Treating EGFR-mutant nonsmall cell lung cancer is no longer a one-size-fits-all approach.

P26.02 A Phase II Trial of Neoadjuvant Osimertinib for Surgically Resectable EGFR-Mutant Non-Small Cell Lung Cancer: Updated Results

e21149 Background: EGFR mutations are detected in 15-62% of patients with non-small cell (NSCLC) lung cancer. We can use tyrosine kinase inhibitors (such as erlotinib, gefitinib, afatinib) to treat patients with EGFR-mutant lung cancer. Tyrosine kinase inhibitors improve the survival outcomes of the patients. This study aimed to assess predictors of overall response rate (complete or partial response) in EGFR-mutant non-small cell lung cancer patients treated with EGFR inhibitors. Methods: Data of the EGFR-mutant lung cancer patients were evaluated retrospectively. Clinical, pathological, radiological, and treatment features of the patients were recorded. SPSS 25 version was used for statistical analysis. Kaplan-Meier and Cox-regression methods were used for survival analysis. Also, predictors of overall response were evaluated with logistic regression analysis. Results: 105 patients were included in the study. The female/male patients ratio was 1.25, and the median age was 61 (range, 33-85) years. Adenocarcinoma (90.4%) was the most common histopathological type. The ratios of Exon 19, exon 21, and other (rare or multiple) mutations were 59%, 25%, and 16%, respectively. 89 (84.9%) patients were de-novo metastatic at diagnosis. Before EGFR inhibitor therapy, the patients had received chemotherapy (22.9%) and palliative radiotherapy (40%). The patients received erlotinib (83.8%) or other EGFR inhibitors (16.2%) for treatment. Median overall survival was 30.8 (range 20.2-41.4) months. Overall response rate (complete or partial response) was 61.9%, stable response 11.4%, and progressive disease 26.7%. In logistic regression analysis, we found that age (p = 0.008), number of metastasis sites (p = 0.037), pathological type (adenocarcinoma or other types) (p = 0.001) were statistically significant for the overall response rate. However, gender (p = 0.98), tumor localizations (left or right lung) (p = 0.39), de-novo metastasis (p = 0.81), EGFR mutations type (p = 0.13), and type of EGFR inhibitör (p = 0.30) were not statistically significant. Conclusions: In this study, we showed real-life outcomes of the patients with EGFR-mutant metastatic non-small cell lung cancer. The data of predictors of overall response for EGFR inhibitors is limited. We detected that age, the number of metastatic organs, and histopathological type of tumor were affected the response of treatment.

BackgroundOsimertinib shows higher effectiveness than first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in the initial treatment of EGFR-mutated non-small cell lung cancer. However, its superiority in terms of overall survival in the Asian population, especially Japanese patients, remains uncertain.ObjectiveTo evaluate the survival benefit of osimertinib over other EGFR-TKIs in Japanese patients, using real-world data.Methods As part of the Tokushukai REAl-world Data project, a retrospective multi-institutional study across 46 hospitals in Japan was conducted to evaluate the overall survival of patients with advanced EGFR-mutated non-small cell lung cancer using propensity score matching. The study involved patients receiving osimertinib as the first-line treatment (1L-Osi), those initially treated with other EGFR-TKIs (1L-non-Osi), and those receiving osimertinib after initial EGFR-TKI treatment (2L/later-Osi) between April 2010 and December 2022 and followed up until April 2023.ResultsAmong 1062 Japanese patients with EGFR-mutated non-small cell lung cancer, 416 (39.2%) received 1L-Osi, while 646 (60.8%) received 1L-non-Osi, including 139 (13.1%) who received 2L/later-Osi. Within these groups, 416 (39.2%), 293 (27.6%), and 75 (7.1%) patients received first-line EGFR-TKI treatment post-osimertinib approval as a later-line treatment in Japan (March 2016). After propensity score matching, the overall survival of the 1L-Osi group was comparable to that of the 1L-non-Osi group in the post-March 2016 subset (n = 283, 42.0 vs 42.4 months). Similar trends were observed in the Del19 and L858R subgroups. The median overall survival of the 2L/later-Osi group was notably long: 60.2 months post-March 2016 (n = 75). A subgroup analysis based on initial EGFR-TKI treatment in the 1L-non-Osi and 2L/later-Osi groups revealed no significant differences among the gefitinib, erlotinib, and afatinib groups.ConclusionsBased on real-world data, osimertinib did not show a significant improvement in overall survival compared to other EGFR-TKIs as a first-line treatment for EGFR-mutated advanced non-small cell lung cancer in the Japanese (Asian) population.Clinical Trial RegistrationThis study was registered at the University Hospital Medical Information Network Clinical Trials Registry on 9 March, 2023 (identification UMIN000050552).

