EGFR-positive Non-small Cell Lung Cancer Research Articles

Difference in efficacy of osimertinib between patients with EGFR-positive NSCLC with postoperative recurrence and those with de novo unresectable disease: A prospective, observational study

BackgroundAlthough clinical trials of systemic chemotherapy for advanced non-small-cell lung cancer (NSCLC) have included both postoperative recurrence and de novo unresectable cases, postoperative recurrence is reported to have a better efficacy and prognosis. However, there are no efficacy data of first-line osimertinib for postoperative recurrence. MethodsWe conducted a post hoc analysis of a multicenter, prospective, observational study that evaluated the efficacy of first-line osimertinib in patients with epidermal growth factor receptor (EGFR)-positive NSCLC. The patients were divided into two groups: those with postoperative recurrence (recurrence group, n = 167) and those with de novo unresectable disease (de novo group, n = 385). ResultsThe recurrence group had a significantly better Eastern Cooperative Oncology Group performance status (ECOG-PS, p < 0.001) and fewer bone metastases (p < 0.001), brain metastases (p < 0.001), cancer pleurisy (p = 0.006), pleural dissemination (p = 0.003), liver metastases (p = 0.017), and adrenal metastases (p = 0.009) at the start of osimertinib than the de novo group. The recurrence group had a significantly better progression-free survival (PFS) and overall survival (OS) than the de novo group (hazard ratio [HR] = 0.62, 95 % confidence interval [CI], 0.49–0.81, p < 0.001; and HR = 0.58, 95 % CI, 0.43–0.79, p < 0.001, respectively). In a 1:1 propensity score-matching analysis, the matched recurrence group had significantly better PFS and OS than the matched de novo group (HR = 0.72, 95 % CI, 0.52–0.99, p = 0.034; and HR = 0.65, 95 % CI, 0.44–0.95, p < 0.001, respectively). ConclusionPatients with EGFR-positive NSCLC and postoperative recurrence have a better ECOG-PS and fewer distant metastases at the start of first-line osimertinib, and better PFS and OS than those with de novo unresectable disease. Postoperative recurrence should be considered as a stratification factor in future clinical trials for advanced EGFR-positive NSCLC.

The benefit and risk of addition of chemotherapy to EGFR tyrosine kinase inhibitors for EGFR-positive non-small cell lung cancer patients with brain metastases: a meta-analysis based on randomized controlled trials.

Combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with chemotherapy (ETC) offers more advantages for patients with EGFR-positive non-small cell lung cancer (NSCLC) than using EGFR TKIs alone (ET). However, whether this conclusion applies to patients with brain metastases (BM) remains controversial. This meta-analysis was performed to evaluate the benefits and risks of the two groups. Six databases were systematically searched for relevant literatures comparing ETC versus ET in treating EGFR-positive NSCLC patients with BM. The primary outcome assessed was overall survival (OS), while secondary outcomes included progression-free survival (PFS), and central nervous system (CNS)-PFS, responses, progression status and safety. Seven studies based on five randomized clinical trials with 550 patients were included. The ETC group exhibited better OS (hazard ratio [HR]: 0.64 [0.48, 0.87]), PFS (HR: 0.42 [0.34, 0.52]), and CNS-PFS (HR: 0.42 [0.31, 0.57]). The benefits in survival for OS, PFS, and CNS-PFS were validated in nearly all subgroups. Meanwhile, the overall objective response rate (ORR) (risk ratio [RR]: 1.25 [1.02, 1.52]) and CNS-ORR (RR: 1.19 [0.93, 1.51]) also tended to favor the ETC group. However, the addition of chemotherapy also brought about more grade 3-5/serious adverse events (AEs). The top five grade 3-5 AEs in the ETC group were alanine aminotransferase increase (11.25%), neutropenia (7.5%), nausea (7.5%), anorexia (5%), and diarrhea (5%). ETC appears to be better than ET in treating EGFR-positive NSCLC patients with BM, with better OS, PFS, CNS-PFS, and responses. However, its poorer safety profile also needs to be taken into consideration. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024551073.

Immuno-PET Imaging of EGFR with 64Cu-NOTA Panitumumab in Subcutaneous and Metastatic Nonsmall Cell Lung Cancer Xenografts.

