Receptor Mutations Research Articles

A heterogeneous tumor immune microenvironment of uncommon epidermal growth factor receptor mutant non-small cell lung cancer.

Common epidermal growth factor receptor (EGFR) mutations are usually not considered for immunotherapy in non-small cell lung cancer (NSCLC) due to poor efficacy. However, whether uncommon EGFR mutations are suitable for immunotherapy has not been thoroughly studied. Thus, we explored the tumor immune microenvironment (TME) features in uncommon EGFR mutant NSCLC. In this study, a total of 41 patients with EGFR mutations were included, the majority (85.4%) of whom were stage I. Among them, 22 patients harbored common mutations, while 19 patients presented with uncommon mutations. Compared with common mutations, uncommon mutations exhibited more infiltrating T cells and fewer M2 macrophages, upregulated expression of antigen processing and a presentation pathway. Unsupervised clustering based on the mIF profile identified two classes with heterogeneous TME in uncommon mutations. Class 1 featured the absence of PD-1+ cytotoxic T cell infiltration, and class 2 displayed a hotter TME because of the downregulated expression of hypoxia (p < 0.001), oxidative phosphorylation (p = 0.009), and transforming growth factor beta signaling (p = 0.01) pathways as well as increased expression of CTLA4 (p = 0.001) and PDCD1 (p = 0.004). The association of CTLA4 and PDCD1 with TME profiles was validated in a TCGA lung adenocarcinoma cohort with uncommon EGFR mutations. Our study reveals the distinct and heterogeneous TME features in uncommon EGFR mutant NSCLC.

Activity of osimeRTInib in non-small-cell lung Cancer with UNcommon epidermal growth factor receptor mutations: retrospective Observational multicenter study (ARTICUNO)

Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted. The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method. Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n= 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n= 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n= 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy. The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.

The clinical features and prognostic implications of the co-mutated TP53 gene in advanced non-small cell lung cancer.

TP53 is a frequently mutated oncogene within non-small cell lung cancer (NSCLC). However, the clinical and prognostic significance of co-mutations in TP53 in patients with advanced NSCLC has not been fully elucidated. A total of 174 patients with advanced NSCLC were enrolled in this study. All patients were subjected to sequencing analysis of tumor-related genes and information such as PD-L1 expression, TMB, and co-mutation changes were collected. Patients were categorized into TP53 mutant and TP53 wild-type groups according to their TP53 mutation status and then statistically analyzed. TP53 mutations were the most common among all patients, accounting for 56.32%, followed by epidermal growth factor receptor mutations at 48.27%. The most common mutation sites in the TP53 mutation group were exons 5-8.TP53 mutations were significantly associated with PD-L1 and TMB levels. Univariate Cox analysis showed that gender and EGFR mutation affected the prognosis of TP53-mutated NSCLC patients, and multivariate Cox regression analysis identified EGFR mutation as an independent risk factor. The OS of NSCLC patients in the TP53 mutation group was significantly shorter than that of the TP53wt group. Survival curves in the TP53/EGFR combined mutation group showed that patients with combined EGFR mutation had a lower survival rate. TP53 mutations are associated with different clinical indicators and have important implications in clinical treatment. TP53 is a poor prognostic factor for NSCLC patients, and TP53/EGFR co-mutation will affect the survival time of patients. TP53/EGFR co-mutation may be a new prognostic marker for NSCLC.

Prediction of Epidermal Growth Factor Receptor Mutation Subtypes in Non–Small Cell Lung Cancer From Hematoxylin and Eosin–Stained Slides Using Deep Learning

Accurate assessment of epidermal growth factor receptor (EGFR) mutation status and subtype is critical for the treatment of non–small cell lung cancer patients. Conventional molecular testing methods for detecting EGFR mutations have limitations. In this study, an artificial intelligence–powered deep learning framework was developed for the weakly supervised prediction of EGFR mutations in non–small cell lung cancer from hematoxylin and eosin–stained histopathology whole-slide images. The study cohort was partitioned into training and validation subsets. Foreground regions containing tumor tissue were extracted from whole-slide images. A convolutional neural network employing a contrastive learning paradigm was implemented to extract patch-level morphologic features. These features were aggregated using a vision transformer-based model to predict EGFR mutation status and classify patient cases. The established prediction model was validated on unseen data sets. In internal validation with a cohort from the University of Science and Technology of China (n = 172), the model achieved patient-level areas under the receiver-operating characteristic curve (AUCs) of 0.927 and 0.907, sensitivities of 81.6% and 83.3%, and specificities of 93.0% and 92.3%, for surgical resection and biopsy specimens, respectively, in EGFR mutation subtype prediction. External validation with cohorts from the Second Affiliated Hospital of Anhui Medical University and the First Affiliated Hospital of Wannan Medical College (n = 193) yielded patient-level AUCs of 0.849 and 0.867, sensitivities of 79.2% and 80.7%, and specificities of 91.7% and 90.7% for surgical and biopsy specimens, respectively. Further validation with The Cancer Genome Atlas data set (n = 81) showed an AUC of 0.861, a sensitivity of 84.6%, and a specificity of 90.5%. Deep learning solutions demonstrate potential advantages for automated, noninvasive, fast, cost-effective, and accurate inference of EGFR alterations from histomorphology. Integration of such artificial intelligence frameworks into routine digital pathology workflows could augment existing molecular testing pipelines.

