Clinical outcomes associated with neoadjuvant therapy for the treatment of resectable non-small cell lung cancer in real-world practice.

BACKGROUND: In order to improve survival outcomes in resectable non-small cell lung cancer (NSCLC), strategies for neoadjuvant therapy need to be revisited. We evaluated and compared the efficacy of different neoadjuvant therapeutic modalities in a real-world setting. METHODS: A total of 258 patients with clinical stage IIA to IIIB NSCLC was included. All the patients underwent surgical resection after one to four cycles of neoadjuvant treatment consisting of chemotherapy (83), immunotherapy (23), and immunotherapy plus chemotherapy (152). RESULTS: The radiologic response rate in the combined immunochemotherapy group was 67.8%, higher than that of 48.2% in the chemotherapy group and 4.3% in the immunotherapy group (p < 0.001). An improved major pathological response (MPR) was also achieved in the combined therapy group compared with the chemotherapy group and the immunotherapy group (53.9% vs. 10.8% vs. 8.7%, p < 0.001). Patients in the combined therapy group had a significant trend toward longer disease-free survival than those in the chemotherapy alone group (3-year disease-free survival [DFS] of 68.79% vs. 50.81%; hazard ratio [HR] for progression or death, 0.477; p = 0.003). Multivariate Cox analysis identified radical surgery (HR, 0.328; p = 0.033), ypN0-1 stage (HR, 0.591; p = 0.038) and MPR result (HR, 0.362; p = 0.007) to be independent prognostic factors for DFS. CONCLUSIONS: Neoadjuvant treatment with a combination of immunotherapy plus chemotherapy appears to achieve higher radiological and pathological responses than monotherapy for IIA-IIIB NSCLC. Log-rank analysis showed that a better outcome could be expected in patients with the addition of immunotherapy to neoadjuvant chemotherapy if compared with patients with chemotherapy alone in terms of DFS.

Multimodal image fusion-assisted endoscopic evacuation of spontaneous intracerebral hemorrhage.

PURPOSE: Although traditional craniotomy (TC) surgery has failed to show benefits for the functional outcome of intracerebral hemorrhage (ICH). However, a minimally invasive hematoma removal plan to avoid white matter fiber damage may be a safer and more feasible surgical approach, which may improve the prognosis of ICH. We conducted a historical cohort study on the use of multimodal image fusion-assisted neuroendoscopic surgery (MINS) for the treatment of ICH, and compared its safety and effectiveness with traditional methods. METHODS: This is a historical cohort study involving 241 patients with cerebral hemorrhage. Divided into MINS group and TC group based on surgical methods. Multimodal images (CT skull, CT angiography, and white matter fiber of MRI diffusion-tensor imaging) were fused into 3 dimensional images for preoperative planning and intraoperative guidance of endoscopic hematoma removal in the MINS group. Clinical features, operative efficiency, perioperative complications, and prognoses between 2 groups were compared. Normally distributed data were analyzed using t-test of 2 independent samples, Non-normally distributed data were compared using the Kruskal-Wallis test. Meanwhile categorical data were analyzed via the Chi-square test or Fisher's exact test. All statistical tests were two-sided, and p < 0.05 was considered statistically significant. RESULTS: A total of 42 patients with ICH were enrolled, who underwent TC surgery or MINS. Patients who underwent MINS had shorter operative time (p < 0.001), less blood loss (p < 0.001), better hematoma evacuation (p = 0.003), and a shorter stay in the intensive care unit (p = 0.002) than patients who underwent TC. Based on clinical characteristics and analysis of perioperative complications, there is no significant difference between the 2 surgical methods. Modified Rankin scale scores at 180 days were better in the MINS than in the TC group (p = 0.014). CONCLUSIONS: Compared with TC for the treatment of ICH, MINS is safer and more efficient in cleaning ICH, which improved the prognosis of the patients. In the future, a larger sample size clinical trial will be needed to evaluate its efficacy.

