EGFR-TKIs Gefitinib Research Articles

Adverse Event Profile of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Non-small Cell Lung Cancer: An Updated Meta-analysis.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remain the frontline standard of care for patients with EGFR-mutant non-small cell lung cancer. An updated toxicity profile of EGFR-TKIs proves valuable in guiding clinical decision making. This study comprehensively assessed the risk of EGFR-TKI-related adverse events (AEs) involving different systems/organs. We systematically searched PubMed, Embase, Web of Science, and Cochrane library for phase III randomized controlled trials comparing EGFR-TKI monotherapy with placebo or chemotherapy in patients with non-small cell lung cancer. The odds ratio (OR) of all-grade and high-grade adverse events (AEs) including dermatologic, gastrointestinal, hematologic, hepatic, and respiratory events was pooled for a meta-analysis. Subgroup analyses based on the control arm (placebo or chemotherapy) and individual EGFR-TKIs (erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib) were conducted. Thirty-four randomized controlled trials comprising 15,887 patients were included. The pooled OR showed EGFR-TKIs were associated with a significantly increased risk of all-grade dermatologic AEs including paronychia, pruritus, rash, skin exfoliation, and skin fissures, gastrointestinal AEs including abdominal pain, diarrhea, dyspepsia, mouth ulceration, and stomatitis, hepatic AEs including elevated alanine aminotransferase and aspartate aminotransferase, and respiratory AEs including epistaxis, interstitial lung disease and rhinorrhea. Furthermore, a significantly increased risk of high-grade rash (OR 7.83, 95% confidence interval [CI] 5.11, 12.00), diarrhea (OR 2.10, 95% CI 1.44, 3.05), elevated alanine aminotransferase (OR 3.93, 95% CI 1.71, 9.03), elevated aspartate aminotransferase (OR 3.22, 95% CI 1.05, 9.92) and interstitial lung disease (OR 2.35, 95% CI 1.38, 4.01) was observed in patients receiving EGFR-TKIs. When stratified by individual EGFR-TKIs, gefitinib showed a significant association with all-grade and high-grade hepatotoxicity and interstitial lung disease. Epidermal growth factor receptor tyrosine kinase inhibitors were associated with a significantly increased risk of various types of AEs. Clinicians should be vigilant about the risks of these EGFR-TKI-related AEs, particularly for severe hepatotoxicity and interstitial lung disease, to facilitate early detection and proper management.

Combination of betulinic acid and EGFR-TKIs exerts synergistic anti-tumor effects against wild-type EGFR NSCLC by inducing autophagy-related cell death via EGFR signaling pathway

BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of lung cancer patients with mutated EGFR. However, the efficacy of EGFR-TKIs in wild-type EGFR tumors has been shown to be marginal. Methods that can sensitize EGFR-TKIs to EGFR wild-type NSCLC remain rare. Hence, we determined whether combination treatment can maximize the therapeutic efficacy of EGFR-TKIs.MethodsWe established a focused drug screening system to investigate candidates for overcoming the intrinsic resistance of wild-type EGFR NSCLC to EGFR-TKIs. Molecular docking assays and western blotting were used to identify the binding mode and blocking effect of the candidate compounds. Proliferation assays, analyses of drug interactions, colony formation assays, flow cytometry and nude mice xenograft models were used to determine the effects and investigate the molecular mechanism of the combination treatment.ResultsBetulinic acid (BA) is effective at targeting EGFR and synergizes with EGFR-TKIs (gefitinib and osimertinib) preferentially against wild-type EGFR. BA showed inhibitory activity due to its interaction with the ATP-binding pocket of EGFR and dramatically enhanced the suppressive effects of EGFR-TKIs by blocking EGFR and modulating the EGFR-ATK-mTOR axis. Mechanistic studies revealed that the combination strategy activated EGFR-induced autophagic cell death and that the EGFR-AKT-mTOR signaling pathway was essential for completing autophagy and cell cycle arrest. Activation of the mTOR pathway or blockade of autophagy by specific chemical agents markedly attenuated the effect of cell cycle arrest. In vivo administration of the combination treatment caused marked tumor regression in the A549 xenografts.ConclusionsBA is a potential wild-type EGFR inhibitor that plays a critical role in sensitizing EGFR-TKI activity. BA combined with an EGFR-TKI effectively suppressed the proliferation and survival of intrinsically resistant lung cancer cells via the inhibition of EGFR as well as the induction of autophagy-related cell death, indicating that BA combined with an EGFR-TKI may be a potential therapeutic strategy for overcoming the primary resistance of wild-type EGFR-positive lung cancers.Graphical abstract

Leucine Zipper Downregulated in Cancer-1 Interacts with Clathrin Adaptors to Control Epidermal Growth Factor Receptor (EGFR) Internalization and Gefitinib Response in EGFR-Mutated Non-Small Cell Lung Cancer.

