First-generation EGFR-TKIs Research Articles

Optimal first-line treatment for EGFR-mutated NSCLC: a comparative analysis of osimertinib and second-generation EGFR-TKIs

BackgroundOsimertinib is an irreversible third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It is the preferred first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC) compared to first-generation EGFR-TKIs. However, limited research has compared its clinical effectiveness with second-generation (2nd G) EGFR-TKIs.Materials and methodsThis study recruited patients diagnosed with stage IIIb-IV EGFR-mutated NSCLC who received first-line treatment with either 2nd G EGFR-TKIs (afatinib and dacomitinib) or osimertinib between April 2020 and April 2023.ResultsThe final analysis included 168 patients, of whom 113 received 2nd G EGFR-TKIs (afatinib or dacomitinib) and 55 received osimertinib. The median progression-free survival (PFS) did not differ significantly between 2nd G EGFR-TKIs and osimertinib (del 19: 17.6 months; L858R: 20.0 months vs. 28.3 months, p = 0.081). In patients with the EGFR exon 19 deletion, osimertinib conferred a longer median PFS (28.3 vs. 17.6 months, p = 0.118) and time to treatment failure (30.2 vs. 22.7 months, p = 0.722) than 2nd G EGFR-TKIs. However, the differences were not statistically significant. In patients with with the EGFR exon 19 deletion and central nervous system metastasis, the median PFS did not differ significantly between those treated with osimertinib (14.3 months) and those treated with 2nd G EGFR-TKIs (17.6 months; p = 0.881). Multivariate regression analysis revealed that the NSCLC stage was the only independent negative predictor of PFS. The treatment patterns in the second line also differed significantly between groups (p = 0.008).ConclusionsThis study found comparable effectiveness between osimertinib and 2nd G EGFR-TKIs as first-line treatment for advanced EGFR-mutated NSCLC, with only the NSCLC stage identified as a negative predictor of PFS. However, whether the different second-line treatments affect overall survival should be examined.

First-line treatment of EGFR-mutated non-small cell lung cancer with brain metastases: a systematic review and meta-analysis

This systematic review and network meta-analysis evaluates first-line treatment options for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and brain metastases. We analyzed 24 randomized controlled trials (RCTs) involving 2,682 patients, comparing various EGFR tyrosine kinase inhibitors (TKIs) and combination therapies. Direct comparisons showed that the addition of bevacizumab or chemotherapy to first-generation (1G) EGFR-TKIs improved overall survival (OS) compared to 1G TKIs alone, with HRs of 0.704 (95% CI: 0.433–0.973) and 0.682 (95% CI: 0.464–0.899), respectively. However, third-generation (3G) TKI monotherapy did not significantly improve OS compared with 1G TKIs, with an HR of 0.855 (95% CI: 0.511–1.198). Indirect comparisons suggested that the combination of 3G TKIs with chemotherapy provided the most significant improvements in OS and progression-free survival (PFS), significantly outperforming 3G TKIs, with HRs of OS 1.69 (95% CI: 1.14–3.4) and PFS 2.13 (95% CI: 1.28–3.54). Intracranial PFS was best with 1G TKIs plus bevacizumab. Our findings suggest that 3G EGFR-TKIs in combination with chemotherapy may be the most effective strategy for patients with EGFR-mutant NSCLC and brain metastases, though further head-to-head trials are needed for validation.

EGFR mutations in patients with lung adenocarcinoma and malignant pleural effusion: a propensity score-matched analysis of a single-center database.

