EGFR-mutant Non-small Cell Lung Cancer Research Articles

The Effectiveness of Afatinib as First-Line Treatment in Vietnamese Patients With EGFR-Mutant Non-Small Cell Lung Cancer and Brain Metastases.

The role of afatinib in the first-line treatment of EGFR-mutant advanced non-small cell lung cancer (NSCLC) patients has been proven through clinical trials and real-world studies. However, additional data on the effectiveness of afatinib in patients with brain metastases are lacking. EGFR-mutant NSCLC patients with brain metastases were retrospectively reviewed across nine cancer centers in Vietnam from April 1, 2018 to June 1, 2022. The primary endpoints included central nervous system progression-free survival (CNS-PFS) and overall survival (OS). The secondary endpoints were the objective response rate (ORR) and CNS-ORR. Among 87 enrolled patients, 21.8%, 17.2%, and 60.9% received whole-brain radiation, gamma knife, and no locoregional therapy, respectively. With a median follow-up of 32.2 months for CNS-PFS and 35.3 months for OS, the median CNS-PFS and OS were 17.9 and 29.9 months, respectively. In multivariate analysis, patients receiving whole-brain radiation had significantly shorter CNS-PFS than those untreated with local therapy (16.1 vs. 22.6 months, p = 0.019), but not translating to an inferior OS. Furthermore, both the CNS-PFS and OS of patients with uncommon mutations were significantly worse than those of patients with Del19 (11.3 vs. 24.2 months, p = 0.013 and 17.7 vs. 34.0 months, p = 0.003, respectively). Univariate and multivariate analyses showed that a lower afatinib starting dose did not significantly affect CNS-PFS or OS. The CNS-ORR and ORR were 77.4% and 71.3%, respectively. In our real-world study, afatinib showed encouraging effectiveness in Vietnamese patients with EGFR-mutant NSCLC and brain metastases at baseline.

A Podcast Discussion on the Intracranial Efficacy of Antibody-Drug Conjugates in Patients with EGFR-Mutated NSCLC with Brain Metastases.

The incidence of brain metastases is higher in patients with non-small cell lung cancer (NSCLC) than in patients with most other cancers, and the development of brain metastases is associated with poor prognosis. The objective of the podcast is to provide information about current and future treatments for brain metastases that develop in patients with EGFR-mutated NSCLC. The panel discusses surveillance and management of patients with brain metastases, different types of currently used treatments, and recent data on the intracranial efficacy of antibody-drug conjugates (ADCs). The panel also discusses current and future studies of ADCs in patients with EGFR-mutated NSCLC with brain metastases. This podcast discussion, among four oncologists (two thoracic oncologists, one radiation oncologist, and one neurologist/neuro-oncologist), is for healthcare professionals (HCPs) at community practices and research institutions.

Plasma metabolomics profiling of EGFR-mutant NSCLC patients treated with third-generation EGFR-TKI

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the latest and a vital treatment option for non-small cell lung cancer (NSCLC) patients. Although EGFR-sensitive mutations are an indication for third-generation EGFR-TKI therapy, 30% of NSCLC patients lack response and all patients inevitably progress. There is a lack of biomarkers to predict the efficacy of EGFR-TKI therapy. In this report, we performed comprehensive plasma metabolomic profiling on 186 baseline and 20 post-treatment samples, analyzing 1,019 metabolites using four ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) methods. The dataset contains detailed clinical and metabolic information for 186 patients. Rigorous quality control measures were implemented. No significant differences in body mass index and biochemical metabolic parameters were observed between responders and non-responders. The datasets were utilized to characterize the responsive metabolic traits of third-generation EGFR-TKI therapy. All datasets are available for download on the OMIX website. We anticipate that these datasets will serve as valuable resources for future studies investigating NSCLC metabolism and for the development of personalized therapeutic strategies.