The epidermal growth factor receptor (EGFR) is a common driver of non-small cell lung cancer (NSCLC). Clathrin-mediated internalization (CMI) sustains EGFR signaling. AXL is associated with resistance to EGFR-tyrosine kinase inhibitors (TKIs) in EGFR-mutated (EGFRM) NSCLC. We investigated the effects of Leucine zipper downregulated in cancer-1 (LDOC1) on EGFR CMI and NSCLC treatment. Coimmunoprecipitation, double immunofluorescence staining, confocal microscopy analysis, cell surface labelling assays, and immunohistochemistry studies were conducted. We revealed that LDOC1 interacts with clathrin adaptors through binding motifs. LDOC1 depletion promotes internalization and plasma membrane recycling of EGFR in EGFRM NSCLC PC9 and HCC827 cells. Membranous and cytoplasmic EGFR decreased and increased, respectively, in LDOC1 (-) NSCLC tumors. LDOC1 depletion enhanced and sustained activation of EGFR, AXL, and HER2 and enhanced activation of HER3 in PC9 and HCC827 cells. Sensitivity to first-generation EGFR-TKIs (gefitinib and erlotinib) was significantly reduced in LDOC1-depleted PC9 and HCC827 cells. Moreover, LDOC1 downregulation was significantly associated (p < 0.001) with poor overall survival in patients with EGFRM NSCLC receiving gefitinib (n = 100). In conclusion, LDOC1 may regulate the efficacy of first-generation EGFR-TKIs by participating in the CMI of EGFR. Accordingly, LDOC1 may function as a prognostic biomarker for EGFRM NSCLC.

Spatiotemporal roles of AMPK in PARP-1- and autophagy-dependent retinal pigment epithelial cell death caused by UVA

BackgroundAlthough stimulating autophagy caused by UV has been widely demonstrated in skin cells to exert cell protection, it remains unknown the cellular events in UVA-treated retinal pigment epithelial (RPE) cells.MethodsHuman ARPE-19 cells were used to measure cell viability, mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP), mitochondrial mass and lysosomal mass by flow cytometry. Mitochondrial oxygen consumption rate (OCR) was recorded using Seahorse XF flux analyzer. Confocal microscopic images were performed to indicate the mitochondrial dynamics, LC3 level, and AMPK translocation after UVA irradiation.ResultsWe confirmed mitochondrial ROS production and DNA damage are two major features caused by UVA. We found the cell death is prevented by autophagy inhibitor 3-methyladenine and gene silencing of ATG5, and UVA induces ROS-dependent LC3II expression, LC3 punctate and TFEB expression, suggesting the autophagic death in the UVA-stressed RPE cells. Although PARP-1 inhibitor olaparib increases DNA damage, ROS production, and cell death, it also blocks AMPK activation caused by UVA. Interestingly we found a dramatic nuclear export of AMPK upon UVA irradiation which is blocked by N-acetylcysteine and olaparib. In addition, UVA exposure gradually decreases lysosomal mass and inhibits cathepsin B activity at late phase due to lysosomal dysfunction. Nevertheless, cathepsin B inhibitor, CA-074Me, reverses the death extent, suggesting the contribution of cathepsin B in the death pathway. When examining the role of EGFR in cellular events caused by UVA, we found that UVA can rapidly transactivate EGFR, and treatment with EGFR TKIs (gefitinib and afatinib) enhances the cell death accompanied by the increased LC3II formation, ROS production, loss of MMP and mass of mitochondria and lysosomes. Although AMPK activation by ROS-PARP-1 mediates autophagic cell death, we surprisingly found that pretreatment of cells with AMPK activators (A769662 and metformin) reverses cell death. Concomitantly, both agents block UVA-induced mitochondrial ROS production, autophagic flux, and mitochondrial fission without changing the inhibition of cathepsin B.ConclusionUVA exposure rapidly induces ROS-PARP-1-AMPK-autophagic flux and late lysosomal dysfunction. Pre-inducing AMPK activation can prevent cellular events caused by UVA and provide a new protective strategy in photo-oxidative stress and photo-retinopathy.

Epigallocatechin gallate circumvents drug-induced resistance in non-small-cell lung cancer by modulating glucose metabolism and AMPK/AKT/MAPK axis.

Upon prolonged use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC), acquired drug resistance inevitably occurs. This study investigates the combined use of EGFR-TKIs (gefitinib or osimertinib) with epigallocatechin gallate (EGCG) to overcome acquired drug resistance in NSCLC models. The in vitro antiproliferative effects of EGFR-TKIs and EGCG combination in EGFR-mutant parental and resistant cell lines were evaluated. The in vivo efficacy of the combination was assessed in xenograft mouse models derived from EGFR-TKI-resistant NSCLC cells. We found that the combined use of EGFR-TKIs and EGCG significantly reversed the Warburg effect by suppressing glycolysis while boosting mitochondrial respiration, which was accompanied by increased cellular ROS and decreased lactate secretion. The combination effectively activated the AMPK pathway while inhibited both ERK/MAPK and AKT/mTOR pathways, leading to cell cycle arrest and apoptosis, particularly in drug-resistant NSCLC cells. The in vivo results obtained from mouse tumor xenograft model confirmed that EGCG effectively overcame osimertinib resistance. This study revealed that EGCG suppressed cancer bypass survival signaling and altered cancer metabolic profiles, which is a promising anticancer adjuvant of EGFR-TKIs to overcome acquired drug resistance in NSCLC.

