Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK-positive non-small-cell lung cancer (NSCLC). Data on the efficacy and safety of adjuvant alectinib as compared with chemotherapy in patients with resected ALK-positive NSCLC are lacking. METHODS: We conducted a global, phase 3, open-label, randomized trial in which patients with completely resected, ALK-positive NSCLC of stage IB (tumors ≥4 cm), II, or IIIA (as classified according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer and Union for International Cancer Control) were randomly assigned in a 1:1 ratio to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy in four 21-day cycles. The primary end point was disease-free survival, tested hierarchically among patients with stage II or IIIA disease and then in the intention-to-treat population. Other end points included central nervous system (CNS) disease-free survival, overall survival, and safety. RESULTS: In total, 257 patients were randomly assigned to receive alectinib (130 patients) or chemotherapy (127 patients). The percentage of patients alive and disease-free at 2 years was 93.8% in the alectinib group and 63.0% in the chemotherapy group among patients with stage II or IIIA disease (hazard ratio for disease recurrence or death, 0.24; 95% confidence interval [CI], 0.13 to 0.45; P<0.001) and 93.6% and 63.7%, respectively, in the intention-to-treat population (hazard ratio, 0.24; 95% CI, 0.13 to 0.43; P<0.001). Alectinib was associated with a clinically meaningful benefit with respect to CNS disease-free survival as compared with chemotherapy (hazard ratio for CNS disease recurrence or death, 0.22; 95% CI, 0.08 to 0.58). Data for overall survival were immature. No unexpected safety findings were observed. CONCLUSIONS: Among patients with resected ALK-positive NSCLC of stage IB, II, or IIIA, adjuvant alectinib significantly improved disease-free survival as compared with platinum-based chemotherapy. (Funded by F. Hoffmann-La Roche; ALINA ClinicalTrials.gov number, NCT03456076.).

Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC.

BACKGROUND: Among patients with resected, epidermal growth factor receptor (EGFR)-mutated, stage IB to IIIA non-small-cell lung cancer (NSCLC), adjuvant osimertinib therapy, with or without previous adjuvant chemotherapy, resulted in significantly longer disease-free survival than placebo in the ADAURA trial. We report the results of the planned final analysis of overall survival. METHODS: In this phase 3, double-blind trial, we randomly assigned eligible patients in a 1:1 ratio to receive osimertinib (80 mg once daily) or placebo until disease recurrence was observed, the trial regimen was completed (3 years), or a discontinuation criterion was met. The primary end point was investigator-assessed disease-free survival among patients with stage II to IIIA disease. Secondary end points included disease-free survival among patients with stage IB to IIIA disease, overall survival, and safety. RESULTS: Of 682 patients who underwent randomization, 339 received osimertinib and 343 received placebo. Among patients with stage II to IIIA disease, the 5-year overall survival was 85% in the osimertinib group and 73% in the placebo group (overall hazard ratio for death, 0.49; 95.03% confidence interval [CI], 0.33 to 0.73; P<0.001). In the overall population (patients with stage IB to IIIA disease), the 5-year overall survival was 88% in the osimertinib group and 78% in the placebo group (overall hazard ratio for death, 0.49; 95.03% CI, 0.34 to 0.70; P<0.001). One new serious adverse event, pneumonia related to coronavirus disease 2019, was reported after the previously published data-cutoff date (the event was not considered by the investigator to be related to the trial regimen, and the patient fully recovered). Adjuvant osimertinib had a safety profile consistent with that in the primary analysis. CONCLUSIONS: Adjuvant osimertinib provided a significant overall survival benefit among patients with completely resected, EGFR-mutated, stage IB to IIIA NSCLC. (Funded by AstraZeneca; ADAURA ClinicalTrials.gov number, NCT02511106.).

Correlation of distribution characteristics and dynamic changes of gut microbiota with the efficacy of immunotherapy in EGFR-mutated non-small cell lung cancer.