Malignant pleural effusion (MPE) is associated with poor prognosis in patients with advanced lung adenocarcinoma (LUAD), and abnormal activation of epidermal growth factor receptor (EGFR) plays a crucial role in the development of LUAD. This study aimed to investigate the correlation between EGFR mutations and the occurrence of MPE in patients with LUAD and evaluate the effect of EGFR mutations on the prognosis of patients with LUAD with MPE. A case-control study design was adopted that included patients pathologically diagnosed with LUAD. Clinical data were collected, and patients were divided into the MPE group and the non-MPE (N-MPE) group based on the presence of MPE. Propensity score matching (PSM) was used to control for confounding factors. The correlation between EGFR mutations and the occurrence of MPE in LUAD was initially examined. Additionally, various factors affecting the overall survival (OS) of patients with LUAD and MPE were evaluated. A total of 849 patients were included in the study. After 1:2 PSM, there were 180 patients in the MPE group and 360 in the N-MPE group. The EGFR mutation rate was significantly higher in the MPE group compared to the N-MPE group [62.7% vs. 50.2%; odds ratio (OR) =1.668; P=0.006]. This difference was primarily attributed to the T790M mutation (8.3% vs. 1.3%; OR =8.015; P<0.001), but no significant differences observed in other mutation sites between the groups. Further evaluation of factors affecting OS in patients with LUAD and MPE revealed that EGFR mutation was an independent protective factor for OS [hazard ratio (HR) 0.662, 95% CI: 0.456-0.962; P=0.03]. For patients with LUAD, MPE, and EGFR mutations, treatment with third-generation EGFR-tyrosine kinase inhibitors (TKIs) alone (HR 0.466, 95% CI: 0.233-0.930; P=0.03) or sequential first- and third-generation EGFR-TKIs (HR 0.385, 95% CI: 0.219-0.676; P=0.001) was associated with better median OS compared to first-generation EGFR-TKIs alone (first-generation EGFR-TKIs: 35 months, 95% CI: 28.4-41.6; third-generation EGFR-TKIs: 50 months, 95% CI: 37.3-62.7; sequential first- and third-generation EGFR-TKIs: 51 months, 95% CI: 45.6-56.4; P<0.001). This study found there to be a positive correlation between EGFR mutations, particularly the T790M mutation, and MPE in patients with LUAD. EGFR mutation was associated with improved OS in patients with LUAD and MPE. For patients with LUAD, MPE, and EGFR mutations, sequential treatment with first- and third-generation EGFR-TKIs or third-generation EGFR-TKIs alone is recommended, as these regimens provide significant benefit to OS.

CIB2 mediates acquired gefitinib resistance by inducing ZEB1 expression and epithelial-mesenchymal transition.

EGFR-TKIs have been used as frontline treatment in patients with advanced non-small cell lung cancer (NSCLC) suffering from the EGFR mutation. Gefitinib, the first-generation EGFR-TKI, has greatly improved survival rates in lung cancer patients, whereas acquired gefitinib resistance is still a critical issue that needs to be overcome. In our research, high expression levels of CIB2 were found in gefitinib-resistant lung cancer cells. CIB2 knockout rendered gefitinib-resistant cells more sensitive to gefitinib, and overexpression of CIB2 in parental cells was sufficient to induce more resistance to gefitinib. Inhibition of CIB2 in gefitinib-resistant lung cancer cells significantly induced cell apoptosis. To clarify the major molecular mechanism by which CIB2 increases gefitinib resistance, we demonstrated that raised CIB2 in lung cancer cells promoted epithelial-to-mesenchymal transition (EMT) through upregulation of ZEB1. Moreover, FOSL1 transcriptionally regulated CIB2 expression. Finally, CIB2 rendered tumors resistant to gefitinib treatment in vivo. Our results explored a new mechanism: upregulated CIB2 promoted EMT through ZEB1 to regulate gefitinib resistance, which could be a candidate therapeutic target for overcoming acquired resistance to EGFR-TKIs in NSCLC patients.

Heterogeneity in PD-L1 expression between primary and metastatic lymph nodes: a predictor of EGFR-TKI therapy response in non-small cell lung cancer

BackgroundThere is inconclusive evidence to suggest that the expression of programmed cell death ligand 1 (PD-L1) is a putative predictor of response to EGFR-TKI therapy in advanced EGFR-mutant non-small cell lung cancer (NSCLC). We evaluated the heterogeneity in PD-L1 expression in the primary lung site and metastatic lymph nodes to analyze the association between PD-L1 expression and response for patients treated with EGFR-TKI.MethodsThis study reviewed 184 advanced NSCLC patients with EGFR mutations who received first-generation EGFR-TKI as first-line treatment from 2020 to 2021 at Shanghai Chest Hospital. The patients were divided into the primary lung site group (n = 100) and the metastatic lymph nodes group (n = 84) according to the biopsy site. The patients in each group were divided into TPS < 1%, TPS 1–49%, and TPS ≥ 50% groups according to PD-L1 expression.ResultsThe median PFS was 7 (95% CI: 5.7–8.3) months, and the median OS was 26 (95% CI: 23.5–28.5) months for all patients. No correlation existed between PFS or OS and PD-L1 expression. The median PFS in the primary lung site group was 11 months (95% CI: 9.6–12.4) in the TPS < 1% group, 8 months (95% CI: 6.6–9.4) in TPS 1–49% group, and 4 months (95% CI: 3.2–4.8) in TPS ≥ 50% group, with statistically significant differences (p = 0.000). The median OS of the TPS < 1% group and TPS ≥ 50% group showed a statistically significant difference (p = 0.008) in the primary lung site group. In contrast, PD-L1 expression in the lymph nodes of EGFR-mutant patients was unrelated to PFS or OS after EGFR-TKI therapy.ConclusionPD-L1 expression from the primary lung site might predict clinical benefit from EGFR-TKI, whereas PD-L1 from metastatic lymph nodes did not.Trial registration: This retrospective study was approved by the Ethics Committee of Shanghai Chest Hospital (ID: IS23060) and performed following the Helsinki Declaration of 1964 (revised 2008).