Pedunculoside inhibits epithelial-mesenchymal transition and overcomes Gefitinib-resistant non-small cell lung cancer through regulating MAPK and Nrf2 pathways

BackgroundLung cancer is the primary cause of cancer-related mortality worldwide owing to its strong metastatic ability. EGFR-TKI (Gefitinib) has demonstrated efficacy in metastatic lung cancer therapy, but most patients ultimately develop resistance to Gefitinib, leading to a poor prognosis. Pedunculoside (PE), a triterpene saponin extracted from Ilex rotunda Thunb., has shown anti-inflammatory, lipid-lowering and anti-tumor effects. Nevertheless, the therapeutic effect and potential mechanisms of PE on NSCLC treatment are unclear. PurposeTo investigate the inhibitory effect and prospective mechanisms of PE on NSCLC metastases and Gefitinib-resistant NSCLC. MethodsIn vitro, A549/GR cells were established by Gefitinib persistent induction of A549 cells with a low dose and shock with a high dose. The cell migratory ability was measured using wound healing and Transwell assays. Additionally, EMT-related Markers or ROS production were assessed by RT-qPCR, immunofluorescence, Western blotting, and flow cytometry assays in A549/GR and TGF-β1-induced A549 cells. In vivo, B16-F10 cells were intravenously injected into mice, and the effect of PE on tumor metastases were determined using hematoxylin-eosin staining, Caliper IVIS Lumina, DCFH2-DA staining, and western blotting assays. ResultsPE reversed TGF-β1-induced EMT by downregulating EMT-related protein expression through MAPK and Nrf2 pathways, decreasing ROS production, and inhibiting cell migration and invasion ability. Moreover, PE treatment enabled A549/GR cells to retrieve the sensitivity to Gefitinib and mitigate the biological characteristics of EMT. PE also significantly inhibited lung metastasis in mice by reversing EMT proteins expression, decreasing ROS production, and inhibiting MAPK and Nrf2 pathways. ConclusionsCollectively, this research presents a novel finding that PE can reverse NSCLC metastasis and improve Gefitinib sensitivity in Gefitinib-resistant NSCLC through the MAPK and Nrf2 pathways, subsequently suppressing lung metastasis in B16-F10 lung metastatic mice model. Our findings indicate that PE is a potential agent for inhibiting metastasis and improving Gefitinib resistance in NSCLC.

Abstract 3886: Analysis of concomitant genetic alterations in advanced EGFR-mutated lung adenocarcinoma by targeted NGS: A multicenter prospective and real world study

Abstract Background:The response of 1st-line EGFR-TKI treatment in advanced EGFR-mutated lung adenocarcinoma patients are highly effective, but its sustainability and clinical course are quite variable from patient to patient. In this study, we investigated the clinical impact of concomitant genetic mutations analyzed by targeted NGS on PFS and acquired resistance in advanced EGFR-mutated lung adenocarcinoma patients. Methods: Eighty-five advanced NSCLC patients harboring EGFR mutations were enrolled prospectively in multi-centers from 2019 to 2022 (NCT04122833). We performed the targeted next generation sequencing on 324 cancer-related genes by Foundation One CDx with pre-treated tumor samples. First- or second-generation EGFR-TKIs(gefitinib, afatinib, or erlotinib) were administered in 1st-line setting. After the progression, tissue re-biopsy or plasma liquid biopsy (FoundationOne Liquid CDx) for NGS if tissue biopsy is difficult or risk was performed. Results: Of the 85 patients (70.6% of female, 65.8% of nonsmoker, 56.4% of E19del and 38.8% of E21 L858R mutation), 50 patients experienced a disease progression in November, 2022. The median PFS was 20 months (95 %CI: 15.2-24.8). The most frequent co-mutations were TP53 (47.1%), CDKN2A/B loss (34.1%), MTAP loss (20%), NKX2-1amp(15.3%), MDM2amp (14.1%), RMB10, CCNE/CCND1 amp, NFKB1 amp (11.8%) and CDK4/6 amp (10.6%). Patients with TP53, CDK4/6 amp and MYC amp were independently associated with shorter PFS. In a multivariate analysis, tumors with copy number alterations such as CDK4/6 amp or Myc amp were also independently associated with shorter PFS. However, the CDKN2A/2B loss, MTAP loss, and MDM amp were not related with the PFS. In the number of co-mutations, patients harboring ≥5 co-mutations identified by NGS had shorter median PFS than patients with 0-1 or 2-4 co-mutations. (mPFS 0-1: 2-4: ≥5 co-mutations=35: 18: 9.3 months, p&amp;lt;0.001). At progression, 22 patients harbored an acquired T790M mutation (25.8%). Before TKI treatment, patients with CDKN2A/B loss, MTP loss or CCND/CCNE1 amp in pretreatment tumor have more acquired T790M mutation after progression significantly (p&amp;lt;0.05) Conclusion: We have demonstrated that concomitant mutations detected by targeted NGS analysis provide significant impact on the drug response and clinical course of advanced EGFR-mutated adenocarcinoma patients treated by 1st-line EGFR-TKIs. It is suggested that targeted NGS along with PCR-based detection will be necessary for precision medicine-based individualized practice of 1st-line EGFR-TKI-based combination treatment. Citation Format: In Ae Kim, Seung Joon Kim, Sung Yong Lee, Chang Min Choi, Jae Cheol Lee, Tae Won Jang, Seung Hun Jang, Chan Kwon Park, Wan Seop Kim, Jae Young Hur, Hee Joung Kim, Young Whan Kim, Key Young Lee. Analysis of concomitant genetic alterations in advanced EGFR-mutated lung adenocarcinoma by targeted NGS: A multicenter prospective and real world study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3886.

