Harboring Epidermal Growth Factor Receptor Mutations Research Articles

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.

Clinical outcome of bevacizumab or ramucirumab combined with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as the first line therapy in susceptible EGFR-mutated advanced non-small-cell lung.

Combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with an anti- vascular endothelial growth factor (VEGF) agent, bevacizumab or ramucirumab, is indicated for advanced lung adenocarcinoma harboring EGFR mutation. This study aimed to show the real-world data of combination therapy and compare the effectiveness between bevacizumab and ramucirumab in combination with an EGFR-TKI. This retrospective study enrolled 47 patients diagnosed of stage IV lung adenocarcinoma with exon 19 deletion or L858R point mutation, receiving a first-line EGFR-TKI with anti-VEGF agent, including 34 (72%) and 13 (28%) patients receiving bevacizumab and ramucirumab, respectively. The response rate was similar in both groups (p = 0.38). Patients receiving bevacizumab had similar progression free survival (PFS) as those receiving ramucirumab (median PFS: 21.9 vs. 24.2 months, p = 0.4871); similar finding was noted in overall survival (OS) (median OS: 33.5 months vs. not reached, p = 0.4618). Patients receiving ramucirumab experienced a significantly high-grade hypertension compared to those receiving bevacizumab (p = 0.0351). Multivariable Cox regression analysis found independent risk factors for worse PFS included poorer ECOG performance status, multiple (≥3) metastatic sites, brain metastasis, and pleural metastasis/effusion, while the type of anti-VEGF agent was not a risk factor. Pericardial metastasis/effusion was the only one independent risk factor for worse OS. In summary, ramucirumab may have similar effectiveness as bevacizumab in combination with an EGFR-TKI as first line therapy for advanced lung adenocarcinoma harboring susceptible EGFR mutation. Further large-scale registry-based cohort studies may be needed to validate our findings.

Abstract 5840: Identifying drug tolerant persister to neoadjuvant osimertinib in resectable non-small cell lung cancer harbouring EGFR mutations (NORA) via single-cell RNA sequencing

Abstract Introduction: Adjuvant osimertinib is the standard of care for resected, stage IB-IIIA non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutation. Yet, the role of neoadjuvant osimertinib is not clear. In the NORA trial (NCT04816838), we aimed to identify the drug tolerant persister (DTP) after neoadjuvant osimertinib for surgically resectable, EGFR-mutated stage IA-IIIA NSCLC. Methods: Patients harboring EGFR Exon 19 deletion or L858R at clinical stage IA-IIIA were given 80 mg of neoadjuvant osimertinib daily for two 28-day cycles followed by surgical resection and adjuvant osimertinib for 3 years. The key exploratory endpoint was to characterize the DTP via single-cell RNA sequencing (scRNA-seq) with pre and post-osimertinib samples. Results: We performed scRNA-seq on twenty-five patients enrolled at Yonsei Cancer Center from June 2021 to March 2022. Patients with stage IA (n=8, 32%), IB (n=7, 28%), IIA (n=4, 16%), IIB (n=4, 16%), and IIIA (n=2, 8%) were included. For EGFR mutation, exon 19 del and L858R accounted for 10 (40%) patients and 15 (60%) patients, respectively. The ORR (all partial response) was 44% (n=11), major pathologic response (MPR) rate was 24% (n=6), and pathologic complete response rate was 0%. ScRNA-seq revealed a total of 252,339 cells (60 clusters) annotated as epithelial cells (10 clusters), fibroblasts (7 clusters), immune cells (17 clusters), myeloid (15 clusters), endothelial cells (11 clusters) that showed distinct enrichment in post-osimertinib samples, non-MPR, and L858R subset. We found that a distint epithelial subset, namely EP8-AGER, identified as alveolar type 1 (AT1) cells was enriched in the non-MPR subset showing activation of Wnt, Hippo, and YAP/TAZ pathway. Pseudotemporal ordering of this cluster showed activation of signaling pathway for COL4A2/COL4A3 related to structural consistuent of extracellular matrix, and RTKN2 associated with NF-κB. In the fibroblast subset, the proportion of FB6-CD74 associated with chemokine activity and NF-κB was higher in the non-MPR and L858R group. In the myeloid subset, CD8-C1-GZMK identified as CD8+ T cells with activation/effector and cytotoxic signatures was also enriched in the post-osimertinib samples. Among macrophages, 3 clusters (annotated as SELENOP+, SPP1+, PLXDC2+) showed enrichment of cholesterol metabolism with activation of apolipoprotein E that promotes conversion of proinflammatory macrophages into anti-inflammatory phenotypes. Lastly, the proportion of EC9-LYZ, annotated as scavenging endothelial cells was higher in the non-MPR and L858R group. Conclusion: Neoadjuvant osimertinib resulted in the cellular reprogramming in the tumor microenvironment, notably AT1 epithelial cell which may lead to a loop between cancer cells and fibroblasts for the generation of DTP cells. Citation Format: Jii Bum (Joy) Lee, Su-Jin Choi, Young Joon Park, Kyoung-Ho Park, Seung Hyun Yong, Hyo Sup Shim, Byung Jo Park, Chang Young Lee, Min Hee Hong, Byoung Chul Cho, Sun Min Lim. Identifying drug tolerant persister to neoadjuvant osimertinib in resectable non-small cell lung cancer harbouring EGFR mutations (NORA) via single-cell RNA sequencing [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 5840.