ATTLAS, IMpower151 and ORIENT-31: Dusting off IMpower150 for Post-Osimertinib in EGFR-Mutated NSCLC?

Treatment strategies for post-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in EGFR-mutant non-small cell lung cancer (NSCLC) is an ongoing challenge. Previously, the IMPRESS trial comparing platinum doublet chemotherapy with or without EGFR-TKI did not demonstrate any progression-free survival (PFS) benefit. The retrospective subgroup analysis of IMpower150 indicated that the quad regimen (carboplatin, paclitaxel, bevacizumab, atezolizumab) improved PFS and overall survival (OS) in patients with EGFR-mutant NSCLC who progressed on first-generation EGFR-TKIs. Given the retrospective nature of the analysis, the IMpower150 regimen is not approved in the US for post-EGFR-TKI treatment. Currently, osimertinib or other third-generation (3G) EGFR-TKIs is the first-line standard of care for advanced EGFR-mutant NSCLC. MARIPOSA-2 provided the first randomized trial post-osimertinib in EGFR-mutant NSCLC patients with another quad regimen (platinum, pemetrexed, lazertinib, amivantamab). The IMpower150 and MARIPOSA-2 quad regimens differ in the principle of whether to continue or even "double-down" on EGFR inhibition. Recently, three prospective randomized trials conducted in Asia offered promising results, showing that a quad regimen of doublet platinum chemotherapy plus anti-angiogenesis agent and ICI may be as efficacious as MARIPOSA-2 with a lower rate of toxicities and accounting for the PFS difference if 1L chemotherapy plus osimertinib instead of osimertinib monotherapy. In particular, the median PFS achieved by the quad regimens of ATTLAS and IMpower151 is 8.5 months. However, only 8.2% and 17.9% of the EGFR-mutant NSCLC patients who received the quad regimens progressed on 3G EGFR-TKI, respectively. Here, we discuss how the results of IMpower151 and ATTLAS may rejuvenate interest in a non-EGFR containing quad regimen as a potential post-osimertinib monotherapy treatment. Randomized trials comparing the results of these studies, including the quad regimen of MARIPOSA-2 versus the quad regimen of IMpower151/Impower150/ATTLAS in post-osimertinib (or other 3G EGFR-TKI) progression, are urgently needed.

Abstract CT252: Nicotinamide in combination with EGFR-TKIs for the treatment of stage IV lung adenocarcinoma with EGFR mutations: A randomized double-blind (Phase IIb) trial

Abstract Background: RUNX3 is a tumor suppressor gene, which is inactivated in approximately 70% of lung adenocarcinomas. Nicotinamide, a sirtuin inhibitor, has demonstrated potential in re-activating epigenetically silenced RUNX3 in cancer cells. This study assessed the therapeutic benefits of combining nicotinamide with first-generation EGFR-TKIs for patients with stage IV lung cancer carrying EGFR mutations. Patients and Methods: We assessed the impact of nicotinamide on carcinogen-induced lung adenocarcinomas in mice and observed that nicotinamide increased RUNX3 levels and inhibited lung cancer growth. Subsequently, 110 consecutive patients with stage IV lung cancer who had EGFR mutations were recruited: 70 females (63.6%) and 84 never-smokers (76.4%). The patients were randomly assigned to receive either nicotinamide (1 g/day, n = 55) or placebo (n = 55). The primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS), respectively. Results: After a median follow-up of 54.3 months, the nicotinamide group exhibited a median PFS of 12.7 months (95% CI, 10.4-18.3), while the placebo group had a PFS of 10.9 months (9.0-13.2; p = 0.2). The median OS was similar in the two groups (31.0 months with nicotinamide vs. 29.4 months with placebo; p = 0.2). Notably, subgroup analyses revealed a significant reduction in mortality risk for females (p = 0.01) and never-smokers (p = 0.03) treated with nicotinamide. Conclusion: The addition of nicotinamide with EGFR-TKIs demonstrated potential improvements in PFS and OS, with notable survival benefits for female patients and those who had never smoked. (ClinicalTrials.gov Identifier: NCT02416739) Citation Format: Cheol-Kyu Park, Hyung-Joo Oh, Suk-Chul Bae, In-Jae Oh, Kyoung-Mi Jung, Da-Mi Kim, Jung-Won Lee, Chang Kyun Kang, Il Yeong Park, Young-Chul Kim. Nicotinamide in combination with EGFR-TKIs for the treatment of stage IV lung adenocarcinoma with EGFR mutations: A randomized double-blind (Phase IIb) trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT252.