The Role of Brain Radiotherapy before First-Line Afatinib Therapy, Compared to Gefitinib or Erlotinib, in Patients with EGFR-Mutant Non-Small Cell Lung Cancer.

Brain metastasis is common in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) at initial presentation. A previous study showed that brain radiotherapy (RT) before first-generation (first-G) EGFR-tyrosine kinase inhibitor (TKI) therapy is associated with longer overall survival than TKI therapy alone. However, there is no data regarding the role of additional brain RT before afatinib therapy. Between October 2014 and June 2019, EGFR-mutant NSCLC patients with brain metastases who started first-G EGFR-TKIs (gefitinib or erlotinib) or afatinib as first-line therapy were retrospectively analyzed. This study compared overall survival and intracranial progression-free survival (PFS) between patients who received EGFR-TKIs alone and EGFR-TKIs with brain RT and either a first-G EGFR-TKI or afatinib, respectively. The median follow-up duration was 29.6 months (range, 1.5 to 116.9 months). In the first-G EGFR-TKI group (n=155), 94 patients (60.6%) received the first-G EGFR-TKI alone and 61 patients (39.4%) received brain RT prior to their first-G EGFR-TKI. In the afatinib group (n=204), 126 patients (61.8%) received afatinib alone and 78 patients (38.2%) received brain RT prior to afatinib. There was no difference in overall survival rates between the groups with RT (35.6 months: 95% confidence interval [CI], 27.9 to 43.3) and without RT (31.4 months: 95% CI, 23.9 to 38.9) in the afatinib group (p=0.58), but there was a significant difference in overall survival in the first-G EGFR-TKI group in a manner favoring additional brain RT (41.1 months: 95% CI, 30.5 to 51.7 vs. 25.8 months: 95% CI, 20.1 to 31.5; p=0.02). Meanwhile, median intracranial PFS was not different between patients who received EGFR-TKI therapy alone vs. EGFR-TKI therapy with brain RT in both the first-G EGFR-TKI (p=0.39) and afatinib (p=0.24) groups. Afatinib therapy alone showed comparable survival outcomes to those of afatinib with brain RT. The current study suggests that brain RT could be an optional, not mandatory, treatment modality when afatinib therapy is considered in patients with EGFR</>-mutant NSCLC.

364P Tepotinib with an EGFR-tyrosine kinase inhibitor (TKI) in patients with EGFR-mutant MET-amplified NSCLC: A case series

MET amplification (METamp) is a mechanism of acquired resistance to EGFR-TKIs. In the INSIGHT trial (NCT01982955), in patients with EGFR-mutant METamp NSCLC and EGFR-TKI resistance, tepotinib (a potent, highly selective MET-TKI) plus gefitinib (EGFR-TKI) improved outcomes in comparison with chemotherapy. We present a case series highlighting the clinical activity of tepotinib plus an EGFR-TKI (gefitinib and/or osimertinib) in patients with EGFR-mutant METamp NSCLC.

Cost-effectiveness of osimertinib versus standard EGFR-TKI as first-line treatment for EGFR-mutated advanced non-small-cell lung cancer in China

Objective: The purpose of this study was to estimate the cost-effectiveness of osimertinib for the first-line treatment of patients with EGFR-mutated advanced non-small-cell lung cancer (NSCLC) from the perspective of the Chinese healthcare system. Methods: A Markov model was developed to simulate the outcomes and direct medical costs of osimertinib or standard EGFR-TKI in the first-line treatment of patients with previously untreated EGFR-mutated advanced NSCLC. Individual patient survival data were extracted from the FLAURA randomized clinical trial. Clinical costs and utilities’ input estimates were collected from the local hospital and available literature reports. The quality-adjusted life-year (QALY), incremental cost-effectiveness ratio (ICER), incremental net monetary benefit (INMB), and incremental net health benefit (INHB) were calculated for the two treatment strategies over a 10-year lifetime horizon. In addition, one-way sensitivity analysis, probabilistic sensitivity analysis, and subgroup analysis were performed to test the robustness of the model. Results: On baseline analysis, osimertinib achieved additional 0.39 QALYs and $15,443.78 incremental costs compared with standard EGFR-TKI (gefitinib or erlotinib), which resulted in the ICER of $39,369.53/QALY. The INMB was -$755.11, and the INHB was -0.02 QALYs at a WTP threshold of $37,663.26/QALY in China. The one-way sensitivity analysis showed that the utility of PFS had the strongest association with the ICER. Osimertinib had approximately 46.4% probability of being cost-effective at the WTP threshold of $37,663.26/QALY. Conclusion: First-line osimertinib therapy might not be cost-effective in China for patients with EGFR-mutated advanced NSCLC compared with standard EGFR-TKI based on its current marketed price. A significantly more favorable cost-effectiveness could be achieved when the price of osimertinib was reduced by 5%.