Evaluation of Anti-Angiogenic Therapy Combined with Immunotherapy and Chemotherapy as a Strategy to Treat Locally Advanced and Metastatic Non-Small-Cell Lung Cancer

Immunotherapy has made recent improvements in disease-free survival (DFS) and/or overall survival (OS) in all stages of non-small-cell lung cancer (NSCLC). Here, we review the tumor microenvironment and its immunosuppressive effects and discuss how anti-angiogenic therapies may potentiate the anti-carcinogenic effects of immunotherapy. We also review all the past literature and discuss strategies of combining anti-angiogenic therapy and immunotherapy +/− chemotherapy and hypothesize how we can use this strategy for non-small-cell lung cancer in metastatic previously untreated/previously treated settings in previously treated EGFR-mutated NSCLC for the upfront treatment of brain metastases prior to radiation therapy and for the incorporation of this strategy into stage III unresectable disease. We assert the use of anti-angiogenic therapy and immunotherapy when combined appropriately with chemotherapy and radiotherapy has the potential to increase the long-term survivals in both the stage III and metastatic setting so that we can now consider more patients to experience curative treatment.

Persist or resist: Immune checkpoint inhibitors in EGFR-mutated NSCLC.

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), especially third-generation TKIs, have significantly improved the progression-free survival and overall survival of non-small cell lung cancer (NSCLC) patients with EGFR mutation, TKI resistance is inevitable for most patients. Over the past few years, immune checkpoint inhibitors (ICIs) have significantly improved the survival for EGFR-wild type NSCLC patients. However, no significantly improved benefits were observed with ICI monotherapy in EGFR-mutated patients. EGFR-mutated NSCLC shows more heterogeneity in tumor mutational burden (TMB), programmed cell death-ligand 1 (PD-L1), and immune microenvironment characteristics. Whether ICIs are suitable for EGFR-mutated NSCLC patients remains to be elucidated. In this review, we summarized clinical trials of ICIs or combined therapy in EGFR-mutated NSCLC patients. We further discussed the factors determining the efficacy of ICIs in EGFR-mutated NSCLC patients, the mutation subtypes and microenvironment characteristics of potential responders. More importantly, we provided insights into areas worth further investigation in the future.

Real-World Study of EGFR-TKI Rechallenge With Another TKI After First-Line Osimertinib Discontinuation in Patients With EGFR-Mutated Non-Small Cell Lung Cancer: A Subset Analysis of the Reiwa Study.

First-line osimertinib is widely used to treat patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancers (NSCLC). In clinical practice, rechallenge therapy with another EGFR-tyrosine kinase inhibitor (TKI) is often performed after first-line TKI discontinuation owing to resistance or toxicity; however, the efficacy and toxicity of EGFR-TKI rechallenge after first-line osimertinib have not been adequately investigated. This study aimed to examine the efficacy and safety of EGFR-TKI rechallenge with another TKI. This multicenter prospective observational study enrolled patients with EGFR-mutated NSCLC who received first-line osimertinib and another EGFR-TKI as second- or third-line treatment between September 2018 and August 2020. Fifty-three patients received rechallenge with another EGFR-TKI in the second-line (n = 38, 71.7%) or third-line (n = 15, 28.3%) setting. The primary reason for first-line osimertinib discontinuation was toxicity in 32 (60.4%, 17 patients with pneumonitis) and disease progression in 20 (37.7%) patients. The most common rechallenge EGFR-TKI was afatinib (n = 24, 45.3%), followed by gefitinib (n = 16, 30.2%) and erlotinib (n = 8, 15.1%). The real-world time to treatment failure (rwTTF) was 7.3 months. The rwTTF for the toxicity discontinuation and progressive disease discontinuation groups was 9.3 months and 5.1 months, respectively, (HR 1.61, p = 0.119). EGFR-TKI rechallenge was discontinued due to toxicity in nine patients (17.0%), but no patient developed pneumonitis. EGFR-TKI rechallenge with another TKI is well tolerated in patients with EGFR-mutated NSCLC. Thus, it may be a useful treatment option after first-line osimertinib failure, especially after osimertinib discontinuation due to toxicity.