Abstract 5204: Exploring the therapeutic potential of EGFR retreatment: A comprehensive analysis of T790m(+) conversion and prognosis in lung cancer patients

Abstract Background: T790M acquired resistance occurs in 30-40% of cases after first- or second-generation EGFR TKI treatment. However, some patients who did not develop T790M mutation are converted to T790M positive through EGFR TKI retreatment. We conducted a Phase II prospective study analyzing T790m (+) conversion and prognosis in patients who were not induced T790M mutation at 2nd biopsy and were re-treated with first-generation EGFR-TKI as the third-line or later therapy. Methods: We re-administered first-generation EGFR-TKI to 63 patients (gefitinib n=34 or erlotinib n=29) who had previously been treated with first- or second- generation EGFR TKIs and cytotoxic chemotherapy because they were T790M-negative at the 2nd biopsy. Results: Among the 63 patients, a new T790m (+) mutation was identified in 20 patients (32%) with EGFR TKI retreatment. The first EGFR TKI treatment period and EGFR TKI retreatment period were significantly longer in the T790m (+) group than in the T790m (-) group (P-value=0.026, P-value=0.029, respectively). The best response to retreatment was also favorable in the T790m (+) group (P-value=0.038). The median overall survival (OS) in the T790m (+) group was 29.3 months, which was significantly better than the 6.0 months observed in the T790m (-) group (P-value&amp;lt;0.001). In an additional NGS analysis conducted on stored plasma samples from the 24 patients who were negative for T790M in the tumor tissue before retreatment, T790M was detected in five patients. These patients, who were subsequently treated with a third EGFR TKI, demonstrated very favorable overall survival (OS). Conclusions: EGFR retreatment could induce T790m (+) conversion in approximately one-third of cases, and these patients exhibited favorable prognosis. Through NGS analysis using plasma samples, approximately 20% cases of T790m mutation, which were not detected through routine PCR tests at the tumor tissue, could be identified. Retreatment-EGFR TKI and NGS analysis through blood samples could improve patient prognosis through the additional discovery of T790m (+) mutation. Citation Format: Joong Jin Ahn, Jae Cheol Lee, Chang Min Choi, In Ae Kim, Kye Young Lee, Jeong Eun Lee, Seung Hoon Jang, Seong Hoon Yoon, In Jae Oh, Sang Hoon Lee, Eun Young Kim, Juwhan Choi, Sung Yong Lee. Exploring the therapeutic potential of EGFR retreatment: A comprehensive analysis of T790m(+) conversion and prognosis in lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5204.

EGFR-T790M mutation associated with acquired resistance to first-generation EGFR tyrosine kinase inhibitors in Vietnamese Non-Small-Cell Lung Cancer patients

Background: non-small cell lung cancer (NSCLC) patients who had epidermal growth factor receptor (EGFR) mutations sensitive to EGFR tyrosine kinase inhibitors (TKIs) had a high response rate to target therapies. Epidermal growth factor receptor (EGFR) T790M mutation is the most common mechanism of acquired resistance to first-generation EGFR TKIs. Objective: The aim of this study was to analyze the incidence of EGFR T790 mutation, the progression-free survival (PFS) in the patients who progress on the first‑ generation EGFR‑TKIs. This study also investigates the correlation between T790M mutation and clinical, subclinical features, progression-free survival of NSCLC Vietnamese patients.&#x0D; Patients and methods: We analyzed 66 NSCLC patients who had acquired resistance to first-generation EGFR-TKIs. The clinical data, PFS and the mechanism of acquired resistance were obtained. The Kaplan-Meier method and the log-rank test were used to analyze the PFS and compare between subgroups of patient characteristics. The correlations between the patient’s characteristics and EGFR-T790M mutation status were analyzed by Chi-square and Fisher’s exact tests.&#x0D; Results: At the progressive period, EGFR T790M mutation was detected in 54.5% of patients. The median PFS were 14.48 ± 3.9 months (range: 8- 26 months). Patients who were older than 60 years old or had comorbidities had significantly shorter PFS than the subgroups without (P≤0.05). The age, gender, smoking status, comorbidities, pathological features were not significantly correlated with the development of EGFR-T790M (P &gt; 0.05). The average PFS was not significantly different between the EGFR-T790M group and the non-EGFR-T790M group (P=0.642).&#x0D; Conclusion: In our cohort study, more than half of all patients had T790M mutation after being treated with first-generation EGFR TKIs. Age and comorbidities were associated with PFS but the EGFR-T790M mutation was not correlated with PFS.

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.

Deciphering the Dynamics of EGFR-TKI Resistance in Lung Cancer: Insights from Bibliometric Analysis.