EP08.02-162 Tepotinib with an EGFR-Tyrosine Kinase Inhibitor (TKI) in Patients with EGFR-mutant MET-amplified NSCLC: A Case Series

MET amplification (METamp) is a mechanism of acquired resistance to EGFR-TKIs. In INSIGHT (NCT01982955; data cut-off: September 3, 2021), the combination of tepotinib (a potent, highly selective MET-TKI) and the EGFR-TKI gefitinib (n=12) improved outcomes compared with chemotherapy (n=7) in patients with EGFR-mutant METamp NSCLC and EGFR-TKI resistance (progression-free survival hazard ratio [HR]=0.13, 90% confidence interval [CI]: 0.04, 0.43; overall survival HR=0.10, 90% CI: 0.02, 0.36). Tepotinib combined with an EGFR-TKI may therefore overcome MET-related EGFR-TKI resistance.

Abstract 3259: TAS3351 is a 4th-generation EGFR-TKI overcoming T790M and C797S-mediated resistance in NSCLC with EGFR common mutations

Abstract Background: Common mutations (exon 19 deletion; ex19del or L858R point mutation; L858R) of the epidermal growth factor receptor (EGFR) are found in patients with non-small cell lung cancer (NSCLC) and are sensitive to EGFR-tyrosine kinase inhibitors (TKIs), including osimertinib, a third-generation, irreversible EGFR-TKI. Although osimertinib is widely utilized as the standard of care in first-line therapy of NSCLC, resistance inevitably occurs during the treatment. Among EGFR-dependent/on-target resistant mechanisms of osimertinib, the C797S mutation is reported to emerge as the most frequent alteration. The cysteine residue at position 797 of EGFR is covalently bound with osimertinib, and its alteration to serine causes an inability to form a covalent bond, making osimertinib resistant to NSCLC with a C797S mutation. While first-generation, reversible EGFR-TKIs (gefitinib and erlotinib) might be effective for patients with C797S mutation, the T790M mutation is reported to emerge in almost half of patients with EGFR common mutations during treatment with first-generation EGFR-TKIs. Here, we report TAS3351 as a novel, next-generation EGFR-TKI designed to overcome C797S and T790M-mediated resistance in NSCLC patients. Methods: The inhibitory potency of TAS3351 on cellular phospho-EGFR was analyzed by In-cell western assay. In addition, inhibition of cell viability in Ba/F3 cells transformed by human wild type or mutated EGFR, as well as in human NSCLC cell lines whose EGFR harbors common mutations, was tested. Anti-tumor activity of TAS3351 was evaluated in NIH/3T3-EGFR allograft models and human NSCLC xenograft models. Results: TAS3351 exhibited almost comparable inhibitory potency against cellular phosphorylation of EGFR harboring ex19del or L858R with or without C797S and/or T790M while sparing wild type EGFR activity. TAS3351 also showed similar trends in the cell viability assay for Ba/F3-EGFR cells and human NSCLC cell lines. Finally, TAS3351 demonstrated favorable anti-tumor activity in NIH/3T3 allografts transformed by human EGFR harboring ex19del/C797S/T790M. Conclusion: TAS3351 is a fourth-generation EGFR-TKI overcoming T790M and C797S-mediated resistance in NSCLC with common mutations. The present results support the clinical development of TAS3351 as monotherapy in NSCLC patients with EGFR mutations harboring C797S and/or T790M EGFR-TKI resistance mutations. Citation Format: Hidefumi Kasuga, Yuki Kataoka, Fuyuki Yamamoto, Takashi Mizutani, Shingo Tsuji, Sakiho Tanaka, Shinji Mizuarai. TAS3351 is a 4th-generation EGFR-TKI overcoming T790M and C797S-mediated resistance in NSCLC with EGFR common mutations [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 3259.