Combination of radiotherapy and PD-L1 blockade induces abscopal responses in EGFR-mutated lung cancer through activating CD8+ T cells

e20655 Background: ADAURA demonstrated an overall survival (OS) benefit with adjuvant osimertinib in Epidermal Growth Factor Receptor mutant (EGFR-mut) non-small cell lung cancer (NSCLC). However, only 50% of patients underwent a preoperative brain MRI, and PET-CT rates were not reported. Concerns were raised that preoperative imaging rates were not consistent with real world practices, leading to patients being effectively “understaged.” There is limited data on real world rates of preoperative PET-CT and brain MRIs in patients with EGFR-mut NSCLC. Moreover, there is little reported data on the staging impact of preoperative PET-CT and brain MRI. We hypothesized that PET CTs and brain MRIs are performed in the majority of patients with EGFR-mut NSCLC who are evaluated for surgery and lead to detection of metastases missed by CT imaging alone. Methods: We retrospectively analyzed patients with EGFR-mut NSCLC who were evaluated for surgery at three academic New York hospitals between 2016-2021. EGFR-mut was defined as an EGFR exon 19 deletion or EGFR L858R mutation. Results: Between 2016 and 2021,109 patients with EGFR-mut NSCLC underwent preoperative evaluation. The median age was 70 (range: 43-89), and they were predominately female (74%). Forty-three percent of patients were Asian, and 58% of patients had a history of never smoking. Based on initial CT imaging, 71 patients (65%) were clinical stage 1, 16 patients (16%) were clinical stage 2, and 20 patients (19%) patients were clinical stage 3. Of the 109 total patients, 107 (98%) underwent a PET-CT and only 39 patients (36%) had a brain MRI. Of the 107 who had PET-CT, 16 patients (15%) were found to have Stage 4 disease. Of the 39 patients who had a brain MRI, 7 patients (18%) were found to have brain metastases. The use of both PET-CT and brain MRIs for patients evaluated for surgery upstaged 20 (18%) patients out of 109 patients to metastatic disease and resulted in 90 (83%) patients undergoing surgery. Conclusions: Our study demonstrates that in real world practice nearly all patients (97%) who were being evaluated for surgery underwent a PET-CT whereas only subset of patients (37%) had a brain MRI. The use of preoperative PET-CT and brain MRIs led to the detection of metastatic disease in 18% of total patients with EGFR-mut NSCLC. These findings underscore the critical role of comprehensive preoperative imaging. We strongly recommend that both a PET-CT and brain MRI are routinely preformed in all patients with EGFR-mut NSCLC prior to surgery to ensure accurate staging and optimize treatment planning. PET CT and brain MRI impact on staging patients with EGFR NSCLC evaluated for surgery. Patients evaluated for surgery 109 Patients who had a PET CT 107 (98%) Patients who had Brain MRI 39 (36%) Upstaged by PET-CT or Brain MRI to IV Disease 20 (18%)

