Understanding EGFR heterogeneity in lung cancer

Meta-Analysis of EGFR Kinase Inhibitors: Not Always Greater Than the Sum of Its Parts

In a report accompanying our article, Spigel et al present their findings on combining erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), with onartuzumab (MetMAb; Genentech, South San Francisco, CA), a humanized monovalent monoclonal antibody that blocks ligand activation of MET receptor tyrosine kinase (RTK). MET-positive patients (defined by immunohistochemistry) treated with erlotinib and onartuzumab demonstrated improved progression-free and overall survival, whereas MET-negative patients had worse outcomes. This article provides an overview of signaling control by EGFR and MET and the biologic rationale for cotargeting strategies. EGFR and MET are membrane-bound RTKs consisting of extracellular domains that bind to growth factors and intracellular domains that contain a kinase domain (Fig 1). MET is activated by its cognate ligand, hepatocyte growth factor (HGF), which is produced by stromal cells, also in an autocrine fashion. EGFR is activated by several ligands, including EGF, transforming growth factor alpha (TGF ), and heparin-binding EGF. On receptor binding of the ligands, the kinase domain becomes activated, leading to transautophosphorylation of tyrosine residues on the cytoplasmic tail. Phosphorylation of these tyrosine residues creates intramolecular docking sites for proteins containing Src homology 2 domains that serve as readers for tyrosine phosphorylation. This includes adaptor proteins such as growth factor receptor–bound protein 2 (GRB2), GAB1 (GRB2-associated binding protein 1), and Src homology 2–containing transforming protein 1 (SHC1). These proteins serve as scaffolds to support signal transduction to the mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), phospholipase C (PLC), and signal transducer and activator of transcription (STAT) pathways. EGFR and MET use a highly overlapping repertoire of signaling adaptors and downstream effector pathways, highlighting their combined ability to codrive oncogenic signaling. Three general approaches are being employed in clinic to target EGFR and MET. The first uses small-molecule TKIs, such as erlotinib for EGFR and crizotinib for MET, that bind the ATP-binding pocket in the kinase domain and inhibit the kinase function. The second approach uses antibody therapy directed against the extracellular domain of the MET receptor (onartuzumab) or the HGF ligand (ficlatuzumab). The third approach targets downstream proteins involved in signaling, such as inhibitors of PI3K, or molecules regulating receptor trafficking and degradation, such as heat shock proteins. The EGFR pathway can be activated in lung cancer through genomic events, such as activating EGFR mutations or gene amplification, or through tumor environmental events, such as autocrine production of EGFR-activating ligands. Likewise, MET activation occurs through HGF produced in the tumor microenvironment and through MET gene amplification. MET amplification by fluorescent in situ hybridization occurs in approximately 5% to 15% of lung adenocarcinomas. Increased MET is associated with advanced stage of disease, poor outcome, brain metastasis, and high levels of EGFR. Coactivation of EGFR and MET occurs in subsets of lung cancer cell lines and tumor tissues and is associated with aggressive disease. In cells lacking EGFR mutation or high levels of MET, activation of either receptor can produce extensive signaling crosstalk to the opposing RTK and downstream substrates. EGFR activation can induce accumulation of activated MET protein through a c-SRC– dependent mechanism, and dual MET/EGFR inhibition has shown increased activity in xenograft models. Phosphoproteomic analysis of lung tumors and cell lines can identify tumors with concomitant EGFR and MET activation. EGFR, either through mutation or ligand-mediated activation, can also regulate MET levels through hypoxia-inducible factor-1 . Importantly, MET signaling is one actionable mechanism driving resistance to EGFR TKIs. MET activation can drive intrinsic as well as acquired resistance to EGFR through genomic and tumor microenvironment–mediated mechanisms. Primary resistance to anti-EGFR antibody therapy has been associated with MET activation in primary explant models of lung cancer. Approximately 5% of EGFR mutation–positive tumors with acquired resistance to EGFR TKIs are found to have MET gene amplification. Mechanistically, amplified MET co-opts use of ERBB3 to maintain the PI3K pathway activation. Combining MET and EGFR TKIs or EGFR/HSP90 inhibition has been effective in mouse models of lung cancer with T790M EGFR and MET amplification. High levels of HGF are associated with intrinsic or acquired resistance to EGFR TKIs in patients with lung cancer with activating EGFR mutations and in those with other solid tumors. HGF production by stromal fibroblasts leads to fibroblast-induced JOURNAL OF CLINICAL ONCOLOGY U N D E R S T A N D I N G T H E P A T H W A Y VOLUME 31 NUMBER 32 NOVEMBER 1