Abstract 1962: PH009-1, a highly potent, selective and brain-penetrable fourth-generation EGFR-TKI that overcome classic and resistant EGFR mutations in NSCLC

Abstract Background: Epidermal growth factor receptor (EGFR) inhibitors, especially 3rd Gen inhibitor such as osimertinib (Osi), have become the first line therapy for non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. However, treatments with 3rd Gen EGFR inhibitors lead to occurrence of acquired C797S mutation in 10-24% of patients. Though studies showed that double mutations 19Del/C797S (DC) and L858R/C797S (LC) could be inhibited by 1st Gen EGFR TKIs, appearance of triple mutations 19Del/T790M/C797S (DTC) and L858R/T790M/C797S (LTC) always leads to treatment failure. In recent years, 4th Gen EGFR inhibitors have been developed such as BLU-945 and PH009-1. PH009-1 had been reported on AACR annual meeting 2023. Methods: Cell activity and selectivity were determined in engineered Ba/F3 cell lines carrying EGFR wild type (WT, stimulated with EGF), 19Del (D), L858R (L), 19Del/T790M (DT), L858R/T790M (LT), DC, LC, DTC and LTC. The in vivo anti-tumor efficacy and PK-PD studies were performed in cell or patient derived xenograft (CDX or PDX) cancer models (HCC827, D; Ba/F3, LC; PDX, DTC). Brain penetration capability was tested in mice orally treated with PH009-1 for 7 days. Systemic safety of PH009-1 was evaluated in 28-day repeated dosing toxicity studies in rats and dogs following GLP guidelines. Results: PH009-1 displayed potent anti-proliferation activity against Ba/F3 cells harboring EGFR mutations (L, D, LC, DC, LT, DT, LTC, DTC) with IC50 of 2.4, 1.3, 5.2, 1.2, 1.1, 1.5, 2.8, 1.9 nM, respectively, but had very weak effect on EGFR WT Ba/F3 cells (IC50, 1135 nM), suggesting excellent potency and selectivity. In contrast, though BLU-945 potently inhibited DT, LT, DTC, LTC with IC50 less than 5 nM, but its activities on L, D, LC, DC were not strong with IC50 of 31.6, 81.2, 46.2, and 52.0 nM. In in vivo efficacy studies, PH009-1 at a dose of 20 mg/kg BID led to potent inhibition on tumor growth and EGFR phosphorylation, and tumor regression was observed at higher doses in all tested models. In HCC827 model with 19Del (first line therapy setting), mice were treated for more than 200 days, and one tumor relapsed in BLU-945 group but not in PH009-1 or Osi group. Also, deaths were observed in Osi group, but not with PH009-1. After treated mice with PH009-1 at efficacious dose for 7 days, concentrations in cerebrospinal fluids (CSF) at 0-8 h post final dose were more than enough (≥1.5 fold) to cover IC80 on all tested mutations. In GLP toxicity studies, no unexpected toxicity was observed. In dogs. the highest tested dose was determined as highest non-severely toxic dose (HNSTD) and based on high plasma exposure, wide safety margin was confirmed with PH009-1. Conclusion: Our data suggested that PH009-1 overcome T790M/C797S resistant mutations, and also have potential to become a potent and safe approach for first line therapy of NSCLC with EGFR mutations. Citation Format: Feng Gao, Jing Wang, Bin Liu, Yongyong Wu, Liandong Jing, Pengzhi Zhang, Yu Gao, Zhizhong Li, Yongqi Guo. PH009-1, a highly potent, selective and brain-penetrable fourth-generation EGFR-TKI that overcome classic and resistant EGFR mutations in NSCLC [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 1962.

Critical Examination of Modeling Approaches Used in Economic Evaluations of First-Line Treatments for Locally Advanced or Metastatic Non-Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Mutations: A Systematic Literature Review.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with up to 32% of patients with NSCLC harboring an epidermal growth factor receptor (EGFR) mutation. NSCLC harboring an EGFR mutation has a dedicated treatment pathway, with EGFR tyrosine kinase inhibitors and platinum-based chemotherapy often being the therapy of choice. The aim of this study was to systemically review and summarize economic models of first-line treatments used for locally advanced or metastatic NSCLC harboring EGFR mutations, as well as to identify areas for improvement for future models. Literature searches were conducted via Ovid in PubMed, MEDLINE, MEDLINE In-Process, Embase, Evidence-Based Medicine Reviews: Health Technology Assessment, Evidence-Based Medicine Reviews: National Health Service Economic Evaluation Database, and EconLit. An initial search was conducted on 19 December 2022 and updated on 11 April 2023. Studies were selected according to predefined criteria using the Population, Intervention, Comparator, Outcome and Study design (PICOS) framework. Sixty-seven articles were included in the review, representing 59 unique studies. The majority of included models were cost-utility analyses (n=52), with the remaining studies being cost-effectiveness analyses (n=4) and a cost-minimization analysis (n=1). Two studies incorporated both a cost-utility and cost-minimization analysis. Although the model structure across studies was consistently reported, justification for this choice was often lacking. Although the reporting of economic models in NSCLC harboring EGFR mutations is generally good, many of these studies lacked sufficient reporting of justification for structural choices, performing extensive sensitivity analyses and validation in economic evaluations. In resolving such gaps, the validity of future models can be increased to guide healthcare decision making in rare indications.