EGFR-TKI resistance poses a significant challenge in the treatment landscape of non-small cell lung cancer (NSCLC), prompting extensive research into mechanisms and therapeutic strategies. In this study, we conduct a bibliometric analysis to elucidate evolving research hotspots and trends in EGFR-TKI resistance, offering insights for clinical interventions and scientific inquiries. Publications spanning from 1996 to 2024, focusing on EGFR-TKI resistance in NSCLC, were sourced from the Web of Science Core Collection. Utilizing VOSviewer 1.6.19, CiteSpace 6.2. R2, and Scimago Graphica 1.0.35, we analyzed these articles to identify countries/regions and institutions, Journals, publications, key contributors, collaborations, and emerging topics. An analysis of 8051 articles by 38,215 researchers from 86 countries shows growing interest in EGFR-TKI resistance mechanisms. Since 1996, publications have steadily increased, surpassing 500 per year after 2016, with a sharp rise in citations. Research articles make up 84% of publications, emphasizing scholarly focus. Global collaboration, especially among researchers in China, the US, and Japan, is strong. Leading institutions like Dana-Farber and Harvard, along with journals such as "Lung Cancer", are key in sharing findings. Professors Yi-Long Wu and William Pao are prominent contributors. Keyword analysis reveals core themes, including first-generation EGFR-TKIs, emerging agents like osimertinib, and research on the T790M mutation. EGFR-TKI resistance remains a critical issue in NSCLC treatment, driving ongoing research efforts worldwide. Focusing future research on clear identification of resistance mechanisms will guide post-resistance treatment strategies, necessitating further exploration, alongside the validation of emerging drugs through clinical trials. Moreover, "chemo+" treatments following EGFR-TKI resistance require more clinical data and real-world evidence for assessing safety and patient outcomes. As research advances, a multidisciplinary approach will be key to overcoming these challenges. Continued innovation in treatment could greatly enhance patient survival and quality of life.

Significance of micro-EGFR T790M mutations on EGFR-tyrosine kinase inhibitor efficacy in non-small cell lung cancer.

Small amounts of epidermal growth factor receptor (EGFR) T790M mutation (micro-T790M), which is detected using droplet digital PCR (ddPCR) but not conventional PCR, in formalin-fixed and paraffin-embedded (FFPE) samples have been investigated as a predictive factor for the efficacy of EGFR-tyrosine kinase inhibitors (TKIs). However, the predictive value of micro-T790M remains controversial, possibly owing to the failure to examine artificial T790M in FFPE specimens. Therefore, we examined the predictive value of micro-T790M in first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKI efficacy using a new method to exclude FFPE-derived artificial mutations in our retrospective cohort. The primary objective was time to treatment failure (TTF) of 1G, 2G, and 3G EGFR-TKIs according to micro-T790M status. In total, 315 patients with EGFR-positive non-small cell lung cancer treated with 1G, 2G, and 3G EGFR-TKIs were included in this study. The proportion of patients positive formicro-T790M in the 1G, 2G, and 3G EGFR-TKI groups was 48.2%, 47.1%, and 47.6%, respectively. In the micro-T790M-positive group, the TTF was significantly longer in the 2G and 3G EGFR-TKI groups than in the 1G TKI group. No differences in the micro-T790M-negative group were observed. Micro-T790M status detected using ddPCR, eliminating false positives, may be a valuable predictor of EGFR-TKI efficacy.

Stepwise prolongation of overall survival from first- to third-generation EGFR-tyrosine kinase inhibitors in non-small cell lung cancer and the prognostic impact of concomitant antacids.

530 Background: The introduction of new-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has afforded promising overall survival (OS) outcomes in clinical trials for non-small cell lung cancer (NSCLC). However, given the high cost associated with these agents, the extent of their adoption and the resulting impact on OS in real-world clinical settings remains uncertain. Concomitant use of antacids reportedly decreases the absorption of first-generation EGFR-TKIs, accompanied by a reduction in OS. Although concomitant antacids do not reduce the absorption of second- and third-generation EGFR-TKIs, the impact on OS remains unexplored. Methods: We conducted a nationwide retrospective cohort study utilizing data from the Tokushukai Real-world Data project and reviewed clinical data of consecutive patients with NSCLC who were treated with EGFR-TKIs between April 2010 and March 2020. Cox regression analyses were performed to examine the associations between OS and patient/tumor-related factors, hospital volume, hospital type, study period, and first-line EGFR-TKIs. Furthermore, we examined differences in OS between patients treated with and without concomitant antacids. Results: A total of 758 patients (58.5% females; median age, 73 years) were included. Over the study period, we noted increased utilization of osimertinib as the first-line EGFR-TKI. With a median follow up of 15.8 months, median OS was 28.4 months (95% confidence interval, 15.3–31.0). Age, body mass index, disease status, EGFR mutational status, and first-line EGFR-TKI were identified as significant prognostic factors. The 2-year OS rates for gefitinib, erlotinib, afatinib, and osimertinib were 70.1, 67.8, 75.6, and 90.8%, respectively. Low-volume hospitals showed a treatment transition to osimertinib over time and were non-inferior to high-volume hospitals in terms of the OS achieved. Patients administering gefitinib, erlotinib, afatinib, and osimertinib with concomitant antacids had lower OS values than those not taking concomitant antacids, with hazard ratios of 1.742, 1.329, 1.729, and 5.040, respectively. Conclusions: Our real-world data revealed that new-generation EGFR-TKIs could afford a prolonged OS irrespective of the volume and type of the hospital. Surprisingly, the concomitant antacid use was associated with poor OS in patients treated with osimertinib.