CXCR1+ neutrophil infiltration orchestrates response to third-generation EGFR-TKI in EGFR mutant non-small-cell lung cancer

Although third-generation Epidermal growth factor receptor—tyrosine kinase inhibitors (EGFR-TKI) is standard of care for patients with EGFR-mutant Non-small cell lung cancer (NSCLC), little is known about the predictors of response or resistance. Here, we integrated single-cell RNA (scRNA) sequencing, bulk RNA sequencing, multiplexed immunofluorescence and flow cytometry data from pretreatment and post-resistant tumor samples of EGFR-mutant NSCLC patients received third-generation EGFR-TKIs. We show that resistant samples had a markedly enriched CXCR1+ neutrophils infiltration (P < 0.01) than pretreatment samples, which were distinguished from other subtypes of neutrophils and displayed immunosupressive characteristics. Spatial analysis showed that increased CXCR1+ neutrophils predominantly infiltrated into the tumor core in resistant samples and the average distance of neutrophils to tumor cells markedly reduced from 33 to 19 μm. Deep analysis of scRNA and bulk RNA sequencing data revealed the increased interactions between CXCR1+ neutrophils and tumor cells and activated TNF-α/NF-κB signaling pathway in tumor cells of resistant samples. In vitro and in vivo experiments validated that CXCR1+ neutrophils resulted in resistance to third-generation EGFR-TKI via activating TNF-α/NF-κB signaling pathway in tumor cells. Importantly, patients with low pretreatment CXCR1+ neutrophil infiltration abundance had a dramatically longer progression-free survival (11.8 vs. 7.5 months; P = 0.019) and overall survival (33.0 vs. 23.5 months; P = 0.029) than those with high infiltration abundance. Collectively, these findings suggest that CXCR1+ neutrophils infiltration was associated with the efficacy of third-generation EGFR-TKI in patients with EGFR-mutant NSCLC.

Cardiac Events and Survival in Patients With EGFR-Mutant Non–Small Cell Lung Cancer Treated With Osimertinib

Although it has been reported that osimertinib mesylate provides better survival benefits compared with first- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), it remains unclear whether osimertinib is associated with more cancer therapy-related cardiac events (CTRCEs) compared with other EGFR TKIs, as does the extent of the association these adverse effects may have with overall survival. This issue is particularly critical due to the high prevalence of EGFR variants within Asian populations, including that of Taiwan. To compare CTRCEs and their association with survival in patients treated with osimertinib vs other EGFR TKIs. This cohort study was conducted at the National Cheng Kung University Hospital, a college hospital and tertiary academic referral center in Taiwan. The median follow-up duration was 23.2 (IQR, 15.2-31.5) months. A total of 401 patients with EGFR-mutant non-small cell lung cancer (NSCLC) beginning treatment with EGFR TKIs from September 1, 2019, to July 31, 2022, were retrospectively analyzed. CTRCEs included newly emerging arrhythmias, valvular heart diseases (moderate and more), myocardial infarction, and heart failure and were analyzed after adjusting for age, sex, smoking, alcohol consumption, body mass index, cardiovascular comorbidities, thoracic radiotherapy, and cardiovascular medications. Follow-up was completed January 31, 2024. Osimertinib. The Cox proportional hazards model was used to estimate CTRCEs in patients treated with osimertinib or other EGFR TKIs. Considering that death can lower the incidence of CTRCEs, the competing risk method was used to calculate CTRCEs after adjusting for potential confounders. Multivariable Cox proportional hazard regression analysis for overall survival was used to explore whether CTRCEs were independently associated with overall survival. Among the 401 patients (253 [63.1%] female; mean [SD] age, 69.2 [11.3] years), 195 (48.6%) treated with osimertinib were matched with 206 (51.4%) treated with other EGFR TKIs. Occurrence of CTRCEs in patients receiving osimertinib was significantly higher compared with patients treated with other EGFR TKIs (29 [14.9%] vs 9 [4.4%]; hazard ratio [HR], 3.37; 95% CI, 1.56-7.26; P = .002). After adjustment for relevant cardiovascular risk factors, the HR of CTRCEs was significantly higher in the group treated with osimertinib (adjusted subdistribution HR, 4.00; 95% CI, 1.81-8.85; P < .001). In addition, CTRCEs were independently associated with overall survival (HR, 4.02; 95% CI, 2.44-6.63; P < .001). In this cohort study of patients with EGFR-mutant NSCLC, osimertinib was associated with a higher incidence of CTRCEs compared with other EGFR TKIs; CTRCEs were independently associated with overall survival. These findings highlight the need for ongoing cardiac monitoring in these patients, regardless of preexisting cardiac risk factors.