YES1 as a potential target to overcome drug resistance in EGFR-deregulated non-small cell lung cancer.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) such as gefitinib and osimertinib have primarily been used as first-line treatments for patients with EGFR-activating mutations in non-small cell lung cancer (NSCLC). Novel biomarkers are required to distinguish patients with lung cancer who are resistant to EGFR-TKIs. The aim of the study is to investigate the expression and functional role of YES1, one of the Src-family kinases, in EGFR-TKI-resistant NSCLC. YES1 expression was elevated in gefitinib-resistant HCC827 (HCC827/GR) cells, harboring EGFR mutations. Moreover, HCC827/GR cells exhibited increased reactive oxygen species (ROS) levels compared to those of the parent cells, resulting in the phosphorylation/activation of YES1 due to oxidation of the cysteine residue. HCC827/GR cells showed elevated expression levels of YES1-associated protein 1 (YAP1), NF-E2-related factor 2 (Nrf2), cancer stemness-related markers, and antioxidant proteins compared to those of the parent cells. Knockdown of YES1 in HCC827/GR cells suppressed YAP1 phosphorylation, leading to the inhibition of Bcl-2, Bcl-xL, and Cyclin D1 expression. Silencing YES1 markedly attenuated the proliferation, migration, and tumorigenicity of HCC827/GR cells. Dasatinib inhibited the proliferation of HCC827/GR cells by targeting YES1-mediated signaling pathways. Furthermore, the combination of gefitinib and dasatinib demonstrated a synergistic effect in suppressing the proliferation of HCC827/GR cells. Notably, YES1- and Nrf2-regulated genes showed a positive regulatory relationship in patients with lung cancer and in TKI-resistant NSCLC cell lines. Taken together, these findings suggest that modulation of YES1 expression and activity may be an attractive therapeutic strategy for the treatment of drug-resistant NSCLC.

Impact of central nervous system metastasis after complete resection of lung adenocarcinomas harboring common EGFR mutation – A real-world database study in Japan: The CReGYT-01 EGFR study

ObjectivesTo clarify the impact of central nervous system (CNS) metastasis on performance status (PS) at relapse, on subsequent treatment(s), and on survival of patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutation. MethodsWe conducted the multicenter real-world database study for patients with radical resections for lung adenocarcinomas between 2015 and 2018 at 21 centers in Japan. EGFR mutational status was examined at each center. ResultsOf 4181 patients enrolled, 1431 underwent complete anatomical resection for lung adenocarcinoma harboring common EGFR mutations. Three-hundred-and-twenty patients experienced disease relapse, and 78 (24%) had CNS metastasis. CNS metastasis was significantly more frequent in patients with conventional adjuvant chemotherapy than those without (30% vs. 20%, P = 0.036). Adjuvant chemotherapy did not significantly improve relapse-free survival at any pathological stage (adjusted hazard ratio for stage IA2–3, IB, and II-III was 1.363, 1.287, and 1.004, respectively). CNS metastasis did not affect PS at relapse. Subsequent treatment, mainly consisting of EGFR-tyrosine kinase inhibitors (TKIs), could be equally given in patients with or without CNS metastasis (96% vs. 94%). Overall survival after relapse was equivalent between patients with and without CNS metastasis. ConclusionThe efficacy of conventional adjuvant chemotherapy may be limited in patients with lung adenocarcinoma harboring EGFR mutations. CNS metastasis is likely to be found in practice before deterioration in PS, and may have little negative impact on compliance with subsequent EGFR-TKIs and survival after relapse. In this era of adjuvant TKI therapy, further prospective observational studies are desirable to elucidate the optimal management of CNS metastasis.

Bilateral diffuse metastases in advanced lung adenocarcinoma harboring EGFR mutations was associated with a favorable prognosis to EGFR-TKIs.

Bilateral diffuse metastatic lung adenocarcinoma (BLDM-LUAD) is a special imaging pattern of lung adenocarcinoma (LUAD). We retrospectively assessed survival outcomes and co-mutation characteristics of BLDM-LUAD patients harboring epidermal growth factor receptor (EGFR) mutations who were treated with EGFR-yrosine kinase inhibitors (TKIs). From May 2016 to May 2021, among 458 patients who submitted samples for next generation sequencing (NGS) detection in 1125 patients with non-small-cell lung cancer (NSCLC), and 44 patients were diagnosed as BLDM-LUAD. In order to analyze the survival outcomes of BLDM-LUAD patients harboring EGFR mutations who were treated with EGFR-TKIs, the factors age, gender, smoking history, hydrothorax, site of EGFR mutations and EGFR-TKIs treatment were adjusted using propensity score-matching (PSM). The Kaplan-Meier survival curves and log-rank test were used to analyze progression-free survival (PFS) and overall survival (OS). The co-mutation characteristics of BLDM-LUAD patients harboring EGFR mutations were analyzed by NGS panels. 64 patients with advanced lung adenocarcinoma harboring EGFR mutations and first-line treatment of EGFR-TKIs were successfully matched. BLDM-LUAD (n = 32) have significantly longer median PFS than control group (n = 32) (mPFS: 14 vs 6.2 months; p = .002) and insignificantly longer median OS than control group (mOS: 45 vs 25 months; p = .052). The patients with BLDM-LUAD have the higher frequency of EGFR mutation than control group (84.1% vs 62.0%) before PSM. The co-mutation genes kirsten rat sarcoma viral oncogene homolog (KRAS) (9.4%), ataxia telangiectasia-mutated (ATM) (7.4%) and mesenchymal-epithelial transition (MET) (3.1%) only appeared in the control group after PSM. The BLDM-LUAD harboring EGFR mutations was associated with a favorable prognosis to EGFR-TKI.