BACKGROUND: The effects of gut microbiota and metabolites on the responses to immune checkpoint inhibitors (ICIs) in advanced epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) have been studied. However, their effects on EGFR-mutated (EGFR +) NSCLC remain unknown. METHODS: We prospectively recorded the clinicopathological characteristics of patients with advanced EGFR + NSCLC and assessed potential associations between the use of antibiotics or probiotics and immunotherapy efficacy. Fecal samples were collected at baseline, early on-treatment, response and progression status and were subjected to metagenomic next-generation sequencing and ultra-high-performance liquid chromatography-mass spectrometry analyses to assess the effects of gut microbiota and metabolites on immunotherapy efficacy. RESULTS: The clinical data of 74 advanced EGFR + NSCLC patients were complete and 18 patients' fecal samples were dynamically collected. Patients that used antibiotics had shorter progression-free survival (PFS) (mPFS, 4.8 vs. 6.7 months; P = 0.037); probiotics had no impact on PFS. Two dynamic types of gut microbiota during immunotherapy were identified: one type showed the lowest relative abundance at the response time point, whereas the other type showed the highest abundance at the response time point. Metabolomics revealed significant differences in metabolites distribution between responders and non-responders. Deoxycholic acid, glycerol, and quinolinic acid were enriched in responders, whereas L-citrulline was enriched in non-responders. There was a significant correlation between gut microbiota and metabolites. CONCLUSIONS: The use of antibiotics weakens immunotherapy efficacy in patients with advanced EGFR + NSCLC. The distribution characteristics and dynamic changes of gut microbiota and metabolites may indicate the efficacy of immunotherapy in advanced EGFR + NSCLC.

A novel image deep learning-based sub-centimeter pulmonary nodule management algorithm to expedite resection of the malignant and avoid over-diagnosis of the benign.

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.

HERTHENA-Lung02: phase III study of patritumab deruxtecan in advanced EGFR-mutated NSCLC after a third-generation EGFR TKI.

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.

Spontaneous regression of migrated ventriculoperitoneal shunt catheter from scrotum to peritoneum: a case-based review.

OBJECTIVE: The incidence of scrotal migration of a ventriculoperitoneal shunt (VPS) catheter is rare and may lead to life-threatening visceral complications. Management requires prompt removal of the migrated portion of the shunt and closure of the scrotal sac. We report an interesting case of a young child who presented with asymptomatic unilateral swelling of his scrotum secondary to a migrated VPS catheter. A repeat X-ray prior to his surgery to remove the migrated catheter showed that the entire length of the distal VPS catheter was back in the peritoneal cavity. In view of this unusual phenomenon, the case is discussed in corroboration with published literature. METHODS AND RESULTS: A systematic search of publications in the English language is performed in PubMed and Google Scholar. Our findings show that there are 49 reported cases (including our patient) of scrotal migration of shunt catheters in patients less than 18 years old. There is only 1 other case of spontaneous resolution of shunt catheter from the scrotum. Favoured management of choice is repositioning the distal shunt catheter back into the peritoneal cavity and herniotomy in the same setting, if possible. Overall, the literature suggests this is a shunt-related complication that has a good prognosis if intervention is timely. CONCLUSION: Scrotal migration of a VPS catheter is a rare but potentially life-threatening complication in children. Our case report highlights the role of updated preoperative imaging and the need for consistent long-term shunt surveillance in children.

Neonatal intracranial haemorrhage secondary to vein of Galen aneurysmal dilatation.

Paediatric neurovascular anomalies associated with the vein of Galen (VG) comprise of a spectrum of rare, complex, and life-threatening conditions. In this group, the "vein of Galen aneurysmal dilatation" (VGAD) is a distinct entity that often presents with progressive neurological symptoms in older children. Acute haemorrhage in VGAD is uncommon. We present an unusual presentation of VGAD in a neonate and discuss the challenges faced in the management.

IMpower210: A phase III study of second-line atezolizumab vs. docetaxel in East Asian patients with non-small cell lung cancer.

