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Background: The study is to evaluate the efficacy and safety of combined anlotinib and EGFR-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC) who had gradual, oligo, or potential progression after previous EGFR-TKIs treatment. Methods: We conducted an open-label, single-arm, multicenter, phase II trial in China. Eligible patients were 18–75 years old with histologically or cytologically confirmed NSCLC who were EGFR mutation positive and showed gradual, oligo, or potential progression after EGFR-TKIs. Anlotinib (12 mg/day) was administered orally for 2 weeks and then off 1 week in a 3-week cycle. EGFR-TKIs were continue used. The primary endpoint was progression-free survival (PFS). The secondary endpoints included 6- and 12-month PFS rate, objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. Results: From July 2019 to December 2022, 120 patients were enrolled. The median PFS (mPFS) was 9.1 months (95% CI 6.8–11.7). The PFS rates at 6 and 12 months was 68.5% and 38.8% respectively. For 86 patients with first-line 1st /2nd generation EGFR-TKIs, the mPFS was 9.2 months (95% CI 6.7–12.6). For 32 patients with first-line 3rd generation EGFR-TKIs, the mPFS was 10.3 months (95% CI 6.1–13.3). Overall ORR and DCR were 6.7% (95% CI 2.9–12.7) and 87.5% (95% CI 80.2–92.8), respectively. 52.5% of patients had grade 3 or higher treatment-emergent adverse events (TEAEs). Conclusion: Anlotinib in combination with continuation of EGFR-TKIs prolonged the clinical benefit of EGFR-TKIs, demonstrating favorable survival outcomes and manageable toxicity in NSCLC treated with EGFR-TKIs and had specific progression modes, such as gradual progression. Trial registration: NCT04007835. [ABSTRACT FROM AUTHOR]

Metabolism reprogramming within the tumor microenvironment (TME) can have a profound impact on immune cells. Identifying the association between metabolic phenotypes and immune cells in lung adenocarcinoma (LUAD) may reveal mechanisms of resistance to immune checkpoint inhibitors (ICIs). Metabolic phenotypes were classified by expression of metabolic genes. Somatic mutations and transcriptomic features were compared across the different metabolic phenotypes. The metabolic phenotype of LUAD is predominantly determined by reductase-oxidative activity and is divided into two categories: redoxhigh LUAD and redoxlow LUAD. Genetically, redoxhigh LUAD is mainly driven by mutations in KEAP1, STK11, NRF2, or SMARCA4. These mutations are more prevalent in redoxhigh LUAD (72.5%) compared to redoxlow LUAD (17.4%), whereas EGFR mutations are more common in redoxlow LUAD (19.0% vs. 0.7%). Single-cell RNA profiling of pre-treatment and post-treatment samples from patients receiving neoadjuvant chemoimmunotherapy revealed that tissue-resident memory CD8+ T cells are responders to ICIs. However, these cells are significantly reduced in redoxhigh LUAD. The redoxhigh phenotype is primarily attributed to tumor cells and is positively associated with mTORC1 signaling. LUAD with the redoxhigh phenotype demonstrates a lower response rate (39.1% vs. 70.8%, p = 0.001), shorter progression-free survival (3.3 vs. 14.6 months, p = 0.004), and overall survival (12.1 vs. 31.2 months, p = 0.022) when treated with ICIs. The redoxhigh phenotype in LUAD is predominantly driven by mutations in KEAP1, STK11, NRF2, and SMARCA4. This phenotype diminishes the number of tissue-resident memory CD8+ T cells and attenuates the efficacy of ICIs. [ABSTRACT FROM AUTHOR]

Objectives: Primary pulmonary lymphoepithelioma‐like carcinoma (PLELC) is a subtype of lung carcinoma associated with the Epstein–Barr virus (EBV). The clinical predictive biomarkers of immune checkpoint blockade (ICB) in PLELC require further investigation. Methods: We prospectively analysed EBV levels in the blood and immune tumor biomarkers of 31 patients with ICB‐treated PLELC. Viral EBNA‐1 and BamHI‐W DNA fragments in the plasma were quantified in parallel using quantitative polymerase chain reaction. Results: Progression‐free survival (PFS) was significantly longer in EBNA‐1 high or BamHI‐W high groups. A longer PFS was also observed in patients with both high plasma EBNA‐1 or BamHI‐W and PD‐L1 ≥ 1%. Intriguingly, the tumor mutational burden was inversely correlated with EBNA‐1 and BamHI‐W. Plasma EBV load was negatively associated with intratumoral CD8+ immune cell infiltration. Dynamic changes in plasma EBV DNA level were in accordance with the changes in tumor volume. An increase in EBV DNA levels during treatment indicated molecular progression that preceded the imaging progression by several months. Conclusions: Plasma EBV DNA could be a useful and easy‐to‐use biomarker for predicting the clinical activity of ICB in PLELC and could serve to monitor disease progression earlier than computed tomography imaging. [ABSTRACT FROM AUTHOR]

After disease progression on EGFR tyrosine kinase inhibitor (TKI) therapy, patients with EGFR-mutated NSCLC who are then treated with platinum-based chemotherapy (PBC) obtain only limited clinical benefit with transient responses. Therapies with greater efficacy and tolerable safety profiles are needed in this setting. The receptor tyrosine kinase HER3 is widely expressed in NSCLC, and increased expression is associated with poor treatment outcomes. In the U31402-A-U102 phase I trial, HER3-DXd showed promising antitumor activity with manageable safety in heavily pre-treated patients with EGFR-mutated NSCLC across a range of tumor HER3 expression levels and EGFR TKI resistance mechanisms. HERTHENA-Lung02 is the first phase III trial to evaluate the safety and efficacy of HER3-DXd versus PBC in patients with progression on a third-generation EGFR TKI. Clinical Trial Registration:NCT05338970 (clinicaltrials.gov); 2021-005879-40 (EudraCT Number). In some patients with non-small-cell lung cancer, changes (or mutations) in the DNA sequence can alter a protein called EGFR and allow tumors to grow and survive. Drugs called EGFR tyrosine kinase inhibitors (EGFR TKIs for short) are used to treat these tumors by interfering with the abnormal EGFR protein. Treatment with these drugs can work well at first, but some tumors never respond, and for tumors that do respond, the cancer eventually becomes resistant to the EGFR TKI and the drug stops working. Platinum-based chemotherapy is often prescribed after an EGFR TKI stops working; however, platinum-based chemotherapy can provide only temporary control of the tumor growth. Most patients with non-small-cell lung cancer have a protein called HER3 on the surface of their tumor cells. A new drug candidate called patritumab deruxtecan (HER3-DXd) finds tumor cells and attaches to the HER3 protein on their surface. HER3-DXd then moves inside the cancer cells, where a novel antitumor payload is released and kills the tumor cells. This article describes the phase III clinical trial HERTHENA-Lung02 (NCT05338970) that compares the benefit of HER3-DXd to platinum-based chemotherapy for patients who have non-small-cell lung cancer with the abnormal EGFR protein and whose disease stopped responding or never responded to EGFR TKI therapy. [ABSTRACT FROM AUTHOR]