Objectives: Three generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have developed to treat advanced non-small cell lung cancer (NSCLC) with EGFR mutations. However, each generation of TKI has different spectrum of activity against the different mutations. Currently, no EGFR TKIs are approved for NSCLC with EGFR insertion 20 mutation. Previously, we have shown that TAS6417, a novel EGFR TKI, is effective for cells harboring EGFR insertion mutations in vitro and in vivo. In this study, we asked whether TAS6417 is effective for tumors harboring other EGFR mutations observed in clinic. Methods: Genetically engineered Ba/F3 cells expressing EGFR mutants, lung cancer cell lines including newly established cell lines established from tumors harboring EGFR insertion 20 were used to evaluate efficacy of erlotinib, afatinib, osimertinib, poziotinib, and TAS6417 by cell viability analyses. The selectivity indexes (the wild type EGFR/mutant EGFR ratio) were calculated to predict a therapeutic window for each TKI. Effects of each EGFR TKI on EGFR signaling and apoptosis were evaluated by western blotting. Finally, murine xenograft models were used to evaluate efficacy of TAS6417 and all generation of EGFR TKIs for the treatment of NSCLC with EGFR mutations. Results: Cell viability assays demonstrate that TAS6417 was as potent as poziotinib against common EGFR mutations (L868R and exon 19 deletions) and the most potent against cells harboring the T790M resistant mutations. In addition, TAS6417 was effective in cells harboring EGFR rare mutations (G719X L861Q, and S768I). Even though IC50s were higher than those of poziotinib in cells harboring EGFR insertion 20, the selectivity indexes (the wild type EGFR/mutant EGFR ratio) were higher in TAS6417, indicating a wider therapeutic window. TAS6417 was effective in mice injected with cells harboring EGFR mutations with no body weight loss. Conclusions: Our preclinical results confirm that TAS6417 is a potent EGFR TKI with a broader spectrum of activity and a wider therapeutic window and support clinical trials in the near future. Citation Format: Hibiki Udagawa, Shinichi Hasako, Akihiro Ohashi, Naomi Abe, Tomonori Haruma, Toshiharu Komori, Miki Terasaka, Ryoto Fujita, Kaoru Funabashi, Hiroyuki Yasuda, Kazutaka Miyadera, Koichi Goto, Daniel B. Costa, Susumu S. Kobayashi. Preclinical evaluation of TAS6417 as a highly effective, pan-mutation-selective EGFR tyrosine kinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1329.