Introduction: Approximately 50% of patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) develops brain metastases (BM), which is associated with a poor prognosis. Mutations in TP53 are associated with earlier development of resistance to EGFR tyrosine kinase inhibitors, but it is unclear whether patients who develops BM have a higher prevalence of TP53 mutations. Analyses of circulating tumor DNA (ctDNA) in blood have been established as a good alternative to tissue biopsies to assess the genomic landscape of NSCLC. In this study, we aim to analyze ctDNA from patients with advanced EGFR-mutated NSCLC to investigate the prevalence of TP53 mutations in patients with BM, and to explore whether patients with BM exhibit a distinct ctDNA profile compared to patients without. Materials and Methods: Plasma samples collected before treatment commenced from 97 of the 100 patients with EGFR-mutated advanced NSCLC enrolled in the First-line Treatment With Osimertinib in EGFR-mutated Non-small Cell Lung Cancer study (The FIOL study: NCT03804580) were analyzed. Patients were split into cohorts with (n=44) and without BM (n=53) at baseline. The cell-free DNA was isolated and sequenced with targeted next-generation sequencing with the AVENIO ctDNA Surveillance Panel (Roche) containing 197 lung cancer-related genes. Results: Mutations in ctDNA were found in 83 patients (85.6%), with 6 patients with BM having no ctDNA mutations and 8 patients without BM having no ctDNA mutations. Besides EGFR mutations, TP53 was the most frequently mutated gene, with 42 patients (43.3%) harboring TP53 mutations. There was no significant difference in the prevalence of TP53 mutations between the cohort with BM (n=23) and the cohort without (n=19), (p=0.15). There was no difference in the number of identified mutations in the two cohorts (BM: median: 2 (range: 0-6), without BM: median: 2 (range: 0-11), p=0.71). Patients with BM had a numerically lower ctDNA level (median: 45.5 mutant molecules/mL), than patients without BM (median: 75.9 mutant molecules/mL), though the difference was not statistically significant (p=0.68). Conclusion: Prevalence of TP53 mutations in plasma collected before osimertinib treatment initiation in advanced EGFR-mutated NSCLC was similar between patients with and without BM at baseline. Furthermore, there was no difference in the ctDNA profile between these two cohorts. Future experiments will clarify the impact of TP53 mutations in patients with or without BM. Citation Format: Simone Stensgaard, Inger Johanne Z. Eide, Elin Marie Stensland, Åslaug Helland, Simon Ekman, Karin H. Hansen, Saulius Cicenas, Bjørn Henning Grønberg, Peter Meldgaard, Boe S. Sørensen, Odd Terje Brustugun. Mutated TP53 prevalence in EGFR-mutated advanced non-small cell lung cancer patients with brain metastases [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 2413.

The standard first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions is targeted therapy using tyrosine kinase inhibitors (TKIs). However, data are still lacking on the use of TKIs as a neoadjuvant or induction approach. Therefore, this narrative review aims to summarize the current knowledge on resectable EGFR-mutant and ALK-fused NSCLC regarding available perioperative treatment regimens and off-label neoadjuvant use of targeted therapy. The relevant literature was identified by using PubMed and ClinicalTrials.gov (last search phase June 2024) and was restricted to English language. Peer-reviewed manuscripts but also conference abstracts that did not undergo peer-review were included. Patients with EGFR-mutations and ALK-fusions have typically been excluded from available phase III perioperative immunotherapy trials due to lower efficacy and higher toxicity of immunotherapy in those patients. In the adjuvant setting, recent evidence from the phase III ALINA and ADAURA trials demonstrated efficacy and safety of targeted therapy in resected ALK-fused and EGFR-mutant NSCLC. However, to date there is no approval for the use of TKIs as neoadjuvant or induction therapy in those patients. We have therefore identified a number of case series and phase II trials using targeted therapy in resectable EGFR-mutant and ALK-fused NSCLC. Current evidence suggests that targeted therapies might be effective in patients with resectable EGFR-mutant and ALK-positive NSCLC, but ongoing trials will need to provide further evidence on the safety and efficacy of perioperative TKI therapy.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) targeted therapy has become the standard of care for patients with EGFR-mutated metastatic non-small cell lung cancer (NSCLC) on the basis of improved prognosis and reduced toxicities compared with chemotherapy. In view of the therapeutic potential of EGFR-TKIs in EGFR-mutated advanced NSCLC, several scholars have explored the value of preoperative use of EGFR-TKIs in patients with EGFR-mutated resectable NSCLC. However, the field of neoadjuvant targeted therapy for EGFR-mutated resectable NSCLC is currently in its infancy. In this mini-review, we summarize the current evidence on neoadjuvant EGFR-TKIs targeted therapy for resectable EGFR-mutated NSCLC and focus on discussing potential clinical strategies of treating resectable EGFR-mutated patients by preoperative administration of EGFR-TKIs-based multimodality therapy.