This article discusses a study that examines the genetic and molecular characteristics of lung cancer patients who have transformed from one type of lung cancer to another. The study identifies two distinct subtypes based on the RB1 gene status of the patients. The findings suggest that RB1 and SMAD4 alterations are important factors in this transformation, and patients with RB1 mutations tend to have a longer time before the transformation occurs. The article highlights the importance of understanding the heterogeneity within this patient population in order to develop new treatments and improve outcomes. Additionally, the study develops a predictive model to assess the risk of transformation in patients with specific gene mutations. Overall, this research provides valuable insights into the biology of transformed lung cancer and potential targets for therapy. [Extracted from the article]

Background: Some studies of dual-targeted therapy (DTT) targeting epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) have shown promising efficacy in non-small-cell lung cancer (NSCLC). Consequently, patient management following DTT resistance has gained significance. However, the underlying resistance mechanisms and clinical outcomes in these patients remain unclear. Objectives: This study aimed to delineate the molecular characteristics and survival outcomes of patients with NSCLC harboring EGFR mutations and acquired MET amplification after developing resistance to DTT. Design: We conducted a retrospective analysis of patients with NSCLC with EGFR mutations and acquired MET amplification who exhibited resistance to EGFR/MET DTT. Methods: Next-generation sequencing (NGS) was performed on patients with available tissue samples before and/or after the development of resistance to DTT. Stratified analyses were carried out based on data sources and subsequent salvage treatments. Univariate/multivariate Cox regression models and survival analyses were employed to explore potential independent prognostic factors. Results: The study included 77 NSCLC patients, with NGS conducted on 19 patients. We observed many resistance mechanisms, including EGFR-dependent pathways (4/19, 21.1%), MET-dependent pathways (2/19, 10.5%), EGFR/MET co-dependent pathways (2/19, 10.5%), and EGFR/MET-independent resistance mechanisms (11/19, 57.9%). Post-progression progression-free survival (pPFS) and post-progression overall survival (pOS) significantly varied among patients who received the best supportive care (BSC), targeted therapy, or chemotherapy (CT), with median pPFS of 1.5, 3.9, and 4.9 months, respectively (p = 0.003). Median pOS were 2.3, 7.7, and 9.2 months, respectively (p < 0.001). The number of treatment lines following DTT resistance and the Eastern Cooperative Oncology Group performance status emerged as the independent prognostic factors. Conclusion: This study revealed a heterogeneous landscape of resistance mechanisms to EGFR/MET DTT, with a similar prevalence of on- and off-target mechanisms. Targeted therapy or CT, as compared to BSC, exhibited the potential to improve survival outcomes for patients with advanced NSCLC following resistance to DTT. [ABSTRACT FROM AUTHOR]

Objectives: With the popularization of chest computed tomography (CT) screening, there are more sub-centimeter (≤ 1 cm) pulmonary nodules (SCPNs) requiring further diagnostic workup. This area represents an important opportunity to optimize the SCPN management algorithm avoiding "one-size fits all" approach. One critical problem is how to learn the discriminative multi-view characteristics and the unique context of each SCPN. Methods: Here, we propose a multi-view coupled self-attention module (MVCS) to capture the global spatial context of the CT image through modeling the association order of space and dimension. Compared with existing self-attention methods, MVCS uses less memory consumption and computational complexity, unearths dimension correlations that previous methods have not found, and is easy to integrate with other frameworks. Results: In total, a public dataset LUNA16 from LIDC-IDRI, 1319 SCPNs from 1069 patients presenting to a major referral center, and 160 SCPNs from 137 patients from three other major centers were analyzed to pre-train, train, and validate the model. Experimental results showed that performance outperforms the state-of-the-art models in terms of accuracy and stability and is comparable to that of human experts in classifying precancerous lesions and invasive adenocarcinoma. We also provide a fusion MVCS network (MVCSN) by combining the CT image with the clinical characteristics and radiographic features of patients. Conclusion: This tool may ultimately aid in expediting resection of the malignant SCPNs and avoid over-diagnosis of the benign ones, resulting in improved management outcomes. Clinical relevance statement: In the diagnosis of sub-centimeter lung adenocarcinoma, fusion MVCSN can help doctors improve work efficiency and guide their treatment decisions to a certain extent. Key Points: • Advances in computed tomography (CT) not only increase the number of nodules detected, but also the nodules that are identified are smaller, such as sub-centimeter pulmonary nodules (SCPNs). • We propose a multi-view coupled self-attention module (MVCS), which could model spatial and dimensional correlations sequentially for learning global spatial contexts, which is better than other attention mechanisms. • MVCS uses fewer huge memory consumption and computational complexity than the existing self-attention methods when dealing with 3D medical image data. Additionally, it reaches promising accuracy for SCPNs' malignancy evaluation and has lower training cost than other models. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal–epithelial transition (MET) amplification is a crucial oncogenic driver and a resistance mechanism to epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) of non-small-cell lung cancer (NSCLC). Fluorescence in situ hybridization (FISH) is the gold standard for MET amplification detection. However, it is inapplicable when tissue samples are unavailable. Objective: This study assessed the performance of plasma droplet digital polymerase chain reaction (ddPCR) in MET amplification detection in NSCLC patients. Design and methods: A total of 87 NSCLC patients were enrolled, and 94 paired tissue and plasma samples were analyzed for the concordance between FISH and plasma ddPCR/tissue next-generation sequencing (NGS) in detecting MET amplification. In addition, the efficacy of patients with MET amplification using different detection methods who were treated with MET-TKIs was evaluated. Results: Plasma ddPCR showed substantial concordance with FISH (74.1% sensitivity, 92.5% specificity, and 87.2% accuracy with a kappa value of 0.68) and outperformed tissue NGS (kappa value of 0.64) in MET amplification detection. Combined plasma ddPCR and tissue NGS showed substantial concordance with FISH (92.3% sensitivity, 89.2% specificity, and an accuracy of 90.1% with a kappa value of 0.77). The efficacy is comparable in these NSCLC patients with MET amplification detected by FISH and plasma ddPCR who were treated with MET-TKIs. Conclusion: Plasma ddPCR is a potentially reliable method for detecting MET amplification in advanced NSCLC patients. Combined plasma ddPCR and tissue NGS might be an alternative or complementary method to MET amplification detection. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES The aim of this study was to evaluate the performance of consolidation-to-tumour ratio (CTR) and the radiomic models in two- and three-dimensional modalities for assessing radiological invasiveness in early-stage lung adenocarcinoma. METHODS A retrospective analysis was conducted on patients with early-stage lung adenocarcinoma from Guangdong Provincial People's Hospital and Shenzhen People's Hospital. Manual delineation of pulmonary nodules along the boundary was performed on cross-sectional images to extract radiomic features. Clinicopathological characteristics and radiomic signatures were identified in both cohorts. CTR and radiomic score for every patient were calculated. The performance of CTR and radiomic models were tested and validated in the respective cohorts. RESULTS A total of 818 patients from Guangdong Provincial People's Hospital were included in the primary cohort, while 474 patients from Shenzhen People's Hospital constituted an independent validation cohort. Both CTR and radiomic score were identified as independent factors for predicting pathological invasiveness. CTR in two- and three-dimensional modalities exhibited comparable results with areas under the receiver operating characteristic curves and were demonstrated in the validation cohort (area under the curve: 0.807 vs 0.826, P  =   0.059) Furthermore, both CTR in two- and three-dimensional modalities was able to stratify patients with significant relapse-free survival (P  <   0.000 vs P  <   0.000) and overall survival (P  =   0.003 vs P  =   0.001). The radiomic models in two- and three-dimensional modalities demonstrated favourable discrimination and calibration in independent cohorts (P  =   0.189). CONCLUSIONS Three-dimensional measurement provides no additional clinical benefit compared to two-dimensional. [ABSTRACT FROM AUTHOR]