Capabilities of positron emission tomography/computed tomography in a comparative assessment of the effect of various targeted therapy options in patients with &lt;i&gt;EGFR&lt;/i&gt;-mutated non-small-cell lung cancer

BACKGROUND: No publications in the Russian medical literature have examined the potential of positron emission tomography combined with computed tomography through a comparative evaluation of the effect of various targeted therapies involving tyrosine kinase inhibitors in patients with non-small cell lung cancer and mutations in the EGFR gene. AIM: To explore the capabilities of positron emission tomography combined with computed tomography based on the RECIST 1.1 criteria and changes in SUVmax and SUVmean metabolic parameters for the comparative assessment of the tumor response to targeted monotherapy and combination therapy with tyrosine kinase inhibitors in patients with EGFR-mutant non-small cell lung cancer. MATERIALS AND METHODS: The 2019–2022 examination records of positron emission tomography combined with computed tomography with 18F-fluorodeoxyglucose (18F-FDG) in 105 patients with non-small cell lung cancer were analyzed, including 75 patients with EGFR-activating mutation. The radiation exposure was adjusted individually and ranged from 45 to 90 mSv. The volume activity of the 18F-FDG radiopharmaceutical was 260–500 MBq. The change in the total largest diameters of the target lesions and SUVmax and SUVmean metabolic parameters were assessed before treatment initiation and 1.5–2.0 months after it. The follow-up duration for the changes in positron emission tomography combined with computed tomography findings in 17 patients with non-small cell lung cancer was at least 12 months. RESULTS: According to positron emission tomography combined with computed tomography images and SUVmax and SUVmean changes, disease progression was significantly less common (p = 0.043 and p =0.029) in patients with EGFR-mutant non-small cell lung cancer from Groups 2 and 3 who received combination therapy with tyrosine kinase inhibitors and bevacizumab or chemotherapy than in Group 1 and control group (4.2% vs. 20.0%–21.8%). An insignificant trend (p =0.092) to a higher partial response to therapy (58.3% vs. 40.0%) was noted. Similar changes in the total largest diameters of the target lesions at the early stage of therapy appeared to be not significant (p =0.187). Within the long-term follow-up of some patients with non-small cell lung cancer, in at least 50% of cases, changes in the total largest lesion diameters are consistent with the relevant SUVmax and SUVmean alterations found in the first control study. CONCLUSIONS: Based on the positron emission tomography combined with computed tomography data and alterations in SUVmax and SUVmean metabolic parameters, the early tumor response to combined therapy with tyrosine kinase inhibitors and bevacizumab or chemotherapy compared with targeted monotherapy with tyrosine kinase inhibitors or chemotherapy of the control group was characterized by a significantly lower rate of metabolic disease progression, although a similar tendency of the change in the total largest diameters of target lesions according to RECIST 1.1. was not significant. Changes in SUVmax and SUVmean metabolic parameters at the early stage of therapy are at least 50% faster than similar changes in the total largest diameters of the target lesions, which can be used for the timely identification of patients with a high risk of further progression as determined by RECIST 1.1.

Ivacaftor, a CFTR potentiator, synergizes with osimertinib against acquired resistance to osimertinib in NSCLC by regulating CFTR-PTEN-AKT axis.

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has demonstrated significant clinical benefits in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). However, inevitable acquired resistance to osimertinib limits its clinical utility, and there is a lack of effective countermeasures. Here, we established osimertinib-resistant cell lines and performed drug library screening. This screening identified ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, as a synergistic enhancer of osimertinib-induced anti-tumor activity both in vitro and in vivo. Mechanistically, ivacaftor facilitated the colocalization of CFTR and PTEN on the plasma membrane to promote the function of PTEN, subsequently inhibiting the PI3K/AKT signaling pathway and suppressing tumor growth. In summary, our study suggests that activating CFTR enhances osimertinib-induced anti-tumor activity by regulating the PTEN-AKT axis. Furthermore, ivacaftor and osimertinib constitute a potential combination strategy for treating osimertinib-resistant EGFR-mutated NSCLC patients.