B7-H3 is eligible for predicting clinical outcomes in lung adenocarcinoma patients treated with EGFR tyrosine kinase inhibitors

BackgroundNot all lung adenocarcinoma (LUAD) patients with activating epidermal growth factor receptor (EGFR) mutations respond to tyrosine kinase inhibitors (TKIs) as intended. Thus, biomarkers are needed to identify patients who benefit most from EGFR-targeted therapy. Our previous in vitro data has shown that the co-signal molecule B7-H3 determines EGFR-TKI gefitinib susceptibility of EGFR-mutated LUAD cell lines, based on the potential crosslinking between B7-H3-induced signaling and EGFR signaling.MethodsWe detected tumoral B7-H3 expression in the original biopsy from 56 treatment-naïve LUAD patients and analyzed the association between high/low B7-H3 expression with the clinical outcomes of first-line anti-EGFR therapy. The main criteria for the analysis of response were overall response rate (ORR), disease control rate (DCR), and progression-free survival (PFS), and the secondary criterion was overall survival (OS).ResultsIn the subgroups of B7-H3 high and low expression, the ORR were 16.0% (4/25) and 74.2% (23/31) (p<0.001), and the DCR were 36.0% (9/25) and 87.1% (27/31) (p<0.001), respectively. The PFS of B7-H3 high [median 8.7, 95% confidence interval (CI) 4.0–13.4] was significantly worse than that of B7-H3 low (median not reached) [HR 6.54 (95% CI 2.18–19.60), p=0.001]. The median OS was 15.9 (95% CI 10.0–21.8) months in the B7-H3 high cohort and 25.7 (95% CI 9.0–42.4) months in the B7-H3 low subjects [HR 2.08 (95% CI 1.07–4.02), p=0.03], respectively. Both the univariate and multivariate analyses identified B7-H3 as an independent factor associated with poor PFS (p=0.001, p=0.000) and OS (p=0.03, p=0.015).ConclusionB7-H3 may serve as a potential biomarker to predict clinical outcomes in EGFR-mutated LUAD patients treated with first-line EGFR-TKIs.

First-line therapy in non-small cell lung cancer patients with EGFR activating mutations: a consideration of the clinical position of osimertinib based on the subset of Japanese patients in the FLAURA study.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been established as the standard first-line treatment for patients with previously untreated advanced non-small cell lung cancer (NSCLC) with an EGFR activating mutation. In the FLAURA study, osimertinib, third-generation EGFR-TKI, resulted in significantly longer progression-free survival and overall survival (OS) than first-generation EGFR-TKIs (gefitinib or erlotinib) in patients with previously untreated advanced NSCLC with an EGFR activating mutation. Osimertinib is now widely used as first-line therapy for those patients. In Japanese subset analysis of the FLAURA study, the median progression-free survival was prolonged by osimertinib (19.1months) relative to gefitinib (13.8months). However, there was no apparent OS benefit, albeit at the level of an exploratory post-hoc analysis. Although the safety profile in the Japanese subset was generally consistent with the overall population, the incidence of liver enzyme increases in the gefitinib group and that of interstitial lung disease/pneumonitis in the osimertinib group was higher among Japanese patients. There is now an increasing number of first-line treatment options for NSCLC with EGFR mutations, including EGFR-TKIs in combination with platinum-doublet chemotherapy or anti-angiogenic drugs. These combinations show progression-free survival benefits similar to osimertinib regardless of the mutation type. Therefore, a first-line combination regimen followed by osimertinib remains an attractive strategy. We review data from the randomized clinical trials of first-line EGFR-TKIs including a subset of Japanese patients and discuss first-line therapies for patients with NSCLC harbouring EGFR mutations.

Survival Rate in Lung Adenocarcinoma with Mutation of the EGFR Gene with Tyrosine Kinase Inhibitor Treatment

Background: EGFR mutation is a genetic disorder that is often observed and examined in Non-Small Cell Lung Carcinoma. EGFR mutation detection aims to predict sensitivity to EGFR-TKI and acts as first-line therapy. Targeted therapy with EGFR-TKI can increase the survival rate of patients with Non-Small Cell Lung Cancer compared to chemotherapy. This study aims to obtain data on the survival rate of patients with Non-Small Cell Lung Carcinoma who received targeted therapy at H. Adam Malik Hospital. &#x0D; Methods: This study is a descriptive study with a retrospective cohort design carried out at the Oncology Polyclinic at RSUP H Adam Malik Medan for 5 years, from January 2014 to December 2018. The subjects of this study were all patients with lung cancer type adenocarcinoma who had received therapy with generation 1 or 2 EGFR TKI. &#x0D; Results: 99 patients were included as subjects of this study. From the study, the most influential factors on lung cancer were gender, age, and smoking addiction. The study consisted of 60.6% male, 92.9% of the respondents aged 40 years and over, 56.5% active, and 43.4% passive smokers and 41.4% of the respondents with severe Brinkman index. The 30-month survival rate of EGFR-TKI (Gefitinib) patients treated with NSCLC Adenocarcinoma (Gefitinib) from 2014 to 2018 at H. Adam Malik Hospital Medan was 6.3% with a median survival of 7 months. The duration of progression-free survival in patients receiving Erlotinib therapy was 6.6 months (6.6 ± 2.51 months), while the length of progression-free survival for patients treated with Gefitinib was 9.1 months (9.1 ± 6.9 months). The results of statistical tests showed that there was no difference in progression-free survival rate between those who received Erlotinib and Gefitinib (P = 0.82). &#x0D; Conclusion: The 30-month survival rate of lung adenocarcinoma patients treated with EGFR-TKI from 2014 to 2018 was 6.1% with a median survival of 7 months. Those who received Erlotinib therapy experienced Progression-Free Survival for 6.6 months and those who received Gefitinib experienced Progression-Free Survival for 9.1 months.