Purpose: This large-scale, multicenter, retrospective observational study aimed to evaluate the clinicopathological and molecular profiles associated with programmed death-ligand 1 (PD-L1) expression in precancerous lesions and invasive adenocarcinoma in subcentimeter pulmonary nodules. Patients and Methods: Patients with histologically confirmed atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (ADC) were included. PD-L1 expression was evaluated at each center using a PD-L1 immunohistochemistry 22C3 pharmDx kit (Agilent, Santa Clara, CA, USA). The tumor proportion score (TPS) cutoff values were set at ≥ 1% and ≥ 50%. Results: A total of 2022 nodules from 1844 patients were analyzed. Of these, 9 (0.45%) nodules had PD-L1 TPS ≥ 50%, 187 (9.25%) had PD-L1 TPS 1–49%, and 1826 (90.30%) had PD-L1 TPS < 1%. A total of 378 (18.69%), 1016 (50.25%), and 628 (31.06%) nodules were diagnosed as AAH/AIS, MIA, and ADC, respectively, by pathology. A total of 1377 (68.10%), 591 (25.67%), and 54 (2.67%) nodules were diagnosed as pure ground-glass opacity (GGO), mixed GGO, and solid nodules, respectively, by computed tomography. There was a significant difference between PD-L1 expression and anaplastic lymphoma kinase (ALK) mutation status (P < 0.001). PD-L1 expression levels were significantly different from those determined using the International Association for the Study of Lung Cancer (IASLC) grading system (P < 0.001). Conclusions: PD-L1 expression was significantly associated with radiological and pathological invasiveness and driver mutation status in subcentimeter pulmonary nodules. The significance of PD-L1 expression in the evolution of early-stage lung adenocarcinoma requires further investigation. [ABSTRACT FROM AUTHOR]

A superhard carbon phase with Pmmm (D2h1, 47) symmetry is predicted by using a recently developed particle swarm optimization method for searching for crystal structures. The carbon phase is an orthorhombic crystal system that contains 16 atoms per unit cell, named oC16, which has an all-sp3-hybridized bonding network and contains a large cavity. oC16 has a distinct topology, including zigzag four-, five-, six-, and eightfold carbon rings. The dynamic, elastic, and electronic properties of oC16 are investigated by first-principles calculations, and the results show that oC16 is more energetically stable than the experimentally synthesized T-carbon, BC8, and BC12. The phonon spectra and elastic constants confirm its dynamical and mechanical stability at zero pressure, respectively. The calculated bulk moduli and hardness indicate that oC16 is an ultra-incompressible and superhard material. Analyzing its electronic band structure reveals that oC16 has insulation characteristics with an indirect bandgap of 4.42 eV. Also investigated is how the elastic moduli of the oC16 phase depend on the crystal orientation. Because of its superhard and porous properties, the potential uses of oC16 include hydrogen storage, molecular sieves, coating, and tools for cutting, polishing, and grinding. [ABSTRACT FROM AUTHOR]

Background: Pralsetinib is a potent, selective RET inhibitor targeting oncogenic RET alterations. As part of the global, phase 1/2 ARROW trial (NCT03037385), the efficacy and safety of pralsetinib in Chinese patients with advanced RET fusion‐positive non–small cell lung cancer (NSCLC) were evaluated. Methods: Adult patients with advanced, RET fusion–positive NSCLC with or without prior platinum‐based chemotherapy were enrolled into two cohorts receiving 400‐mg once‐daily oral pralsetinib. Primary end points were objective response rates assessed by blinded independent central review and safety. Results: Of 68 patients enrolled, 37 had received prior platinum‐based chemotherapy (48.6% with ≥3 prior systemic regimens) and 31 were treatment‐naïve. As of March 4, 2022 (data cutoff), of the patients with measurable lesions at baseline, a confirmed objective response was observed in 22 (66.7%; 95% confidence interval [CI], 48.2–82.0) of 33 pretreated patients, including 1 (3.0%) complete response and 21 (63.6%) partial responses; and in 25 (83.3%; 95% CI, 65.3–94.4) of 30 treatment‐naïve patients, including two (6.7%) complete responses and 23 (76.7%) partial responses. Median progression‐free survival was 11.7 months (95% CI, 8.7–not estimable) in pretreated patients and 12.7 months (95% CI, 8.9–not estimable) in treatment‐naïve patients. The most common grade 3/4 treatment‐related adverse events in 68 patients were anemia (35.3%) and decreased neutrophil count (33.8%). Eight (11.8%) patients discontinued pralsetinib because of treatment‐related adverse events. Conclusion: Pralsetinib showed robust and durable clinical activity with a well‐tolerated safety profile in Chinese patients with RET fusion‐positive NSCLC. Clinical trial registration: NCT03037385. This study assessed efficacy and safety of pralsetinib in Chinese patients with RET fusion‐positive non–small cell lung cancer who had previously received platinum‐based chemotherapy (n = 37) or were treatment‐naïve (n = 31). Pralsetinib has demonstrated a robust, rapid antitumor activity and an overall well‐tolerated safety profile in Chinese patients with RET fusion–positive non–small cell lung cancer. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard first-line option for non-small-cell lung cancer (NSCLC) harboring active EGFR mutations. The overall survival of patients with advanced NSCLC has improved dramatically with the development of comprehensive genetic profiles and targeted therapies. However, resistance inevitably occurs, leading to disease progression after approximately 10–18 months of EGFR-TKI treatment. Platinum-based chemotherapy is the standard treatment for patients who have experienced disease progression while undergoing EGFR-TKI treatment, but its efficacy is limited. The management of extensively pretreated patients with EGFR -mutant NSCLC is becoming increasingly concerning. New agents have shown encouraging efficacy in clinical trials for this patient population, including fourth-generation EGFR-TKIs, EGFR-TKIs combined with counterpart targeted drugs, and novel agents such as antibody–drug conjugates. We review current efforts to manage extensively pretreated patients with EGFR -mutant NSCLC. [ABSTRACT FROM AUTHOR]