The changing treatment landscape of EGFR-mutant non-small-cell lung cancer.

The discovery of the association between EGFR mutations and the efficacy of EGFR tyrosine-kinase inhibitors (TKIs) has revolutionized the treatment paradigm for patients with non-small-cell lung cancer (NSCLC). Currently, third-generation EGFR TKIs, which are often characterized by potent central nervous system penetrance, are the standard-of-care first-line treatment for advanced-stage EGFR-mutant NSCLC. Rational combinations of third-generation EGFR TKIs with anti-angiogenic drugs, chemotherapy, the EGFR-MET bispecific antibody amivantamab or local tumour ablation are being investigated as strategies to delay drug resistance and increase clinical benefit. Furthermore, EGFR TKIs are being evaluated in patients with early stage or locally advanced EGFR-mutant NSCLC, with the ambitious aim of achieving cancer cure. Despite the inevitable challenge of acquired resistance, emerging treatments such as new TKIs, antibody-drug conjugates, new immunotherapeutic approaches and targeted protein degraders have shown considerable promise in patients with progression of EGFR-mutant NSCLC on or after treatment with EGFR TKIs. In this Review, we describe the current first-line treatment options for EGFR-mutant NSCLC, provide an overview of the mechanisms of acquired resistance to third-generation EGFR TKIs and explore novel promising treatment strategies. We also highlight potential avenues for future research that are aimed at improving the survival outcomes of patients with this disease.

Long-Term Outcomes in Patients with EGFR Positive Lung Adenocarcinoma and Subgroup Analysis Based on Presence of Liver Metastases

Lung cancer represents the most common cause of cancer related death. Patients with non-small cell lung cancer (NSCLC) and liver metastases (LM) have worse prognosis with an overall survival (OS) of three to six months. The aim of this study was to investigate long-term outcomes in patients with EGFR mutated (EGFRmut) lung adenocarcinoma as well as the presence of LM. (A total of 105 patients were included in the analysis). They were divided into two groups based on the presence of LM. OS was 13 months for the whole group and also 13 months for patients with and without LM. The 9-year survival rate for patients with and without LM was 12.5% and 3.4%, respectively. Further, the 9-year survival rate for the whole group of patients was 4.8%. There are few data about survival rates beyond 5 years for patients with locally advanced and metastatic EGFRmut NSCLC, mainly because patients with lung cancer rarely live for such a long time. Regarding patients with liver metastases, the results of our study showed similar outcomes compared to patients without LM. As these patients represent a significant number of patients, we need a wider range of therapeutic options. It might be that combination therapies represent a better therapeutic option.

Abstract C025: Identification of cell-cell signaling programs across the tumor-tumor microenvironment ecosystem and associated with clinical status in neoadjuvant osimertinib treated patient samples revealed by spatial profiling