Background: NSCLC accounts for nearly 85% of all lung cancers. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for EGFR mutated NSCLCs, but these drugs often stop working after EGFR acquires additional mutations. Preclinical and clinical data suggest a stronger antitumor effect with dual blockade of the EGFR and vascular endothelial growth factor (VEGF) pathways in EGFR-mutated NSCLC. RELAY, a randomized, double-blind, phase 3 trial, demonstrated superior progression-free survival (PFS) with ramucirumab (RAM) + erlotinib compared with placebo + erlotinib in patients with untreated EGFR-mutated advanced NSCLC. Additionally, RAM was tested in a Phase 1 study with the third-generation irreversible EGFR TKI osimertinib (OSI); AstraZeneca) in NSCLC patients with advanced T790M-positive EGFR mutant tumors after progression on first-line EGFR TKI therapy. OSI can be used with L858R, exon 19 del and T790M EGFR mutant tumors. We investigated the combined use of OSI+RAM in EGFR mutated NSCLC PDX mouse models. Materials and Methods: The antimurine VEGFR2 antibody DC101 (40 mg/kg, BIW) and the EGFR TKI OSI (10 mg/kg, QD) were used in this study. Twenty-seven PDX NSCLC mouse models carrying EGFR activating and/or T790M resistance mutations, commonly detected in patients with advanced NSCLC, were evaluated at 3 independent sites. Mice were divided into 4 treatment arms: vehicle (PBS), DC101, OSI and combination (DC101+OSI). Each study arm included two transplanted mice per model. Sensitivity to DC101 and OSI monotherapies, enhancement of anti-tumor activity with the combination therapy and durability of the response were evaluated. Desirability score, a weighted composite score of six features of tumor growth curves including best median % response, number of days in best response category, time to doubling, re-growth rate (last 5 observations) relative to vehicle growth rate, last observed tumor volume and last observed day, was calculated for each treatment arm. Analysis of variance was used to compare summary scores per animal across treatments. Results: OSI alone and OSI+DC101 combination therapy had stronger antitumor effects than DC101 monotherapy in significantly more models 11 vs 1 and 12 vs 0, respectively. A small but consistent shift in favor of OSI+DC101 vs OSI was observed across most of the models. Paired t-test analyses showed a moderate but significant benefit with combination OSI+DC101 vs OSI. Overall desirability score was statistically improved with OSI+DC101 compared to either single agent. Conclusions: Dual inhibition of EGFR and VEGFR2 with OSI+DC101 had a stronger antitumor effect than those of the respective monotherapies in EGFR mutated NSCLCs in vivo. Future studies will investigate the molecular mechanisms underlying the enhanced antitumor effect of OSI+DC101 combination therapy. Citation Format: Sudhakar Chintharlapalli, Anthony Fischl, Chun Ping Yu, Philip Iversen. Enhanced antitumor effect of dual EGFR and VEGFR2 inhibition in EGFR-mutated non-small cell lung cancer (NSCLC) patient-derived tumor xenograft (PDX) models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1675.

