Combination Of EGFR Tyrosine Kinase Inhibitors Research Articles

Combination of EGFR-TKI and Chemotherapy Versus EGFR-TKI Monotherapy as Neoadjuvant Treatment of Stage III-N2 EGFR-Mutant Non-Small Cell Lung Cancer.

The efficacy of neoadjuvant treatment with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) monotherapy in patients with stage III-N2 EGFR-mutant remains unsatisfactory. This study explored the potential benefits of combining first-generation EGFR-TKI with chemotherapy as a neoadjuvant treatment for patients with stage III-N2 EGFR-mutant non-small cell lung cancer (NSCLC). The medical records of patients with III-N2 EGFR-mutant NSCLC who received neoadjuvant therapy with EGFR-TKI at Shanghai Chest Hospital from October 2011 to October 2022 were retrospectively reviewed. Patients with stage III-N2 EGFR-mutant NSCLC who received first-generation TKI combined with chemotherapy as neoadjuvant treatment were included in the combination group, and those who received EGFR-TKI monotherapy were included in the monotherapy group. The study assessed the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, disease-free survival (DFS), overall survival (OS), downstaging rates of pathologic lymph nodes (from stage N2 to N1 or N0), major pathologic response (MPR) rate, pathological complete response (PCR) rate, and safety. A total of 74 631 patients with EGFR-mutant NSCLC were screened, and 60 patients were included, 7 of whom did not undergo surgery after neoadjuvant targeted therapy. Of the remaining 53 patients, 15 received first-generation EGFR-TKI combined with chemotherapy as neoadjuvant treatment, and 38 received EGFR-TKI monotherapy. The median follow-up time was 44.12 months. The ORR was 50.0% (9/18) in the combination group and 40.5% (17/42) in the monotherapy group (P = .495). The MPR rate was 20.0% (3/15) and 10.5% (4/38) in the combination and monotherapy groups, respectively (P = .359). No patients achieved PCR in the combination group, while 3 (7.89%) attained PCR in the monotherapy group. The 2 groups did not differ in N2 downstaging rate (P = .459). The median DFS was not reached in the combination group, while it was 23.6 months (95% CI: 8.16-39.02) in the monotherapy group (P = .832). Adverse events observed were consistent with those commonly associated with the 2 treatments. Combination therapy with first-generation EGFR-TKI and chemotherapy could be considered a neoadjuvant treatment option for patients with stage III-N2 EGFR-mutant NSCLC, exhibiting acceptable toxicity. However, regarding short-term efficacy, combination therapy did not demonstrate superiority over EGFR-TKI monotherapy. Long-term follow-up is warranted for a more accurate assessment of the DFS and OS.

Clinical advances in EGFR-TKI combination therapy for EGFR-mutated NSCLC: a narrative review.

Mutations located in epidermal growth factor receptor (EGFR) tyrosine kinase domains have been described as the 'Achilles heel' of non-small cell lung cancer (NSCLC) and can be targeted by epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). However, the clinical benefits of EGFR-TKIs are limited, and drug resistance inevitably occurs in NSCLC patients after long-term exposure to certain drugs. EGFR-TKI combination therapies, including combined targeted therapy, radiotherapy, chemotherapy, and immunotherapy, have shown promise in addressing this issue. This literature review analyzed the rationale and controversies of clinical research related to various EGFR-TKI combination therapies. The PubMed database was searched to retrieve articles published from January 1, 2001 to April 15, 2023 using the following Medical Subject Headings (MeSH) terms: "EGFR-mutated non-small cell lung cancer" and "clinical trial". Google Scholar was also reviewed to retrieve additional articles. The search was limited to articles published in English. In this review, we summarized EGFR-TKI combination therapies, including combined targeted therapy, radiotherapy, chemotherapy, and immunotherapy, most of which have shown efficacy and safety in patients with EGFR-mutated NSCLC. A number of clinical studies with large sample sizes have analyzed the activity and toxicity of combined therapies and explored potential and well-tolerated treatment options. EGFR mutations have been detected in many NSCLC patients and can be targeted by EGFR-TKIs. However, drug resistance after long-term exposure remains a significant challenge for this type of treatment. Most clinical trials have shown that the combination of EGFR-TKIs and targeted therapy, chemotherapy, radiotherapy or immunotherapy is efficacious and safe in the treatment of EGFR-mutated NSCLC. It should be noted that in some instances, serious adverse events have led to the termination of trials. However, EGFR-TKI combination therapy is indeed an effective approach for the treatment of patients with EGFR-mutated NSCLC and deserves further development.