Background: Camrelizumab has shown encouraging efficacy in advanced non-small cell lung cancer (NSCLC), either as monotherapy or combined with chemotherapy. However, evidence of neoadjuvant camrelizumab for NSCLC remains lacking. Methods: Patients with NSCLC treated with neoadjuvant camrelizumab-based therapy followed by surgery between December 2020 and September 2021 were retrospectively reviewed. Demographic and clinical data, details of neoadjuvant therapy and surgical information were retrieved. Results: In this multicenter retrospective real-world study, 96 patients were included. Ninety-five patients (99.0%) received neoadjuvant camrelizumab combined with platinum-based chemotherapy, with a median of 2 cycles (range 1–6). The median interval from the last dose to surgery was 33 days (range 13–102 days). Seventy patients (72.9%) underwent minimally invasive surgery. Lobectomy was the most frequent surgical procedure (94 [97.9%]). The median estimated intraoperative blood loss was 100 mL (range 5–1200 mL), and the median operative time was 3.0 h (range 1.5–6.5 h). The R0 resection rate was 93.8%. Twenty-one patients (21.9%) experienced postoperative complications, with the most common being cough and pain (both 6 [6.3%]). The overall response rate was 77.1% (95% CI 67.4–85.0%), and the disease control rate was 93.8% (95% CI 86.9–97.7%). Twenty-six patients (27.1%, 95% CI 18.5–37.1%) had pathological complete response. Neoadjuvant treatment-related adverse events of grade ≥ 3 were reported in seven patients (7.3%), with the most frequent being abnormal liver enzymes (two [2.1%]). No treatment-related deaths were reported. Conclusion: The real-world data indicated that camrelizumab-based therapy had promising efficacy for NSCLC in the neoadjuvant setting, with manageable toxicities. Prospective studies investigating neoadjuvant camrelizumab are warranted. [ABSTRACT FROM AUTHOR]

Tumor response T cells, which have specific T cell receptor (TCR) rearrangements in tumor-infiltrating lymphocytes, determine their ability to interact with the mutation-derived neoantigens presented by antigen-presenting cells. Little is known about the genetic alterations related to specific TCR clones in non-small cell lung cancer (NSCLC) patients who have an epidermal growth factor receptor (EGFR) mutation. In this study, tumor tissues were collected from 101 patients with stage II/III resectable NSCLC with an EGFR mutation (57 patients were treated with gefitinib and 44 were treated with chemotherapy) in the ADJUVANT-CTONG1104 trial for high-throughput TCRβ V region and exome sequencing. Ten clonal TCRs were associated with EGFR exon 19 deletion (del), EGFR exon 21 mutation (L858R), RB1 alteration, TP53 exon 4/5 missense mutation, TP53 nonsense mutation, or copy number gains in NKX2-1 and CDK4. Among the TCRs, there was frequent use of Vβ20-1Jβ2-3 specifically for EGFR exon 19 del or Vβ9Jβ2-1 specifically for EGFR exon 21 mutation (L858R), and these were significantly associated with favorable overall survival (OS) for NSCLC patients harboring EGFR exon 19 del or exon 21 L858R, particularly in the adjuvant gefitinib setting. Moreover, in comparison with the chemotherapy-preferable (CP) group, higher frequencies of Vβ20-1Jβ2-3 and Vβ9Jβ2-1 were found in the highly TKI-preferable (HTP) or TKI-preferable (TP) groups. Altogether, we identified ten TCR rearrangements specific for genetic alterations in NSCLC. Importantly, high abundance Vβ20-1Jβ2-3 or Vβ9Jβ2-1 may be an immune biomarker for guiding adjuvant gefitinib decisions for NSCLC patients harboring EGFR exon 19 del or EGFR exon 21 L858R. [ABSTRACT FROM AUTHOR]

Background: Circulating tumor cells (CTCs) are prognostic biomarker in non-small-cell lung cancer (NSCLC). CTCs could also be used as predictor of efficacy of systemic treatments in advanced NSCLC. Objectives: We described the dynamic changes of CTCs during first-line platinum-based chemotherapy in advanced NSCLC and clarified the correlation between CTC counts and efficacy of chemotherapy. Design: Chemotherapy is administered and blood specimens are collected at four time points from baseline to disease progression for CTC detection. Methods: This multicenter prospective study enrolled patients with previously untreated stage III or IV NSCLC fit for standard platinum-based chemotherapy. Bloods were sampled as per standard operating procedures at baseline, cycle 1 and cycle 4 of chemotherapy, and at disease progression for CTC analysis using the CellSearch system. Results: Among 150 patients enrolled, median overall survival (OS) was 13.8, 8.4, and 7.9 months in patients with CTC−, KIT−CTC, and KIT+CTC at baseline (p = 0.002). Patients with persistent negative CTC (46.0%) had longer progression-free survival [5.7 months, 95% confidence interval (CI): 5.0–6.5 versus 3.0 months, 0.6–5.4; hazard ratio (HR): 0.34, 95% CI: 0.18–0.67) and OS (13.1 months, 10.9–15.3 versus 5.6 months, 4.1–7.1; HR: 0.17, 0.08–0.36) compared with patients with persistent positive CTC (10.7%), which was not impacted by chemotherapy. Chemotherapy decreased CTC from 36.0% (54/150) to 13.7% (13/95). Conclusions: CTC persistent presence during treatment represents poor prognosis and resistance to chemotherapy in advanced NSCLC. Chemotherapy could effectively eliminate CTCs. Molecular characterization and the functionalization of CTC will be warranted for further intensive investigation. Trial registration: NCT01740804. [ABSTRACT FROM AUTHOR]