TPS3161 Background: Although first-line treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib improved survival in patients (pts) with advanced/metastatic EGFR-mutated ( EGFRm) non-small cell lung cancer (NSCLC), therapy after acquired resistance to osimertinib remains an unmet need. HER3 is expressed in the majority of EGFRm NSCLCs. HER3-DXd is a novel, investigational, HER3-directed antibody-drug conjugate that demonstrated preliminary single-agent clinical activity in EGFRm NSCLC. In preclinical models of EGFRm NSCLC, osimertinib increased membrane HER3 expression, improved the internalization rate of HER3-DXd, and enhanced tumor growth inhibition by HER3-DXd. Therefore, HER3-DXd with osimertinib might improve outcomes in pts with disease that progressed with osimertinib therapy. This phase 1 study (NCT04676477; U31402-A-U103) evaluates HER3-DXd in combination with osimertinib in pts with advanced EGFRm NSCLC that has progressed with first-line osimertinib therapy. Methods: This is an open-label, 2-part study of HER3-DXd in combination with osimertinib. Pts are enrolling in North America, Europe, and Asia. Dose escalation enrolls pts with locally advanced/metastatic NSCLC with an EGFR-activating mutation (exon 19 del or L858R) and progression during or after osimertinib therapy. Pts receive HER3-DXd 1.6, 3.2, 4.8, or 5.6 mg/kg intravenously (IV) every 3 weeks (Q3W) in combination with osimertinib 40 or 80 mg orally (PO) once daily (QD). Pts are enrolled in each cohort guided by safety (dose-limiting toxicities) using a Bayesian logistic regression model. Primary objectives of dose escalation are to assess safety and tolerability of the combination and identify a recommended combination dose (RCD). In dose expansion, pts will be randomized 1:1 to receive either HER3-DXd and osimertinib at the RCD (arm 1, [≈60 pts]) or HER3-DXd 5.6 mg/kg IV Q3W (arm 2, [≈60 pts]). A third arm (arm 1b, [≈60 pts]) may be added to evaluate 2 provisional RCDs of HER3-DXd + osimertinib. The primary objective of dose expansion (arms 1, 2, and 1b) is to evaluate efficacy of the combination vs that of monotherapy. The primary endpoint is objective response rate (ORR) as assessed by blinded independent central review. Other efficacy endpoints include ORR by investigator and duration of response, disease control rate, time to response, progression-free survival, and overall survival. If the RCD includes an osimertinib dose of 80 mg PO QD, ≈30 pts with advanced EGFRm NSCLC without prior treatment will be enrolled and treated at the RCD in a separate cohort; the primary objective is to assess safety and tolerability. A tumor sample after progression with osimertinib (or prior to entry) is required for pts enrolled in dose expansion for retrospective evaluation of HER3 and biomarker analyses. Clinical trial information: NCT04676477.

Osimertinib (AZD9291) has an efficacy superior to that of standard EGFR-tyrosine kinase inhibitors for the first-line treatment of EGFR-mutant advanced non-small cell lung cancer (NSCLC) patients. However, patients treated with osimertinib eventually acquire drug resistance, and novel therapeutic strategies to overcome acquired resistance are needed. In clinical or preclinical models, several mechanisms of acquired resistance to osimertinib have been elucidated. However, the acquired resistance mechanisms when osimertinib is initially used for EGFR-mutant NSCLC remain unclear. In this study, we experimentally established acquired osimertinib-resistance cell lines from EGFR-mutant NSCLC cell lines and investigated the molecular profiles of resistant cells to uncover the mechanisms of acquired resistance. Various resistance mechanisms were identified, including the acquisition of MET amplification, EMT induction, and the upregulation of AXL. Using targeted next-generation sequencing with a multi-gene panel, no secondary mutations were detected in our resistant cell lines. Among three MET-amplified cell lines, one cell line was sensitive to a combination of osimertinib and crizotinib. Acquired resistance cell lines derived from H1975 harboring the T790M mutation showed AXL upregulation, and the cell growth of these cell lines was suppressed by a combination of osimertinib and cabozantinib, an inhibitor of multiple tyrosine kinases including AXL, both in vitro and in vivo. Our results suggest that AXL might be a therapeutic target for overcoming acquired resistance to osimertinib. Citation Format: Kei Namba, Kazuhiko Shien, Yuta Takahashi, Hiroki Sato, Takahiro Yoshioka, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Shuta Tomida, Shinichi Toyooka. Activation of AXL as a preclinical acquired resistance mechanism against osimertinib treatment in EGFR-mutant non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4762.