Blockade of CD93 in pleural mesothelial cells fuels anti-lung tumor immune responses.

Background: CD93 reportedly facilitates tumor angiogenesis. However, whether CD93 regulates antitumor immunity remains undeciphered. Methods: Lung tumor tissues, malignant pleural effusions (MPEs) were obtained from lung cancer patients. Blood was obtained from healthy volunteers and lung cancer patients with anti-PD-1 therapy. Furthermore, p53fl/flLSL-KrasG12D, Ccr7-/-, Cd93-/- mice and CD11c-DTR mice were generated. Specifically, EM, NTA and western blotting were utilized to identify Tumor extracellular vesicles (TEVs). EV labeling, detection of EV uptake in vitro and in vivo, degradation of EV proteins and RNAs were performed to detect the role of TEVs in tumor progression. Pleural mesothelial cells (pMCs) were isolated to investigate related signaling pathways. Recombinant proteins and antibodies were generated to test which antibody was the most effective one to increase CCL21a in p-pMCs. RNA-Seq, MiRNA array, luciferase reporter assay, endothelial tube formation assay, protein labeling and detection, transfection of siRNAs and the miRNA mimic and inhibitor, chemotaxis assay, immunohistochemical staining, flow cytometry, Real-time PCR, and ELISA experiments were performed. Results: We show that CD93 of pMCs reduced lung tumor migration of dendritic cells by preventing pMCs from secreting CCL21, thereby suppressing systemic anti-lung tumor T-cell responses. TEV-derived miR-5110 promotes CCL21 secretion by downregulating pMC CD93, whereas C1q, increasing in tumor individuals, suppresses CD93-mediated CCL21 secretion. CD93-blocking antibodies (anti-CD93) inhibit lung tumor growth better than VEGF receptor-blocking antibodies because anti-CD93 inhibit tumor angiogenesis and promote CCL21 secretion from pMCs. Anti-CD93 also overcome lung tumor resistance to anti-PD-1 therapy. Furthermore, lung cancer patients with higher serum EV-derived miR-5193 (human miR-5110 homolog) are more sensitive to anti-PD-1 therapy, while patients with higher serum C1q are less sensitive, consistent with their regulatory functions on CD93. Conclusions: Our study identifies a crucial role of CD93 in controlling anti-lung tumor immunity and suggests a promising approach for lung tumor therapy.

Ficonalkib (SY-3505) in Advanced ALK-Positive NSCLC: A Multicenter, Open-Label, Single-Arm, Phase 1/2 Study.

INTRODUCTION: Treatment options for second-generation (2nd-gen) ALK tyrosine kinase inhibitor (TKI)-resistant patients are limited. We evaluated the safety, pharmacokinetics, and efficacy of ficonalkib (SY-3505), a third-generation (3rd-gen) ALK TKI, in patients with advanced ALK-positive non-small cell lung cancer. METHODS: This first-in-human, phase 1/2 study (Chinese Clinical Trial Registry identifier: ChiCTR1900025619; ClinicalTrials.gov identifier: NCT05257512) had two parts. Phase 1 included a dose-escalation phase (25-800 mg quaque die [QD]) and a dose-expansion phase (500 mg QD or 600 mg QD). Phase 2 enrolled patients treated at recommended phase 2 dose. Primary end points were safety in phase 1 and objective response rate (ORR) in phase 2. RESULTS: Between April 21, 2020, and August 31, 2023, a total of 127 patients with advanced ALK-positive non-small cell lung cancer were enrolled, with 62 in phase 1. Ficonalkib was well absorbed and tolerated, with one dose-limited toxicity event occurring at 800 mg QD. Treatment-related adverse events occurred in 85.5% of patients, with 19.4% experienced greater than or equal to grade 3 events. The ORR was 38.3% (23 of 60, 95% confidence interval [CI]: 26.1%-51.8%) in phase 1, and 600 mg QD was established as recommended phase 2 dose. In phase 2, a total of 65 patients received ficonalkib at 600 mg QD. In total, 88 patients received ficonalkib at 600 mg QD in phase 1/2, and all had received prior 2nd-gen ALK TKI treatment. Furthermore, 90.9% of the patients experienced treatment-related adverse events and 14.8% experienced greater than or equal to grade 3 events. The ORR in efficacy-assessable patients who received ficonalkib at 600 mg QD was 47.5% (38 of 80, 95% CI: 36.2%-59.0%), with an intracranial ORR of 37.5% (12 of 32, 95% CI: 21.1%-56.3%) in these patients with measurable brain lesions at baseline. CONCLUSIONS: Ficonalkib (SY-3505) was well tolerated, with favorable safety profiles and promising efficacy in patients resistant to prior 2nd-gen ALK TKI.