A real-world study and network pharmacology analysis of EGFR-TKIs combined with ZLJT to delay drug resistance in advanced lung adenocarcinoma

ObjectiveThis study aimed to explore the efficacy and safety of combining epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) with ZiLongJin Tablet (ZLJT) in delaying acquired resistance in advanced EGFR-mutant lung adenocarcinoma (LUAD) patients. Furthermore, we employed network pharmacology and molecular docking techniques to investigate the underlying mechanisms.MethodsA retrospective comparative study was conducted on stage IIIc/IV LUAD patients treated with EGFR-TKIs alone or in combination with ZLJT at the Second Affiliated Hospital of the Air Force Medical University between January 1, 2017, and May 1, 2023. The study evaluated the onset of TKI resistance, adverse reaction rates, safety indicators (such as aspartate aminotransferase, alanine aminotransferase, and creatinine), and inflammatory markers (neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio) to investigate the impact of EGFR-TKI combined with ZLJT on acquired resistance and prognostic indicators. Additionally, we utilized the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, the Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine, PubChem, UniProt, and Swiss Target Prediction databases to identify the active ingredients and targets of ZLJT. We obtained differentially expressed genes related to EGFR-TKI sensitivity and resistance from the Gene Expression Omnibus database using the GSE34228 dataset, which included sensitive (n = 26) and resistant (n = 26) PC9 cell lines. The "limma" package in R software was employed to detect DEGs. Based on this, we constructed a protein‒protein interaction network, performed gene ontology and KEGG enrichment analyses, and conducted pathway network analysis to elucidate the correlation between the active ingredients in ZLJT and signaling pathways. Finally, molecular docking was performed using AutoDockVina, PYMOL 2.2.0, and Discovery Studio Client v19.1.0 software to simulate spatial and energy matching during the recognition process between predicted targets and their corresponding compounds.Results(1) A total of 89 patients were included, with 40 patients in the EGFR-TKI combined with ZLJT group (combination group) and 49 patients in the EGFR-TKI alone group (monotherapy group). The baseline characteristics of the two groups were comparable. There was a significant difference in the onset of resistance between the combination group and the monotherapy group (P < 0.01). Compared to the monotherapy group, the combination group showed a prolongation of 3.27 months in delayed acquired resistance. There was also a statistically significant difference in the onset of resistance to first-generation TKIs between the two groups (P < 0.05). (2) In terms of safety analysis, the incidence of adverse reactions related to EGFR-TKIs was 12.5% in the combination group and 14.3% in the monotherapy group, but this difference was not statistically significant (P > 0.05). There were no statistically significant differences in serum AST, ALT, CREA, TBIL, ALB and BUN levels between the two groups after medication (P > 0.05). (3) Regarding inflammatory markers, there were no statistically significant differences in the changes in neutrophil-to-lymphocyte Ratio(NLR) and Platelet-to-lymphocyte Ratio(PLR) values before and after treatment between the two groups (P > 0.05). (4) Network pharmacology analysis identified 112 active ingredients and 290 target genes for ZLJT. From the GEO database, 2035 differentially expressed genes related to resistant LUAD were selected, and 39 target genes were obtained by taking the intersection. A "ZLJT-compound-target-disease" network was successfully constructed using Cytoscape 3.7.0. GO enrichment analysis revealed that ZLJT mainly affected biological processes such as adenylate cyclase-modulating G protein-coupled receptor. In terms of cellular components, ZLJT was associated with the cell projection membrane. The molecular function primarily focused on protein heterodimerization activity. KEGG enrichment analysis indicated that ZLJT exerted its antitumor and anti-drug resistance effects through pathways such as the PI3K-Akt pathway. Molecular docking showed that luteolin had good binding activity with FOS (-9.8 kJ/mol), as did tanshinone IIA with FOS (-9.8 kJ/mol) and quercetin with FOS (-8.7 kJ/mol).ConclusionZLJT has potential antitumor progression effects. For patients with EGFR gene-mutated non-small cell LUAD, combining ZLJT with EGFR-TKI treatment can delay the occurrence of acquired resistance. The underlying mechanisms may involve altering signal transduction pathways, blocking the tumor cell cycle, inhibiting tumor activity, enhancing cellular vitality, and improving the bioavailability of combination therapy. The combination of EGFR-TKI and ZLJT represents an effective approach for the treatment of tumors using both Chinese and Western medicine.