Objective: About 65-90% of nonsmall cell lung cancer (NSCLC) express the epithelial growth factor receptor (EGFR) as a transmembrane protein that is activated by binding of specific ligands, including epidermal growth factor and transforming growth factor α (TGFα). Identifying EGFR as an oncogene has led to the development of anticancer therapeutics directed against EGFR, including the full-length human IgG2 monoclonal antibody panitumumab. The main goal of the present study was to investigate 64Cu-labeled panitumumab with immuno-PET in subcutaneous and metastatic EGFR-positive NSCLC xenografts. Methods: Bifunctional chelating agent 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclo-nonane-1,4,7-triacetic acid (NOTA-NCS) was attached to panitumumab. The number of chelators per panitumumab was determined using matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy. The incorporation efficiency of 64Cu into NOTA-panitumumab was measured by using radio-TLC. EGFR-expressing epithelial-like H1299-luc+ NSCLC cells were used for in vitro and in vivo experiments. Cell uptake of [64Cu]Cu-NOTA-panitumumab was measured in the presence and absence of panitumumab. Subcutaneous and metastatic H1299-luc tumor models were grown in male NSG mice. The presence of tumors at lung and metastatic sites was analyzed by [18F]FLT PET. Immuno-PET with [64Cu]Cu-NOTA-panitumumab was performed as static PET imaging at 2, 24, and 48 h postinjection in both tumor models. Proof-of-target was confirmed by blocking experiments with panitumumab. Detailed ex vivo biodistribution experiments were performed in both animal tumor models to confirm biodistribution profiles obtained by immuno-PET imaging. Results: MALDI analysis confirmed the attachment of ∼1.5 NOTA per antibody. Radiolabeling efficiency with [64Cu]CuCl2 was 93.8 ± 5.7% and a molar activity of 0.65 MBq/μg. Cellular uptake studies with [64Cu]Cu-NOTA-panitumumab in H1299 cells demonstrated increasing uptake over time, reaching 29.1 ± 2.9% radioactivity(Bq)/mg protein (n = 3) and plateauing at 45 min. Addition of 25 μg of panitumumab reduced radioligand uptake to 1.22 ± 0.06% radioactivity/mg protein (n = 3). PET imaging revealed high uptake of [64Cu]Cu-NOTA-panitumumab in subcutaneous tumors: Standardized uptake values (SUV)mean reached 4.70 ± 0.42 and 5.37 ± 0.40 (n = 5) after 24 and 48 h postinjection, respectively. Administration of 1 mg panitumumab reduced tumor uptake significantly to 1.94 ± 0.22 and 1.66 ± 0.08 (n = 4; p < 0.001). In the metastatic model, the following SUVmean were analyzed from liver and lung lesions: 5.55 ± 0.34 and 6.28 ± 0.46 (both n = 23 lesions from 6 mice) after 24 and 48 h postinjection, which was also significantly reduced to 2.53 ± 0.39 and 2.31 ± 0.15 (both n = 16 lesions from 4 mice; p < 0.001) after injection of 1 mg panitumumab. Detailed ex vivo biodistribution confirmed immuno-PET analysis in both models. Panitumumab reduced radioactivity uptake into subcutaneous tumors from 11.01 ± 0.72 (n = 4) to 3.67 ± 0.33% ID/g (n = 5; p < 0.001), and in metastatic liver lesions from 29.44 ± 8.14 (n = 4) to 8.35 ± 1.30% ID/g (n = 5; p < 0.001), respectively. Conclusions: [64Cu]Cu-NOTA-panitumumab was successfully used for immuno-PET imaging of EGFR-expressing subcutaneous and metastatic NSCLC tumors. This result represents the basis for developing radiotheranostics for targeting EGFR in cancers and for selecting the right patients for the right treatment at the right time.

Benmelstobart plus anlotinib in patients with EGFR-positive advanced NSCLC after failure of EGFR TKIs therapy: a phase I/II study

The effect of immune‐based therapies on patients with epidermal growth factor receptor (EGFR)-positive advanced non-small cell lung cancer (NSCLC) resistant to EGFR tyrosine kinase inhibitor (TKI) therapy remains unclear. The ALTER-L038 study aimed to evaluate efficacy and safety of a chemotherapy-free combination of benmelstobart, an anti-programmed cell death ligand 1 antibody, and anlotinib, a small-molecule multi-target anti-angiogenic TKI, in EGFR-positive advanced NSCLC patients who progressed after EGFR TKI therapy. Patients were enrolled in a phase I/II study. In phase I (dose-escalation), patients received anlotinib (8, 10, 12 mg) plus benmelstobart (1200 mg). Recommended phase II dose, determined during phase I, was used in phase II dose-expansion cohort. Primary endpoints were maximum tolerable dose in phase I and progression-free survival (PFS) in phase II. At the data cutoff date (March 10, 2024), 55 patients were enrolled in phase II dose-expansion cohort. Median PFS of patients included in phase II cohort was 9.0 months, median overall survival was 28.9 months, objective response rate was 25.5%, disease control rate was 87.3%, and median duration of response was 19.8 months. Incidence of grade ≥3 treatment-related adverse events in study population was 25.5% (14/55), whereas grade ≥3 immune-related adverse events occurred in 10.9% (6/55) of patients. Benmelstobart plus anlotinib showed promising anti-tumor efficacy with tolerable safety profile, supporting the value of further development of this convenient chemotherapy-free regimen for patients with EGFR-positive advanced NSCLC who progressed after EGFR TKI therapy. Trial Registration: ChiCTR1900026273.