An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO) offers timely clinical direction to ASCO's membership following publication or presentation of potentially practice-changing data from major studies. This PCO addresses the clinical utility of using epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer (NSCLC) to predict the benefit of taking a first-line EGFR tyrosine kinase inhibitor (TKI). Patients with EGFR-mutated NSCLC have a significantly higher rate of partial responses to the EGFR TKIs gefitinib and erlotinib. In the United States, approximately 15% of patients with adenocarcinoma of the lung harbor activating EGFR mutations. EGFR mutation testing is widespread at academic medical centers and in some locales in community practice. As of yet, there is no evidence of an overall survival (OS) benefit from selecting treatment based on performing this testing. One large phase III trial (the Iressa Pan-Asia Study [IPASS] trial), three smaller phase III randomized controlled trials using progression-free survival as the primary end point, and one small phase III trial with OS as the primary end point, all involving first-line EGFR TKIs and chemotherapy doublets, form the basis of this PCO. On the basis of the results of five phase III randomized controlled trials, patients with NSCLC who are being considered for first-line therapy with an EGFR TKI (patients who have not previously received chemotherapy or an EGFR TKI) should have their tumor tested for EGFR mutations to determine whether an EGFR TKI or chemotherapy is the appropriate first-line therapy. NOTE. ASCO's provisional clinical opinions (PCOs) reflect expert consensus based on clinical evidence and literature available at the time they are written and are intended to assist physicians in clinical decision making and identify questions and settings for further research. Because of the rapid flow of scientific information in oncology, new evidence may have emerged since the time a PCO was submitted for publication. PCOs are not continually updated and may not reflect the most recent evidence. PCOs cannot account for individual variation among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine the best course of treatment for the patient. Accordingly, adherence to any PCO is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances. ASCO PCOs describe the use of procedures and therapies in clinical practice and cannot be assumed to apply to the use of these interventions in the context of clinical trials. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO's PCOs, or for any errors or omissions.

Simple SummaryCo-mutations may affect EGFR-TKIs efficacy in advanced EGFR mutated NSCLC and could be associated with worse prognosis. Using a clinical next-generation sequencing (NGS) panel we retrospectively assessed the impact of co-alterations in 106 consecutive patients treated with front-line EGFR-TKIs. Clinical and molecular data were retrieved. According to our data, co-mutations do not seem to have any predictive nor prognostic role. Co-mutations are associated with younger age at diagnosis and lymph nodes metastases at baseline. No association with PD-L1 expression level was observed.Background: Tyrosine kinase inhibitors (TKIs) show variable efficacy in epidermal growth factor receptor mutation-positive (EGFR+) NSCLC patients, even in patients harbouring the same mutation. Co-alterations may predict different outcomes to TKIs. Methods: We retrospectively analysed all consecutive EGFR+ advanced NSCLC treated with first-line TKIs at our Institutions. NGS with a 22 genes clinical panel was performed on diagnostic specimens. PD-L1 expression was also evaluated. Results: Of the 106 analysed specimens, 59 showed concomitant pathogenic mutations. No differences in OS (mOS 22.8 vs. 29.5 months; p = 0.088), PFS (mPFS 10.9 vs. 11.2 months; p = 0.415) and ORR (55.9% vs. 68.1%; p = 0.202) were observed comparing patients without and with co-alterations. Subgroup analysis by EGFR mutation type and TKIs generation (1st/2nd vs. 3rd) did not show any difference too. No correlations of PD-L1 expression levels by co-mutational status were found. Significant associations with presence of co-alterations and younger age (p = 0.018) and baseline lymph nodes metastases (p = 0.032) were observed. Patients without concomitant alterations had a significant higher risk of bone progression (26.5% vs. 3.3%, p = 0.011). Conclusions: Pathogenic co-alterations does not seem to predict survival nor efficacy of EGFR TKIs in previously untreated advanced NSCLC.

Epidermal growth factor receptor tyrosine kinase inhibitors as initial therapy for non-small cell lung cancer: Focus on epidermal growth factor receptor mutation testing and mutation-positive patients

The vast majority of epidermal growth factor receptor (EGFR) mutations occur in lung adenocarcinoma, and even rare cases of other subtypes with this mutation, such as adenosquamous cell carcinoma, are associated with adenocarcinoma histology. According to this adenocarcinoma-specific nature of EGFR mutation, analysis of EGFR mutations with small cell lung cancers (SCLC) may provide a clue to its histogenesis. The mutational status of the EGFR gene was accessed in a cohort of 122 patients with SCLC; all patients were from a single institute. When the EGFR mutated, its gene copy number was also examined. EGFR mutations were detected in five SCLCs (4%). The patients were mainly in the light smoker and histologic combined subtype. All but one of the tumors harbored gene amplifications. Notably, in three tumors of the combined SCLC subtype, both components of adenocarcinoma and SCLC harbored an EGFR mutation, whereas gene amplification was detected only in the adenocarcinoma component. A partial response was achieved in a patient (with an EGFR mutation) who was treated with gefitinib. Although EGFR mutations are rare in SCLC, a combined subtype of SCLC with adenocarcinoma in light smokers may have a chance of harboring EGFR mutations. For patients with an EGFR mutation, EGFR tyrosine kinase inhibitor can be a treatment option. In terms of molecular pathogenesis, it is suggested that some SCLCs may have developed from pre-existing adenocarcinomas with EGFR mutations, but the development may not be simply linear, taking into consideration the discordant distribution of EGFR amplification.