Efficacy and safety of EGFR-TKIs in combination with angiogenesis inhibitors as first-line therapy for advanced EGFR-mutant non-small-cell lung cancer: a systematic review and meta-analysis

BackgroundFor patients with advanced non-small-cell lung cancer (NSCLC) with EGFR mutations, the suggested course of action is epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Even with a high disease control rate, a majority of patients develop acquired EGFR-TKIs resistance and eventually advance. To increase the benefits of treatment, clinical trials are increasingly exploring the value of EGFR-TKIs combined with angiogenesis inhibitors as a first-line treatment in advanced NSCLC carrying EGFR mutations.MethodUsing PubMed, EMBASE and Cochrane Library, to locate published full-text articles in print or online, a thorough literature search was done from the database's inception to February 2021. Additionally, oral presentation RCTs from ESMO and ASCO were obtained. We sifted out RCTs that used EGFR-TKIs along with angiogenesis inhibitors as first-line therapy for advanced EGFR-mutant NSCLC. ORR, AEs, OS, and PFS were the endpoints. Review Manager version 5.4.1 was used for data analysis.ResultsOne thousand eight hundred twenty-one patients were involved in 9 RCTs. According to the results, combining EGFR-TKIs with angiogenesis inhibitors therapy prolonged PFS of advanced EGFR-mutation NSCLC patients on the whole [HR:0.65 (95%CI: 0.59~0.73, P<0.00001)]. No significant statistical difference was identified between the combination group and single drug group in OS(P=0.20) and ORR (P=0.11). There are more adverse effects when EGFR-TKIs are used in combination with angiogenesis inhibitors than when used alone.ConclusionThe combination of EGFR-TKIs and angiogenesis inhibitors prolonged PFS in patients with EGFR-mutant advanced NSCLC, but the OS and ORR benefit was not significant, and the risk of adverse events was higher, more pronounced with hypertension and proteinuria; PFS in subgroups suggested that the combination was associated with better PFS in the smoking, liver metastasis, and no brain metastasis groups, and the included studies suggested that the smoking group , liver metastasis group, and brain metastasis group may have a potential OS benefit.

Therapeutic effects of combination with EGFR-TKIs and radiotherapy on the prognosis of stage IV lung adenocarcinomas harboring 19-Del or 21-L858R: A retrospective study.

e21067 Background: To evaluate the therapeutic effects of combining epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) with radiotherapy on the prognosis of patients with stage IV lung adenocarcinomas (LUAD) that harbor either exon 19 deletion (19-Del) or exon 21 L858R mutation (21-L858R). Methods: Clinical data in the real-world study were retrospectively collected and analyzed from 177 stage IV LUAD patients who received the combination of EGFR-TKIs and radiotherapy at Shandong Cancer Hospital between June 2012 and August 2017. And the primary endpoint of the study was overall survival (OS). Results: The results revealed that the stage IV LUAD patients harboring 19-Del showed similar clinical characteristics as those harboring 21-L858R (all P &gt; 0.05). The median OS (mOS) of all patients was 32.0 (95%CI, 28.6-35.5) months. Multivariate analysis identified EFGR mutations and thoracic radiotherapy as the independent factors in predicting OS ( P = 0.001, 0.013, respectively). Moreover, subgroup analysis showed that patients who received EGFR-TKIs plus bone metastasis radiotherapy or thoracic radiotherapy showed a longer OS in 19-Del group than those in 21-L858R group (mOS, 34.7 vs. 25.1 months, 51.0 vs. 29.6 months; P = 0.0056, 0.0013, respectively), while not observed for patients with brain metastasis radiotherapy (mOS, 34.7 vs. 25.1 months; P = 0.088). Conclusions: Although there were no significant differences in clinical characteristics of stage IV LUAD patients between 19-Del group and 21-L858R group, patients harboring 19-Del could still achieve longer OS than those harboring 21-L858R after receiving EGFR-TKIs in combination with radiotherapy.

Abstract 1300: Targeted therapies prime lung cancer cells for macrophage-mediated destruction

Abstract The CD47/SIRPa axis is an immune checkpoint that regulates macrophage anti-tumor function. Therapies that block CD47 on cancer cells show promise in clinical trials for solid and hematologic malignancies, particularly when combined with other anticancer agents. However, the best combination strategies for using CD47-blocking therapies remain unknown. In this study, we developed a novel in vitro screening platform to identify drugs that render cancer cells more vulnerable to macrophage attack. We performed an unbiased screen of 800 FDA-approved drugs using primary human macrophages and PC9 cells, a human EGFR mutant lung cancer cell line. We identified EGFR tyrosine kinase inhibitors (TKIs) as drugs that act on the cancer cells and specifically enhance macrophage-mediated cytotoxicity (&amp;gt;4-fold enhancement, p&amp;lt;0.01). In contrast, conventional chemotherapy drugs either showed no significant enhancement or abrogated macrophage activation. The combination of EGFR TKIs with anti-CD47 antibodies elicited maximal phagocytosis across a range of cell lines and conditions. In long-term co-culture assays with macrophages, the combination of EGFR TKIs and anti-CD47 antibodies eliminated persister cells to prevent TKI resistance. Importantly, these findings extended to lung cancers with other RTK-MAPK pathway mutations, such as ALK-rearranged cancers (treated with lorlatinib, alectinib, or crizotinib) or KRAS G12C mutant cancers (treated with sotorasib or adagrasib). In xenograft and syngeneic mouse models, the combination of targeted therapies with CD47 ablation was able to dramatically reduce tumor burden. To understand the mechanism of synergy, we generated 8 different lung cancer cell lines resistant to EGFR, ALK, or KRAS inhibitors. The resistant lines significantly upregulated CD47 and concomitantly became more sensitive to macrophage attack in vitro and in vivo. By RNA sequencing, we identified multiple mechanisms contributing to vulnerability, including secretion of the cytokine MIP-3 by the cancer cells and alteration of other immunoregulatory molecules. Overall, we have identified a novel therapeutic strategy to enhance the efficacy of RTK-MAPK pathway inhibitors by combining them with anti-CD47 therapies. Our findings suggest cross-sensitivity occurs such that lung cancer cells that become resistant to targeted therapies also become more sensitive to macrophage attack. Our findings provide rationale for testing this combination approach in patients with lung cancers bearing driver mutations. Citation Format: Kyle Vacarro, Juliet Allen, Asaf Maoz, Sarah Reeves, Aaron Hata, Kipp Weiskopf. Targeted therapies prime lung cancer cells for macrophage-mediated destruction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1300.