Clinical characteristics of patients treated with immune checkpoint inhibitors in EGFR-mutant non-small cell lung cancer: CS-Lung-003 prospective observational registry study

PurposeImmune checkpoint inhibitors (ICIs) are ineffective against epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). This study aimed to investigate the clinical characteristics of patients who were treated or not treated with ICIs, and of those who benefit from immunotherapy in EGFR-mutant NSCLC.MethodsWe analyzed patients with unresectable stage III/IV or recurrent NSCLC harboring EGFR mutations using a prospective umbrella-type lung cancer registry (CS-Lung-003).ResultsA total of 303 patients who met the eligibility criteria were analyzed. The median age was 69 years; 116 patients were male, 289 had adenocarcinoma, 273 had major mutations, and 67 were treated with ICIs. The duration of EGFR-TKI treatment was longer in the Non-ICI group than in the ICI group (17.1 vs. 12.7 months, p < 0.001). Patients who received ICIs for more than 6 months were categorized into the durable clinical benefit (DCB) group (24 patients), and those who received ICIs for less than 6 months into the Non-DCB group (43 patients). The overall survival in the DCB group exhibited longer than the Non-DCB group (69.3 vs. 47.1 months), and an equivalent compared to that in the Non-ICI group (69.3 vs. 68.9 months). Multivariate analysis for time to next treatment (TTNT) of ICIs showed that a poor PS was associated with a shorter TTNT [hazard ratio (HR) 3.309; p < 0.001]. Patients who were treated with ICIs and chemotherapy combination were associated with a longer TTNT (HR 0.389; p = 0.003). In addition, minor EGFR mutation was associated with a long TTNT (HR 0.450; p = 0.046).ConclusionICIs were administered to only 22% of patients with EGFR-mutated lung cancer, and they had shorter TTNT of EGFR-TKI compared to other patients. ICI treatment should be avoided in EGFR mutated lung cancer with poor PS but can be considered for lung cancer with EGFR minor mutations. Pathological biomarker to predict long-term responders to ICI are needed.

Sublobar Resection in Early Non-Small Cell Lung Cancer With Epidermal Growth Factor Receptor Mutant

BackgroundLobectomy is a standard surgical procedure for peripherally located early-stage non-small cell lung cancers (NSCLCs) measuring 2 to 4 cm. However, it is unclear whether sublobar resections, such as wedge resection and segmentectomy, are effective in treating tumors with driver mutations in the epidermal growth factor receptor (EGFR). MethodsWe analyzed the clinicopathologic findings and surgical outcomes of 1395 patients with radiologically solid-dominant NSCLC measuring 2 to 4 cm, without clinical lymph node involvement, who underwent complete resection between 2010 and 2020. The patients, who underwent sublobar resections (n = 231) or lobectomy (n = 1164), were categorized by their EGFR mutation status and the surgical procedures performed. The follow-up was conducted for a median of 45.3 months. ResultsThe 5-year overall survival (OS) rates after sublobar resections (n = 39) were comparable to those after lobectomy (n = 359) in patients with EGFR mutation-positive tumors (80.5% [95% CI, 51.3%-93.2%] vs 88.8% [95% CI, 84.1%-92.1%], respectively; P = .16). Multivariable Cox regression analysis of OS revealed that the surgical procedure was an independent prognostic predictor in the entire cohort (hazard ratio, 0.6; 95% CI, 0.4-1.0; P = .028), but it was not an independent prognostic predictor in patients with EGFR-mutated tumors (hazard ratio, 0.6; 95% CI, 0.2-1.7; P = .32). ConclusionsSublobar resection with a secure surgical margin could be a viable option for appropriately selected patients with peripheral early-stage NSCLC tumors measuring 2 to 4 cm and harboring EGFR mutations, because it provides comparable OS to that of lobectomy.

Comparison of osimertinib plus bevacizumab against osimertinib alone in NSCLC harboring EGFR mutations: a systematic review and meta-analysis.