Objective To investigate the epidermal growth factor receptor(EGFR)mutation status and the corresponding clinical characteristics of advanced lung adenocarcinoma in patients over 60 years and the efficacy of first-line therapy. Methods A total of 243 cases aged 60 years and over with histologically confirmed advanced lung adenocarcinoma from January 2011 to December 2015 at Beijing Hospital were included in this retrospective study.The EGFR mutation status was detected by the amplification refractory mutation system.Clinical characteristics including gender, smoking status, and incidence of brain metastasis at initial presentation were recorded.Data for 163 cases aged below 60 years during the same period were collected as controls.The characteristics of EGFR mutation status of elderly patients were analyzed.Besides, differences between the groups in EGFR mutation status, other clinical characteristics and therapeutic efficacy of first-line treatment were compared. Results The EGFR mutation rate was 53.1%(129/243). Basic clinical features were not statistically different between the groups.For elderly patients harboring EGFR mutations, the incidences of the exon 19 deletion and the exon 21 L858R mutation accounted for 46.2%(55/119)and 53.8%(64/119), respectively, whereas for younger patients with EGFR mutations, the prevalence of the exon 19 deletion and the exon 21 L858R mutation were 66.2%(49/74)and 33.8%(25/74), respectively.The proportion with the exon 21 L858R mutation was statistically higher in elderly patients(P=0.007). Eighty-two out of 129 patients with sensitive EGFR mutations received first-line EGFR tyrosine kinase inhibitors, with an objective response rate(ORR)of 62.2%(51/82) and a progression-free survival(PFS)of 8.1 months.For the other 152 patients who received chemotherapy, the ORR was 24.3%(37 cases) and the PFS was 6.0 months.The efficacy of first-line therapy was similar between the groups. Conclusions The incidence of EGFR mutations and clinical characteristics for elderly patients with advanced lung adenocarcinoma are similar to those for younger patients, whereas the proportion of the EGFR exon and the 21 L858R mutation is higher in the elderly.Considering similar benefits from fist-line treatment between different age groups, elderly lung cancer patients should receive similar treatment. Key words: Lung neoplasms; receptor epidermal growth factor; Mutation

<div>Abstract<p><b>Purpose:</b> Clinical features of epidermal growth factor receptor (EGFR) mutations, L858R, deletions in exon 19, T790M, and insertions in exon 20, in non–small cell lung cancer (NSCLC) are well known. The clinical significance of other uncommon EGFR mutations, such as their association with the effectiveness of EGFR tyrosine kinase inhibitors (TKI), is not well understood. This study aimed to improve the understanding of these uncommon EGFR mutations of unknown clinical significance.</p><p><b>Patients and Methods:</b> Specimens from 1,261 patients were tested for EGFR mutations. We surveyed the clinical data and the effectiveness of gefitinib and erlotinib in NSCLC patients with uncommon EGFR mutations.</p><p><b>Results:</b> Of the 1,261 patients, 627 (49.8%) had EGFR mutations. This included 258 patients with deletions in exon 19, 260 patients with L858R, 25 patients with insertions or duplications in exon 20, 6 patients with <i>de novo</i> T790M, and 78 (12.4%) patients with uncommon mutations. Of the 78 patients, 62 received either gefitinib or erlotinib treatment. The response rate of TKIs treatment was 48.4%, and the median progression-free survival (PFS) was 5.0 months. Mutations on G719 and L861 composed a major part (28 of 62) of uncommon mutations, and were associated with a favorable effectiveness of EGFR TKIs (response rate, 57.1%; median PFS, 6.0 months). Mutations other than G719 and L861 led to a worse response to EGFR TKIs (response rate, 20.0%; median PFS, 1.6 months).</p><p><b>Conclusions:</b> Uncommon EGFR mutations constituted a distinct part of the whole group of EGFR mutations. Their composition was heterogeneous, and their associations with EGFR TKIs differed. <i>Clin Cancer Res; 17(11); 3812–21. ©2011 AACR</i>.</p></div>