Hype or hope - Can combination therapies with third-generation EGFR-TKIs help overcome acquired resistance and improve outcomes in EGFR-mutant advanced/metastatic NSCLC?

Three generations of epidermal growth factor receptor - tyrosine kinase inhibitors (EGFR-TKIs) have been developed for treating advanced/metastatic non-small cell lung cancer (NSCLC) patients harboring EGFR-activating mutations, while a fourth generation is undergoing preclinical assessment. Although initially effective, acquired resistance to EGFR-TKIs usually arises within a year due to the emergence of clones harboring multiple resistance mechanisms. Therefore, the combination of EGFR-TKIs with other therapeutic agents has emerged as a potential strategy to overcome resistance and improve clinical outcomes. However, results obtained so far are ambiguous and ideal therapies for patients who experience disease progression during treatment with EGFR-TKIs remain elusive. This review provides an updated landscape of EGFR-TKIs, along with a description of the mechanisms causing resistance to these drugs. Moreover, it discusses the current knowledge, limitations, and future perspective regarding the use of EGFR-TKIs in combination with other anticancer agents, supporting the need for bench-to-bedside approaches in selected populations.

Co-delivery of gefitinib and hematoporphyrin by aptamer-modified fluorinated dendrimer for hypoxia alleviation and enhanced synergistic chemo-photodynamic therapy of NSCLC

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs)-based molecular targeted therapy are proved to be effective in the treatment of non-small cell lung cancer (NSCLC) with EGFR mutation, its efficacy is limited by the acquired drug resistance. The combination of EGFR-TKIs with photodynamic therapy (PDT) has been explored to combat NSCLC with promising synergistic results. However, hypoxic tumor microenvironment is associated with the development of EGFR-TKIs resistance and severely limits the efficacy of PDT. Here, we synthesized an aptamer modified fluorinated dendrimer (APF) as a drug carrier and prepared nanocomplexes APFHG by encapsulation of gefitinib (Gef) and hematoporphyrin (Hp). APF has good oxygen-carrying capacity, high drug entrapment efficiency, and could release Gef and Hp in response to intracellular pH. APF can specifically recognize EGFR-positive NSCLC cells and effectively improve the tumor hypoxic microenvironment due to the targeting effect of aptamer and the good oxygen-carrying capacity of the fluorinated dendrimer. Under the laser irradiation, APFHG can significantly increase the production of the intracellular reactive oxygen species and produce a synergistic therapeutic effect in inhibition of cellular growth and induction of cell cycle arrest and apoptosis on both Gef-sensitive and Gef-resistant EGFR-mutant NSCLC cells through PDT/molecular targeted therapy. This work indicates that fluorinated dendrimer could be a potent drug delivery platform to overcome hypoxia-related resistance and the co-delivery of EGFR-TKI and photosensitizer by the fluorinated dendrimer could be a promising therapeutic approach for reversal of EGFR-TKIs resistance in EGFR mutation-positive NSCLC.

Cigarette smoke-induced LKB1/AMPK pathway deficiency reduces EGFR TKI sensitivity in NSCLC

Smoker patients with non-small cell lung cancer (NSCLC) have poorer prognosis and survival than those without smoking history. However, the mechanisms underlying the low response rate of those patients to EGFR tyrosine kinase inhibitors (TKIs) are not well understood. Here we report that exposure to cigarette smoke extract enhances glycolysis and attenuates AMP-activated protein kinase (AMPK)-dependent inhibition of mTOR; this in turn reduces the sensitivity of NSCLC cells with wild-type EGFR (EGFRWT) to EGFR TKI by repressing expression of liver kinase B1 (LKB1), a master kinase of the AMPK subfamily, via CpG island methylation. In addition, LKB1 expression is correlated positively with sensitivity to TKI in patients with NSCLC. Moreover, combined treatment of EGFR TKI with AMPK activators synergistically increases EGFR TKI sensitivity. Collectively, the current study suggests that LKB1 may serve as a marker to predict EGFR TKI sensitivity in smokers with NSCLC carrying EGFRWT and that the combination of EGFR TKI and AMPK activator may be a potentially effective therapeutic strategy against NSCLC with EGFRWT.