Comparison of first-generation EGFR-TKIs (gefitinib, erlotinib, and icotinib) as adjuvant therapy in resected NSCLC patients with sensitive EGFR mutations.

BackgroundSeveral randomized controlled trials have suggested that adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were associated with prolonged disease-free survival (DFS) in EGFR-mutated NSCLC patients after radical resection, comparing with chemotherapy or placebo. We aimed to compare the effectiveness of different first-generation EGFR-TKIs as adjuvant treatment in real-world setting.MethodsEarly-stage EGFR mutated NSCLC patients who underwent radical resection and treated with first-generation EGFR-TKIs (gefitinib, erlotinib, icotinib) as adjuvant therapy between Feb 2010 and Jan 2019 were retrieved from a prospectively-maintained database in our center. The primary endpoint was DFS in stage II/III (TNM 8th) patients with exploratory endpoint regarding DFS in stage I patients. Sensitivity analyses were based on propensity score matched (PSM) cohorts. Treatment failure patterns among different TKIs were also compared.ResultsOf 588 eligible patients, 198 patients (33.7%) received gefitinib, 106 patients (17.9%) received erlotinib, and 284 patients (48.2%) received icotinib. The median DFS of stage II/III patients in the gefitinib, erlotinib and icotinib group were 36.1 months (95% CI, 23.9–49.4), 42.8 months (95% CI, 29.6–97.8), and 32.5 months (95% CI, 23.9–49.4), respectively, with no significant difference (log-rank test P=0.22). There was also no significant difference in DFS among stage I patients receiving different TKIs (P=0.12). PSM adjustments and multivariate analyses adjusting for other confounders revealed similar results. In addition, there were no significant differences in treatment failure pattens in different EGFR-TKI arms, especially in terms of brain metastases (6.1% in gefitinb, 7.5% in erlotinib, 3.9% in icotinib) and bone metastases (8.6% in gefitinb, 9.4% in erlotinib, 7.0% in icotinib).ConclusionsThis first and largest real-world study showed that gefitinib, erlotinib, and icotinib demonstrated comparable clinical effectiveness as adjuvant therapy for patients with early-stage EGFR mutated NSCLC.

P51.05 Sequential Afatinib and Osimertinib in Patients With Advanced EGFRm+ NSCLC and Acquired T790M: The Real-World UpSwinG study

The ErbB family blockers, afatinib and dacomitinib, and the third-generation EGFR TKI, osimertinib, confer significant clinical benefit versus first-generation EGFR TKIs (erlotinib and gefitinib) in patients with EGFR mutation-positive (EGFRm+) NSCLC. However, no prospective data exist directly comparing afatinib, dacomitinib and osimertinib. In terms of overall survival (OS), outcomes are highly dependent on the availability and implementation of subsequent therapy following acquired resistance to first-line therapy.

Abstract 377: Molecular features-based model for predicting benefit from Bevacizumab combined with first-generation EGFR-tyrosine kinase inhibitor

Abstract Introduction: Two phase 3 clinical studies, NEJ026 and CTONG1509, have consistently demonstrated better anti-tumor activity of adding bevacizumab to erlotinib regimen in the treatment of patients with epidermal growth factor receptor (EGFR)-mutant advanced non-squamous non-small-cell lung cancer (NSCLC); however, the subset of patients that benefits more with the addition of bevacizumab to their EGFR-TKI regimen still remains to be identified. In this study, we aimed to investigate the clinical and molecular factors that affect the efficacy of first-generation EGFR-TKI regimen with or without bevacizumab as first-line treatment of patients with EGFR-mutant NSCLC. Methods: A total of 176 patients with EGFR-mutant stage IIIB-IV relapsed or metastatic NSCLC and received first-generation EGFR-TKI gefitinib or erlotinib monotherapy (T; n=88) or combined with bevacizumab (A+T; n=88) were included in our study. The two groups had comparable baseline clinical characteristics. Retrospective analysis was performed on clinical data, survival outcomes, and mutation profiles at baseline and progression. A nomogram model to predict PFS was constructed with the following variables identified from Cox multivariate analysis: treatment group (A+T) and mutations in EGFR L858R, exon 19 deletion, TP53, CDK4, FGF3, and NFkB signaling pathway. Another nomogram was constructed to predict overall survival with treatment group (A+T) and mutations in TP53 signaling pathway as the variables. Results: As compared to the T group, progression-free survival (PFS) was significantly longer among patients who received A+T and harbored concurrent EGFR amplification (16.1 vs 9.0 months; HR: 0.267, 95%CI: 0.110-0.651; p=0.004), and hotspot and loss-of-function mutations in TP53 (16.1 vs 8.0 months; HR: 0.215, 95%CI: 0.108-0.426; p&amp;lt;0.001). At progression, EGFR T790M, detected from 35% in the A+T group and 42% in the T group, was the major resistance mechanism in both groups. No statistical difference was found between the acquired resistance mechanisms of the two groups (p=0.787). Cox multivariate analysis demonstrated that receiving A+T is an independent predictor of longer PFS (HR: 0.51, 95%CI: 0.35-0.75; p=0.001) and overall survival (HR: 0.62, 95%CI: 0.38-0.99; p=0.045). Cross-validation of both nomograms using data from 144 evaluable patients in the cohort stratified into low-risk and high-risk groups based on the variables predicted the risk for disease progression (c-index: 0.676; p&amp;lt;0.001) and the risk for poor prognosis (c-index: 0.593; p&amp;lt;0.001) of the high-risk groups. Conclusions: Our study demonstrated the clinical value of the nomogram model in predicting the subset of patients who benefits from first-generation EGFR-TKI regimen with or without bevacizumab. Citation Format: Yongchang Zhang, Analyn Lizaso. Molecular features-based model for predicting benefit from Bevacizumab combined with first-generation EGFR-tyrosine kinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 377.