EP.12A.31 Clinical Characteristics and Outcomes of EGFR-Positive Non-Small Cell Lung Cancer with Acquired RET Fusions

EP.12A.31 Clinical Characteristics and Outcomes of EGFR-Positive Non-Small Cell Lung Cancer with Acquired RET Fusions

Prognostic Impact of Postoperative Recurrence in Patients With Epidermal Growth Factor Receptor-Positive Non-Small Cell Lung Cancer.

Mutations in the epidermal growth factor receptor (EGFR) gene are the most common targetable gene alterations in non-small cell lung cancer (NSCLC). In Japan, approximately 40% of patients who undergo surgical resection for non-squamous NSCLC have EGFR mutations. However, no long-term studies have been conducted including a large number of EGFR-positive NSCLC patients with postoperative recurrence (PR). We conducted a retrospective observational study of the data of EGFR-positive NSCLC patients with PR who had undergone surgery at the Shizuoka Cancer Center between October 2002 and November 2017. We evaluated post-recurrence overall survival (PRS) and postoperative overall survival (POS) using the Kaplan-Meier method and identify any associations between the clinical variables at recurrence and PRS using univariate and multivariate analysis. We enrolled 162 patients. The median observation time for PRS was 4.95 years (range, 0.82-13.25) and POS was 5.81 years (range, 2.84-16.71). The median PRS was 5.17 years (95% confidence interval [CI], 3.90-5.61) and POS was 7.07 years (95% CI, 5.88-8.01). Univariate analysis identified male sex (median PRS: 3.32 vs. 5.39 years; p < 0.05), bone metastasis (median PRS: 2.43 vs. 5.33 years; p < 0.05), and central nervous system (CNS) metastasis (median PRS: 3.05 vs. 5.39 years; p < 0.05) and multivariate analysis identified bone metastasis (hazard ratio [HR], 2.01; 95% CI, 1.23-3.28; p < 0.05) and CNS metastasis (HR, 1.84; 95% CI, 1.14-2.98; p < 0.05) as poor prognostic factors. The pattern of recurrence (oligo vs. non-oligo recurrence) was not a prognostic factor. Logistic regression analysis revealed the association between sex and the presence bone/CNS metastasis at recurrence. Our data may help visualize future prospects and determine the timing of osimertinib initiation. New treatment strategies need to be developed for patients with bone/CNS metastasis at the first recurrence.

Real-World Treatment Patterns, Health Outcomes, and Healthcare Resource Use in Advanced Common EGFR-Positive Non-Small Cell Lung Cancer Patients Treated with Osimertinib in Alberta.

There is limited information on the treatment trajectory and outcomes of patients with advanced cEGFRm NSCLC treated with osimertinib in routine clinical practice in Canada. By using and analyzing population-based administrative data and detailed chart abstraction in the province of Alberta, our objective was to capture Canadian-specific real-world treatment patterns, health outcomes, and healthcare resource utilization (HCRU) in advanced cEGFRm NSCLC patients who were (a) treated with osimertinib and (b) those receiving treatment after osimertinib. In our study cohort, we found that the overall survival rates for real-world patients receiving osimertinib were less favorable than those observed in clinical trials (24.0 versus 38.6 months). The attrition rate after osimertinib was substantial and high HCRU persisted across many years after diagnosis and treatment. This study provides important real-world evidence on contemporary survival, treatment patterns, and healthcare use among cEGFRm NSCLC patients treated with osimertinib and suggests that further research efforts are needed to improve therapeutic options in both the first and subsequent line settings.

The Advantage of Targeted Next-Generation Sequencing over qPCR in Testing for Druggable EGFR Variants in Non-Small-Cell Lung Cancer.