Abstract Lung cancer is the leading cause of cancer mortality, and despite improvements in treatment, tumors typically respond incompletely and resume growth after acquisition of drug resistance. Recent completion of a neoadjuvant osimertinib Phase II trial treating patients with surgically resectable stage I-IIIA EGFR-mutated non-small cell lung cancer (EGFRm NSCLC) (NCT03433469) (Blakely et. Al, JCO 2024) has highlighted the importance of further identifying non-genomic mechanisms of persistence and resistance to targeted therapy. Here we analyzed these patient samples to identify transcriptionally regulated signaling patterns enriched at Residual Disease (RD) after neoadjuvant osimertinib treatment compared to treatment naïve samples (TN), as well as signaling patterns enriched at RD in patients who ultimately develop disease recurrence after surgical resection compared to those who remain disease-free. Spatially resolved transcriptomic sequencing was performed, using the 10X Genomics Visium platform, on 36 tissue sections (n=9 TN, n=19 RD, n=4 Progressive Disease (PD), n=4 Tumor Adjacent Normal), from 25 patients. TN and PD samples were from standard-of-care surgical resections. 18 of 19 RD samples were from NCT03433469. The Visium array spots that tile the sequencing capture area are 55 µm in diameter, and thus can contain an estimated 1-10 cells within each array spot. After quality control, 91,582 array spots remained for downstream analysis. We identified high confidence tumor array spots annotated both as “Cancer” by a board-certified pathologist and with tumor characteristic copy number variations. Through dimensionality reduction clustering, we identified 10 major array spot clusters, including the high confidence tumor array spot cluster. These clusters were further subset into 44 high resolution clusters of array spot niches, 32 of which were shared across at least nine patients. Because array spots are not single-cell resolution, these niches represent spots with similar mixed cell type composition and transcriptional signatures. We identified significant increases in the CCL14+ Endothelial Cell Niche, CXCL2+ Endothelial Cell Niche, Lymphocytes + Endothelial Niche, and CXCL12+ Fibroblast Niche in RD samples compared to TN. We identified a cell signaling program defined by spatially co-expressed ligand-receptor pairs associated with focal adhesion, enriched in PD samples. This same pattern was enriched in RD samples from patients who had recurrent disease after surgical resection compared to RD samples from patients who remained disease free. These data describe an increase in immune trafficking in RD samples, as well as identify an EGFR- alternative signaling pathway correlating with osimertinib resistance. Identification of spatially resolved, differential architectural organization and signaling patterns in RD and PD states will expand our understanding of targeted therapy resistance in EGFRm NSCLC, with the potential to identify additional clinically actionable targets. Citation Format: Whitney Tamaki, Daniel L. Kerr, Wei Wu, Grant Eilers, Anatoly Urisman, Yu-Ting Chou, Philippe Gui, Shigeki Nanjo, Johannes R. Kratz, David M. Jablons, Trever G. Bivona, Collin M. Blakely. Identification of cell-cell signaling programs across the tumor-tumor microenvironment ecosystem and associated with clinical status in neoadjuvant osimertinib treated patient samples revealed by spatial profiling [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C025.

MDM2 drives resistance to Osimertinib by contextually disrupting FBW7-mediated destruction of MCL-1 protein in EGFR mutant NSCLC

BackgroundOvercoming resistance to Osimertinib in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) is clinically challenging because the underlying mechanisms are not fully understood. The murine double minute 2 (MDM2) has been extensively described as a tumor promotor in various malignancies, mainly through a negative regulatory machinery on the p53 tumor suppressor. However, the significance of MDM2 on the sensitivity to Osimertinib has not been described.MethodsOsimertinib resistant cells were generated by standard dose escalation strategy and individual resistant clones were isolated for MDM2 testing. The MDM2 and its mutant constructs (ΔPBD, ΔRING, C464A) were introduced into PC-9, HCC827 and H1975 cells and evaluated for the sensitivity to Osimertinib by MTT assay, colony formation, EdU assay and TUNEL assay. MDM2 expression in resistant cells was manipulated by pharmacological and molecular approaches, respectively. Proteins that were implicated in PI3K/Akt, MAPK/Erk and apoptosis signaling were measured by Western blot analysis. Candidate proteins that interacted with MDM2 were captured by immunoprecipitation and probed with indicated antibodies.ResultsIn comparison with parental PC-9 cells, the PC-9 OR resistant cells expressed high level of MDM2. Ectopic expression of MDM2 in PC-9, HCC827 and H1975 sensitive cells generated an Osimertinib resistant phenotype, regardless of p53 status. MDM2 promoted resistance to Osimertinib through a PI3K/Akt and MAPK/Erk-independent machinery, in contrast, MDM2 selectively stabilized MCL-1 protein to arrest Osimertinib-induced cancer cell apoptosis. Mechanistically, MDM2 acted as a E3 ligase to ubiquitinate FBW7, a well-established E3 ligase for MCL-1, at Lys412 residue, which resulted in FBW7 destruction and MCL-1 stabilization. Targeting MDM2 to augment MCL-1 protein breakdown overcame resistance to Osimertinib in vitro and in vivo. Finally, the clinical relevance of MDM2-FBW7-MCL-1 regulatory axis was validated in mouse xenograft tumor model and in NSCLC specimen.ConclusionOverexpression of MDM2 is a novel resistant mechanism to Osimertinib in EGFR mutant NSCLC. MDM2 utilizes its E3 ligase activity to provoke FBW7 destruction and sequentially leads to MCL-1 stabilization. Cancer cells with aberrant MDM2 state are refractory to apoptosis induction and elicit a resistant phenotype to Osimertinib. Therefore, targeting MDM2 would be a feasible approach to overcome resistance to Osimertinib in EGFR mutant NSCLC.