Frequent failures observed in some trials comparing the efficacy and safety of osimertinib plus bevacizumab to osimertinib monotherapy in advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) alterations have brought questions. To evaluate the efficacy and safety of these two treatment regimens in advanced NSCLC patients harboring EGFR mutations. This study is a systematic review and meta-analysis. PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang, and VIP databases were extensively searched for relevant randomized controlled trials (RCTs) on 14 May 2023. Two researchers independently screened the literature, assessed quality, and extracted data. The primary outcomes were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). The secondary outcomes were adverse events (AEs) and PFS stratified by patients' characteristics. STATA 17.0 software (StataCorp LLC, USA) was adopted for meta-analysis. A total of four RCTs involving 390 patients were included. Overall, the risk of bias across the studies was moderate to low. Pooled results showed that compared to osimertinib alone, the addition of bevacizumab to osimertinib failed to show prolongation of PFS [hazard ratio (HR) = 1.00, 95% confidence interval (CI): 0.78-1.27], OS (HR = 1.01, 95% CI: 0.73-1.41), or improvement of the ORR (risk ratio = 1.12, 95% CI: 0.90-1.38), while an increased incidence of some AEs was observed, such as nausea, oral mucositis, hypertension, and proteinuria. Notably, combination treatment did significantly prolong the PFS in the subset of smokers (HR = 0.64, 95% CI: 0.44-0.94). A mild trend toward PFS benefit under the combined regimen was also noted in patients with brain metastases and first-line treatment, though not reaching statistical significance. Based on the available evidence, the addition of bevacizumab to osimertinib could not provide additional survival benefits with higher but manageable toxicity for EGFR-mutant NSCLC patients. Osimertinib monotherapy remains the prioritized treatment. Further investigation is warranted.

Proteomics-based Model for Predicting the Risk of Brain Metastasis in Patients with Resected Lung Adenocarcinoma carrying the EGFR Mutation.

Introduction: Epidermal growth factor receptor (EGFR) mutation is common in Chinese patients with lung adenocarcinoma (LUAD). Brain metastases (BMs) is high and associated with poor prognosis. Identification of EGFR-mutant patients at high risk of developing BMs is important to reduce or delay the incidence of BMs. Currently, there is no literature on the prediction and modeling of EGFR brain metastasis at the proteinomics level. Methods: We conducted a retrospective study of BMs in postoperative recurrent LUAD with EGFR mutation in the First Affiliated Hospital of Guangzhou Medical University. Tissue proteomic analysis was applied in the primary tumors of resected LUAD in this study using liquid chromatography-mass spectrometry (LC-MS/MS). To identify potential markers for predicting LUAD BM, comparative analyses were performed on different groups to evaluate proteins associated with high risk of BMs. Results: A combination of three potential marker proteins was found to discriminate well between distal metastasis (DM) and local recurrence (LR) of postoperative LUAD with EGFR mutation. Gene Ontology (GO) analysis of significantly altered proteins between BM and non-BM (NBM) indicated that lipid metabolism and cell cycle-related pathways were involved in BMs of LUAD. And the enriched pathways correlated with BMs were found to be quite different in the comparison groups of postoperative adjuvant therapy, tyrosine kinase inhibitor (TKI), and chemotherapy groups. Finally, we developed a random forest algorithm model with eight proteins (RRS1, CPT1A, DNM1, SRCAP, MLYCD, PCID2, IMPAD1 and FILIP1), which showed excellent predictive value (AUC: 0.9401) of BM in patients with LUAD harboring EGFR mutation. Conclusions: A predictive model based on protein markers was developed to accurately predict postoperative BM in operable LUAD harboring EGFR mutation.

Molecular features and clinical outcomes of EGFR-mutated, MET-amplified non-small-cell lung cancer after resistance to dual-targeted therapy.

Some studies of dual-targeted therapy (DTT) targeting epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) have shown promising efficacy in non-small-cell lung cancer (NSCLC). Consequently, patient management following DTT resistance has gained significance. However, the underlying resistance mechanisms and clinical outcomes in these patients remain unclear. This study aimed to delineate the molecular characteristics and survival outcomes of patients with NSCLC harboring EGFR mutations and acquired MET amplification after developing resistance to DTT. We conducted a retrospective analysis of patients with NSCLC with EGFR mutations and acquired MET amplification who exhibited resistance to EGFR/MET DTT. Next-generation sequencing (NGS) was performed on patients with available tissue samples before and/or after the development of resistance to DTT. Stratified analyses were carried out based on data sources and subsequent salvage treatments. Univariate/multivariate Cox regression models and survival analyses were employed to explore potential independent prognostic factors. The study included 77 NSCLC patients, with NGS conducted on 19 patients. We observed many resistance mechanisms, including EGFR-dependent pathways (4/19, 21.1%), MET-dependent pathways (2/19, 10.5%), EGFR/MET co-dependent pathways (2/19, 10.5%), and EGFR/MET-independent resistance mechanisms (11/19, 57.9%). Post-progression progression-free survival (pPFS) and post-progression overall survival (pOS) significantly varied among patients who received the best supportive care (BSC), targeted therapy, or chemotherapy (CT), with median pPFS of 1.5, 3.9, and 4.9 months, respectively (p = 0.003). Median pOS were 2.3, 7.7, and 9.2 months, respectively (p < 0.001). The number of treatment lines following DTT resistance and the Eastern Cooperative Oncology Group performance status emerged as the independent prognostic factors. This study revealed a heterogeneous landscape of resistance mechanisms to EGFR/MET DTT, with a similar prevalence of on- and off-target mechanisms. Targeted therapy or CT, as compared to BSC, exhibited the potential to improve survival outcomes for patients with advanced NSCLC following resistance to DTT.