Investigation of age and smoking in NSCLC patients with uncommon EGFR mutations.

In addition to the two common epidermal growth factor receptor (EGFR) mutations, there are many uncommon mutations. Due to the high number of uncommon types, as well as the rarity of patients, there is lack of information regarding patient demographics, especially age distribution and smoking status. Against this background, we conducted an analysis to clarify the background of patients with uncommon EGFR mutations, especially considering their age distribution and smoking status. We retrospectively reviewed the medical records of non-small cell lung cancer (NSCLC) patients diagnosed in a multicenter clinical practice from 2002 to 2023. Patients included all cases of non-advanced and advanced NSCLC with uncommon EGFR mutations. Information on 158 patients with uncommon EGFR mutation was collected. Median age was 72 years, with the age distribution showing that most patients were in their 70s. There was a significant difference between the proportion of patients aged up to 59 years and the proportion aged 75 years or older. In 88 patients with a smoking habit history, a significant correlation was found between smoking index and age. Among non-smokers, there was a peak between ages 70 and 74, which was older than the peak among smokers. Even in elderly patients and NSCLC patients with a history of smoking, although it is unclear whether EGFR mutation is common or uncommon, EGFR gene testing should be performed considering the possibility of these patients being EGFR-positive.

PD-L1 expression in patients with non-small-cell lung cancer is associated with sex and genetic alterations: A retrospective study within the Caucasian population.

Programmed cell death-ligand 1 (PD-L1) expression is a well-established biomarker for predicting responses to immune checkpoint inhibitors and certain targeted therapies. As a result, treatment strategies for patients vary based on their PD-L1 expression status. Understanding the clinical features of patients with distinct PD-L1 levels is crucial for personalized treatment approaches. Demographic and clinicopathological characteristics of 227 patients (54% male, mean age 67 ± 9.9 years) newly diagnosed with non-small-cell lung cancer (NSCLC) between April 2020 and December 2022 were retrospectively compared among three groups based on the PD-L1 expression: PD-L1 Tumor Proportion Score (TPS) negative, 1-50%, and ≥50%. Logistic regression analysis was performed to evaluate predictors for high PD-L1 expression ≥50%. PD-L1 expression levels were distributed as follows: negative in 29% of patients, between 1% and 50% in 41%, and greater than 50% (high) in 29%. In comparison to negative PD-L1 expression, low and high PD-L1 expression was associated with female sex (32.9% vs. 52.7% vs. 50.7%, p = 0.031), with the absence of epidermal growth factor receptor (EGFR) mutations (83.6% vs. 91.1% vs. 98.1% p = 0.029), and with the absence of ERBB2 (HER2) tyrosine kinase mutations (90.9% vs. 100% vs. 98.1% p = 0.007), respectively. Age, smoking status, histological subtype, and disease stage showed no significant differences among the three patient groups. In the univariate logistic regression, EGFR mutation appeared to be the only predictor for PD-L1 expression, although it did not reach statistical significance (p = 0.06). Although sex and genomic alterations are associated with PD-L1 expression in patients with NSCLC, no clinical characteristics seem to predict PD-L1 expression significantly.

Novel mutation of transferrin receptor 2 causing hereditary hemochromatosis type 3 in a Japanese patient

Novel mutation of transferrin receptor 2 causing hereditary hemochromatosis type 3 in a Japanese patient

Impact of smoking on resected lung cancer depends on epidermal growth factor receptor mutation.