Objective: IMpower210 (NCT02813785) explored the efficacy and safety of single-agent atezolizumab vs. docetaxel as second-line treatment for advanced non-small cell lung cancer (NSCLC) in East Asian patients. Methods: Key eligibility criteria for this phase III, open-label, randomized study included age ≥18 years; histologically documented advanced NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system (7th edition); Eastern Cooperative Oncology Group performance status of 0 or 1; and disease progression following platinum-based chemotherapy for advanced or metastatic NSCLC. Patients were randomized 2:1 to receive either atezolizumab (1,200 mg) or docetaxel (75 mg/m2). The primary study endpoint was overall survival (OS) in the intention-to-treat (ITT) population with wild-type epidermal growth factor receptor expression (ITT EGFR-WT) and in the overall ITT population. Results: Median OS in the ITT EGFR-WT population (n=467) was 12.3 [95% confidence interval (95% CI), 10.3-13.8] months in the atezolizumab arm (n=312) and 9.9 (95% CI, 7.8-13.9) months in the docetaxel arm [n=155; stratified hazard ratio (HR), 0.82; 95% CI, 0.66-1.03]. Median OS in the overall ITT population was 12.5 (95% CI, 10.8-13.8) months with atezolizumab treatment and 11.1 (95% CI, 8.4-14.2) months (n=377) with docetaxel treatment (n=188; stratified HR, 0.87; 95% CI, 0.71-1.08). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 18.4% of patients in the atezolizumab arm and 50.0% of patients in the docetaxel arm. Conclusions: IMpower210 did not meet its primary efficacy endpoint of OS in the ITT EGFR-WT or overall ITT populations. Atezolizumab was comparatively more tolerable than docetaxel, with a lower incidence of grade 3/4 TRAEs.

Efficacy and safety of pralsetinib in patients with advanced RET fusion-positive non-small cell lung cancer.

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.

Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer.

BACKGROUND: Osimertinib is standard-of-care therapy for previously untreated epidermal growth factor receptor (EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC). The efficacy and safety of osimertinib as adjuvant therapy are unknown. METHODS: In this double-blind, phase 3 trial, we randomly assigned patients with completely resected EGFR mutation-positive NSCLC in a 1:1 ratio to receive either osimertinib (80 mg once daily) or placebo for 3 years. The primary end point was disease-free survival among patients with stage II to IIIA disease (according to investigator assessment). The secondary end points included disease-free survival in the overall population of patients with stage IB to IIIA disease, overall survival, and safety. RESULTS: A total of 682 patients underwent randomization (339 to the osimertinib group and 343 to the placebo group). At 24 months, 90% of the patients with stage II to IIIA disease in the osimertinib group (95% confidence interval [CI], 84 to 93) and 44% of those in the placebo group (95% CI, 37 to 51) were alive and disease-free (overall hazard ratio for disease recurrence or death, 0.17; 99.06% CI, 0.11 to 0.26; P<0.001). In the overall population, 89% of the patients in the osimertinib group (95% CI, 85 to 92) and 52% of those in the placebo group (95% CI, 46 to 58) were alive and disease-free at 24 months (overall hazard ratio for disease recurrence or death, 0.20; 99.12% CI, 0.14 to 0.30; P<0.001). At 24 months, 98% of the patients in the osimertinib group (95% CI, 95 to 99) and 85% of those in the placebo group (95% CI, 80 to 89) were alive and did not have central nervous system disease (overall hazard ratio for disease recurrence or death, 0.18; 95% CI, 0.10 to 0.33). Overall survival data were immature; 29 patients died (9 in the osimertinib group and 20 in the placebo group). No new safety concerns were noted. CONCLUSIONS: In patients with stage IB to IIIA EGFR mutation-positive NSCLC, disease-free survival was significantly longer among those who received osimertinib than among those who received placebo. (Funded by AstraZeneca; ADAURA ClinicalTrials.gov number, NCT02511106.).

Identification of TCR rearrangements specific for genetic alterations in EGFR-mutated non-small cell lung cancer: results from the ADJUVANT-CTONG1104 trial.

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 TCRß 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 Vß20-1Jß2-3 specifically for EGFR exon 19 del or Vß9Jß2-1 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 Vß20-1Jß2-3 and Vß9Jß2-1 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 Vß20-1Jß2-3 or Vß9Jß2-1 may be an immune biomarker for guiding adjuvant gefitinib decisions for NSCLC patients harboring EGFR exon 19 del or EGFR exon 21 L858R.

PLEK2 and IFI6, representing mesenchymal and immune-suppressive microenvironment, predicts resistance to neoadjuvant immunotherapy in esophageal squamous cell carcinoma.

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.

Neoadjuvant Camrelizumab for Non-Small Cell Lung Cancer: A Retrospective Multicenter, Real-World Study (CTONG2004).

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.

Heterogeneity in the immune microenvironment of bone metastasis in driver-positive non-small cell lung cancer.