Gefitinib, an effective treatment option for patients with pulmonary enteric adenocarcinoma harboring compound EGFR L858R and A871G mutation.

Pulmonary enteric adenocarcinoma (PEAC) is a rare lung adenocarcinoma with morphological and immunohistochemical similarities to colorectal adenocarcinoma and intestinal differentiation. PEAC belongs to the group of non-small-cell lung carcinoma (NSCLC) and is defined as having a more than 50% intestinal differentiation component. We report a postoperative (T4N2M0 stage IIIb) PEAC patient with EGFR L858R + A871G combined mutation. Following surgery, the patient underwent treatment with the first-generation EGFR-TKI, gefitinib, and achieved an impressive 5-year progression-free survival (PFS). This suggests that gefitinib may serve as an effective treatment option for PEAC patients with EGFR L858R + A871G compound mutations.

Achievement of pathological complete response with osimertinib for EGFR-mutated lung adenocarcinoma

BackgroundTyrosine-kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) usually provide a potent anti-tumor efficacy with robust radiographic response for non-small cell lung cancer (NSCLC) harboring activating mutations in the EGFR gene. However, first-generation EGFR-TKIs may provide only modest pathological response in the majority of EGFR-mutated NSCLC. Here, we present a case of EGFR-mutated adenocarcinoma in which a pathological complete response was revealed in histological specimens obtained during conversion surgery following systemic treatment using a third-generation EGFR-TKI.Case presentationA 61-year-old Japanese man was admitted to our hospital for salvage surgery. Four months prior to the admission, he had been diagnosed with unresectable adenocarcinoma (clinical stage IIIA/T4N1MO) originating from the right lower lobe. Chest computed tomography had revealed a 3.4-cm tumor and enlarged hilar nodes that invaded into the left atrium through the lower pulmonary vein. An activating EGFR-mutation (L858R) had been detected in the tumor specimen. Osimertinib monotherapy had provided a dramatic radiographic response. The patient was diagnosed with potentially resectable disease after 4 months’ osimertinib treatment and was referred to our hospital. Complete resection with right lower lobectomy and combined resection of the left atrium was achieved. Pathological examination showed no viable tumor cells in the resected specimens. Postoperative course was uneventful. The patient is alive without tumor recurrence at 2 years after surgery.ConclusionsPathological complete response was achieved with systemic treatment with osimertinib prior to surgery. Conversion surgery after osimertinib treatment may be safe and effective for NSCLC harboring activating EGFR-mutations.

Concordance of Abundance for Mutational EGFR and Co-Mutational TP53 with Efficacy of EGFR-TKI Treatment in Metastatic Patients with Non-Small-Cell Lung Cancer.

The present study aimed to investigate the influence of the mutation abundance of the epidermal growth factor receptor (EGFR) and its co-mutation with TP53 on the therapeutic efficacy of tyrosine kinase inhibitor (TKI) treatment in patients with metastatic lung adenocarcinoma (LUAD). In total, 130 patients (January 2018-September 2022) with metastatic LUAD from the Second Affiliated Hospital of Zhejiang University were included. Kaplan-Meier analysis was performed to measure the duration of drug application (DDA) and the log-rank test was used to compare differences. Univariate and multivariate analyses of Cox proportional hazard regression models were used to evaluate the association between the relevant clinicopathological factors and DDA. Hazard ratios with 95% confidence intervals were also calculated. Among the 130 patients who were treated with first-generation EGFR-TKIs, 86 showed high-EGFR mutation abundance (>22.0%) and 44 showed low-EGFR mutation abundance (≤22.0%). Patients in the high-EGFR group had a greater DDA than those in the low-EGFR group (p < 0.05). The results of the subgroup analysis were consistent with those of the total mutation population (exon19: >18.5% vs. ≤18.5%, 14 months vs. 10 months, p = 0.049; exon21: >22.0% vs. ≤22.0%, 15 months vs. 9 months, p = 0.005). In addition, the mutation abundance of TP53 was negatively correlated with the DDA (p < 0.05). Patients in the combination group had a better DDA than those in the monotherapy group (p < 0.05). Subgroup analysis showed that, among the low mutation abundance of the EGFR exon 21 or 19 cohort, the combination group had a better DDA than the monotherapy group (p < 0.05). An EGFR mutation abundance greater than 22.0% was a positive predictor of DDA in patients with metastatic LUAD. However, a TP53 mutation abundance higher than 32.5% could reverse this situation. Finally, first-line treatment with EGFR-TKIs plus chemotherapy is a potential treatment strategy for patients with low-abundance EGFR mutations.