Integrase Interactor 1 (INI1) Deficiency in a Lung Cancer Patient Presents Nonresponse to Immunotherapy and Tazemetostat: A Case Report.

Integrase interactor 1 (INI1)-deficient lung cancer is extremely rare, often with poor prognosis, and lacks effective treatment. Previous studies have reported the efficacy of immunotherapy and enhancer of the zeste homolog 2 (EZH2) inhibitor tazemetostat in various types of INI1-deficient tumors, such as sarcomas. However, the effectiveness of these treatments in INI1-deficient lung cancer has not yet been verified. We hereby report a case of a patient who was diagnosed with advanced squamous lung cancer with INI1 deficiency and received chemotherapy, immunotherapy, and tazemetostat treatments successively. The patient showed optimal response in the initial chemotherapy combined with anti-programmed cell death protein 1 (PD-1) immunotherapy, made rapid progress in the subsequent stage of maintenance immunotherapy, and showed nonresponse to tazemetostat. To the best of our knowledge, this is the first case of a lung cancer patient with INI1 deficiency who received tazemetostat treatment.

D-1553 (Garsorasib), a Potent and Selective Inhibitor of KRASG12C in Patients With NSCLC: Phase 1 Study Results.

INTRODUCTION: D-1553 (garsorasib) is a potent and selective oral KRASG12C inhibitor. We report results from a phase I dose-escalation and dose-expansion study of D-1553 in patients with KRAS G12C-mutated NSCLC in multiple sites in the People's Republic of China. METHODS: Patients with KRAS G12C-mutated NSCLC have administrated D-1553 600 mg orally once daily, 800 mg once daily, 1200 mg once daily, 400 mg twice a day, or 600 mg twice a day in dose escalation. In dose-expansion, all patients received 600 mg twice a day. The safety, pharmacokinetics, and efficacy of D-1553 were evaluated. RESULTS: Among a total of 79 treated patients, 75 patients (94.9%) reported treatment-related adverse events with 30 patients experiencing grade 3 or 4 events (38.0%). Most of the adverse events were manageable and the patients tolerated the study treatment well. Among 74 patients assessable for efficacy analysis, 30 patients had a partial response and 38 had stable disease with a confirmed objective response rate (ORR) and disease control rate (DCR) of 40.5% and 91.9%, respectively. The median progression-free survival was 8.2 months, and the median duration of response was 7.1 months. Among 62 patients assessable for response at the recommended phase 2 dose, partial response occurred in 24 patients (ORR, 38.7%) and stable disease in 32 patients (DCR, 90.3%). The median progression-free survival and duration of response were 7.6 months and 6.9 months, respectively. In patients with brain metastasis, ORR and DCR were 17% and 100%, respectively. CONCLUSIONS: D-1553 represents a promising therapeutic option for patients with KRAS G12C-mutated NSCLC with a well-tolerated safety profile and encouraging antitumor activity.

Tumor extracellular vesicles mediate anti-PD-L1 therapy resistance by decoying anti-PD-L1.