Lung cancer remains one of the most prevalent and deadly malignancies globally, with non-small cell lung cancer (NSCLC) comprising approximately 84% of all cases. Despite advances in treatment, the overall 5-year survival rate for NSCLC remains at 15%. Among NSCLC cases, 15-20% are driven by activating mutations (such as L858R) in the epidermal growth factor receptor (EGFR), which are treated with EGFR tyrosine kinase inhibitors (TKIs). Although three generations of TKIs have been developed, a number of genetic mutations (T790M and C797S) have been shown to evolve that confer resistance in most patients. This has spurred interest in combination therapies, particularly with PD-1 and PD-L1 immune checkpoint inhibitors (ICIs), however, these have limited efficacy in patients with EGFR-mutant NSCLC. Therefore, understanding the immune landscape of these tumors is critical. We developed a mouse model of EGFR-mutant lung cancer using a transgenic mouse model expressing an EGFR carrying L858R activating, as well as T790M and C797S resistance mutations. We demonstrate the expression of this gene after intranasal delivery of an adenovirus carrying GFP-Cre (Ad-GFP-Cre) from a CAG promoter, along with expression of Td-tomato and Luciferase to allow for tumor tracking and visualization. In a time-course experiment, we monitored tumor progression and immune infiltration. By 4-6 weeks post-Ad-GFP-Cre injection, we observed consistent and palpable tumor growth, establishing a critical window for therapeutic intervention. At 2 weeks post-injection, lung tissues showed robust infiltration of CD8+ T cells, highlighting a strong initial immune response. However, levels of regulatory T cells (Tregs) increased significantly over time. This accumulation of Tregs coincided with tumor growth and suppression of cytotoxic T cell activity, suggesting a shift toward an immunosuppressive microenvironment. CD4+ T cells remained relatively constant, underscoring the specific role of Tregs in facilitating immune evasion. Systemic adaptive immunity against EGFR was detected in all tumor bearing mice, demonstrating the potency of local immune suppression in EGFR+ tumor evolution. To evaluate the therapeutic relevance of these findings, we treated mice with a PD-1 inhibitor starting at 4 weeks post-injection. Tumor response was minimal, mirroring clinical observations of limited efficacy for ICIs in EGFR-mutant NSCLC. The early wave of cytotoxic immune activity followed by Treg-mediated suppression offers insights into potential therapeutic targets. This will be a useful model to study the impact of different EGFR TKIs, as well as the combination of these agents with different immunotherapeutic modalities to identify strategies to optimize combination therapies. This work has the potential to inform innovative approaches for treating EGFR-mutant NSCLC and improving patient outcomes. Citation Format: Anchit Bhagat, Cong-Xiao Liu, Xiao Yang, Melissa Gajda, Jason McBane, Herbert K. Lyerly, Zachary C. Hartman. Uncovering immune evasion in EGFR-mutant and treatment resistant NSCLC: insights from a novel mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2197.