With the development of molecular pathology, many types of epidermal growth factor receptor (EGFR) mutations have been identified. The efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) patients with different types of EGFR mutations, especially in patients with single rare mutations or complex mutations (co-occurrence of two or more different mutations), has not been fully understood. This study aimed to examine the efficacy of EGFR-TKIs in NSCLC patients with different types of EGFR mutations. Clinical data of 809 NSCLC patients who harbored different types of EGFR mutations and treated from January 2012 to October 2016 at Renmin Hospital and Zhongnan Hospital, Wuhan, were retrospectively reviewed. The clinical characteristics of these patients and the efficacy of EGFR-TKIs were analyzed. Among these patients, 377 patients had only the EGFR del-19 mutation, 362 patients the EGFR L858R mutation in exon 21, 33 patients single rare mutations and 37 patients complex mutations. Among these 809 patients, 239 patients were treated with EGFR-TKIs. In all the 239 patients, the disease control rate (DCR) was 93.7% with two patients (0.2%) achieving complete response (CR), the median progression free survival (PFS) was 13.0 months (95% confidence interval [CI], 11.6-14.4 months), and the median overall survival (OS) was 55.0 months (95% CI, 26.3-83.7 months). Subgroup analysis revealed that the DCR in patients harboring single rare or complex mutations of EGFR was significantly lower than in those with del-19 or L858R mutation (P<0.001). Patients with classic mutations (del-19 and/or L858R mutations) demonstrated longer PFS (P<0.001) and OS (P=0.017) than those with uncommon mutations (single rare and/or complex mutations). Furthermore, the patients with single rare mutations had shorter median OS than in those with other mutations. Multivariate Cox regression analysis identified that the type of EGFR mutations was an independent risk factor for PFS (hazard ratio [HR]=0.308, 95% CI, 0.191-0.494, P<0.001) and OS (HR=0.221, 95% CI, 0.101-0.480, P<0.001). The results suggest that the single rare or complex EGFR mutations confer inferior efficacy of EGFR-TKIs treatment to the classic mutations. The prognosis of the single rare EGFR mutations is depressing. EGFR-TKIs may be not a good choice for NSCLC patients with single rare mutations of EGFR. Further studies in these patients with uncommon mutations (especially for the patients with single rare mutations) are needed to determine a better precision treatment.

Most patients with non‐small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) mutations, such as deletions in exon 19 or the L858R mutation in exon 21, respond dramatically to EGFR tyrosine kinase inhibitors (EGFR‐TKI), and their sensitivities to various EGFR‐TKI have been well characterized. Our previous article showed the in vitro sensitivities of EGFR exon 18 mutations to EGFR‐TKI, but little information regarding the sensitivities of other uncommon EGFR mutations is available. First, stable transfectant Ba/F3 cell lines harboring EGFR L858R (Ba/F3‐L858R), L861Q (Ba/F3‐L861Q) or S768I (Ba/F3‐S768I) mutations were created and their drug sensitivities to various EGFR‐TKI were examined. Both the Ba/F3‐L861Q and Ba/F3‐S768I cell lines were less sensitive to erlotinib, compared with the Ba/F3‐L858R cell line, but their sensitivities to afatinib were similar to that of the Ba/F3‐L858R cell line. The Ba/F3‐L861Q cell line was similarly sensitive and the Ba/F3‐S768I cell line was less sensitive to osimertinib, compared with the Ba/F3‐L858R cell line. The results of western blot analyses were consistent with these sensitivities. Next, similar experiments were also performed using the KYSE270 (L861Q) and KYSE 450 (S768I) cell lines, and their results were compatible with those of the transfectant Ba/F3 cell lines. Our findings suggest that NSCLC harboring the EGFR L861Q mutation might be sensitive to afatinib or osimertinib and that NSCLC harboring the EGFR S768I mutation might be sensitive to afatinib. Overall, afatinib might be the optimal EGFR‐TKI against these uncommon EGFR mutations.