The emergence of targeted therapies in non-small-cell lung cancer (NSCLC), including inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase, has increased the need for robust companion diagnostic tests. Nowadays, detection of actionable variants in exons 18-21 of the EGFR gene by qPCR and direct DNA sequencing is often replaced by next-generation sequencing (NGS). In this study, we evaluated the diagnostic usefulness of targeted NGS for druggable EGFR variants testing in clinical NSCLC material previously analyzed by the IVD-certified qPCR test with respect to DNA reference material. We tested 59 NSCLC tissue and cytology specimens for EGFR variants using the NGS 'TruSight Tumor 15' assay (Illumina) and the qPCR 'cobas EGFR mutation test v2' (Roche Diagnostics). The sensitivity and specificity of targeted NGS assay were evaluated using the biosynthetic and biological DNA reference material with known allelic frequencies (VAF) of EGFR variants. NGS demonstrated a sufficient lower detection limit for diagnostic applications (VAF < 5%) in DNA reference material; all EGFR variants were correctly identified. NGS showed high repeatability of VAF assessment between runs (CV% from 0.02 to 3.98). In clinical material, the overall concordance between NGS and qPCR was 76.14% (Cohen's Kappa = 0.5933). The majority of discordant results concerned false-positive detection of EGFR exon 20 insertions by qPCR. A total of 9 out of 59 (15%) clinical samples showed discordant results for one or more EGFR variants in both assays. Additionally, we observed TP53 to be a frequently co-mutated gene in EGFR-positive NSCLC patients. In conclusion, targeted NGS showed a number of superior features over qPCR in EGFR variant detection (exact identification of variants, calculation of allelic frequency, high analytical sensitivity), which might enhance the basic diagnostic report.

Neoadjuvant targeted therapy versus targeted combined with chemotherapy for resectable EGFR-mutant non-small cell lung cancer: a retrospective controlled real-world study.

This study aimed to assess the role and effect of neoadjuvant targeted therapy (TT) versus targeted combined with chemotherapy (TC) for resectable EGFR-mutant non-small cell lung cancer (NSCLC). Between March 2021 and June 2023, 20 patients with stage IA3-IIIB NSCLC were enrolled in the study. Eleven patients received EGFR-TKIs in the TT group, while nine patients received EGFR-TKIs and two cycles of cisplatin-based doublet chemotherapy (TC group). We compare the differences between the two groups through the following variables, including age, sex, surgical approach, postoperative complications, neoadjuvant therapy adverse events, complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), objective response rate (ORR), major pathologic response (MPR), and pathologic complete response (pCR). Patients were predominantly female (75%) and never-smokers (95%). The average age was 59.2 years (range 46-79 years). Fifty-five percent harbored an exon 19 EGFR mutation and 45% an exon 21 mutation. The average targeted drug dosing time was 2.91 ± 1.7 (range 1-6) months in the TT group and 3.56 ± 3.54 (range 1-12) months in the TC group (P=0.598). The most common side effects were rash and diarrhea. No grade 5 events with neoadjuvant therapy were observed. The rate of R0 resection was 100% in all patients. Among the 11 patients in the TT group, 6 achieved a PR and 5 had SD, resulting in an ORR of 54.5%. Among the 9 patients in the TC group, 6 had PR and the remaining 3 had SD, resulting in an ORR of 66.6%. one patient (11.1%) in the TC group achieved pCR, while no patients in the TT group achieved pCR (P = 0.142). Two patients (18.2%) in the TT group reached MPR, and 2 patients (22.2%) in the TC group reached MPR (P = 0.257). The overall clinical downstage rate is 60%. Only 9 (45%) cases of yield clinical TNM (ycTNM) were consistent with yield pathologic TNM (ypTNM). Results from this retrospective controlled research indicate that the neoadjuvant TT group is likely to be more effective outcomes and has safer profile in patients with EGFR-positive NSCLC than the neoadjuvant TC group. However, our results need to be validated in a multicenter, large sample prospective study.

Osimertinib-Related QTc Prolongation: Real-World Incidence and Impact of Drug Dosing on Recurrence Risk

Background: Osimertinib is associated with increased risk of QTc interval prolongation compared to other epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, real-world data on its incidence, risk factors, and association with drug dosing is limited. Methods: This retrospective study analysed data from 970 Chinese patients with EGFR-positive non-small cell lung cancer (NSCLC) who received osimertinib between 1 November 2017 and 18 November 2023. Patients underwent pre-osimertinib (baseline) and regular electrocardiogram (ECG) monitoring while on osimertinib. QTc prolongation was graded according to Common Terminology Criteria for Adverse Events guidelines version 5.0. Clinical outcomes of patients with grade 3 or above QTc prolongation were collated. Results: Out of 970 patients, 9 (0.9%) developed grade 3 QTc prolongation. Median onset time from drug initiation was 49 days (range 14 to 371). No patients experienced arrhythmic events (grade 4) or death (grade 5). Notably, baseline QTc was above 450 ms (grade 1 or 2) in 7 of them (78%), comparing to 21% (102 out of 497) in patients without grade 3 QTc prolongation (p<0.001). Rechallenging osimertinib at 80mg daily dose resulted in recurrent grade 3 QTc prolongation in 3 out of 4 patients, while only 1 out of 9 experienced recurrences with dose reduction. Conclusion: The real-world incidence of osimertinib-induced grade 3 QTc prolongation was similar to that reported in clinical trials. Baseline QTc prolongation may be a potential risk factor. Dose reduction mitigated recurrence risk, while rechallenging osimertinib at same dose conferred high recurrence risk.