PD-L1+ tumor-derived extracellular vesicles (TEVs) cause systemic immunosuppression and possibly resistance to anti-PD-L1 antibody (αPD-L1) blockade. However, whether and how PD-L1+ TEVs mediate αPD-L1 therapy resistance is unknown. Here, we show that PD-L1+ TEVs substantially decoy αPD-L1 and that TEV-bound αPD-L1 is more rapidly cleared by macrophages, causing insufficient blockade of tumor PD-L1 and subsequent αPD-L1 therapy resistance. Inhibition of endogenous production of TEVs by Rab27a or Coro1a knockout reverses αPD-L1 therapy resistance. Either an increased αPD-L1 dose or macrophage depletion mediated by the clinical drug pexidartinib abolishes αPD-L1 therapy resistance. Moreover, in the treatment cycle with the same total treatment dose of αPD-L1, high-dose and low-frequency treatment had better antitumor effects than low-dose and high-frequency treatment, induced stronger antitumor immune memory, and eliminated αPD-L1 therapy resistance. Notably, in humanized immune system mice with human xenograft tumors, both increased αPD-L1 dose and high-dose and low-frequency treatment enhanced the antitumor effects of αPD-L1. Furthermore, increased doses of αPD-L1 and αPD-1 had comparable antitumor effects, but αPD-L1 amplified fewer PD-1+ Treg cells, which are responsible for tumor hyperprogression. Altogether, our results reveal a TEV-mediated mechanism of αPD-L1-specific therapy resistance, thus providing promising strategies to improve αPD-L1 efficacy.

Construction of a predictive model for immunotherapy efficacy in lung squamous cell carcinoma based on the degree of tumor-infiltrating immune cells and molecular typing.

BACKGROUND: To construct a predictive model of immunotherapy efficacy for patients with lung squamous cell carcinoma (LUSC) based on the degree of tumor-infiltrating immune cells (TIIC) in the tumor microenvironment (TME). METHODS: The data of 501 patients with LUSC in the TCGA database were used as a training set, and grouped using non-negative matrix factorization (NMF) based on the degree of TIIC assessed by single-sample gene set enrichment analysis (GSEA). Two data sets (GSE126044 and GSE135222) were used as validation sets. Genes screened for modeling by least absolute shrinkage and selection operator (LASSO) regression and used to construct a model based on immunophenotyping score (IPTS). RNA extraction and qPCR were performed to validate the prognostic value of IPTS in our independent LUSC cohort. The receiver operating characteristic (ROC) curve was constructed to determine the predictive value of the immune efficacy. Kaplan-Meier survival curve analysis was performed to evaluate the prognostic predictive ability. Correlation analysis and enrichment analysis were used to explore the potential mechanism of IPTS molecular typing involved in predicting the immunotherapy efficacy for patients with LUSC. RESULTS: The training set was divided into a low immune cell infiltration type (C1) and a high immune cell infiltration type (C2) by NMF typing, and the IPTS molecular typing based on the 17-gene model could replace the results of the NMF typing. The area under the ROC curve (AUC) was 0.82. In both validation sets, the IPTS of patients who responded to immunotherapy were significantly higher than those who did not respond to immunotherapy (P = 0.0032 and P = 0.0451), whereas the AUC was 0.95 (95% CI = 1.00-0.84) and 0.77 (95% CI = 0.58-0.96), respectively. In our independent cohort, we validated its ability to predict the response to cancer immunotherapy, for the AUC was 0.88 (95% CI = 1.00-0.66). GSEA suggested that the high IPTS group was mainly involved in immune-related signaling pathways. CONCLUSIONS: IPTS molecular typing based on the degree of TIIC in the TME could well predict the efficacy of immunotherapy in patients with LUSC with a certain prognostic value.

S100A8 accelerates wound healing by promoting adipose stem cell proliferation and suppressing inflammation.