Smokers comprise the majority of surgical patients with primary lung cancer. Epidermal growth factor receptor (EGFR) mutation-negative status impacts the treatment of recurrence. However, the prognostic impact of cigarette smoking stratified by EGFR mutation status has not been reported. Therefore, we assessed its impact on patients with resected lung cancer. We retrospectively analysed 362 consecutive patients who underwent complete resection for stage 1 primary lung cancer at our institution between 2012 and 2021. The EGFR mutation status was evaluated using the real-time polymerase chain reaction. We compared the overall survival (OS) and disease-free survival (DFS) between patients with and without a history of smoking. The EGFR mutation-negative group included 194 patients, of whom 160 (83%) had a history of smoking. Male sex (P < 0.01), forced expiratory volume in 1 s (P < 0.01) and adenocarcinoma (P < 0.01) showed significant differences between the groups. In the EGFR mutation-positive group, the 5-year OS and DFS were similar regardless of smoking status (OS: 86% vs 75%; DFS: 73% vs 73%). In the EGFR mutation-negative group, the 5-year OS and DFS were significantly poorer in the smoking group (OS: 87% vs 65%, P = 0.05; DFS: 84% vs 54%, P = 0.01). Deaths from other diseases were relatively high (n = 19, 53%). Cigarette smoking may be associated with a poor prognosis in EGFR mutation-negative lung cancer but had no impact on the prognosis of the EGFR mutation-positive group. This finding underscores the potential influence of smoking on the treatment of lung cancer recurrence but also highlights its significance in contributing to death from other diseases.

Functional Investigation of IGF1R Mutations in Multiple Myeloma.

High expression of the receptor tyrosine kinase (RTK) insulin-like growth factor-1 receptor (IGF1R) and RTK mutations are associated with high-risk/worse prognosis in multiple myeloma (MM). Combining the pIGF1R/pINSR inhibitor linsitinib with the proteasome inhibitor (PI) bortezomib seemed promising in a clinical trial, but IGF1R expression was not associated with therapy response. Because the oncogenic impact of IGF1R mutations is so far unknown, we investigated the functional impact of IGF1R mutations on survival signaling, viability/proliferation and survival response to therapy. We transfected four human myeloma cell lines (HMCLs) with IGF1RWT, IGF1RD1146N and IGF1RN1129S (Sleeping Beauty), generated CRISPR-Cas9 IGF1R knockouts in the HMCLs U-266 (IGF1RWT) and L-363 (IGF1RD1146N) and tested the anti-MM activity of linsitinib alone and in combination with the second-generation PI carfilzomib in seven HMCLs. IGF1R knockout entailed reduced proliferation. Upon IGF1R overexpression, survival signaling was moderately increased in all HCMLs and slightly affected by IGF1RN1129S in one HMCL, whereby the viability remained unaffected. Expression of IGF1RD1146N reduced pIGF1R-Y1135, especially under serum reduction, but did not impact downstream signaling. Linsitinib and carfilzomib showed enhanced anti-myeloma activity in six out of seven HMCL irrespective of the IGF1R mutation status. In conclusion, IGF1R mutations can impact IGF1R activation and/or downstream signaling, and a combination of linsitinib with carfilzomib might be a suitable therapeutic approach for MM patients potentially responsive to IGF1R blockade.

Diverse Fgfr1 signaling pathways and endocytic trafficking regulate mesoderm development.

The fibroblast growth factor (FGF) pathway is a conserved signaling pathway required for embryonic development. Activated FGF receptor 1 (FGFR1) drives multiple intracellular signaling cascade pathways, including ERK/MAPK and PI3K/AKT, collectively termed canonical signaling. However, unlike Fgfr1-null embryos, embryos containing hypomorphic mutations in Fgfr1 lacking the ability to activate canonical downstream signals are still able to develop to birth but exhibit severe defects in all mesodermal-derived tissues. The introduction of an additional signaling mutation further reduces the activity of Fgfr1, leading to earlier lethality, reduced somitogenesis, and more severe changes in transcriptional outputs. Genes involved in migration, ECM interaction, and phosphoinositol signaling were significantly downregulated, proteomic analysis identified changes in interactions with endocytic pathway components, and cells expressing mutant receptors show changes in endocytic trafficking. Together, we identified processes regulating early mesoderm development by mechanisms involving both canonical and noncanonical Fgfr1 pathways, including direct interaction with cell adhesion components and endocytic regulation.

Custom-Designed Probes for the Accurate Determination of Epidermal Growth Factor Receptor Mutations and Their Allelic Configuration.