Validation of article analysis by ChatGPT: Using a cohort of patients with EGFR mutation-positive non-small cell lung cancer treated with first-line osimertinib.

e20542 Background: The rapid advancement of large language models like ChatGPT has shown potential in various fields, including medicine. However, their applicability in clinical practice, especially in complex medical knowledge interpretation, remains unclear. This study developed a framework for article analysis, retrieval of additional information, and knowledge updating using ChatGPT and tested its clinical validity by comparing it to clinical data. Methods: To simplify the prompt to ChatGPT by selecting monotherapy, patients with EGFR mutation-positive non-small cell lung cancer (NSCLC) who had received 1st -line treatment with Osimertinib, were included in this study. ChatGPT analyzed published FLAURA trial data and developed a scoring system for predicting treatment efficacies for comparison with clinical data. Treatment efficacies were evaluated by using progression-free survival (PFS) and overall survival (OS). ChatGPT searched for papers needed to update the scoring system and extracted 5 papers. To reduce the bias of the search, the extraction of papers by ChatGPT was repeated 10 times and the top 5 papers were selected. The revised scoring system, incorporating insights from these 5 papers, was applied to data from Shizuoka Cancer Center (1st-line osimertinib initiated during 2018-2022.3). The clinical validity of analyses by ChatGPT was evaluated in terms of whether the scoring system reflects clinical practice. Analysis with ChatGPT was performed using GPT4 and natural language prompts. Results: Based on the FLAURA study, ChatGPT created a scoring system consisting of the following items: EGFR mutation type, presence of CNS metastasis, smoking history, sex, and performance status (PS). ChatGPT extracted two prospective studies and three retrospective studies. The scoring system, updated by ChatGPT included EGFR mutation type: exon 19 del /L858R (3/1point), sex: female/male (2/1), smoking history: never-smoker/smoker (2/1), CNS metastases: without/with (2/1), PS 0/1/2/3/4 (2/1/0/-1/-2), age: &lt; 75/≥ 75 years (2/1) PD-L1 expression &lt; 50%/≥ 50% (2/0); liver metastasis, without/with (2/0). Group A showing better efficacies to treatment was defined as patients with a cutoff value of 11 or higher. The scoring system was fitted to validate cohort (140 patients without missing scoring system items). Group A (n = 98, ≥11points) outperformed Group B (n = 42, &lt; 11) in both PFS and OS (medianPFS 22.6 months vs. 9.7 months HR 0.32, 95% CI 0.20-0.50, p &lt; 0.0001, medianOS 54.4 months vs. 21.7 months HR 0.28, 95%CI 0.16-0.49, p &lt; 0.0001). Conclusions: The scoring system created by using ChatGPT reflected the efficacies in a cohort of EGFR-positive NSCLC patients treated with 1st-line osimertinib. The framework for article analysis, retrieval of additional information, and knowledge update using ChatGPT is potentially applicable to other cohorts.

Prognostic value of skeletal muscle measured by CT at the T4 level in advanced EGFR-positive non-small cell lung cancer patients treated with ecotinib

Objective: To investigate the prognostic value of skeletal muscle measured by CT at the level of the fourth thoracic vertebra (T4) in advanced epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) patients treated with ecotinib. Methods: The study retrospectively reviewed clinical and pathological characteristics of 176 patients with advanced EGFR-positive NSCLC who received ecotinib and underwent chest CT scans at Wuhan Union Hospital between January 2017 and October 2020. Among them, 70 were male and 106 were female, with ages ranging from 27 to 80 (58.6±10.6) years. As of August 21, 2021, the median follow-up duration was 19.2 months (95%CI: 15.3 to 23.7 months). The optimal cut-off value of skeletal muscle density (T4-SMD) on CT images at the T4 level were determined using X-tile software. Kaplan-Meier analysis and log-rank test were used to plot progression-free survival curves. Cox proportional hazards regression models were employed to analyze factors influencing 1-year progression-free survival (PFS), and a nomogram prognostic model was constructed accordingly. Receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) were utilized to evaluate the predictive value of the nomogram. Results: The T4-SMD [M (Q1,Q3)] of 176 patients was 42.56 (37.05, 45.93) HU. Patients were divided into low T4-SMD group (n=122) and high T4-SMD group (n=54) based on the cut-off value (The values for males and females were 49.44 and 41.41 HU, respectively) of T4-SMD. The median PFS time and 1-year PFS rate in the low T4-SMD group were significantly lower than those in the high T4-SMD group [10.4 (95%CI: 9.3-11.8) vs 13.7 (95%CI: 11.1-18.5) months, 36.1% vs 59.3%, respectively, P=0.034]. Eastern Cooperative Oncology Group performance status (HR=3.308, 95%CI: 1.183-9.247, P=0.023), lactate dehydrogenase level (HR=1.852, 95%CI: 1.037-3.307, P=0.037), systemic immune-inflammation index (HR=1.772, 95%CI: 1.019-3.080, P=0.043), and T4-SMD (HR=0.563, 95%CI: 0.325-0.974, P=0.040) were prognostic factors for 1-year PFS in advanced EGFR-positive NSCLC patients treated with ecotinib. A nomogram for predicting 1-year PFS of advanced EGFR-positive NSCLC patients treated with ecotinib was constructed based on the four indicators selected by multivariate Cox regression analysis. The area under the ROC curve of the nomogram was 0.775 (95%CI: 0.676-0.874). The calibration curve showed good consistency between the predicted and actual 1-year PFS. DCA demonstrated good clinical prediction effectiveness of the nomogram. Conclusion: Low T4-SMD is a prognostic risk factor for patients with advanced EGFR-positive NSCLC receiving icotinib therapy.