Cutaneous Adverse Events of Osimertinib in Diverse Patient Populations with EGFR-mutated Non-Small Cell Lung Cancer: A Retrospective Cohort Analysis

Cutaneous Adverse Events of Osimertinib in Diverse Patient Populations with EGFR-mutated Non-Small Cell Lung Cancer: A Retrospective Cohort Analysis

EGFR-TKIs or EGFR-TKIs combination treatments for untreated advanced EGFR-mutated NSCLC: a network meta-analysis

BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and EGFR-TKI combination treatments have become the standard first-line treatments for EGFR-mutated non-small cell lung cancer (NSCLC) patients. However, the best option has yet to be determined. This study compares the efficacy and safety of various first-line EGFR-TKI monotherapies and combination treatments for advanced EGFR-mutated NSCLC.MethodsWe searched PubMed, Embase, the Cochrane Central Register of Controlled Clinical Trials databases, and several international conferences to identify randomized controlled trials reporting on first-line EGFR-TKI treatments for patients with advanced EGFR-mutated NSCLC. The study quality was assessed using the revised tool for risk of bias in randomized trials. The efficacy and safety outcomes of the included treatments were compared by network meta-analysis based on a frequentist approach.ResultsWe identified 26 trials (8,359 patients) investigating 14 treatment groups, including first, second, and third-generation EGFR-TKIs and their combination treatments. Osimertinib plus chemotherapy and lazertinib plus amivantamab showed the highest efficacy in improving progression-free survival. New third-generation EGFR-TKIs demonstrated comparable efficacy to osimertinib alone but did not surpass it. Subgroup analyses revealed slight variation in treatment efficacy based on mutation types and patient demographics. Combination treatments were associated with a higher incidence of adverse events.ConclusionThese results reveal that osimertinib plus chemotherapy and lazertinib plus amivantamab are superior first-line options for patients with advanced EGFR-mutated NSCLC. However, these combinations are associated with higher adverse event rates.

In brief: A new non-small cell lung cancer indication for osimertinib (Tagrisso).

The oral kinase inhibitor osimertinib (Tagrisso – AstraZeneca), which has been available for years for treatment of non-small cell lung cancer (NSCLC) in adults with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, has now been approved for treatment of unresectable stage III EGFR-mutated NSCLC.1 About 20-30% of patients with NSCLC have locally advanced stage III NSCLC, and 60-90% of these patients have unresectable disease. Osimertinib is the first targeted therapy to be approved for the new indication.

Loss of CDKN2A Enhances the Efficacy of Immunotherapy in EGFR Mutant Non-Small Cell Lung Cancer.

Mutant epidermal growth factor receptor (EGFR) is a common driver of non-small cell lung cancer (NSCLC). While mutant EGFR has been reported to limit the efficacy of immunotherapy, a subset of EGFR mutant NSCLC patients benefit from treatment with immune checkpoint inhibitors. A better understanding of how co-occurring genomic alterations in oncogenic driver genes impact immunotherapy efficacy may provide a more complete understanding of cancer heterogeneity and identify biomarkers of response. Here, we investigated the effects of frequent EGFR co-mutations in EGFR mutant lung cancer models and identified loss-of-function mutation of CDKN2A as a potential sensitizer to anti-PD-1 treatment in vitro and in vivo. Mechanistically, CDKN2A loss impacted the composition of the tumor immune microenvironment (TIME) by promoting the expression of PD-L2 through reduced ubiquitination of c-Myc, and mutant EGFR cooperated to upregulate c-Myc and PD-L2 by activating the MAPK pathway. Blocking PD-L2 induced anti-tumor immune responses mediated by CD8+ T cells in EGFR/CDKN2A co-mutated lung cancer. Importantly, a small-molecule PD-L2 inhibitor, zinc undecylenate, remodeled the TIME of EGFR/CDKN2A co-mutant tumors and enhanced the anti-tumor efficacy of EGFR-tyrosine kinase inhibitors. Collectively, these results identify EGFR/CDKN2A co-mutation as a distinct subtype of NSCLC that shows superior sensitivity to immune checkpoint blockade and reveals a potential combined therapeutic strategy for treating this NSCLC subtype.