Abstract B099: Targeting Non Small Cell Lung Cancer EGFR-Mutant and EGFR-Inhibitor resistant cell lines by ferroptosis induction: A potential therapeutic approach

Abstract The epidermal growth factor receptor (EGFR) is a crucial signaling protein involved in regulating cellular growth, survival, and proliferation. EGFR mutations, particularly in non-small cell lung cancer (NSCLC), have been extensively studied due to their role in driving tumor progression and resistance to conventional therapies. While EGFR-mutant tumors initially respond well to EGFR inhibitors, emergence of resistance remains a significant challenge. Ferroptosis is a recently discovered form of regulated cell death characterized by accumulation of lipid peroxides and oxidative stress. It has gained attention as a potential therapeutic strategy in combating drug resistance. However, the vulnerability of various EGFR-mutant and resistant NSCLC cells to ferroptosis induction remains poorly understood. To bridge the existing knowledge gap, we investigated the responsiveness of both EGFR-mutant and their resistant counterpart NSCLC cell lines to ferroptosis induction. Interestingly, NSCLC cell lines and patients’ tumors which harbor EGFR mutations are distinct from those carrying STK11 and KEAP1 mutations, which are known to contribute to resistance to ferroptosis. This observation prompted us to test whether ferroptosis inducers could effectively target this specific subset of NSCLC. In our experimental approach, we first utilized a panel of commercially available EGFR mutant cell lines (n=3), including one harboring T790M resistance mutation, which is a common mechanism of acquired resistance to first-generation inhibitors. We subjected the EGFR-mutant cell lines in vitro to a process of acquiring resistance against three generations of EGFR inhibitors (n=4). Subsequently, upon confirmation of resistance, we evaluated their susceptibility to our proprietary ferroptosis inducer. Exome sequencing data of EGFR-inhibitor resistant cell lines and their age-matched control cell lines revealed that the former acquired genetic alterations that have previously been found to confer resistance in EGFR-inhibitor resistant patients’ tumors, suggesting that our approach is valid for modeling relevant resistance mechanisms. Our results indicate that both EGFR-mutant and resistant cell lines exhibit sensitivity to ferroptosis induction. Furthermore, we observed that EGFR-mutant patient-derived cells, which are refractory to EGFR inhibitors of several generations, were strongly cytostatic to our ferroptosis inducer. These findings provide valuable insights into the interplay between EGFR mutations, drug resistance, and ferroptosis. Exploiting the vulnerability of EGFR-inhibitor resistant NSCLC cells to ferroptosis could offer novel therapeutic options for overcoming drug resistance in EGFR-driven cancers. Further investigations into the underlying molecular mechanisms of ferroptosis inducers in NSCLC are warranted for the development of effective therapies. Citation Format: Taronish Dubash, Maria Cristina Munteanu, Cristian Nunez, Shrouq Farah, Laurence Jadin, Branko Radetich, Francesco M Marincola, Darby Schmidt, Nadia Gurvich. Targeting Non Small Cell Lung Cancer EGFR-Mutant and EGFR-Inhibitor resistant cell lines by ferroptosis induction: A potential therapeutic approach [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B099.

Abstract C025: Trial in progress: First-in-human study of BBT-207 in advanced non-small cell lung cancer harboring EGFR mutation after treatment with EGFR TKI

Abstract Background: There is a high unmet need for an effective therapy for the treatment of non-small cell lung cancer (NSCLC) following osimertinib or other 3rd generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) failure, especially when resistance is driven by the occurrence of the C797S mutation. BBT-207 is a fourth-generation EGFR inhibitor. Preclinically BBT-207 has shown activity against treatment-emergent complex EGFR mutations containing T790M and/or C797S as well as drug-naïve mutants providing a possibility to overcome resistance to prior TKIs. Activity to intracranial lesions is also anticipated from animal models. Methods: Study BBT207-ONC-001 is an open-label, phase 1/2 study evaluating safety, tolerability, pharmacokinetic profile, pharmacodynamic characterization, and preliminary antitumor activity of BBT-207 monotherapy in approximately 92 patients with EGFR-mutant NSCLC. It consists of 3 phases: Phase 1a (dose escalation), phase 1b (recommended phase 2 dose selection), and phase 2 (dose expansion). Key eligibility criteria include patients ≥18 years of age with advanced stage and refractory NSCLC with an activating EGFR mutation, documented partial response, complete response, or durable stable disease after treatment of an EGFR TKI, and previous treatment with all standard therapeutic options and at least one third-generation EGFR TKI. There is no limit on the number of previous treatments received. Phase 1a requires confirmation that the tumor harbors a classical EGFR mutation (19Del or L858R), and phase 1b and phase 2 require confirmation that the tumor or the blood harbors complex EGFR mutations containing C797S. Patients with asymptomatic brain metastases who are on stable dose of corticosteroid are eligible. Primary endpoints are to determine recommended dose range (RDR) which is defined between the minimal reproducibly active dose, and the maximum tolerated dose or maximum administered dose and to characterize the overall safety and tolerability of BBT-207 (phase 1a); to determine the recommended phase 2 dose (phase 1b); to evaluate preliminary antitumor activity with objective response rate (phase 2). Phase 1a dose escalation will be guided by Bayesian logistic regression model. The safety monitoring committee will determine RDR and two recommended dose levels (RDs) within the RDR to be explored in phase 1b. In phase 1b, up to 20 patients will be randomized to each of the two RDs. At the end of phase 1b, a futility test will be performed in the dose level to be treated with the RP2D using Bayesian analysis. Phase 2 will be a non-randomized, open-label phase with up to 20 patients. Patients may receive treatment until disease progression or unacceptable toxicity. Treatment continuation beyond progression will be allowed if potential benefits are justified. Investigational new drug application was cleared by the U.S. FDA. Patient enrollment will begin in approximately August 2023 in the U.S. and Republic of Korea. Clinical trial information: NCT05920135. Citation Format: NaEun Jeon, Alexander Spira, Douglas Orr, Lyudmila Bazhenova, Misako Nagasaka, Jin Seok Ahn, Dong-Wan Kim, Yu Jung Kim, Jimin Cho, Agnes Jung, Eunsoo Jung, Chul-Won Kim, Taiguang Jin, Yong-Hee Lee, Sang-Yoon Lee. Trial in progress: First-in-human study of BBT-207 in advanced non-small cell lung cancer harboring EGFR mutation after treatment with EGFR TKI [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C025.