Abstract 4084: Potent anti-tumor activity of ABN202 (anti-EGFR antibody-interferon-beta mutein) through direct cytotoxicity and indirect immune activation against non-small cell lung cancer, regardless of EGFR mutation status

Abstract Epidermal growth factor receptor (EGFR) is overexpressed or mutated in many patients with non-small cell lung cancer (NSCLC). Targeting EGFR mutation by tyrosine kinase inhibitors (TKIs) has significantly improved overall survival (OS) in patients with EGFR mutations. However, many patients experience tumor recurrence due to various resistance mechanisms. Therefore, there is an unmet medical need for new treatment strategies for patients with EGFR-positive NSCLC, regardless of EGFR mutation status. ABN202 is an antibody-cytokine fusion protein (ACFP) that serves as a platform technology compromising the IFN-β mutein (ABN102) fused to various antibodies for specific tumor targeting. In a previous study, we designed ABN202 (αEGFR) to comprise an EGFR targeting antibody (Cetuximab) and IFN-β mutein (ABN102) and we confirmed anti-cancer activities of ABN202 against EGFR-positive NSCLC. In this study, the direct cytotoxicity of ABN202 (αEGFR) was evaluated in human NSCLC cell lines with various driving mutations and EGFR expression levels. The indirect immune activation was tested in human peripheral blood mononuclear cells (PBMCs) and human IFNAR1/2 knock-in (KI) mice. The in vivo efficacy was evaluated in human NSCLC xenograft mouse models and human IFNAR1/2 KI mouse models. ABN202 (αEGFR) demonstrates potent anti-tumor activity through direct cytotoxicity and indirect immune activation in NSCLC, regardless of EGFR mutation status. Taken together, we suggest that ABN202 (αEGFR) is a promising drug candidate against NSCLC, regardless of EGFR mutation status. Citation Format: Hee Geon Park, Sung Hun Cho, Ha Yeon Park, Mi Gyoung Jo, Ji Hyun Park, Myeung Ryun Seo, Ji Hyun Kim, Sung Youl Hong, Kyoung Song, Chan Gyu Lee, Hae Min Jeong, Sae Hyung Lee, Na Young Kim, Jun Young Choi, Young Kee Shin. Potent anti-tumor activity of ABN202 (anti-EGFR antibody-interferon-beta mutein) through direct cytotoxicity and indirect immune activation against non-small cell lung cancer, regardless of EGFR mutation status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4084.

Radiation pneumonitis after concurrent aumolertinib and thoracic radiotherapy in EGFR-mutant non-small cell lung cancer patients

BackgroundThe superior efficacy of concurrent thoracic radiotherapy (TRT) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has been proven in locally advanced and advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, the high incidence of radiation pneumonitis (RP) reduced by concurrent TRT and TKIs has attracted widespread attention. Thus, this study was designed to investigate the rate and risk factors for RP in EGFR-positive NSCLC patients simultaneously treated with aumolertinib and TRT. MethodsWe retrospectively evaluated stage IIIA-IVB NSCLC patients treated with concurrent aumolertinib and TRT between May 2020 and December 2022 at Shandong Cancer Hospital and Institute, Shandong, China. RP was diagnosed by two senior radiologists and then graded from 1 to 5 according to the Common Terminology Criteria for Adverse Events v5.0. All risk factors were evaluated by univariate and multivariate logistic regression analyses.ResultsA total of 49 patients were included, the incidence of grade ≥ 2 RP was 42.9%. Grade 2 and 3 RP were observed in 28.6% and 14.3% of patients, respectively. Grade 4 to 5 RP were not observed. the gross total volume (GTV) ≥ 21 ml and ipsilateral lung V20 ≥ 25% were risk factors for RP. The median progression-free survival (PFS) in the first-line therapy group and second-line therapy group were 23.5 months and 17.2 months, respectively (p = 0.10).ConclusionsBetter local control is achieved with concurrent TRT and aumolertinib, and special attention should be given to controlling ipsilateral lung V20 and GTV to reduce the risk of RP.