Efficacy and safety of osimertinib plus bevacizumab versus osimertinib alone for advanced non-small-cell lung cancer with EGFR mutations: A meta-analysis of randomized controlled trials.

To systematically evaluate the efficacy and safety of osimertinib plus bevacizumab in treating advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Up to May 26, 2024, the databases of PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, Chinese Biomedical Literature, China Science and Technology Journal, and Wanfang were searched, and the randomized controlled clinical trials (RCTs) of osimertinib plus bevacizumab in the treatment of advanced EGFR-mutant NSCLC were included. Two researchers independently screened the literature, assessed the quality of the included literature, and extracted the literature data. Revman5.4 software was used for meta-analysis. A total of 824 patients were included in 10 RCTs. The results of meta-analysis showed that compared with the control group (osimertinib alone), the experimental group (osimertinib plus bevacizumab) had a higher objective response rate (ORR) (relative risk [RR] = 1.23, 95% confidence interval [CI] = 1.03-1.47, P = .02), and the experimental group could significantly reduce the expression levels of carcinoembryonic antigen (mean difference [SMD] = 0.82, 95% CI = 0.30-1.35, P = .002), vascular endothelial growth factor (SMD = 0.43, 95% CI = 0.13-0.73, P = .005), neuron-specific enolase (SMD = 0.88, 95% CI = 0.60-1.17, P < .00001), cytokeratin 19 fragments (SMD = 1.33, 95% CI = 0.34-2.33, P = .009), and carbohydrate antigen 125 (SMD = 0.46, 95% CI = 0.15-0.77, P = .004) in serum. However, the experimental group did not significantly improve the disease control rate (DCR) (RR = 1.17, 95% CI = 1.00-1.36, P = .05), 1- and 2-year progression-free survival (PFS) rates (RR = 1.15, 95% CI = 1.00-1.33, P = .05; RR = 1.02, 95% CI = 0.74-1.40, P = .92), 1- and 2-year overall survival (OS) rates (RR = 1.11, 95% CI = 0.92-1.36, P = .28; RR = 0.99, 95% CI = 0.84-1.18, P = .95). Interestingly, the results of subgroup analysis showed that the experimental group significantly improved ORR, DCR, 1-year PFS, and OS rates in the Chinese population and patients under 65 years old (P < .05). In addition, when the dose of bevacizumab was 7.5 mg/kg q3w in the experimental group, ORR, DCR, 1-year PFS, and OS rates were significantly better than those in the control group (P < .05). In terms of adverse events of drugs, the incidence of proteinuria, hypertension, oral mucositis, bleeding, nausea, and vomiting in the experimental group was higher than that in the control group (P < .05). For patients with advanced EGFR-mutant NSCLC, osimertinib plus bevacizumab has some clinical benefit compared with osimertinib alone. Still, it does not provide additional long-term survival benefits and has higher toxicity. More well-designed, multicenter RCTs are needed to identify the subgroups of patients most likely to benefit from this combination regimen and to validate the optimal dose of this combination regimen.

Osimertinib in Early-Stage EGFR-Mutated Non-small Cell Lung Cancer: A Narrative Review of Its Impact on Survival, Safety, and Clinical Outcomes

Osimertinib in Early-Stage EGFR-Mutated Non-small Cell Lung Cancer: A Narrative Review of Its Impact on Survival, Safety, and Clinical Outcomes