Adipose-derived stem cells (ADSCs) are stem cells with multidirectional differentiation potential isolated from adipose tissue. They have the same immunomodulatory effect as bone marrow mesenchymal stem cells in wound repair and immune regulation as bone marrow. The mechanism of action of ADSCs in skin wound repair has not been elucidated. S100A8 is a calcium and zinc binding protein, but its role in skin wound healing is rarely reported. We herein show that S100A8 overexpression significantly promoted ADSC proliferation and differentiation, whereas S100A8 knockdown yielded the opposite results. A skin injury model with bone exposure was created in rats by surgically removing the skin from the head and exposing the skull. The wounds were treated with S100A8-overexpressing or S100A8-knockdown ADSCs, and wound healing was monitored. The serum levels of the inflammation-related factors tumor necrosis factor-α and interleukin-6 were decreased significantly after S100A8 overexpression, while the angiogenic factor vascular endothelial growth factor and connective tissue generating factor showed the opposite trend. Histological staining revealed that granulation tissue neovascularization was more pronounced in wounds treated with S100A8-overexpressing ADSCs than that in the control group. We conclude that S100A8 promotes the proliferation of ADSCs and inhibits inflammation to improve skin wound healing.

Case Report: Short-Term Response to First-Line Crizotinib Monotherapy in a Metastatic Lung Adenocarcinoma Patient Harboring a Novel TPR-ROS1 Fusion.

ROS1-rearranged patients account for 1-2% of non-small cell lung cancer (NSCLC) cases. Approximately 10 fusion partners have been discovered, while clinical practice is actively generating knowledge of new ones and their therapeutic responses. Herein, we report a patient with stage IV NSCLC that harbored a novel TPR-ROS1 fusion, which demonstrated a rapid but short partial response to first line crizotinib and primary resistance to subsequent ceritinib. Computed tomography detected a pulmonary nodule in a 53-year-old woman who presented with persistent cough. Histopathologic and molecular examination of the tissue biopsy indicated a poorly differentiated adenocarcinoma staining negative for PD-L1 but harbored a novel translocated promoter region (TPR)-ROS1 (T4:R35) gene fusion. Frontline crizotinib monotherapy elicited a rapid partial response after 1 month, although the disease progressed another 2 months later. After another 3 months of continued crizotinib treatment, the patient manifested newly emerged and enlarged lung and brain lesions. Genomic profiling still identified TPR-ROS1 as the only aberration, while a lymph node biopsy indicated PD-L1 immunopositivity. The patient was then treated with ceritinib and progressed within 1 month. She was started on chemotherapy with pemetrexed plus carboplatin and has achieved rapid partial response as of the latest follow-up. In summary, we provided clinical evidence of a novel TPR-ROS1 fusion and its roles as an oncogenic driver in metastatic NSCLC. To the best of our knowledge, ours is the first case to report this fusion in NSCLC. This case was characterized by a rapid yet short-term response to first line crizotinib and primary resistance to subsequent ceritinib, while no known genetic resistance mechanism was identified and other mechanisms including histologic transformation were unlikely. Future research is needed to unveil the resistance mechanism and formulate effective treatment strategies.

Increased alveolar epithelial TRAF6 via autophagy-dependent TRIM37 degradation mediates particulate matter-induced lung metastasis.

Epidemiological and clinical studies have shown that exposure to particulate matter (PM) is associated with an increased incidence of lung cancer and metastasis. However, the underlying mechanism remains unclear. Here, we demonstrated the central role of PM-induced neutrophil recruitment in promoting lung cancer metastasis. We found that reactive oxygen species (ROS)-mediated alveolar epithelial macroautophagy/autophagy was essential for initiating neutrophil chemotaxis and pre-metastatic niche formation in the lungs in response to PM exposure. During PM-induced autophagy, the E3 ubiquitin ligase TRIM37 was degraded and protected TRAF6 from proteasomal degradation in lung epithelial cells, which promoted the NFKB-dependent production of chemokines to recruit neutrophils. Importantly, ROS blockade, autophagy inhibition or TRAF6 knockdown abolished PM-induced neutrophil recruitment and lung metastasis enhancement. Our study indicates that host lung epithelial cells and neutrophils coordinate to promote cancer metastasis to the lungs in response to PM exposure and provides ideal therapeutic targets for metastatic progression.Abbreviations: ACTA2/α-SMA: actin alpha 2, smooth muscle, aorta; ATII: alveolar type II; Cho-Traf6 siRNA: 5'-cholesterol-Traf6 siRNA; EMT: epithelial-mesenchymal transition; HBE: human bronchial epithelial; HCQ: hydroxychloroquine; MAPK: mitogen-activated protein kinase; NAC: N-acetyl-L-cysteine; NFKB: nuclear factor of kappa light polypeptide gene enhancer in B cells; NS: normal saline; PM: particulate matter; ROS: reactive oxygen species; TRAF6: TNF receptor-associated factor 6; TRIM37: tripartite motif-containing 37.