Epidermal growth factor receptor (EGFR) mutations are the second most common oncogenic driver event in non-small cell lung cancer (NSCLC). Classical activating mutations (exon 19 deletions and the L858R point mutation) comprise the vast majority of EGFR mutations and are well defined as strong predictors for good clinical response to EGFR tyrosine kinase inhibitors (EGFRi). However, low frequency mutations including point mutations, deletions, insertions and duplications occur within exons 18–25 of the EGFR gene in NSCLC and are associated with poorer responses to EGFRi. Despite an increased uptake of more sensitive detection methods to identify rare EGFR mutations in patients, our understanding of the biology of these rare EGFR mutations is poor compared to classical mutations. In particular, clinical data focused on these mutations is lacking due to their rarity and challenges in trial recruitment, resulting in an absence of effective treatment strategies for many low frequency EGFR mutations. In this review, we describe the structural and mechanistic features of rare EGFR mutations in NSCLC and discuss the preclinical and clinical evidence for EGFRi response for individual rare EGFR mutations. We also discuss EGFRi sensitivity for complex EGFR mutations, and conclude by offering a perspective on the outstanding questions and future steps required to make advances in the treatment of NSCLC patients that harbour rare EGFR mutations.

Epidermal growth factor receptor (EGFR) mutations, including the L858R activating mutation in exon 21, are major drivers of non-small cell lung cancer (NSCLC) and are targeted by EGFR tyrosine kinase inhibitors (TKIs). However, despite significant initial clinical benefits, resistance to EGFR TKIs frequently develops due to secondary mutations such as T790M and C797S, which reduce the therapeutic efficacy of second- and third-generation inhibitors. Consequently, extensive efforts have been made to develop new small molecule inhibitors to overcome this resistance, including novel approaches such as proteolysis targeting chimera (PROTAC) technology. We identified a promising heterobifunctional degrader, SC2073, designed to target a unique allosteric binding site on mutant EGFR while sparing wild-type EGFR. SC2073 effectively induced the degradation of EGFR proteins harboring single, dual, or triple mutations through the ubiquitin-proteasome system. It exhibited potent anti-proliferative activity against Ba/F3 cells with common EGFR resistance mutations, including L858R, L858R/T790M, L858R/C797S, and L858R/T790M/C797S as well as NCI-H1975 (L858R/T790M) cells without affecting the expression levels of GSPT1 and SALL4, which are substrates of the E3 ligase protein (CRBN). Notably, SC2073 showed no effect on the proliferation of Ba/F3 and A549 cells expressing wild-type EGFR, thereby minimizing potential toxic side effects associated with wild-type EGFR inhibition. SC2073 demonstrated a favorable pharmacokinetic profile, rapidly degrading mutant EGFR in tumors within 6 hours of oral administration and maintaining efficacy for 24 hours. Further investigations confirmed that oral administration of SC2073 resulted in a dose-dependent, robust anti-tumor activity in allograft and xenograft models resistant to EGFR TKIs by promoting the degradation of mutant EGFR. In this study, we present SC2073, an orally bioavailable, highly potent, and mutant-selective degrader with the potential to provide more durable, safer, and improved therapeutic responses. SC2073 effectively inhibited the proliferation of Ba/F3 cell expressing EGFR mutants while sparing WT EGFR cells and it demonstrated robust anti-tumor activity in EGFR mutation-driven in vivo tumor models. Our data suggests that SC2073 could be a promising treatment option for NSCLC patients harboring various EGFR mutations, including L858R, T790M, and C797S, which are associated with acquired resistance to EGFR inhibitors. Citation Format: Jihoon Choi, Jun Gyu Kim, Ok Young Lee, Young Jun Park, Young Min Jeong, Chung Sil Lee, Sun Ho Choi, Hye Yeon Lee, Yu Jin Lee, Punna Reddy Ullapu, Dae Young Lee, Hye Sun Lee, Jong Ryoul Choi, Daseul Yoon, Yanghun Tae, Ji-Young An, Hyo Ju Lee, Bong Tae Kim, Mi-Kyung Kim. Discovery of SC2073, a potent and mutant selective EGFR degrader that overcomes 3rd generation EGFR inhibitors resistance in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5513.

Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) are effective for many patients with lung cancer with EGFR mutations. However, not all patients are responsive to EGFR TKIs, including even those harboring EGFR-sensitizing mutations. In this study, we quantified the cells and cellular interaction features of the tumor microenvironment (TME) using routine H&E-stained biopsy sections. These TME features were used to develop a prediction model for survival benefit from EGFR TKI therapy in patients with lung adenocarcinoma and EGFR-sensitizing mutations in the Lung Cancer Mutation Consortium 1 (LCMC1) and validated in an independent LCMC2 cohort. In the validation data set, EGFR TKI treatment prolonged survival in the predicted-to-benefit group but not in the predicted-not-to-benefit group. Among patients treated with EGFR TKIs, the predicted-to-benefit group had prolonged survival outcomes compared with the predicted not-to-benefit group. The EGFR TKI survival benefit positively correlated with tumor-tumor interaction image features and negatively correlated with tumor-stroma interaction. Moreover, the tumor-stroma interaction was associated with higher activation of the hepatocyte growth factor/MET-mediated PI3K/AKT signaling pathway and epithelial-mesenchymal transition process, supporting the hypothesis of fibroblast-involved resistance to EGFR TKI treatment.

Lung microinvasive adenocarcinoma (MIA) is a newly-defined subtype of early stage non-small cell lung cancer (NSCLC). However, its epidermal growth factor receptor (EGFR) mutation status and clinical significance remain unclear. The present study aimed to determine EGFR mutation characteristics and identify their significance in patients with resected lung MIA. The present study also analyzed clinicopathological differences between EGFR molecular subgroups defined as 19Del and L858R. The present study examined EGFR mutations in 79 consecutive lung MIA resection specimens and compared the differences in clinicopathological features between the EGFR wild-type and mutation groups, as well as between the 19Del and L858R subgroups. EGFR mutations were detected in 60 (75.95%) tumors. The most common mutations were 19Del (28 cases; 35.44%) and L858R (30 cases; 37.97%). Two patients harbored rare mutations and one of them had a concomitant double mutation. EGFR mutations were significantly associated with microinvasion component, thyroid transcription factor 1 (TTF-1) expression, intratumoral fibrosis and inflammatory cell infiltration. Subgroup evaluation indicated that there was a significant association between 19Del and tumor size, maximum diameter of microinvasion, presence of intratumoral fibrosis and inflammatory cell infiltration. Similar associations were observed for the L858R subgroup, and L858R was associated with TTF-1 expression. In particular, 19Del occurred more frequently in MIA with a smaller size, with a smaller microinvasive area, without TTF-1 expression, and lacking intratumoral fibrosis and inflammatory cell infiltration. By contrast, L858R was detected more frequently in MIA with entirely different tumor features. In conclusion, the results of the present study indicated that surgically resected MIA cases harboring different EGFR gene statuses exhibit distinct clinicopathological features. Significant differences in pathological features associated with the tumor microenvironment were identified in MIA with 19Del or L858R mutations. Therefore, the present study proposed that MIA should be classified into molecular subgroups based on EGFR mutation subtypes. The molecular sub-classification should be taken into account for prognostic evaluation and clinical management of MIA.