1, every 3 weeks) and GM-CSF (125 μg/m2 d1-d14, cycle 1) within 3 weeks after SBRT. Sintilimab would be given continuously until disease progression, unacceptable toxicity, or up to 35 cycles. Primary end point is ORR. Secondary end points are safety, out-of-field response rate, overall survival (OS), progression free survival (PFS). The trial was designed to enroll 56 patients and if ≥17 pts evaluated had an objective response, it was regarded as positive. Results: By the time of 2022/10/30, the trial was early closed after 18 of the 51pts enrolled from 6 academic centers documented PR. The majority of pts were male, ECOG 1 and non-squamous NSCLC, having more than 5 lesions at baseline, with a median age of 62 (range, 32-74). The sites of SBRT included lung (n = 20), regional lymph node (n = 16), pleural nodule (n = 5), vertebra (n = 3), distant lymph node (n = 3), liver (n = 2) and others (n = 2). Treatment-related adverse event (TRAE) occurred in most pts and grade 3 TRAE occurred in 6 (11.8%) pts. No grade 4-5 TRAE occurred and the most common grade 3 TRAEs were ALT/AST elevation (n = 2), transient acute heart failure (recovered within 7 days) (n = 1), leucopenia/neutropenia (n = 2), pneumonitis (n = 1) and creatinine elevation (n = 1). With a median follow-up of 19.2 (range, 4.6-35.4) months, 49 pts had evaluable efficacy, with 18 PR, 15 SD and 16 PD. Median PFS and OS were 5.9 (95% CI, 3.9-9.2) and 16.2 (95% CI, 12.6-34.1) months, respectively. The results of biomarker testing will also be presented. Conclusions: Triple combination of Sintilimab, SBRT and GM-CSF is safe and shows promising efficacy in metastatic EGFR/ALK negative NSCLC. Clinical trial information: NCT04106180 .
Patients harboring uncommon EGFR exon 19delins variants of advanced non-small-cell lung cancer and response to osimertinib: A multi-center retrospective study.
Authors: Lu Zhiqin , Yi Yali , Luo Yuxi , Zeng Zhimin , Luo Hui , Shu Yun , Liu Anwen 
Published: June 2023

e21184 Background: This study aims to investigate the efficacy of different EGFR inhibitors therapy in patients with advanced non-small-cell lung cancer (NSCLC) harboring atypical EGFR exon 19delins variants. Methods: Targeted sequencing database of 1426 treatment-naive patients with advanced NSCLC were retrospectively screened for EGFR exon 19 deletion (19del) variants in a multi-center study from January 2017 to January 2022, and 34 patients with uncommon EGFR exon 19 deletion-insertions (19delins) were included. The response rate, and progression-free survival (PFS) were analyzed according to the radiographic images. Results: We identified 3 previously unreported uncommon EGFR exon 19delins variants. Among the 34 patients who had uncommon EGFR19delins, 24 patients received first-generation, and 10 patients received third-generation as front-line EGFR TKI therapy, the median progression-free survival (mPFS) was significantly longer for patients who received first-generation than those with third-generation (19.1 months vs 6.9 months; HR: 0.18, 95% CI: 0.062-0.507; p < 0.001). At progression, EGFR T790M was the main acquired mechanism of resistance (8/14; 57.2%). There were 22 patients who received osimertinib therapy, the overall ORR and DCR were 54.5% and 81.8%, respectively, and the overall mPFS was 6.9 months. But no significant difference was observed in mPFS between first-line osimertinib and second-line osimertinib therapy (6.9 months vs. 3.8 months; p = 0.206). Conclusions: The uncommon EGFR exon 19delins variants of advanced NSCLC have longer mPFS for the first-generation compared with the third-generation as front-line EGFR TKI therapy, and respond poor to third-generation EGFR inhibitors, regardless of whether osimertinib was used as first-line or second-line therapy. Patients with uncommon EGFR exon 19delins may be a biomarker of poor efficacy with the third-generation EGFR TKI therapy.