Mefatinib as first-line treatment of patients with advanced EGFR-mutant non-small-cell lung cancer: a phase Ib/II efficacy and biomarker study.

EGFR inhibitors have revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC). Mefatinib is a novel, bioavailable, second-generation, irreversible pan-EGFR inhibitor. This phase Ib/II open-label, single-arm, multi-center study investigated the efficacy, safety, biomarker, and resistance mechanisms of mefatinib in the first-line treatment of patients with advanced EGFR-mutant NSCLC. This study included 106 patients with EGFR-mutant stage IIIB-IV NSCLC who received first-line mefatinib at a daily dose of either 60 mg (n = 51) or 80 mg (n = 55). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. The cohort achieved an ORR of 84.9% and DCR of 97.2%. The median PFS was 15.4 months and the median OS was 31.6 months. Brain metastasis was detected in 29% of patients (n = 31) at diagnosis and demonstrated an ORR of 87.1%, PFS of 12.8 months, and OS of 25.2 months. Adverse events primarily involved skin and gastrointestinal toxicities, which were well-tolerated and manageable. Analyses of mutation profiles were performed using targeted sequencing of plasma samples at baseline, first follow-up 6 weeks from starting mefatinib therapy (F1), and at progression. Patients with concurrent TP53 mutations had comparable PFS as wild-type TP53 (14.0 vs 15.4 months; p = 0.315). Furthermore, circulating tumor DNA clearance was associated with longer PFS (p = 0.040) and OS (p = 0.002). EGFR T790M was the predominant molecular mechanism of mefatinib resistance (42.1%, 16/38). First-line mefatinib provides durable PFS and an acceptable toxicity profile in patients with advanced EGFR-mutant NSCLC.

Research progress on neonatal Fc receptor and its application.

Neonatal Fc receptor (FcRn) is a specific receptor for immunoglobulin G (IgG) and albumin, which binds to them in a pH-dependent manner and prevents them from lysosomal degradation to keep a long plasma half-life. In addition, FcRn plays an important role in transmembrane transport of IgG and albumin and in antigen presentation. In autoimmune diseases, anti-FcRn antibody can promote the degradation of pathogenic IgG by competitive binding to FcRn. In infectious diseases, the half-life of drugs can be prolonged by increasing the affinity between therapeutic antibody and FcRn, while the combination of viral antigen and Fc fragment of IgG can cause local immune response of mucosa for disease prevention and treatment. In cancer, albumin as a carrier of anticancer drugs can achieve efficient drug delivery, and FcRn itself may be used as a predictor of the prognosis of cancer patients. This review details the functions of FcRn, highlights its role in autoimmune diseases, infectious diseases and cancer, as well as the mechanism of drug development based on FcRn, to provide a reference for the clinical application and drug development of FcRn.

The predictive and prognostic effects of PD-L1 expression on TKI treatment and survival of EGFR-mutant NSCLC: A meta-analysis.