Elevated NOX4 promotes tumorigenesis and acquired EGFR-TKIs resistance via enhancing IL-8/PD-L1 signaling in NSCLC.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been widely used for human non-small-cell lung cancer (NSCLC) treatment. However, acquired resistance to EGFR-TKIs is the major barrier of treatment success, and new resistance mechanism remains to be elucidated. In this study, we found that elevated NADPH oxidase 4 (NOX4) expression was associated with acquired EGFR-TKIs resistance. Gefitinib is the first-generation FDA-approved EGFR-TKI, and osimertinib is the third-generation FDA-approved EGFR-TKI. We demonstrated that NOX4 knockdown in the EGFR-TKI resistant cells enabled the cells to become sensitive to gefitinib and osimertinib treatment, while forced expression of NOX4 in the sensitive parental cells was sufficient to induce resistance to gefitinib and osimertinib in the cells. To elucidate the mechanism of NOX4 upregulation in increasing TKIs resistance, we found that knockdown of NOX4 significantly down-regulated the expression of transcription factor YY1. YY1 bound directly to the promoter region of IL-8 to transcriptionally activate IL-8 expression. Interestingly, knockdown of NOX4 and IL-8 decreased programmed death ligand 1 (PD-L1) expression, which provide new insight on TKIs resistance and immune escape. We found that patients with higher NOX4 and IL-8 expression levels showed a shorter survival time compared to those with lower NOX4 and IL-8 expression levels in response to the anti-PD-L1 therapy. Knockdown of NOX4, YY1 or IL-8 alone inhibited angiogenesis and tumor growth. Furthermore, the combination of NOX4 inhibitor GKT137831 and gefitinib had synergistic effect to inhibit cell proliferation and tumor growth and to increase cellular apoptosis. These findings demonstrated that NOX4 and YY1 were essential for mediating the acquired EGFR-TKIs resistance. IL-8 and PD-L1 are two downstream targets of NOX4 to regulate TKIs resistance and immunotherapy. These molecules may be used as potential new biomarkers and therapeutic targets for overcoming TKIs resistance in the future.

Comparison of clinical outcomes of osimertinib and first-generation EGFR-tyrosine kinase inhibitors (TKIs) in TKI-untreated EGFR-mutated non-small-cell lung cancer with leptomeningeal metastases

Leptomeningeal metastases (LM) are devastating complications of epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). Although osimertinib, a third-generation EGFR-tyrosine kinase inhibitor (TKI), has better penetration into the central nervous system than first-generation EGFR-TKIs, data on the distinct activity of EGFR-TKIs in untreated advanced EGFR-mutated NSCLC with LM are lacking. We retrospectively reviewed patients treated with EGFR-TKIs for TKI-untreated common EGFR-mutated NSCLC with LM between July 2002 and July 2021 at the National Cancer Center Hospital. The patients were divided into two groups: patients treated with osimertinib (Osi group) and those treated with gefitinib or erlotinib [first-generation (1G)-TKI group]. Of the 967 patients, 71 were eligible, including 29 in the Osi group and 42 in the 1G-TKI group. The median progression-free survival (PFS) and overall survival (OS) in the Osi group were better than those in the 1G-TKI group (PFS: 16.9 months versus 8.6 months, P= 0.007, and OS: 26.6 months versus 20.0 months, P= 0.158). The LM-overall response rate (ORR) and LM-PFS were significantly better in the Osi group than in the 1G-TKI group (LM-ORR: 62.5% versus 25.7%, P= 0.007; LM-PFS: 23.4 months versus 12.1 months, P= 0.021). In the subgroup analysis of EGFR mutation status, LM-PFS for patients with exon 19 deletion was significantly longer in the Osi group than in the 1G-TKI group (32.7 months versus 13.4 months, P= 0.013), whereas those with L858R mutation in exon 21 did not differ between the two groups. In the multivariate analysis, osimertinib and exon 19 deletion were significant factors for better LM-PFS and OS. Osimertinib can be more effective for untreated common EGFR-mutated NSCLC patients with LM, especially those with exon 19 deletion, compared to first-generation TKIs.