The efficacy of upfront craniocerebral radiotherapy and epidermal growth factor receptor-tyrosine kinase inhibitors in patients with epidermal growth factor receptor-positive non-small cell lung cancer with brain metastases.

This is a retrospective study that involved 213 patients with EGFR-NSCLC and BMs, with the patients divided into two groups: the upfront cranial RT (ucRT) group (n = 96) and the non-ucRT group (n = 117). All patients were administered with osimertinib, and those in the ucRT group also underwent RT. The overall survival (OS), progression-free survival (PFS) and intracranial PFS (IPFS) of the two groups were compared. The ucRT group manifested a markedly higher IPFS than the non-ucRT group (29.65 months vs 21.8 months; P < 0.0001). The subgroup analysis revealed that patients with oligometastases (OLOGO-BMs; 1-3 BMs) demonstrated a notably longer OS (44.5 months vs 37.3 months; P < 0.0001), PFS (32.3 months vs 20.8 months; P = 0.6884) and IPFS (37.8 months vs 22.1 months; P < 0.0001) in the ucRT group than in the non-ucRT group. However, for patients with multiple BMs, there was no significant difference in OS (27.3 months vs 34.4 months; P = 0.0710) and PFS (13.7 months vs 13.2 months; P = 0.0516) between the ucRT group and the non-ucRT group; the ucRT group exhibited a higher IPFS (26.4 months vs 21.35 months; P = 0.0028). Cox's multivariate analysis of patients with OLOGO-BM indicated that the use of ucRT was linked to a better OS (heart rate [HR] = 0.392; 95% confidence interval [CI]: 0.178-0.863; P = 0.020) and PFS (HR = 0.558; 95% CI: 0.316-0.986; P = 0.044). Upfront cerebral cranial stereotactic radiosurgery can improve outcomes in EGFR-positive patients with NSCLC and OLOGO-BM. However, for patients with multiple BMs, the preferable strategy may be pre-treatment with EGFR-TKIs.

Simulation analysis of EGFR mutation detection: Oncomine Dx target test and AmoyDx panel impact on lung cancer treatment decisions

Lung cancer is a leading cause of cancer-related deaths worldwide. Epidermal growth factor receptor (EGFR) driver mutations are crucial for treatment decisions for patients with non-small cell lung cancer (NSCLC). This study aimed to assess the differences in EGFR mutation detection between two companion diagnostic (CDx) tests—the Oncomine Dx Target Test (ODxTT) and the AmoyDx Pan Lung Cancer PCR Panel—and their impact on treatment applicability. To this end, we used an in-house targeted sequencing dataset of 282 samples from 127 EGFR-mutated NSCLC patients to simulate the concordance between the EGFR variants targeted by the ODxTT and AmoyDx panel, the oncogenicity of the variants, and their therapeutic potential. Of the 216 EGFR mutations identified by the in-house panel, 51% were detectable by both CDx tests, 3% were specific to ODxTT, and 46% were not targeted by either test. Most non-targeted mutations did not have oncogenicity and were located outside exons 18–21. Notably, 95% of the mutations detectable by both tests had potential oncogenicity. Furthermore, among the 96 patients harboring actionable EGFR mutations, 97% had mutations detectable by both CDx tests and 1% by ODxTT, while 2% had mutations not covered by either test. These findings suggest that while both CDx tests are effective in detecting almost all actionable EGFR mutations, ODxTT provides slightly broader coverage. These results emphasize the importance of selecting appropriate CDx tests to inform treatment decisions for EGFR-positive NSCLC patients.

Significance of micro-EGFR T790M mutations on EGFR-tyrosine kinase inhibitor efficacy in non-small cell lung cancer.

Small amounts of epidermal growth factor receptor (EGFR) T790M mutation (micro-T790M), which is detected using droplet digital PCR (ddPCR) but not conventional PCR, in formalin-fixed and paraffin-embedded (FFPE) samples have been investigated as a predictive factor for the efficacy of EGFR-tyrosine kinase inhibitors (TKIs). However, the predictive value of micro-T790M remains controversial, possibly owing to the failure to examine artificial T790M in FFPE specimens. Therefore, we examined the predictive value of micro-T790M in first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKI efficacy using a new method to exclude FFPE-derived artificial mutations in our retrospective cohort. The primary objective was time to treatment failure (TTF) of 1G, 2G, and 3G EGFR-TKIs according to micro-T790M status. In total, 315 patients with EGFR-positive non-small cell lung cancer treated with 1G, 2G, and 3G EGFR-TKIs were included in this study. The proportion of patients positive formicro-T790M in the 1G, 2G, and 3G EGFR-TKI groups was 48.2%, 47.1%, and 47.6%, respectively. In the micro-T790M-positive group, the TTF was significantly longer in the 2G and 3G EGFR-TKI groups than in the 1G TKI group. No differences in the micro-T790M-negative group were observed. Micro-T790M status detected using ddPCR, eliminating false positives, may be a valuable predictor of EGFR-TKI efficacy.