ABSTRACT: Whether programmed death-ligand 1 (PD-L1) expression could predict the outcome of tyrosine kinase inhibitor (TKI) treatment and prognosis of epidermal growth factor receptor (EGFR)-mutant nonsmall cell lung cancer (NSCLC) is remaining controversial.Potential studies were search from PubMed, Embase, and Web of Science databases. Pooled odds ratio of objective response rate was used to describe the relationship between PD-L1 expression and primary resistance to EGFR-TKIs. Pooled hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS) were included to assess the effects of PD-L1 status on the outcome of EGFR-TKI treatment and survival of EGFR-mutant NSCLCs.Eighteen eligible studies (1986 EGFR-mutant NSCLCs) were included in this meta-analysis. Positive PD-L1 expression correlated with lower objective response rate of EGFR-TKI treatment (odds ratio [95% confidence interval {CI}] = 0.52 [0.28-0.98], P = .043), while PFS (adjusted HR [95% CI] = 1.49 [0.96-1.89], P = .332) and OS (HR [95% CI] = 1.24 [0.70-2.20], P = .456) of EGFR-TKI treatment did not correlated with PD-L1 status. Furthermore, PD-L1 expression was not a predictive biomarker for the OS (HR [95% CI] = 1.43 [0.98-2.08], P = .062) in overall EGFR-mutant cohort.Positive PD-L1 expression indicated a higher incidence of primary resistance, but did not correlate with the PFS or OS of EGFR-TKI therapy. In addition, PD-L1 expression was unlikely a predictive biomarker for prognosis of EGFR-mutant NSCLCs.

Lung Adenocarcinoma Patient Harboring EGFR-KDD Achieve Durable Response to Afatinib: A Case Report and Literature Review.

The rapid development of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutations including but not limited to exon 19 deletions (19 del) and point mutation L858R in exon 21. However, the efficacy of EGFR-TKIs in patients with rare mutations, such as EGFR-kinase domain duplication (KDD), remains elusive. EGFR-KDD often results from in-frame tandem duplication of EGFR exons 18-25, causing subsequent constitutive activation of EGFR signaling. Several case reports have revealed the efficacies of EGFR-TKIs in advanced lung adenocarcinoma (LUAD) with EGFR-KDD but yielded variable antitumor responses. In the present study, we report a 61-year-old male patient diagnosed with T1N3M0 (stage IIIB) LUAD harboring EGFR-KDD involving exons 18-25. He was treated with afatinib and achieved partial response (PR) with progression-free survival (PFS) of 12 months and counting. Our work, confirming EGFR-KDD as an oncogenic driver and therapeutic target, provides clinical evidence to administer EGFR-TKIs in patients with advanced LUAD harboring EGFR-KDD.

A heavily pre-treated adenocarcinoma patient with EGFR exon 20 insertion mutation responded to pembrolizumab plus nab-paclitaxel/bevacizumab: a case report.

Non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) exon 20 insertions are often associated with poor clinical outcomes due to low response rate to EGFR tyrosine kinase inhibitors. Although recent studies have demonstrated that several novel small molecule compounds could selectively inhibit these mutations, there are still some patients who cannot benefit from them. Another potential therapeutic approach is the use of immune checkpoint inhibitors. Growing evidence suggests that patients harboring EGFR mutations show low efficacy with the use of immunotherapy. However, according to the different immunogenicity of different EGFR mutations, the role of immunotherapy in EGFRex20ins NSCLCs needs further confirmation. Herein we report a case of a 39-year-old woman with NSCLC harboring EGFRex20ins who was diagnosed as postoperative recurrence of lung cancer. She failed with oral poziotinib, then underwent four cycles of systemic chemotherapy with pemetrexed plus carboplatin and bevacizumab. CT scan after chemotherapy showed the metastatic tumors increased in size. The patient then received osimertinib plus cetuximab. CT evaluation performed one month after treatment revealed the enlargement of bilateral lung metastasis. Pembrolizumab plus nab-paclitaxel/bevacizumab was given every three weeks afterwards. Significant shrinkage in multiple metastatic tumors was observed through CT, resulting in a partial response and a progression-free survival of more than 5.0 months. This case highlighted that the use of pembrolizumab in combination with nab-paclitaxel/bevacizumab could help in the management of the uncommon EGFRex20ins in heavily pretreated patients.