Research on biomarker-driven therapy and immune check-point blockade in non-small cell lung cancer (NSCLC) is rapidly evolving. The width and depth of clinical trials have also dramatically improved in an unprecedented speed. The personalized treatment paradigm evolved every year. In this review, we summarize the promising agents that have shifted the treatment paradigm for NSCLC patients across all stages, including targeted therapy and immunotherapy using checkpoint inhibitors. Based on recent evidence, we propose treatment algorithms for NSCLC and propose several unsolved clinical issues, which are being explored in ongoing clinical trials. The results of these trials are likely to impact future clinical practice. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy has largely improved clinical outcome of patients with esophageal squamous cell carcinoma (ESCC). However, a proportion of patients still fail to benefit. Thus, biomarkers predicting therapeutic resistance and underlying mechanism needs to be investigated. Methods: Transcriptomic profiling was applied in FFPE tissues from 103 ESCC patients, including surgical samples from 66 treatment-naïve patients with long-term follow-up, and endoscopic biopsies from 37 local advanced ESCC cases receiving neoadjuvant immunotherapy plus chemotherapy. Unsupervised clustering indicated an aggressive phenotype with mesenchymal character in 66 treatment-naïve samples. Univariant logistic regression was applied to identify candidate biomarkers potentially predicted resistance to neoadjuvant immunotherapy within the range of mesenchymal phenotype enriched genes. These biomarkers were further validated by immunohistochemistry. Putative mechanisms mediating immunotherapy resistance, as indicated by microenvironment and immune cell infiltration, were evaluated by transcriptomic data, and validated by multiplex immunofluorescence. Results: PLEK2 and IFI6, highly expressed in mesenchymal phenotype, were identified as novel biomarkers relating to non-MPR in neoadjuvant immunotherapy cohort [PLEK2high, OR (95% CI): 2.15 (1.07–4.33), P = 0.032; IFI6high, OR (95% CI): 2.21 (1.16–4.23), P = 0.016). PLEK2high and IFI6 high ESCC patients (versus low expressed patients) further exhibit higher chance of non-major pathological remissions (90%, P = 0.004) in neoadjuvant immunotherapy cohort and high mortality (78.9%, P = 0.05), poor prognosis in retrospective cohort. PLEK2high/IFI6high ESCC recapitulated mesenchymal phenotype, characterized by extracellular matrix composition and matrix remodeling. In addition, PLEK2high or IFI6high ESCC displayed an immune-unfavored microenvironment, represented by positive correlating with regulatory T cells, Helper 2 T cell as well as less infiltration of B cells, effector T cells and mast cells. Conclusions: PLEK2 and IFI6 was discovered of first time to identify a distinct ESCC subpopulation cannot be benefited from neoadjuvant immunotherapy and present a poor survival, which putatively associated with mesenchymal and immune-suppressive microenvironment. [ABSTRACT FROM AUTHOR]

Background: ADJUVANT-CTONG1104 reported a favorable survival outcome from adjuvant gefitinib treatment over chemotherapy in EGFR-mutant non-small cell lung cancer (NSCLC) patients. However, heterogeneous benefit from EGFR-TKIs and chemotherapy demands further biomarker exploration for patient selection. Previously, we identified certain TCR sequences with predictive value for adjuvant therapies from the CTONG1104 trial and found a relationship between the TCR repertoire and genetic variations. It remains unknown which TCR sequences could further enhance the prediction for only adjuvant EGFR-TKI. Methods: In this study, 57 tumor and 12 tumor-adjacent samples, respectively, from gefitinib-treated patients in the CTONG1104 were collected for TCR β gene sequencing. We attempted to constitute a predictive model for prognosis and favorable adjuvant EGFR-TKI outcome for patients with early-stage NSCLC and EGFR mutations. Results: The TCR rearrangements demonstrated significant prediction for overall survival (OS). A combined model of high frequent Vβ7-3Jβ2-5 and Vβ24-1Jβ2-1 with lower frequent Vβ5-6Jβ2-7 and Vβ28Jβ2-2 constituted the best value for predicting OS (P < 0.001; Hazard Ratio [HR] = 9.65, 95% confidence interval [CI]: 2.27 to 41.12) or DFS (P = 0.02; HR = 2.61, 95% CI: 1.13 to 6.03). In Cox regression analyses, when multiple clinical data were included, the risk score remained an independent prognostic predictor for OS (P = 0.003; HR = 9.49; 95% CI: 2.21 to 40.92) and DFS (P = 0.015; HR = 3.13; 95% CI: 1.25 to 7.87). Conclusions: In this study, a predictive model was constituted with specific TCR sequences for prognosis prediction and gefitinib benefit in the ADJUVANT-CTONG1104 trial. We provide a potential immune biomarker for EGFR-mutant NSCLC patients who might benefit from an adjuvant EGFR-TKI. [ABSTRACT FROM AUTHOR]

Background: Activated immune cells (IC) in the tumor microenvironment (TME) are critical for anti-tumor efficacy. Greater understanding of the dynamic diversity and crosstalk between IC is needed to clarify their association with immune checkpoint inhibitor efficacy. Methods: Patients from three tislelizumab monotherapy trials in solid tumors (NCT02407990, NCT04068519, NCT04004221) were retrospectively divided into subgroups by CD8+ T-cell and macrophage (Mφ) levels, assessed via multiplex immunohistochemistry (mIHC; n = 67) or gene expression profiling (GEP; n = 629). Results: A trend of longer survival was observed in patients with both high CD8+ T-cell and Mφ levels versus other subgroups in the mIHC analysis (P = 0.11), which was confirmed with greater statistical significance in the GEP analysis (P = 0.0001). Co-existence of CD8+ T cells and Mφ was coupled with elevated CD8+ T-cell cytotoxicity, T-cell trafficking, MHC class I antigen presentation signatures/genes, and enrichment of the pro-inflammatory Mφ polarization pathway. Additionally, a high level of pro-inflammatory CD64+ Mφ density was associated with an immune-activated TME and survival benefit with tislelizumab (15.2 vs. 5.9 months for low density; P = 0.042). Spatial proximity analysis revealed that closer proximity between CD8+ T cells and CD64+ Mφ was associated with a survival benefit with tislelizumab (15.2 vs. 5.3 months for low proximity; P = 0.024). Conclusions: These findings support the potential role of crosstalk between pro-inflammatory Mφ and cytotoxic T cells in the clinical benefit of tislelizumab. Trial registration: NCT02407990, NCT04068519, NCT04004221. [ABSTRACT FROM AUTHOR]