The identification of single nucleotide polymorphisms (SNPs) is of paramount importance for disease diagnosis and clinical prognostication. In the context of nonsmall cell lung cancer (NSCLC), the emergence of resistance mutations, exemplified by the epidermal growth factor receptor (EGFR) T790 M and C797S, is intricately linked to the therapeutic efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Herein, a highly efficient and specific SNP detection platform for T790 M and C797S mutations has been engineered through the integration of an asymmetric polymerase chain reaction (PCR) and an ingeniously tailored four-way junction (4WJ) probe. Notably, a molecular beacon (MB) probe was judiciously designed to discern the allelic configuration of these mutations. The administration of first- and third-generation EGFR-TKIs demonstrates therapeutic efficacy solely when the mutations are in the trans configuration, characterized by a low fluorescence signal. In contrast, significant fluorescence by the MB probe is indicative of the C797S mutation being in a cis arrangement with T790M, thereby rendering the cells refractory to the therapeutic interventions of both first- and third-generation EGFR-TKIs. The assay is capable of concurrently detecting two point-mutations and ascertaining their allelic positions in a single test within 1.5 h, enhancing both efficiency and simplicity. It also exhibits high accuracy in the identification of clinical samples, offering promising implications for therapeutic guidelines. By enabling tailored treatment plans based on specific genetic profiles, our approach not only advances the precision of NSCLC treatment strategies but also marks a significant contribution to personalized medicine.

Impact of PD-L1 Expression on the Overall Survival of Caucasian Patients with Advanced EGFR-Mutant NSCLC Treated with Frontline Osimertinib.

The treatment of advanced non-small cell lung cancer (NSCLC) harboring an oncogenic epidermal growth factor receptor mutation (EGFRm) is currently based on osimertinib, a third-generation tyrosine kinase inhibitor (TKI). High Programmed death ligand 1 (PD-L1) expression ≥ 50% demonstrated to be a negative prognostic factor, mostly among Asian populations treated with 1st/2nd generation TKI. We investigated the impact of PD-L1 expression on the progression free survival (PFS) and overall survival (OS) within a cohort of patients receiving osimertinib as first-line treatment. Our bi-centre French retrospective study included all newly diagnosed patients with an advanced EGFRm (common and uncommon) NSCLC, between May 2018 and November 2022, treated with osimertinib. The primary endpoint was OS according to tumor proportion score PD-L1 expression (low/intermediate < 50% vs high ≥ 50%). Survival analyses were performed using Kaplan-Meier method and Cox model for adjusted multivariate analysis. Of 96 patients, median age was 71 (IQR 62-76), 70 were women (72.9%), 81 had a performance status (PS) 0-1 (84.3%). Median follow-up was 22.6 months (95% CI 20.5-24.7). Twenty patients (20.8%) had high PD-L1 expression ≥ 50%. No significant differences in baseline characteristics were observed based on PD-L1 status. Patients with PD-L1 ≥ 50% had significant shorter PFS and OS than those with PD-L1 < 50%, respectively 9.3 vs 17.5 months (p = 0.044 months) and 14.3 vs 26.0 months (p = 0.025). Multivariable adjustment for baseline characteristics found that PS ≥ 2 (HR 2.79, 95% CI 1.12-6.93, p = 0.027), PD-L1 ≥ 50% (HR 2.61, 95% CI 1.31 to 5.22, p = 0.007) and uncommon EGFR mutation (HR 4.59, 95% CI 1.95-10.80, p = <0.001) were associated with a shorter OS. Brain metastases at diagnosis and age ≥ 65 were not, respectively HR 1.66 (95% CI 0.90-3.06, p = 0.11) and HR 0.95 (95% CI 0.50-1.80, p=0.9). Our study found that PD-L1 expression ≥ 50% was associated with a shorter OS in EGFRm NSCLC patients treated with first line osimertinib. Further research is warranted to understand the underlying molecular and cellular mechanisms of this correlation.

Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC

BackgroundOsimertinib is a recommended treatment for advanced non–small-cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation and as adjuvant treatment for resected EGFR-mutated NSCLC. EGFR tyrosine kinase inhibitors have shown preliminary efficacy in unresectable stage III EGFR-mutated NSCLC.MethodsIn this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with unresectable EGFR-mutated stage III NSCLC without progression during or after chemoradiotherapy to receive osimertinib or placebo until disease progression occurred (as assessed by blinded independent central review) or the regimen was discontinued. The primary end point was progression-free survival as assessed by blinded independent central review.ResultsA total of 216 patients who had undergone chemoradiotherapy were randomly assigned to receive osimertinib (143 patients) or placebo (73 patients). Osimertinib resulted in a significant progression-free survival benefit as compared with placebo: the median progression-free survival was 39.1 months with osimertinib versus 5.6 months with placebo, with a hazard ratio for disease progression or death of 0.16 (95% confidence interval [CI], 0.10 to 0.24; P<0.001). The percentage of patients who were alive and progression free at 12 months was 74% (95% CI, 65 to 80) with osimertinib and 22% (95% CI, 13 to 32) with placebo. Interim overall survival data (maturity, 20%) showed 36-month overall survival among 84% of patients with osimertinib (95% CI, 75 to 89) and 74% with placebo (95% CI, 57 to 85), with a hazard ratio for death of 0.81 (95% CI, 0.42 to 1.56; P=0.53). The incidence of adverse events of grade 3 or higher was 35% in the osimertinib group and 12% in the placebo group; radiation pneumonitis (majority grade, 1 to 2) was reported in 48% and 38%, respectively. No new safety concerns emerged.ConclusionsTreatment with osimertinib resulted in significantly longer progression-free survival than placebo in patients with unresectable stage III EGFR-mutated NSCLC. (Funded by AstraZeneca; LAURA ClinicalTrials.gov number, NCT03521154.)