Emerging Blood-Based Biomarkers for Predicting Response to Checkpoint Immunotherapy in Non-Small-Cell Lung Cancer.

Immune checkpoint inhibitors (ICIs) have brought impressive clinical benefits in a variety of malignancies over the past years, which dramatically revolutionized the cancer treatment paradigm. Monotherapy or in combination with chemotherapy of ICIs targeting programmed death 1/programmed death ligand 1 (PD-L1) has emerged as an alternative treatment for patients with advanced non-small-cell lung cancer (NSCLC). However, constrained by primary or acquired resistance, most patients obtain limited benefits from ICIs and occasionally suffer from severe immune-related adverse events. Moreover, owing to the complexity of the tumor microenvironment and the technical limitations, clinical application of PD-L1 and tumor mutation burden as biomarkers shows many deficiencies. Thus, additional predictive biomarkers are required to further advance the precision of proper patient selection, avoiding the exposure of potential non-responders to unnecessary immunotoxicity. Nowadays, an increasing number of investigations are focusing on peripheral blood as a noninvasive alternative to tissue biopsy in predicting and monitoring treatment outcomes. Herein, we summarize the emerging blood-based biomarkers that could predict the clinical response to checkpoint immunotherapy, specifically in patients with NSCLC.

A rare EGFR mutation L747P conferred therapeutic efficacy to both gefitinib and osimertinib: A case report.

EGFR mutations, primarily sensitizing mutations such as exon 19 deletion and exon 21 point mutations, have been proven to act as predictive biomarkers for the response to tyrosine kinase inhibitors (TKIs). How patients harboring EGFR L747 P (a rare mutation located in exon 19) respond to EGFR-TKI is controversial. Some studies have described EGFR L747 P as providing intrinsic resistance to EGFR-TKIs, but others support this rare mutation as a sensitive mutation. Hence, we reported a patient with advanced lung adenocarcinoma harboring an EGFR L747 P who benefited from first-line treatment with gefitinib. This patient achieved stable disease (SD) and had a progression-free survival (PFS) of 18 months. After disease progression, this patient was subsequently administered osimertinib and responded, as evidenced by a significant reduction in nodular lesions. This case revealed that EGFR L747 P rendered both gefitinib and osimertinib therapeutically efficacious.

Preoperative Risk Assessment of Lymph Node Metastasis in cT1 Lung Cancer: A Retrospective Study from Eastern China.

BACKGROUND: Lymph node status of clinical T1 (diameter ≤ 3 cm) lung cancer largely affects the treatment strategies in the clinic. In order to assess lymph node status before operation, we aim to develop a noninvasive predictive model using preoperative clinical information. METHODS: We retrospectively reviewed 924 patients (development group) and 380 patients (validation group) of clinical T1 lung cancer. Univariate analysis followed by polytomous logistic regression was performed to estimate different risk factors of lymph node metastasis between N1 and N2 diseases. A predictive model of N2 metastasis was established with dichotomous logistic regression, externally validated and compared with previous models. RESULTS: Consolidation size and clinical N stage based on CT were two common independent risk factors for both N1 and N2 metastases, with different odds ratios. For N2 metastasis, we identified five independent predictors by dichotomous logistic regression: peripheral location, larger consolidation size, lymph node enlargement on CT, no smoking history, and higher levels of serum CEA. The model showed good calibration and discrimination ability in the development data, with the reasonable Hosmer-Lemeshow test (p = 0.839) and the area under the ROC being 0.931 (95% CI: 0.906-0.955). When externally validated, the model showed a great negative predictive value of 97.6% and the AUC of our model was better than other models. CONCLUSION: In this study, we analyzed risk factors for both N1 and N2 metastases and built a predictive model to evaluate possibilities of N2 metastasis of clinical T1 lung cancers before the surgery. Our model will help to select patients with low probability of N2 metastasis and assist in clinical decision to further management.