Some of the non-small cell lung cancer (NSCLC) cases enhance somatic mutations of the epidermal growth factor receptor (EGFR) gene within the tyrosine kinase inhibitor (TKI) domain. In such cases, first-line treatments are EGFR-TKIs, including osimertinib, erlotinib, or gefitinib. Therefore, this meta-analysis aims to assess the safety and efficacy of first-line targeted therapies for EGFR-mutated advanced NSCLC patients, focusing on osimertinib, erlotinib, and gefitinib. A systematic electronic search was conducted on 3 electronic databases-Scopus, PubMed, and Web of Science-from inception to May 2024 to locate relevant trials reporting the safety and efficacy of osimertinib, erlotinib, or gefitinib in treating EGFR-mutated advanced NSCLC. No language or data restriction was applied to the search strategy. The assessed effects were objective response rate (ORR) and disease control rate (DCR). RoB 2 tool was utilized to determine the risk of bias while R programming language performed all the statistical synthesis. Out of 15,275 search results, only 19 trials were eligible for this meta-analysis. All the 3 EGFR-TKIs depicted effectiveness and safety among NSCLC patients, but osimertinib improved the ORR by 72% (95% CI: 65%, 78%) as compared with erlotinib (69% [95% CI: 58%, 79%]) and gefitinib (64% [95% CI: 64%, 78%]). Overall, the 3 EGFR-TKIs were effective by improving ORR 68% (95% CI: 63%, 73%). Similarly, osimertinib demonstrated highly effective impacts in disease control among NSCLC patients by 94% (95% CI: 91%, 97%) compared with gefitinib (68% [95% CI: 41%, 89%]). Overall, the 2 EGFR-TKIs were effective in disease control among NSCLC patients (82% [95% CI: 67%, 93%]). The pooled analyses have shown that erlotinib, gefitinib, and osimertinib are safe and effective first-line treatment options for patients with EGFR-mutated advanced NSCLC. The meta-analysis outcomes have demonstrated that osimertinib, erlotinib, or gefitinib positively impact overall response rate and disease control.

Central Nervous System Outcomes of Lazertinib Treatment in EGFR-Mutated Advanced NSCLC: Pooled Analysis From LASER201 and LASER301.

BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard first-line therapy for patients with EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC). Although many patients benefit from targeted therapies, a significant proportion of patients experience suboptimal outcomes. The mechanisms underpinning this poor efficacy and the prognostic factors influencing outcomes remain insufficiently explored. This study aims to identify the genetic and clinical biomarkers that influence treatment efficacy in patients with advanced EGFRm NSCLC.MethodsOverall, 102 patients were enrolled. The clinical data of 77 patients with EGFRm NSCLC were retrospectively analyzed in a discovery cohort. Next-generation sequencing was performed using a lung cancer panel consisting of 139 genes. An external cohort of 690 patients with genetically profiled tissue samples from the cBioPortal database was used for external validation.ResultsIn the discovery cohort, the median progression-free survival (PFS) was 17.20 months and the median overall survival (OS) was 37.47 months. A history of smoking [hazard ratio (HR) 2.25, 95% confidence interval (CI): 0.99–5.12, P=0.046] and male sex (HR 2.18, 95% CI: 1.03–4.60, P=0.04) were significantly associated with poor outcomes. Treatment with third-generation EGFR-TKIs significantly prolonged PFS compared with first- and second-generation TKIs (HR 3.01, 95% CI: 1.17–7.73, P=0.02). EGFR copy number variations predicted shorter PFS across the different TKI generations. Patients with TP53 mutations exhibited poor OS (HR 8.74, 95% CI: 1.07–71.21, P=0.02), whereas those with CTNNB1 mutations exhibited good OS (HR 0.13, 95% CI: 0.02–1.02, P=0.02). In addition, higher maximum somatic allele fraction was correlated with a poor prognosis. The findings were validated in the external cohort.ConclusionsThis study identified key biomarkers associated with the efficacy of EGFR-TKIs and survival in patients with EGFRm NSCLC, thereby providing new insights for personalized therapeutic strategies based on genetic risk stratification.