Characteristics, treatment patterns, and prognostic factors in small cell lung cancer transformation of advanced non-small cell lung cancer with epidermal growth factor receptor mutation after tyrosine kinase inhibitor therapy.

e20569 Background: Small cell lung cancer transformation in advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation following tyrosine kinase inhibitor (TKI) therapy poses a challenging clinical scenario. This study aims to explore the characteristics, treatment patterns, and prognostic factors associated with this transformation. Methods: A total of 41 patients with transformed SCLC (tSCLC) were included. Patient characteristics, treatment details, and laboratory data were collected. Re-biopsy specimens and subsequent treatments were analyzed. Statistical analyses were conducted to identify factors associated with treatment response and survival outcomes. Results: The median age of the patients was 61.7 years old, with a median time from TKI treatment to small cell transformation of 22.2 months. The majority were female (58.5%), never smokers (80.5%), with 53.7% having stage IVB disease prior to EGFR-TKI treatment. The most prevalent initial EGFR mutation was exon 19 deletion (56.1%), and afatinib (46.3%) was the most commonly used EGFR-TKI. EGFR mutation analysis was performed in 68.3% of the tSCLC specimen, and acquired T790M was detected in 7.1% of the patients. Treatment patterns after transformation included various systemic therapies, with the most (63.4%) receiving etoposide plus platinum (EP) based chemotherapy in the first line setting. Among all the patients, 56.1% received EGFR-TKI and 22% received immune checkpoint inhibitors (ICI) throughout the post-transformation treatment course. Anemia (Hgb &lt; 10g/dL) and ever use of EP were significant factors associated with post-transformation survival. The median progression-free survival (PFS) of the first line treatment was 3.27 months, and the overall survival (OS) was 10.43 months post transformation. Conclusions: Small cell lung cancer transformation in advanced NSCLC with EGFR mutation after TKI therapy is associated with diverse clinical characteristics and dismal outcomes. We presented the complexity of managing these cases in real-world practice. Anemia and ever use of EP affected post-transformation survival. Further research is warranted to optimize therapeutic strategies for this unique subset of patients.

High-dose almonertinib in treatment-naïve EGFR-mutated NSCLC with CNS metastases: Efficacy and biomarker analysis.

2007 Background: Central nervous system (CNS) metastases is inevitable for epidermal growth factor receptor (EGFR)mutant non-small cell lung cancer (NSCLC). The pre-specified analysis of the FLAURA and other phase III studies has unveiled encouraging results in patients with CNS metastasis. Nevertheless, the availability of limited biomarkers poses a challenge for the early prediction of clinical effects. Methods: We launched a prospective, open-label, single-arm clinical trial across multiple centers (ACHIEVE). Participants, all diagnosed with EGFR-mutated NSCLC with CNS metastases, received first line treatment with high dose Almonertinib through once-daily oral administration, with each dose being 165 mg. The primary endpoints focused on progression free survival (PFS). Concurrently, we gathered baseline and end-of-first-cycle plasma samples, subjecting them to a comprehensive 520 gene-based sequencing analysis. Results: A total of 63 patients were selected and enrolled between Jul 6,2021 and Aug 31,2022. The median follow-up time, until Nov 30,2023, was 538 days. The confirmed Overall Response Rate (ORR) was 88.9% (56/63), while 42.9% (27/63) of patients progressed, with a median PFS of 17.71 months (11.96-NE). Moreover, a notable 88.9% (56/63) of intracranial lesions achieved either a Complete Response (CR) in 21 cases (33.3%) or a Partial Response (PR) in 35 cases (55.6%). To guide and enhance clinical strategy selection, we conducted a comprehensive biomarker evaluation using cell-free DNA (cfDNA) sequencing. Of the 60 baseline plasmas that passed quality control, 81.7% (46/60) were identified as having at least one somatic mutation (ctDNA+). No significant differences were observed between ctDNA+ and ctDNA- groups in terms of ORR (p = 0.33), intracranial ORR (p = 0.499), PFS (p = 0.363, HR = 1.75), and intracranial PFS (p = 0.562, HR = 1.56). Furthermore, we developed a novel algorithm named MedSR (Median Short cfDNA fragment Ratio) based on cfDNA fragment distribution patterns to quantify ctDNA amount. Notably, higher baseline MedSR values (above the median) predicted significantly poorer PFS (p = 0.001, HR = 0.22) and intracranial PFS (p = 0.067, HR = 0.35), demonstrating superior efficacy compared to traditional cfDNA biomarkers like maxAF. On Cycle 2, those achieving ctDNA clearance in C2D1, regardless of their ctDNA status on baseline, exhibited significantly improved PFS (p &lt; 0.001, HR = 4.63) and intracranial PFS (p = 0.001, HR = 5.71). Conclusions: High dose Almonertinib exhibited promising efficacy and maintained tolerable safety as a first-line therapy in EGFR-mutated NSCLC with CNS metastases. The novel MedSR score demonstrated potential value in predicting the efficacy of TKI treatment. Clinical trial information: NCT04808752 .