Aumolertinib with chemotherapy or alone compared with osimertinib in patients with EGFR-mutant non–small-cell lung cancer (TREBLE).

TPS9153 Background: Aumolertinib is a novel third-generation (3G) epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Safety and efficacy of aumolertinib have been demonstrated in patients with EGFR-mutated locally advanced or metastatic (LA/m) NSCLC. (Lu, 2021; Lu, 2022) A phase 3 study in these patients in the first-line setting showed a significant improvement in progression-free survival (PFS) for aumolertinib vs gefitinib (median 19.3 months versus 9.9 months; P &lt; 0.0001). Aumolertinib was generally well-tolerated. (Lu, 2022) Aumolertinib is approved in China for patients with LA/m NSCLC who have an EGFR T790M resistance mutation upon disease progression and for treatment naïve patients with EGFR-mutated NSCLC. Studies evaluating first-generation EGFR-TKI + chemotherapy (chemo) showed improved PFS in select patient populations. (Hosomi, 2019) It is unclear if the addition of chemo to a 3G EGFR-TKI will improve PFS in patients with EGFR-mutated LA/m NSCLC. As the addition of chemo to a 3G EGFR-TKI may prove warranted, there is a need to understand the relative efficacy and safety in the diversity of patients encountered in routine clinical practice. (Tanaka, 2021). Methods: This is a randomized, multi-regional, phase 3 clinical trial comparing aumolertinib + chemo or aumolertinib monotherapy with osimertinib monotherapy. Patients are eligible if they have stage IIIB, IVA, or IVB NSCLC; harbor ex19del or L858R EGFR mutations alone or with other EGFR mutations; and have an ECOG PS of ≤2. Patients are ineligible if they received prior systemic therapy for mNSCLC or are a candidate for curative intent therapy. Eligible patients will be randomized 2:2:1 and stratified by mutation status (ex19del or L858R), ECOG PS (0 vs 1/2), and race (White vs Asian vs other races combined). Anticipated enrollment is 500 patients; 200 to receive aumolertinib + chemo (110 mg PO QD aumolertinib + investigator's choice chemo), 200 to receive osimertinib (80 mg PO QD), and 100 to receive aumolertinib (110 mg PO QD). The primary endpoint is PFS, by blinded independent review committee (BICR) per RECIST 1.1, for aumolertinib + chemo vs osimertinib. Overall survival (OS) is a key secondary endpoint for aumolertinib + chemo vs osimertinib. Additional efficacy endpoints will be assessed for aumolertinib + chemo vs osimertinib and aumolertinib vs osimertinib, as well as safety and patient reported outcomes. Exploratory endpoints include characterizing mechanisms of acquired resistance across all arms, CNS efficacy, and exposure-response relationship. Enrollment began in July 2022. The study is currently recruiting and will include approximately 200 sites globally. The study design will provide a power of 80% at a 2-sided Type I error of 0.05 for the primary endpoint. If the primary endpoint is statistically significant, a sequential test method will be used to evaluate OS. Clinical trial information: NCT05493501 .

Targeting CD73 to Overcomes Resistance to First-Generation EGFR Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer.

In patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), EGFR tyrosine kinase inhibitors (TKIs) improve response rate and survival. However, most patients eventually develop resistance. This study aimed to identify the role of CD73 in EGFR-mutant NSCLC and explore whether CD73 inhibition may serve as a therapeutic strategy in NSCLC patients with acquired resistance to EGFR-TKIs. We evaluated the prognostic role of CD73 expression in EGFR-mutant NSCLC using tumor samples from a single institution. We silenced CD73 in EGFR-TKI-resistant cell lines using short hairpin RNA (shRNA) targeting CD73 and also transfected a vector alone as a negative control. Using these cell lines, cell proliferation and viability assays, immunoblot assays, cell cycle analysis, colony-forming assays, flow cytometry, and apoptosis analysis were performed. High expression of CD73 was associated with shorter survival in patients with metastatic EGFR-mutant NSCLC treated with first-generation EGFR-TKI. CD73 inhibition synergistically inhibited cell viability with first-generation EGFR-TKI treatment compared with the negative control. When CD73 inhibition and EGFR-TKI treatment were combined, G0/G1 cell cycle arrest was induced through the regulation of p21 and cyclin D1. In addition, the apoptosis rate was increased in CD73 shRNA-transfected cells treated with EGFR-TKI. High expression of CD73 adversely affects the survival of patients with EGFR-mutant NSCLC. The study demonstrated that inhibiting CD73 in EGFR-TKI-resistant cell lines resulted in increased apoptosis and cell cycle arrest, which overcame the acquired resistance to first-generation EGFR-TKIs. Further research is needed to determine whether blocking CD73 plays a therapeutic role in EGFR-TKI-resistant patients with EGFR-mutant NSCLC.