Immunotherapy strategies for EGFR-mutated advanced NSCLC after EGFR tyrosine-kinase inhibitors failure.

This study aimed to investigate the efficacy of immunotherapy, as monotherapy or in combination, comparing to chemotherapy with or without anti-angiogenesis for advanced non-small cell lung cancer (NSCLC) patients progressing to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). We retrospectively analyzed patients with advanced NSCLC harboring EGFR mutations who received immune checkpoint inhibitors (ICI) and/or chemotherapy after EGFR-TKIs failure at Shanghai Chest Hospital between Aug 2016 and Oct 2022. According to the subsequent immunotherapy regimen, the patients were assigned to ICI monotherapy (IM), IO plus anti-angiogenesis (IA), ICI plus chemotherapy (IC), ICI plus chemotherapy plus anti-angiogenesis (ICA). Eligible patients undergoing standard chemotherapy were assigned to chemotherapy plus anti-angiogenesis (CA) and chemotherapy alone (CM). Efficacy was evaluated according to the RECIST 1.1version, and calculated the objective response rate (ORR) and disease control rate (DCR). Survival curves were plotted using the Kaplan-Meier method, and the median progression-free survival (PFS) was calculated. Differences among survival curves of the six groups were assessed using the log-rank test. A total of 237 advanced NSCLC patients with EGFR mutations were included in this study. Of the 160 patients who received immunotherapy, 57 received ICI monotherapy, 27 received ICI plus anti-angiogenesis therapy, 43 received ICI plus chemotherapy, and 33 received ICI plus anti-angiogenesis plus chemotherapy. 77 patients received standard chemotherapy, of which 30 received chemotherapy plus anti-angiogenesis and 47 received chemotherapy alone. Patients in ICA group showed significant longer PFS than IM (7.2 vs 1.9 months, P=0.011), IA (7.2 vs 4.8 months, P=0.009) and CM group (7.2 vs 4.4 months, P=0.005). There was no significant difference in PFS between the ICA and IC (7.2 vs 5.6 months, P=0.104) or CA (7.2 vs 6.7 months, P=0.959) group. Meanwhile, the ICA group showed the highest ORR and DCR (36.4% and 90.9%) compared to the other five groups. The IC group had a higher ORR than the IA and CA group (32.6% vs 7.4% vs 10.0%, respectively), but the DCR was comparable (79.1% vs 74.1% vs 76.7%, respectively). The ORR of the CM group was 6.4% and the DCR was 66.0%. IM group showed the lowest ORR and DCR (1.8% and 36.8%). Treatment-related adverse events (TRAEs) of grade 3 or worse occurred in 9 (27.3%) patients in the ICA group, 6 (20.0%) in the CA group, 7 (14.9%) in the CM group, 5 (11.6%) in the IC group, 5 (8.8%) in the IM group, and 2 (7.4%) in the IA group. NSCLC patients with positive EGFR mutations after EGFR-TKIs failure received subsequent immunotherapy plus anti-angiogenesis and chemotherapy are likely to have more benefits in ORR, DCR and mPFS.

Thyroid transcription factor 1 (TTF-1) negativity as a predictor of unfavorable response to EGFR-TKI therapy in advanced lung adenocarcinoma patients with EGFR mutations.

The absence of thyroid transcription factor 1 (TTF-1) is associated with a lower frequency of epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma (LUAD). The aim of this study was to assess the impact of TTF-1 expression on the clinical response to EGFR-tyrosine kinase inhibitor (TKI) treatment in patients with advanced LUAD. The data of patients with advanced LUAD who were admitted to the Beijing Tiantan Hospital and Peking University Cancer Hospital (China) between April 2009 and May 2023 was retrospectively analyzed. A total of 227 patients diagnosed with advanced LUAD were included, of which 28.2% (64/227) had TTF-1-negative adenocarcinoma, while 54.6% (124/227) harbored EGFR mutations. Negative TTF-1 expression significantly correlated with male sex (68.8% vs. 42.3%, p < 0.001), history of heavy smoking (57.8% vs. 36.2%, p = 0.003), poorly differentiated tumors (86.5% vs. 43.2%, p < 0.001), and lower frequency of EGFR mutations (26.6% vs. 65.6%, p < 0.001) compared with TTF-1 positivity. Multivariable logistic regression showed that low prevalence of EGFR mutations (p < 0.001) and male sex (p = 0.006) were independent predictive factors for the negative expression of TTF-1. Patients lacking TTF-1 also exhibited worse overall response rate (ORR; 23.5% vs. 54.2%, p = 0.019), disease control rate (DCR; 58.8% vs. 89.7%, p = 0.003), and median progression-free survival (PFS; 2.9 vs. 11.6 months, p < 0.001) following treatment with EGFR-TKIs compared to the TTF-1-positive patients with EGFR mutations. Patients with TTF-1-negative and EGFR-mutant LUAD show a diminished response to EGFR-TKIs.