Aim: Report the final analysis from ASTRIS, the largest real-world study of second-/later-line osimertinib in advanced/metastatic EGFR T790M non-small-cell lung cancer (NSCLC). Methods: Patients with advanced/metastatic EGFR T790M NSCLC and prior EGFR-TKI treatment, received once-daily osimertinib 80 mg. Primary end point: overall survival (OS); secondary end points: progression-free survival (PFS), time-to-treatment discontinuation (TTD) and response rate. Safety was also recorded. Results: In 3014 patients, median OS: 22.8 months (21.6–23.8), median PFS: 11.1 months (11.0–12.0), median TTD: 13.5 months (12.6–13.9), and response rate: 57.3% (55.5–59.2). All end points reported with 95% CIs. Numerically longer median OS was observed in patients with baseline WHO performance status <2 versus 2 (24.0 vs 11.1 months) and those without versus with brain/leptomeningeal metastases (25.4 vs 18.0 months). No new safety signals were identified. Conclusion: Second-/later-line osimertinib demonstrated real-world clinical benefit and safety in advanced/metastatic EGFR T790M NSCLC. Clinical Trial Registration:NCT02474355 (ClinicalTrials.gov) Osimertinib is a drug that blocks the activity of a protein called EGFR on cancer cells, reducing their growth and spread. ASTRIS is the largest real-world study that evaluated the outcomes with osimertinib treatment for patients with advanced non-small-cell lung cancer (NSCLC), and the EGFR T790M mutation, who had received previous treatment for their cancer. There were 3014 patients included in this study. The main aim of this study was to measure the time at which half of the patients were still alive after starting osimertinib treatment, this was 22.8 months. The study also measured the time at which half of the patients had experienced worsening (progression) of their cancer (11.1 months) and the time when half of the patients had stopped receiving osimertinib treatment (13.5 months). None of the patients experienced any unexpected side effects of the treatment. These data are consistent with those observed in comparable clinical trials with osimertinib, supporting the use of osimertinib treatment for patients with advanced NSCLC and the EGFR T790M mutation after their initial cancer treatment has stopped working. [ABSTRACT FROM AUTHOR]

Objective: NF1 is a tumor suppressor gene that encodes the neurofibromin protein and negatively regulates Ras signaling. This study was aimed to investigate the molecular, clinical characteristics, and prognostic features of NF1 gene in EGFR mutant lung cancer patients. Method: The next‐generation sequencing (NGS) was used to analyze the data from lung cancer patients in the Guangdong Lung Cancer Institute (GLCI) from June 2016 to December 2020. Results: Somatic NF1 mutations were present in 4.2% (135/3220) of Chinese lung cancer patients. NF1 mutations where clearly enriched in older (p < 0.001), male (p < 0.001), and smoking (p < 0.001) patients. Patients with NF1 mutations were more likely to have TP53 (p = 0.003), BRAF (p = 0.001) and RASA1 (p = 0.026) mutations and mutually exclusive with EGFR mutations (p = 0.006). TP53 mutation had worsen prognosis in cases of NF1 mutant (p = 0.026) or EGFR/NF1 co‐mutant (p = 0.031) lung adenocarcinomas (LUAD) patients. There was no effect on overall survival (OS) in LUAD patients with and without NF1 mutations, even in LUAD driver‐gene negative patients. NF1/EGFR co‐mutation patients had a longer OS than a single mutation of either the EGFR gene (median OS: 47.7 m vs. 30.2 m, hazard ratio [95% CI], 0.47 [0.30–0.74], p = 0.004) or NF1 gene (47.7 m vs. 19.0 m, 0.44 [0.27–0.73], p = 0.003). Furthermore, NF1 mutations significantly prolonged OS in EGFR mutant/TP53 wild‐type LUAD patients (106.5 m vs. 25.5 m, 0.28 [0.13–0.59], p = 0.003) but not in patients with EGFR/TP53 co‐mutations (36.8 m vs. 30.2 m, 0.70 [0.39–1.26], p = 0.280). Conclusion: Our results indicated NF1 mutations served as a good prognostic factor in EGFR mutant/TP53 wild‐type lung cancer patients in this single‐center study. TP53 mutation was obviously enriched in NF1 mutant patients and had shorter OS. [ABSTRACT FROM AUTHOR]

The evolution of immune profile from primary tumors to distant and local metastases in non-small cell lung cancer (NSCLC), as well as the impact of the immune background of primary tumors on metastatic potential, remains unclear. To address this, we performed whole-exome sequencing and immunohistochemistry for 73 paired primary and metastatic tumor samples from 41 NSCLC patients, and analyzed the change of immune profile from primary tumors to metastases and involved genetic factors. We found that distant metastases tended to have a decreased CD8+ T cell level along with an increased chromosomal instability (CIN) compared with primary tumors, which was partially ascribed to acquired DNA damage repair (DDR) deficiency. Distant metastases were characterized by immunosuppression (low CD8+ T cell level) and immune evasion (high PD-L1 level) whereas local metastases (pleura) were immune-competent with high CD8+ T cell, low CD4+ T cell and low PD-L1 level. Primary tumors with high levels of CD4+ T cells were associated with distant metastases rather than local metastases. Analysis of TCGA data and a single-cell RNA-sequencing dataset revealed a decreasing trend of major immune cells, such as CD8+ T cells, and an increasing trend of CD4 T helper cells (Th2 and Th1) in primary tumors with metastases from local to distant sites. Our study indicates that there are differences in the immune evolution between distant and local metastases, and that acquired DDR deficiency contributes to the immunosuppression in distant metastases of NSCLC. Moreover, the immune background of primary tumors may affect their metastatic potential. [ABSTRACT FROM AUTHOR]