Hypoxia Induces Resistance to EGFR Inhibitors in Lung Cancer Cells via Upregulation of FGFR1 and the MAPK Pathway.

Development of resistance remains the key obstacle to the clinical efficacy of EGFR tyrosine kinase inhibitors (TKI). Hypoxia is a key microenvironmental stress in solid tumors associated with acquired resistance to conventional therapy. Consistent with our previous studies, we show here that long-term, moderate hypoxia promotes resistance to the EGFR TKI osimertinib (AZD9291) in the non-small cell lung cancer (NSCLC) cell line H1975, which harbors two EGFR mutations including T790M. Hypoxia-induced resistance was associated with development of epithelial-mesenchymal transition (EMT) coordinated by increased expression of ZEB-1, an EMT activator. Hypoxia induced increased fibroblast growth factor receptor 1 (FGFR1) expression in NSCLC cell lines H1975, HCC827, and YLR086, and knockdown of FGFR1 attenuated hypoxia-induced EGFR TKI resistance in each line. Upregulated expression of FGFR1 by hypoxia was mediated through the MAPK pathway and attenuated induction of the proapoptotic factor BIM. Consistent with this, inhibition of FGFR1 function by the selective small-molecule inhibitor BGJ398 enhanced EGFR TKI sensitivity and promoted upregulation of BIM levels. Furthermore, inhibition of MEK activity by trametinib showed similar effects. In tumor xenografts in mice, treatment with either BGJ398 or trametinib enhanced response to AZD9291 and improved survival. These results suggest that hypoxia is a driving force for acquired resistance to EGFR TKIs through increased expression of FGFR1. The combination of EGFR TKI and FGFR1 or MEK inhibitors may offer an attractive therapeutic strategy for NSCLC. SIGNIFICANCE: Hypoxia-induced resistance to EGFR TKI is driven by overexpression of FGFR1 to sustain ERK signaling, where a subsequent combination of EGFR TKI with FGFR1 inhibitors or MEK inhibitors reverses this resistance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/21/4655/F1.large.jpg.

Combination of EGFR-TKIs and chemotherapy in advanced EGFR mutated NSCLC: Review of the literature and future perspectives.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improved clinical outcome compared to chemotherapy in EGFR mutated advanced non-small cell lung cancer (NSCLC) patients. Nonetheless, acquired resistance develops within 10-14 months and 20-30% of EGFR-mutated patients do not respond to EGFR-TKI. In order to delay or overcome acquired resistance to EGFR-TKIs, combination therapies of EGFR-TKIs with chemotherapy has been investigated with conflicting results. Early studies failed to show a survival benefit because of a lack of patient selection, but more recently clinical studies in EGFR mutated patients have shown promising results. This review summarizes preclinical and clinical studies of combination of EGFR-TKIs, including the third-generation TKI osimertinib, with chemotherapy in first- and second-line settings, using concurrent or intercalated treatment strategies. In the new era of third-generation EGFR-TKIs, new studies of this combination strategy are warranted.

P1.01-100 Effect of Osimertinib in Non-Small Cell Lung Cancer Patients with Brain Metastases After Progression Following Front-Line EGFR-TKI Therapy

Osimertinib has been adopted as the standard of care for T790M-mediated acquired epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance. In this study, we aim to investigate the effect of osimertinib in advanced NSCLC with brain metastases after the failure of first-line therapy. We retrospectively studied 43 NSCLC patients with BM received osimertinib after progression following front-line EGFR-TKI therapy from January 2013 to December 2016 at our institution. Overall survival (OS) was measured from the date of brain metastases. Among the 43 patients, 25(58.1%) received EGFR-TKIs as first-line therapy, 15(34.9%) were treated with EGFR-TKIs therapy after the progression of chemotherapy, and there’re also 3(7.0%) received the combination of EGFR-TKIs and chemotherapy as first-line therapy. 16(37.2%) were EGFR T790M positive, 4(9.3%) were EGFR T790M negative and 23(53.5%) were unknown T790M status. 34(79.1%) patients had received local radiation therapies (RT). The median overall survival (OS), and the median intracranial progression free survival (iPFS) was 32.0 months, 14 months, respectively. Patients with EGFR T790M mutation had the median OS of 24.7 months, these without T790M mutation had the median OS of 17.0 months, and the patients with unknown status of T790M showed the longest OS of 34.4months, although it did not reach statistical significance (P =0.727). There was also no difference in iPFS among the T790M-positive group, T790M-negetive group and the unknown status group (5.0 vs. 7.0 vs. 18.0 months, P=0.195). Similar results in OS were found among the first line TKIs group, chemotherapy followed by EGFR-TKI therapy group and the combination of TKIs and chemotherapy group (P=0.491). Three patients had leptomeningeal metastasis (LM), showed to have a worse iPFS of 12 months compared to 14 months of these without LM (P=0.991). Osimertinib had a good efficacy in patients with brain metastasis of advanced non–small-cell lung cancer in whom disease had progressed following front-line EGFR-TKIs.