Phase 1/2 clinical trial of JIN-A02, a 4th generation EGFR-TKI, in patients with 3rd generation EGFR-TKI resistance in EGFR mutated advanced/metastatic non-small cell lung cancer (NSCLC).

TPS8658 Background: Epidermal growth factor receptor (EGFR) mutations are the most common driver mutations in NSCLC. EGFR tyrosine kinase inhibitors (TKIs) are the recommended front-line option for EGFR-mutant advanced NSCLC patients, but patients invariably develop acquired resistance and face disease progression. JIN-A02, a 4th generation EGFR-TKI intended for oral administration, selectively and reversibly binds to EGFR mutations, including the C797S and/or T790M mutation that causes resistance to 3rd generation of EGFR-TKIs. Pre-clinical studies with EGFR C797S and/or T790M mutated cell lines showed that JIN-A02 can inhibit cell growth in a dose dependent manner and has a high degree of selectivity over wild-type EGFR. In vivo studies showed that administration of JIN-A02 dose-dependently inhibited tumor growth in the C797S+ xenograft mice model. Moreover, JIN-A02 shown to penetrate blood-brain barrier and exhibit anti-tumor activity in an intracranial tumor model. The strong potency and high selectivity of JIN-A02 for mutant EGFR may offer improved therapeutic window in the clinical setting vs available EGFR-TKIs. Methods: JIN-A02 is being evaluated in this Phase 1/2, multicenter, an open-label trial (NCT05394831) for subjects with advanced NSCLC harboring C797S and/or T790M mutation as a monotherapy. The primary object of this study is to assess safety, tolerability, pharmacokinetics, and anti-tumor effect for determining the recommended phase 2 dose (RP2D) of JIN-A02. The inclusion criteria are that the subject (≥ 18 years) must have an advanced or metastatic NSCLC showed progress disease (PD) after receiving approved standard EGFR-TKI therapies and/or platinum-based anticancer chemotherapy is allowed up to 1 time after using EGFR-TKI treatment with ECOG status 0 or 1. Before enrollment in the study, the EGFR mutation status is determined using either tumor tissue and/or plasma ctDNA. This study comprises three parts, dose escalation (Part A), dose exploration (Part B), and dose expansion (Part C). In Part A, dose escalation, comprised of 5 cohorts ranged from a starting dose of 12.5 mg P.O, QD to a top dose of 150 mg P.O, QD with every three subjects, is carried out where the maximum tolerated dose (MTD) is evaluated in subjects with 28-day cycles. Dose-limiting toxicities (DLT) are evaluated for 21 days. In Part B, dose exploration is carried out to evaluate the safety of JIN-A02 further and to determine the RP2D using 2 preliminary effective dose levels from Part A in subjects. In Part C dose-expansion study, subjects (n=36 for each cohort) are divided into 5 different cohorts based on the EGFR mutation (both or single positive of C797S and T790M), and the anti-tumor activity of JIN-A02 is evaluated according to RECIST v1.1 at RP2D. Clinical trial information: NCT05394831 .

Identification of Potential Biomarkers of EGFR Mutation in Pleural Effusion of Non-Small Cell Lung Cancer Patients Based on Metabolomics.