Simple Summary: Targeted therapy has revolutionized the treatment of non-small cell lung cancer (NSCLC) and MET inhibition is a promising therapy for MET-dysregulated NSCLC. However, due to the lack of effective biomarkers, the clinical efficacy is unsatisfactory. This study aims to investigate the clinical utility of plasma proteomics-derived biomarkers for MET-dysregulated NSCLC (including MET amplification and MET overexpression). We analyzed 89 longitudinal plasma samples from MET-dysregulated advanced-stage NSCLC patients treated with MET inhibitors by the method of mass spectrometry. The results showed that the peripheral plasma proteomic characteristics were associated with the outcomes of patients treated with MET inhibitors. Through biomarker selection, we found a four plasma protein signature (MYH9, GNB1, ALOX12B, and HSD17B4 proteins) could predict the response and progression-free survival of patients treated with MET inhibitors with high accuracy. This study highlighted the clinical utilization of plasma biomarkers to scream patients to receive MET inhibitors. MET inhibitors have shown promising efficacy for MET-dysregulated non-small cell lung cancer (NSCLC). However, quite a few patients cannot benefit from it due to the lack of powerful biomarkers. This study aims to explore the potential role of plasma proteomics-derived biomarkers for patients treated with MET inhibitors using mass spectrometry. We analyzed the plasma proteomics from patients with MET dysregulation (including MET amplification and MET overexpression) treated with MET inhibitors. Thirty-three MET-dysregulated NSCLC patients with longitudinal 89 plasma samples were included. We classified patients into the PD group and non-PD group based on clinical response. The baseline proteomic profiles of patients in the PD group were distinct from those in the non-PD group. Through protein screening, we found that a four-protein signature (MYH9, GNB1, ALOX12B, HSD17B4) could predict the efficacy of patients treated with MET inhibitors, with an area under the curve (AUC) of 0.93, better than conventional fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) tests. In addition, combining the four-protein signature with FISH or IHC test could also reach higher predictive performance. Further, the combined signature could predict progression-free survival for MET-dysregulated NSCLC (p < 0.001). We also validated the performance of the four-protein signature in another cohort of plasma using an enzyme-linked immunosorbent assay. In conclusion, the four plasma protein signature (MYH9, GNB1, ALOX12B, and HSD17B4 proteins) might play a substitutable or complementary role to conventional MET FISH or IHC tests. This exploration will help select patients who may benefit from MET inhibitors. [ABSTRACT FROM AUTHOR]

Background: Nivolumab has been approved in China as second-line treatment for advanced non-small-cell lung cancer (NSCLC) via weight-based infusion, based on the CheckMate 078 study. We investigated the safety and efficacy of 240 mg flat-dose nivolumab in patients with advanced NSCLC, including those with hepatitis B virus (HBV) and epidermal growth factor receptor (EGFR) mutation/ALK receptor tyrosine kinase (ALK) translocation due to high prevalence in China. Methods: CheckMate 870 was a single-arm, open-label, phase IIIb trial in Asian (primarily Chinese) patients with previously treated advanced NSCLC. Patients received flat-dose nivolumab 240 mg every 2 weeks (Q2W) for up to 2 years. The primary endpoint was the incidence and severity of treatment-related select adverse events (TRsAEs) in non-HBV patients; secondary and exploratory endpoints included severity of high-grade TRsAEs in HBV-infected patients, and safety, efficacy and patient-reported outcomes (PROs) in the whole population. Results: Out of 404 patients enrolled, 400 received treatment. Median (standard deviation) age was 60.5 (8.68) years and the majority were male (78.5%). At a median follow-up of 37.6 months, no Grade 5 TRsAEs were reported, and the frequency of Grade 3–4 TRsAEs was low (0.0–5.9%) in non-HBV and HBV NSCLC patients. Median overall survival (OS) and progression-free survival (PFS) in all treated patients were 14.7 (12.3–18.1) and 3.6 (2.3–3.8) months, respectively. Median OS was 14.2 (12.3–18.1) and 22.3 (10.0–NA) months for non-HBV and HBV-infected patients, 19.3 (11.2–31.7) and 13.7 (11.5–18.1) months for EGFR -positive and wild-type subgroups, and 19.3 (12.9–23.5) and 13.3 (10.9–17.7) months for those with programmed death-ligand 1 (PD-L1) expression ⩾1% and <1%, respectively. No notable changes from baseline were observed in PROs throughout the study. Conclusion: Nivolumab 240 mg infusion Q2W was well tolerated, efficacious, and maintained health status and quality of life in Asian patients with previously treated advanced NSCLC regardless of HBV, EGFR, or PD-L1 status. [ABSTRACT FROM AUTHOR]

Background: Sublobectomy for early‐stage non‐small cell lung cancer (NSCLC) remains a matter of debate. This study aimed to discuss the feasibility of sublobectomy in patients with pathological‐stage IA1‐2 confirmed as pathologically invasive but radiologically noninvasive adenocarcinoma. Methods: From 2011 to 2019, we screened clinical stage IA1–IA2 lung cancer patients who underwent surgery at the Guangdong Provincial People's Hospital (GDPH). Inclusion criteria were maximum tumor diameter of 2.0 cm or less, consolidation tumor ratio (CTR) ≤ 0.25, and pathologically confirmed invasive adenocarcinoma. Sublobectomy (segmentectomy and wedge resection) and lobectomy groups were created, and propensity scores were computed. The primary endpoints were lung cancer‐specific overall survival (LCSS) and LCS‐ relapse‐free survival (LCS‐RFS) after adjusting propensity scores. Results: A total of 1731 patients were screened, and 100 patients were enrolled. The lobectomy group had 51 patients and the limited resection group had 49. No cases relapsed, and two patients died from nontumor causes. For the entire cohort, the 5‐year LCSS and 5‐year LCS‐RFS were 100% in the lobectomy and limited resection groups. When propensity scores matched, there were no differences in LCSS and LCS‐RFS between the two groups (LCSS:100%, LCS‐RFS 100% in lobectomy and limited resection, respectively). Discussion: Sublobectomy may be curative for pathologically invasive but radiologically noninvasive adenocarcinoma at pathological stage IA1‐2. [ABSTRACT FROM AUTHOR]

Despite limited efficacy of immunotherapy for advanced non-small-cell lung cancer (NSCLC) with driver mutations, whether neoadjuvant immunotherapy could be clinically valuable in those patients warrants further investigation. We utilized 40 oncogene-mutant NSCLC treated with induction immunotherapy from a large consecutive multicenter cohort. Overall response rate was 62.5% while 2 patients had disease progression. Of 39 patients that received surgery, R0 resection rate was 97.4%. The major pathological response (MPR) rate was 37.5% and the pathological complete response (pCR) rate was 12.5%. Pre-treatment PD-L1 expression was not a predictive biomarker in these patients. Median disease-free survival for all oncogenic mutation and EGFR mutation was 28.5 months. Indirect comparison through integrating CTONG1103 cohort showed neoadjuvant immunotherapy plus chemotherapy yielded the most superior efficacy among erlotinib and chemotherapy for resectable EGFR-mutant NSCLC. No MPR patients were identified with neoadjuvant immunotherapy plus chemotherapy for uncommon EGFR insertion or point mutations. Our results indicated the potential clinical feasibility of neoadjuvant immunotherapy for resectable localized oncogene-mutant NSCLC especially for EGFR-mutant NSCLC. [ABSTRACT FROM AUTHOR]