Hypofractionated EGFR tyrosine kinase inhibitor limits tumor relapse through triggering innate and adaptive immunity.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a first-line therapy for rapidly killing tumors such as those associated with non-small cell lung cancer by blocking oncogenic receptor signaling, but tumor relapse often occurs. Here, we have observed that hypofractionated EGFR TKI treatment (HypoTKI) is more potent than standard hyperfractionated EGFR TKI treatment (HyperTKI), and its antitumor effect associated with preventing tumor relapse depends on T cells. HypoTKI triggers greater innate sensing for type I IFN and CXCL10 production through the Myd88 signaling pathway to enhance tumor-specific T cell infiltration and reactivation. We also demonstrate that timely programmed cell death ligand-1 (PD-L1) blockade can synergize with HypoTKI to control advanced large tumors and effectively limit tumor relapse without severe side effects. Our study provides evidence for exploring the potential of a proper combination of EGFR TKIs and immunotherapy as a first-line treatment for treating EGFR-driven tumors.

EGFR-TKI plus brain radiotherapy versus EGFR-TKI alone in the management of EGFR-mutated NSCLC patients with brain metastases.

It has been confirmed that epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) presented better efficacy than brain radiotherapy (brain RT) in the treatment of brain metastasis (BM) in EGFR mutated NSCLC patients. However, whether the combination of EGFR-TKIs and brain RT is better than EGFR-TKIs alone remains unclear. We aim to compare the outcomes of adding brain RT to EGFR-TKIs and to screen for the beneficial population by a meta-analysis of currently available data. A systematic search for relevant articles was conducted in six databases. The outcomes were overall survival (OS) and intracranial progression-free survival (iPFS) between groups, both were measured as hazard ratios (HRs). Meta-regression and dominant subgroup analysis were used to explore advantageous subgroups. A total of 12 retrospective studies involving 1,553 EGFR mutated patients with BM at the first diagnosis were included. EGFR-TKIs plus brain RT showed a significant prolonged OS (HR =0.64, 95% CI: 0.52-0.78; P<0.001) and iPFS (HR =0.62, 95% CI: 0.50-0.78; P<0.001) compared to EGFR-TKIs alone. Meta-regression analyses showed that potential factors contributed to the heterogeneity were the proportion of ECOG performance score (2+ vs. 0-1, P=0.070) and brain symptomatic patients (no vs. yes, P=0.077) regarding iPFS and was age (younger vs. older, P=0.075) for OS. Dominant subgroup analyses suggested that symptomatic patients (HR 0.46 vs. 0.74, interaction P=0.01) for iPFS, and older patients (HR 0.55 vs. 0.75, interaction P=0.03) and 19Del mutation (HR 0.55 vs. 0.74, interaction P=0.04) for OS, seemed to benefit more from the combination therapy than their counterparts. However, direct subgroup results based on only two studies did not show significant difference in iPFS benefit between age, mutation type and sex subgroup. EGFR-TKIs plus brain RT is superior to EGFR-TKIs alone in the management of EGFR-mutated NSCLC patients with BM, of which the benefits might be influenced by age, BM-related symptoms and mutation type.

AXL degradation in combination with EGFR-TKI can delay and overcome acquired resistance in human non-small cell lung cancer cells

Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has been a major obstacle in the treatment of non-small cell lung cancer (NSCLC) patients. AXL has been reported to mediate EGFR-TKIs. Recently, third generation EGFR-TKI osimertinib has been approved and yet its acquired resistance mechanism is not clearly understood. We found that AXL is involved in both gefitinib and osimertinib resistance using in vitro and in vivo model. In addition, AXL overexpression was correlated with extended protein degradation rate. We demonstrate targeting AXL degradation is an alternative route to restore EGFR-TKIs sensitivity. We confirmed that the combination effect of YD, an AXL degrader, and EGFR-TKIs can delay or overcome EGFR-TKIs-driven resistance in EGFR-mutant NSCLC cells, xenograft tumors, and patient-derived xenograft (PDX) models. Therefore, combination of EGFR-TKI and AXL degrader is a potentially effective treatment strategy for overcoming and delaying acquired resistance in NSCLC.