Malignant pleural effusion (MPE) is a common complication of non-small cell lung cancer (NSCLC). Patients with NSCLC exhibit a high rate of epidermal growth factor receptor (EGFR) mutations. The detection of EGFR mutations is usually time-consuming and costly. This study aimed at identifying potential biomarkers of EGFR mutations in MPE of NSCLC patients by metabolomics. In total, 58 MPE samples from 30 EGFR mutant and from 28 wild-type NSCLC patients were collected and analyzed by using hydrogen nuclear magnetic resonance (1H NMR) based metabolomics and UPLC-MS/MS based amino acid analysis. Our 1H NMR study showed a significant increase in the lysine levels but a significant decrease in the alanine levels in MPE of NSCLC patients with EGFR-mutant. Twelve amino acids in MPE were further determined by UPLC-MS/MS. It showed that alanine in MPE (6.34 ± 1.88 vs. 8.73 ± 3.68) were significantly decreased and leucine (3.13 ± 0.57 vs. 2.22 ± 0.13), lysine (2.19 ± 0.50 vs. 1.53 ± 0.40), and tyrosine (2.69 ± 0.71 vs. 1.89 ± 0.46) were increased in the EGFR mutation group; leucine (2.19 ± 0.50 vs. 1.53 ± 0.40), methionine (2.19 ± 0.50 vs. 1.53 ± 0.40), and threonine (2.19 ± 0.50 vs. 1.53 ± 0.40) in MPE were significantly lower in the EGRF 19 mutation compared with 21 mutation patients. The area under the receiver operating characteristic curve of 0.851 and 0.931 would be achieved by the logistic model for classification of EGFR-mutant patients from the wild-type controls or the exon 19 from exon 21 mutant patients. Amino acids in MPE are significantly altered and helpful in the diagnosis of EGFR-mutant patients from the wild-type controls or the exon 19 from exon 21 mutant patients with high accuracy, which is worthy of further study.

The efficacy and safety of furmonertinib in patients with advanced EGFR-mutated NSCLC and leptomeningeal metastases.

e20525 Background: Leptomeningeal metastasis (LM) is a common and fatal complication in patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor ( EGFR) mutation. This retrospective study aimed to evaluate the efficacy and safety of furmonertinib in patients with advanced EGFR-mutated ( EGFRm) NSCLC and LM. Methods: Eligible patients with confirmed advanced EGFRm NSCLC and LM were treated with furmonertinib. The primary endpoints were LM response rate and progression-free survival (PFS). Secondary endpoints were overall survival (OS) and adverse events (AEs). Results: This retrospective study analyzed the efficacy and safety of 31 EGFRm advanced NSCLC patients with LM at two hospitals between February 2020 to March 2023. The median age was 56 years (rang: 31-75), 22 (71.0%) were females. 19 (61.3%) patients had ECOG PS≥2 and all 31 patients (100%) had adenocarcinoma histology. For the treatment of LM, 19 (61.3%) patients received furmonertinib as first-line treatment, 8 (25.8%) patients as second-line treatment. 16 (51.6%) patients were treated with 240 mg of furmonertinib and 12 (38.7%) patients with 160 mg of furmonertinib. The median follow-up duration was 16.80 months (95% CI 12.71-20.89 months). LM objective response rate (ORR) was 75.0% and LM disease control rate (DCR) was 95.0% according to RANO-LM radiologic criteria. Overall ORR was 22.6% and DCR was 96.8%. Median LM duration of response (DoR) was 12.00 months (95% CI 7.40-16.60 months) and median overall DoR was 7.20 months (95% CI 3.60-10.80 months). 23 (74.2%) of the 31 patients had progressed or died by data cutoff. The median PFS was 11.70 months (95% CI 9.48-13.92 months) and the median OS was 18.40 months (95% CI 12.49-24.21 months). There was no significant difference in survival (median PFS: 11.70 months vs 10.90 months, p = 0.335; median OS: 18.40 months vs 13.50 months, p = 0.196) between the 19 patients who treated with furmonertinib as first-line therapy and those who treated with furmonertinib as second-line therapy. Although data on cerebrospinal fluid (CSF) clearance were not available, we observed improved neurologic function in 18 (75%) of 24 patients with baseline neurologic abnormalities. Logistic regression analysis showed that the therapeutic dose of furmonertinib was a positive predictor of OS in NSCLC patients harboring EGFR mutation with LM [HR: 2.679 (1.004-7.147), P = 0.049]. The most common AEs were rash, diarrhea and decreased appetite. However, most AEs were grade 1-2. Conclusions: Our study provides real-world clinical evidence that furmonertinib shows an encouraging efficacy and a manageable safety profile in patients with EGFRm NSCLC and LM.

GOG3069: Phase 2 study of alpelisib and fulvestrant for PIK3CA-mutated estrogen receptor (ER)-positive endometrioid endometrial cancers.