Treatment outcome and functional characterization of uncommon EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNGM).

9036 Background: The nNGM centralizes molecular diagnostics, treatment recommendations and follow-up reporting in NSCLC in Germany. Uncommon EGFR mutations pose a clinical challenge because they comprise a heterogenous group and analyses of treatment outcome are still scarce. Here, we analyzed follow-up data of patients with rare EGFR mutations and performed functional characterization of recurrent mutations with unknown function. Methods: This multicenter, retrospective analysis of uncommon EGFR mutations (excluding L858R-, T790M mutations and exon 19 deletions) includes stage IV patients with NSCLC from 12 nNGM centers. We categorized EGFR-mutations into 3 groups: uncommon EGFR mutations with known driver function, for instance E709X, G719X, S768I and L861Q (group 1), exon 20 insertions (group 2) and all other very rare mutations (group 3). Functional characterization of unknown mutations was performed by insertion mutagenesis in Ba/F3 cells and monitoring of growth factor-independent proliferation. Results: In total, 834 cases with uncommon EGFR mutations were reported. Follow-up data after EGFR-TKI (Erlotinib, Gefitinib, Afatinib and Osimertinib), chemotherapy and/or mono-PD(L)1 blockade was available for 252 patients. Mean progression free survival (mPFS) on EGFR-TKIs vs. chemotherapy was 6.6 months vs. 5.0 months (HR 0.54, 95%CI 0.35 to 0.81, P =.003) in group 1 (n = 84), and 6.7 months vs. 3.4 months (HR 0.66, 95%CI 0.47 to 0.92, P =.015) in group 3 (n = 104). Mono-anti-PD(L1) blockade was not superior to chemotherapy (group 1, mPFS 3.0 months, HR 1.32, 95% 0.55 – 3.15, P =.535 and group3, mPFS 4.3 months, HR 1.02, 95% CI 0.64 – 1.62, P = 0.951). Exon 20 insertions (group 2, n = 63) did not benefit from EGFR-TKIs or anti-PD(L1) blockade vs. chemotherapy. Overall survival (OS) analysis (n = 218) following chemotherapy (56%) or EGFR-TKI treatment (44%) showed median OS (mOS) of 18.0 months vs. 13.9 months in patients treated with EGFR-TKI and chemotherapy, respectively in group 1 (HR 0.97, 95%CI 0.54 to 1.75, P =.929). In group 3 patients treated with EGFR-TKI and chemotherapy had a mOS of 35.4 months vs. 12.0 months, respectively (HR 0.59, 95%CI 0.35 to 1.01, P =.056). In the Ba/F3 system we could identify 8 recurrent driver and 12 non-driver mutations with a clinically applicable assay turnaround time of 4 weeks to inform clinical decision-making in the future. Conclusions: This real-world dataset confirms that patients with group 1(uncommon) EGFR mutations benefit from EGFR-TKIs and indicates that mono-anti PD(L)1 blockade is not superior to chemotherapy. Furthermore, patients with very rare EGFR mutations (group 3) also experienced a PFS benefit from EGFR-TKI compared to chemotherapy while immune therapy was not beneficial.

Microsecond-timescale MD simulation of EGFR minor mutation predicts the structural flexibility of EGFR kinase core that reflects EGFR inhibitor sensitivity

Approximately 15–30% of patients with lung cancer harbor mutations in the EGFR gene. Major EGFR mutations (>90% of EGFR-mutated lung cancer) are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs). Many uncommon EGFR mutations have been identified, but little is known regarding their characteristics, activation, and sensitivity to various EGFR-TKIs, including allosteric inhibitors. We encountered a case harboring an EGFR-L747P mutation, originally misdiagnosed with EGFR-del19 mutation using a routine diagnostic EGFR mutation test, which was resistant to EGFR-TKI gefitinib. Using this minor mutation and common EGFR-activating mutations, we performed the binding free energy calculations and microsecond-timescale molecular dynamic (MD) simulations, revealing that the L747P mutation considerably stabilizes the active conformation through a salt-bridge formation between K745 and E762. We further revealed why several EGFR inhibitors, including the allosteric inhibitor, were ineffective. Our computational structural analysis strategy would be beneficial for future drug development targeting the EGFR minor mutations.