Combination of EGFR-TKIs with chemotherapy versus chemotherapy or EGFR-TKIs alone in advanced NSCLC patients with EGFR mutation.

PurposeBoth epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy are widely applied for the treatment of advanced non-small-cell lung cancer (NSCLC) with EGFR mutations, and the combination of EGFR-TKIs and chemotherapy has been used for advanced NSCLC patients; however, little is known about the efficacy of the direct comparison among them.Patients and methodsThe demographic and clinical characteristics of 92 patients harboring advanced NSCLC with EGFR mutation were retrospectively reviewed. We evaluated the effects of EGFR-TKIs, chemotherapy, and EGFR-TKIs plus chemotherapy on advanced NSCLC patients with EGFR mutations, and the efficacy of combination of chemotherapy and EGFR-TKIs vs chemotherapy or EGFR-TKIs alone in advanced NSCLC patients was evaluated.ResultsThe statistical results showed that the intercalated combination of EGFR-TKIs plus chemotherapy significantly improved progression-free survival (PFS; HR, 1.76; 95% CI 1.03–3.01; P=0.036; median, 20.5 vs 16 months) compared with EGFR-TKI monotherapy, but no difference in overall survival (OS) was observed between these two groups (HR, 1.52; 95% CI 0.81–2.83; P=0.19; median, 36 vs 29 months). However, patients who received the combination of chemotherapy and EGFR-TKIs had longer PFS (HR, 2.78; 95% CI 1.57–4.93; P<0.0001; median, 20.5 vs 12 months) as well as OS (HR, 2.86; 95% CI 1.56–5.27; P=0.001; median, 36 vs 18 months) than those who received chemotherapy alone. Toxicities were mild among the three treatment groups. Rash and diarrhea were common adverse events (AEs) in the EGFR-TKI group, anemia and nausea in the chemotherapy group, and anemia and diarrhea in the combination group.ConclusionThis study demonstrated that the combination of chemotherapy with EGFR-TKIs as first-line treatment has a significant effect on PFS in patients with advanced NSCLC whose tumors harbor activating EGFR mutations. The combination treatment had more toxicity, but was clinically manageable.

Concurrent EGFR-TKI and Thoracic Radiation Therapy as 1st-Line Treatment of Stage IV NSCLC Patients Harboring EGFR Active Mutation (CERTAIN study)

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has been approved as first-line standard treatment for stage IV non-small cell lung cancer (NSCLC) patients harboring active EGFR mutation. As reported, EGFR-TKI could radiosensitize tumor cells in vitro and thoracic radiotherapy (TRT) could improve the local control of primary lesion. A prospective CERTAIN study on the combination of EGFR-TKI with TRT as first-line treatment for stage IV NSCLC patients has been registered on ClinicalTrials.gov (NCT 02353741). This is an open-labeled, single-arm, phase II clinical trial aiming to evaluate the efficacy and safety of EGFR-TKI combined with TRT as first-line treatment for stage IV NSCLC patients harboring EGFR active mutation. According to ENSURE study (Wu YL, et al. Ann Oncol. 2015, 26(9):1883), the 1-year progression-free survival (PFS) rate of erlotinib group is 43% and the PFS is 11.0 months. In the current study, the estimated 1-year PFS rate is 60%. According to Freedman rule at one-sided α=0.1, β=0.2, the sample size should be 47. Enrolled patients receive EGFR-TKI (gefitinib 250mg or erlotinib 150 mg qd) plus TRT (54-60Gy/27-30F/5.5-6w) within 2 weeks until disease progression or intolerable toxicities. The primary endpoint is 1-year PFS rate. The secondary endpoints include PFS, time to progression of irradiated lesion (iTTP), objective response rate (ORR), overall survival (OS), and side effects. From January 2015 to February 2018, the median follow-up was 14.3 months. Altogether 175 patients were screened, among whom there were 53 patients declining radiotherapy, 79 cases with uncontrolled intracranial metastasis, pleural effusion and bone metastases, 24 cases who previously received chemotherapy, 8 cases who received TRT more than two weeks later, and 2 cases with uncompleted TRT. Finally, 9 patients (5 male and 4 female) with a median age of 53.7 years (range, 40-75) were eligible. The mean dose limit of both lungs was V20 12%, V30 8%, V5 40%, MLD 5.25Gy. Kaplan-Meier analysis showed that the 1-year PFS rate was 44.4%, PFS was 9.6 months. iTTP was 12.6 months, ORR was 77.8% and OS was immature. The incidence of treatment-related side effects of all grades was 44.4% (4/9). The side effects of grade 3 or higher were radiation pneumonia (33.3%, 3/9) and rash (22.2%, 2/9). One patient died of radiation pneumonia. Compared with ENSURE study, the current study showed no significant improvement in 1-year PFS rate or PFS. The iTTP was 12.6 months, suggesting that TRT could achieve a long-term local control. The risk of severe radiation pneumonia should be considered.