TPS5639 Background: Treatment options for persistent, metastatic, or recurrent endometrial cancer continues to evolve as we learn more about the molecular landscape of this disease. Recent studies have shown a benefit to endocrine-based combinations such as aromatase inhibitors with mTOR or CDK4/6 inhibitors especially in patients who had not received prior chemotherapy ( 1– 3). The presence of oncogenic PIK3CA mutations have been shown to impact response to aromatase inhibitors in breast cancer. The combination of alpelisib and fulvestrant was approved for the treatment of metastatic hormone receptor-positive, HER2-negative breast cancer harboring oncogenic mutations in the PIK3CA gene that progressed on prior endocrine therapy( 4). PIK3CA mutations are commonly identified in endometrial cancers and may similarly confer endocrine resistance. GOG3069 is a phase II trial designed to evaluate the efficacy and safety of alpelisib and fulvestrant in a biomarker-selected endometrial cancer patient population. Methods: This is a phase II non-randomized, open label, multicenter, two-stage study. Eligible patients must have advanced (FIGO 2014 Stage III or IV), persistent, or recurrent endometrial carcinoma with measurable disease by RECISTv1.1 criteria. Patients cannot be curable by surgery or radiotherapy. Disease must be of endometrioid histology with positive expression of estrogen receptor (defined as ≥1% of tumor cells demonstrating positive nuclear staining by immunohistochemistry) and oncogenic PIK3CA mutation. Patients may have received no more than 3 prior lines of therapy including 1 prior line of systemic chemotherapy. Enrolled patients will receive treatment with alpelisib 300mg orally daily and fulvestrant 500mg IM on Day 1 and Day 15 of Cycle 1, then 500mg IM on Day 1 of each 28-day cycle. The primary endpoint is overall response rate as measured by RECISTv1.1-defined tumor response. Secondary endpoints include safety, tolerability, progression-free survival, duration of response, and 24-month overall survival rate. GOG3069 activated in November 2023 and expects to enroll across 15 US sites. The statistical plan uses a conditional stratified design factoring differing probabilities of response based on whether the patient had prior chemotherapy exposure. ClinicalTrials.gov Identifier: NCT05154487

Potential role and prognostic value of Globo-H in lung cancer.

e20037 Background: Globo-H (GH), a globo-series carbohydrate antigen highly expressed on multiple epithelial cancers, is a promising target for cancer immunotherapy. Clinical trials have been conducted to evaluate the efficacy of anti-GH vaccine Adagloxad Simolenin/OBI-821 (in Ph 3) and OBI-833/OBI-821 (in Ph 2) in cancer patients. Epidermal growth factor receptor (EGFR) mutations are well known as a frequent class of driver mutations in lung cancer (LC), which are responsible for tyrosine kinase inhibitors. Besides high expression in cancer cells, GH has been implicated in regulation of EGFR signaling pathway. Knockdown of key enzyme involved in GH biosynthesis β1,3-galactosyltransferase V (β3GalT5) induces apoptosis through disruption of EGFR-related signaling protein complex. In addition, GH is reported to associate the EGFR mutant in LC patients. This study aims to further investigate the potential role of GH in LC. Methods: Clinical study: The level of GH expression was evaluated by immunohistochemistry (IHC) using H-score in clinical samples from 141 patients with lung adenocarcinoma. In vitro study: FACS and Western blotting methods were used to measure the levels of total EGFR, phospho-EGFRs or GH in LC cell lines. Microwestern protein array (MWA) analysis was performed in LC NCI-H1975 cells. Results: Clinical study: Positive GH expression (H score≥1; 18.4%) was significantly associated with poor differentiation grade (p = 0.044) in all samples and disease specific survival in patients with metastasis and stage 4 LC (p = 0.033). In vitro study: Inhibition of EGFR by an EGFR-specific shRNA resulted in a decrease of GH expression in LC cells while overexpression of EGFR resulted in an increase of GH levels. β3GalT5 knockout cells and anti-GH-antibody-treated cells showed a reduction of cell proliferation as well as the total level of EGFR and phosphor-EGFRs expression, which is consistent with the results from previous studies. MWA analysis on LC cells with β3GalT5 knockout, GH ceramide-treated β3GalT5 knockout cells and anti-GH Ab-treated LC cells indicated a positive correlation between the level of GH and EGFR-related signaling proteins including phosphor-JNK, phosphor-c-Jun, phosphor-PP2A, phosphor-PP2A, phosphor-AKT, and Cyclin D1 proteins. In addition, JNK signaling inhibitor partially reduced GH expression in NCI-H1975 cells. These results revealed the mechanistic link between GH regulation and tumor promoting signals in LC. Conclusions: GH expression was associated with the worse survival of LC patients in clinical setting. In addition, the level of GH is positively correlated with levels of EGFR and EGFR-related signaling proteins in vitro. Expression of GH can induce the expression of EGFR and vice versa in LC cells. Furthermore, EGFR downstream JNK signaling pathway might involve in GH regulation by EGFR. Taken together, GH-targeting therapy has a potential application for the treatment of LC patients.