A randomized phase II study of afatinib alone or combined with bevacizumab for treating chemo-naïve patients with non-small cell lung cancer harboring EGFR mutations

BackgroundAdding bevacizumab to first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) prolonged the progression-free survival (PFS), but limited data are available for second-generation EGFR-TKIs. AfaBev-CS is a randomized, phase II trial comparing afatinib plus bevacizumab and afatinib alone as first-line treatment. Patients and methodsUntreated patients with non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations (Del19 or L858R) were enrolled and randomly assigned to receive either afatinib (30 mg) plus bevacizumab (AfaBev group) or afatinib (40 mg) monotherapy (Afa group). The primary endpoint was PFS. The power was >50% under the assumptions of a median PFS of 12 months for the Afa group and hazard ratio (HR) of 0.6 for the AfaBev group. ResultsBetween August 2017 and September 2019, 100 patients were enrolled. There was no significant difference in PFS between the groups. The median PFS was 16.3 and 16.1 months for the AfaBev and Afa groups, respectively, with an HR of 0.865 (95% confidence interval [CI], 0.539 to 1.388; p = 0.55). In terms of overall survival, there was no significant difference between the groups (HR, 0.84; 95% CI, 0.39 to 1.83; p = 0.67). The overall response rate was 82.6% and 76.6% in the AfaBev and Afa groups, respectively (p = 0.61). Grade ≥ 3 diarrhea, hypertension, acneiform rash, paronychia, and stomatitis were frequently observed in the AfaBev group. ConclusionsThis study failed to show efficacy of AfaBev over Afa for improving PFS in untreated patients with EGFR-mutated NSCLC.

Long non-coding RNAs in non-small cell lung cancer: implications for EGFR-TKI resistance.

Non-small cell lung cancer (NSCLC) is one of the most common types of malignant tumors as well as the leading cause of cancer-related deaths in the world. The application of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has dramatically improved the prognosis of NSCLC patients who harbor EGFR mutations. However, despite an excellent initial response, NSCLC inevitably becomes resistant to EGFR-TKIs, leading to irreversible disease progression. Hence, it is of great significance to shed light on the molecular mechanisms underlying the EGFR-TKI resistance in NSCLC. Long non-coding RNAs (lncRNAs) are critical gene modulators that are able to act as oncogenes or tumor suppressors that modulate tumorigenesis, invasion, and metastasis. Recently, extensive evidence demonstrates that lncRNAs also have a significant function in modulating EGFR-TKI resistance in NSCLC. In this review, we present a comprehensive summary of the lncRNAs involved in EGFR-TKI resistance in NSCLC and focus on their detailed mechanisms of action, including activation of alternative bypass signaling pathways, phenotypic transformation, intercellular communication in the tumor microenvironment, competing endogenous RNAs (ceRNAs) networks, and epigenetic modifications. In addition, we briefly discuss the limitations and the clinical implications of current lncRNAs research in this field.

Arsenic Inhibits Proliferation and Induces Autophagy of Tumor Cells in Pleural Effusion of Patients with Non-Small Cell Lung Cancer Expressing EGFR with or without Mutations via PI3K/AKT/mTOR Pathway.

To clarify whether arsenic could exert inhibitory effects on tumor cells in pleural effusions of patients with non-small cell lung cancer (NSCLC), 36 NSCLC pleural effusion samples were collected from Changzheng Hospital and Ruijin Hospital, from 2019 to 2022. The genotype of epidermal growth factor receptor (EGFR) was identified. Tumor cells were isolated and treated with arsenic trioxide (ATO) or/and gefitinib. Additionally, six patients were intrapleurally administrated with ATO. Results showed that 25 samples bore EGFR wild type (WT) and 11 harbored EGFR mutations, including 6 with L858R, 3 with ΔE746-A750, and 2 with T790M. ATO diminished the number of tumor cells from patients with WT and mutant EGFR, down-regulated the expression or phosphorylation of EGFR, pmTOR, PI3K, PTEN, and p4E-BP1, and up-regulated the expression of LC3. Immunofluorescent experiments showed that ATO enhanced LC3 and P62. By contrast, gefitinib was only effective in those harboring EGFR sensitizing mutations. Notably, in patients with intrapleural ATO injection, the pleural effusion underwent a bloody to pale yellow color change, the volume of the pleural effusion was reduced, and the number of the tumor cells was significantly reduced. In conclusion, arsenic is effective against NSCLC with various EGFR genotypes in vitro and in vivo, and potentially circumvents gefitinib resistance.