First-line therapy for advanced non-small cell lung cancer with activating EGFR mutation: is combined EGFR-TKIs and chemotherapy a better choice?

As the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation, EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have significantly improved the median progression-free survival (PFS) up to 18.9months. However, almost all patients eventually develop acquired resistance to EGFR-TKIs, which limits the first-line PFS. To overcome the resistance and improve overall survival, researchers have tried to identify the resistance mechanisms and develop new treatment strategies, among which a combination of EGFR-TKIs and cytotoxic chemotherapy is one of the hotspots. The data from preclinical and clinical studies on combined EGFR-TKIs and chemotherapy have shown very interesting results. Here, we reviewed the available preclinical and clinical studies on first-line EGFR-TKIs-chemotherapy combination in patients with advanced NSCLC harboring activating EGFR mutation, aiming to provide evidences for more potential choices and shed light on clinical treatment.

Potential influence of interleukin-6 on the therapeutic effect of gefitinib in patients with advanced non-small cell lung cancer harbouring EGFR mutations

Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a key therapy used for patients with EGFR-mutant non-small cell lung cancer (NSCLC), some of whom do not respond well to its therapy. Cytokine including IL-6 secreted by tumour cells is postulated as a potential mechanism for the primary resistance or low sensitivity to EGFR-TKIs. Fifty-two patients with advanced EGFR-mutant NSCLC who had received gefitinib were assessed retrospectively. The protein expression of IL-6 in the tumour cells was assessed by immunostaining and judged as positive if ≥ 50 of 100 tumour cells stained positively. Of the 52 patients, 24 (46%) and 28 (54%) were defined as IL-6-postitive (group P) and IL-6-negative (group N), respectively. Group P had worse progression-free survival (PFS) than that of group N, which was retained in the multivariate analysis (hazard ratio: 2.39; 95 %CI: 1.00–5.68; p < 0.05). By contrast, the PFS after platinum-based chemotherapy did not differ between groups P and N (p = 0.47). In cell line-based model, the impact of IL-6 on the effect of EGFR-TKIs was assessed. The combination of EGFR-TKI and anti-IL-6 antibody moderately improved the sensitivity of EGFR-TKI in lung cancer cell with EGFR mutation. Interestingly, suppression of EGFR with EGFR-TKI accelerated the activation of STAT3 induced by IL-6. Taken together, tumour IL-6 levels might indicate a subpopulation of EGFR-mutant NSCLC that benefits less from gefitinib monotherapy.

Abstract 1618: Immune-modulating effect of bevacizumab in EGFR mutated lung adenocarcinoma

Abstract Background: Host immunity affect treatment effect of lung cancer. Peripheral blood S100A9+ monocytic myeloid derived suppressor cells (MDSCs) is a predictive factor for treatment response of chemotherapy and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) of lung adenocarcinoma patients. Bevacizumab have immune-modulating effect, including decreasing MDSCs, and improve treatment effect in combination with immunotherapy. However, the effect of immune modulation in combination of bevacizumab and EGFR-TKI in EGFR mutated lung adenocarcinoma patients is not clear. Methods: Stage IV lung adenocarcinoma harboring sensitive EGFR mutation patients receiving first line EGFR-TKI or combination EGFR-TKI and bevacizumab were enrolled. The peripheral blood mononuclear cell (PBMCs) were collected, and S100A9+ MDSCs percentage was calculated by flow cytometry from CD14+S100A9+ in PBMC. Clinical data was collected. Results: Eight patients receiving EGFR-TKI and bevacizumab, as combination group, and twenty patients received EGFR-TKI alone, as control group, were enrolled. PBMC S100A9+ MDSC decreased in combination group (decrease 39±18% from baseline), but not in control group. Combination group had longer progress free survival (PFS) comparing with control group. (Median PFS combination vs control group: 15.2 vs 9.9 months, Log Rank test, p=0.05) Increased of peripheral blood cytotoxic T cells also had trend in combination group but not in control group. Conclusion: Besides the anti-angiogenesis effect, bevacizumab had immune modulated effect, especially in decreasing circulating S100A9+ MDSC in EGFR mutated lung adenocarcinoma patients. This might partially explain the longer PFS in combination of EGFR-TKI of anti-angiogenesis agent treatment. Citation Format: Po-Hao Feng, Kang-Yun Lee. Immune-modulating effect of bevacizumab in EGFR mutated lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1618. doi:10.1158/1538-7445.AM2017-1618