Selpercatinib, a first-in-class, highly selective and potent central nervous system-active RET kinase inhibitor demonstrated clinically meaningful activity with manageable toxicity in pretreated and treatment-naive advanced/metastatic RET fusion-positive non-small-cell lung cancer (NSCLC). LIBRETTO-432 is a global, randomized, double-blind, phase III trial evaluating selpercatinib versus placebo in stage IB-IIIA, RET fusion-positive NSCLC, previously treated with definitive surgery or radiation; participants must have undergone available anti-cancer therapy (including chemotherapy or durvalumab) or not be suitable for it, per investigator's discretion. The primary end point is investigator-assessed event-free survival (EFS) in the primary analysis population (stage II-IIIA RET fusion-positive NSCLC). Key secondary end points include EFS in the overall population, overall survival, and time to distant disease recurrence in the central nervous system. Selpercatinib is approved in multiple countries for the treatment of advanced or metastatic RET-altered lung cancers. Selpercatinib has shown promising efficacy and safety results in patients with advanced/metastatic RET fusion-positive NSCLC. This is a summary of the LIBRETTO-432 study which compares selpercatinib with placebo in patients with earlier stages (stage IB-IIIA) of RET fusion-positive NSCLC, who have already undergone surgery or radiotherapy and applicable adjuvant chemotherapy. This study is active and currently recruiting new participants. This trial will evaluate how long people live without evidence of cancer recurrence, both during and after treatment. Side effects will also be evaluated in this study. Clinical Trial Registration: NCT04819100 (ClinicalTrials.gov) [ABSTRACT FROM AUTHOR]

Major pathological response (MPR) is a potential surrogate for overall survival. We determined whether the dynamic changes in 18F‐labeled fluoro‐2‐deoxyglucose positron emission tomography/computed tomography (18F‐FDG PET/CT) were associated with MPR in patients receiving neoadjuvant immunotherapy. Forty‐four patients with stage II–III non‐small cell lung cancer (NSCLC) who received neoadjuvant immunotherapy and radical surgery were enrolled. Moreover, 18F‐FDG PET/CT scans were performed at baseline and within 1 week before surgery to evaluate the disease. All histological sections were reviewed to assess MPR. The detailed clinical features of the patients were analyzed. The reliability of the clinical variables was assessed in differentiating between MPR and non‐MPR using logistic regression. Receiver‐operating characteristic (ROC) curve analysis identified the SUVmax changes threshold most associated with MPR. Most of the patients were pathologically diagnosed with squamous cell carcinoma and received anti‐PD‐1 antibodies plus chemotherapy. The immunotherapy regimens included nivolumab, pembrolizumab, and camrelizumab. MPR was observed in more than half of lesions. Tumors with MPR had a higher decrease in the longest dimension on dynamic PET/CT than those without MPR. Furthermore, the decline in SUVmax was significantly different between MPR and non‐MPR diseases, and MPR lesions had a prominent mean reduction in SUVmax. SUVmax reduction was independently associated with MPR in the multivariate regression. On ROC analysis, the threshold of SUVmax decrease in 60% was associated with MPR. Dynamic changes in SUVmax were associated with MPR. The tumors with MPR showed a greater PET/CT response than those without MPR. A SUVmax decrease of more than 60% is more likely to result in an MPR after receiving neoadjuvant immunotherapy. [ABSTRACT FROM AUTHOR]

Selpercatinib, a first-in-class, highly selective and potent central nervous system-active RET kinase inhibitor demonstrated clinically meaningful activity with manageable toxicity in pretreated and treatment-naive advanced/metastatic RET fusion-positive non-small-cell lung cancer (NSCLC). LIBRETTO-432 is a global, randomized, double-blind, phase III trial evaluating selpercatinib versus placebo in stage IB-IIIA, RET fusion-positive NSCLC, previously treated with definitive surgery or radiation; participants must have undergone available anti-cancer therapy (including chemotherapy or durvalumab) or not be suitable for it, per investigator's discretion. The primary end point is investigator-assessed event-free survival (EFS) in the primary analysis population (stage II-IIIA RET fusion-positive NSCLC). Key secondary end points include EFS in the overall population, overall survival, and time to distant disease recurrence in the central nervous system. [ABSTRACT FROM AUTHOR]

Opinion Statement: Tyrosine kinase inhibitors (TKIs) have dramatically improved tumor response rates and survival benefits in advanced oncogenic non-small-cell lung cancer (NSCLC). Given the impressive success, a renewed interest has been raised in the study of these agents in the perioperative setting. Preliminary data have shown dramatic effectiveness compared to conventional chemotherapy. Given the explicit need to induce durable responses and raise cure rates, we summarize the current progression, identify key challenges, and raise potential opportunities for perioperative targeted therapy that range from precise biomarkers to optimal adjuvant regimens for individual patients. As perioperative treatment indeed provides researchers with a unique platform to address the challenges mentioned above, investigators could obtain a comprehensive analysis of genomic profiling and trace resistance mechanisms. Multidisciplinary collaboration and adaptive clinical trial designs are warranted to integrate translational research into personalized perioperative TKI treatment paradigms. [ABSTRACT FROM AUTHOR]

Objective: In recent years, the lung cancer incidence has grown and the population is younger. We intend to find out the true detection rate of pulmonary nodules and the incidence of lung cancer in the population and search for the risk factors. Method: Hospital employees ≥40 years old who underwent low‐dose computed tomography (CT) lung cancer screening from January 2019 to March 2022 were selected to record CT‐imaging characteristics, pathology, staging, and questionnaires to investigate past history, smoking history, diet, mental health, etc. PM2.5 and radiation intake in radiation‐related occupation received monitoring in hospital. Result: The detection rate of suspicious pulmonary nodules was 9.1% (233/2552), and the incidence rate of lung cancer (including adenocarcinoma in situ) was 4.0% (103/2552). Morbidity among doctors, nurses, technicians, administers, and logistics was no difference (p = 0.184), but higher in women than in men (4.7% vs 2.4% p = 0.002). The invasiveness increased with age and CT density of nodules (p = 0.018). The relationship between lung cancer morbidity and PM2.5 was not clear (p = 0.543); and no lung cancer has been found in employees related ionizing radiation. Conclusion: The high screening rate has brought about a high incidence of lung cancer. At present, the risk factor analysis of lung cancer based on small samples cannot find the direct cause. Most of the ground glass opacity (GGO)s detected by LDCT screening are indolent, but there are also rapidly progressive lung cancer. A predictive model to identify active and indolent GGO is necessary. [ABSTRACT FROM AUTHOR]