Prognostic Significance of Pretreatment Plasma D-dimer Levels in EGFR-Positive Advanced Non-Small Cell Lung Cancer Patients Receiving Osimertinib: A Multicentre Retrospective Study.

This study examined the association between plasma D-dimer levels and overall survival (OS) in advanced non-small cell lung cancer (NSCLC) patients treated with osimertinib. In this multicenter study, 88 patients with advanced non-small cell lung cancer (NSCLC) carrying epidermal growth factor receptor (EGFR) mutations and receiving osimertinib were enrolled. The target independent and dependent variables were the D-dimer levels before osimertinib treatment and OS time, respectively. The t-test or chi-square test was utilized to analyze the variances among various groups. The predictive significance of D-dimer for overall survival (OS) was assessed using Kaplan-Meier survival analysis and the Cox proportional hazard regression model. The selected patients had an average age of 58.01±10.72 years, with females comprising 54.55%. Based on their D-dimer levels, the patients were categorized into three groups: low-level (< 0.6 mg/L), middle-level (0.6 ~ 2 mg/L), and high-level (≥ 2 mg/L). After accounting for possible confounding variables, the Cox proportional hazard model showed that increased D-dimer levels were linked to a greater likelihood of death (HR 2.28, 95% CI = 1.09 ~ 4.76, p = 0.029). Importantly, there was a significant trend indicating that as D-dimer levels rose, the risk of mortality also increased (p for trend, HR 1.15, 95% CI = 1.03 ~ 1.28, p = 0.012). Consistently comparable outcomes were noted in the majority of subcategories. Patients with low-middle and high D dimer levels had a median OS of 28.6 and 17 months, respectively (p =0.014). In conclusion, elevated levels of D-dimer in the bloodstream were found to have a significant negative correlation with the overall survival (OS) of patients with EGFR-positive non-small cell lung cancer (NSCLC) who underwent treatment with osimertinib.

EE380 Cost-Effectiveness Analysis of Erlotinib Plus Bevacizumab As First-Line Therapy for Advanced EGFR Mutation-Positive Non-Squamous Non-Small Cell Lung Cancer in Japan

Although erlotinib plus bevacizumab significantly prolonged progression-free survival compared to erlotinib monotherapy in Japanese patients with EGFR mutation-positive non-small cell lung cancer (NSCLC), its cost-effectiveness is not necessarily clear. This study aimed to evaluate the cost-effectiveness of erlotinib plus bevacizumab compared with erlotinib alone in Japanese patients with EGFR positive NSCLC.

Biomarker analysis of the phase II JO25567 study comparing erlotinib with or without bevacizumab in first-line advanced EGFR+non-small-cell lung cancer.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), such as erlotinib, are standard-of-care for patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC), but most patients progress within 1 year. Previously, we demonstrated that erlotinib plus bevacizumab (EB) improved progression-free survival (PFS) in patients with EGFR-positive non-squamous NSCLC in the randomized JO25567 study. To understand this effect, we conducted comprehensive exploratory biomarker analyses. Using blood and tissue specimens from patients enrolled in the JO25567 study, angiogenesis-related serum factors, plasma vascular endothelial growth factor-A (pVEGFA), angiogenesis-related gene polymorphisms, and messenger RNAs (mRNAs) in tumor tissue were analyzed. Interactions between potential predictors and treatment effect on PFS were analyzed in a Cox model. Continuous variable predictors were evaluated by multivariate fractional polynomial interaction methodology and subpopulation treatment effect pattern plotting (STEPP). Overall, 152 patients treated with EB or erlotinib alone (E) were included in the analysis. Among 26 factors analyzed in 134 baseline serum samples, high follistatin and low leptin were identified as potential biomarkers for worse and better outcomes with EB, with interaction P values of 0.0168 and 0.0049, respectively. Serum concentrations of 12 angiogenic factors were significantly higher in patients with high follistatin. Low pVEGFA levels related to better outcomes with EB, interaction P=0.033. VEGF-A165a was the only predictive tissue mRNA, showing a similar trend to pVEGFA. No valid results were obtained in 13 polymorphisms of eight genes. EB treatment showed better treatment outcomes in patients with low pVEGFA and serum leptin, and limited efficacy in patients with high serum follistatin.