Mutations in epidermal growth factor receptor and anaplastic lymphoma kinase are common driver events in non-small cell lung cancer (NSCLC), which are associated with a high frequency of bone metastases (BMs). While the bone marrow represents a specialized immune microenvironment, the immune repertoire of BMs remains unknown. Considering the higher incidence of BMs in driver gene-positive NSCLCs, and the unique biology of the bone, herein, we assessed the infiltrating immune cells and T cell receptor (TCR) profile of BMs in driver-positive NSCLCs. Immune profile of BMs in driver gene-positive NSCLC were assessed in 10 patients, where 6 had driver gene-positive mutation. TCR and bulk RNA sequencing were performed on malignant bone samples. The diversity and clonality of the TCR repertoire were analyzed. The cellular components were inferred from bulk gene expression profiles computationally by CIBERSORT. Although BMs were generally regarded as immune-cold tumors, immune cell composition analyses showed co-existence of cytotoxic and suppressor immune cells in driver-positive BM samples, as compared to primary lung. Analysis of the TCR repertoire indicated a trend of higher diversity and similar clonality in the driver-positive compared with the driver-negative subsets. In addition, we identified two cases that showed the opposite response to immune checkpoint blockade. A comparison of these two patients' BM samples showed more highly amplified clones, fewer M2 macrophages and more activated natural killer cells in the responder. In summary, BMs in NSCLC are heterogeneous in their immune microenvironment, which might be related to differential clinical outcomes to immune checkpoint blockade.

Expression Changes in Programmed Death Ligand 1 from Precancerous Lesions to Invasive Adenocarcinoma in Subcentimeter Pulmonary Nodules: A Large Study of 2022 Cases in China.

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.

Plain language summary of the updated results from the CROWN study comparing lorlatinib with crizotinib in people with advanced non-small-cell lung cancer.

WHAT IS THIS SUMMARY ABOUT?: This summary shows the updated results of an ongoing research study called CROWN that was published in The Lancet Respiratory Medicine in December 2022. In the CROWN study, researchers looked at the effects of two study medicines called lorlatinib and crizotinib. The study included people with advanced non-small-cell lung cancer (NSCLC) that had not been treated previously. All people in the study had cancer cells with changes (known as alterations) in a gene called anaplastic lymphoma kinase, or ALK. This ALK gene is involved in cancer growth. In this updated study, researchers looked at the continued benefit in people who took lorlatinib compared with people who took crizotinib after 3 years. WHAT DID THIS STUDY FIND?: After 3 years of being observed, people who took lorlatinib were more likely to be alive without their cancer getting worse than people who took crizotinib. At 3 years, 64% of people who took lorlatinib were alive without their cancer getting worse compared with 19% of people who took crizotinib. The cancer was less likely to have spread within or to the brain in people who took lorlatinib than in people who took crizotinib. After 3 years of being observed, 61% of people were still taking lorlatinib and 8% of people were still taking crizotinib. People who took lorlatinib had more severe side effects than people who took crizotinib. However, these side effects were manageable. The most common side effects with lorlatinib were high levels of cholesterol or high levels of triglycerides (a type of fat) in the blood. Life-threatening side effects were seen in 13% of people who took lorlatinib and 8% in crizotinib. Two people who took lorlatinib died because of side effects from lorlatinib. WHAT DO THE RESULTS OF THE STUDY MEAN?: The updated results from the CROWN study showed that a larger percentage of people who took lorlatinib continued to benefit from their treatment after being observed for 3 years compared with those who took crizotinib.

A real-world study of second or later-line osimertinib in patients with EGFR T790M-positive NSCLC: the final ASTRIS data.

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.

Clinical nurse adherence to professional ethics: A grounded theory.

BACKGROUND: Professional ethics is the regulation and discipline of nurses' daily nursing work. Nurses often encounter various ethical challenges and problems in their clinical work, but there are few studies on nurses' adherence to professional ethics. RESEARCH AIM: An analysis of nursing adherence to nursing ethics from the perspective of clinical nurses in the Chinese public health system. RESEARCH DESIGN: This study adopts the grounded theory approach proposed by Strauss and Corbin. PARTICIPANTS AND RESEARCH CONTEXT: Between July 2021 and January 2022, Clinical nurses were recruited for online video interviews using purposive and theoretical sampling methods in seven hospitals in Beijing, Tianjin, Shanxi, Henan, Guangdong, and Fujian, China. Data analysis was conducted using Strauss and Corbin's coding approach. ETHICAL CONSIDERATIONS: This study was approved by the Ethics Committee of Sanming First Hospital (MingYiLun 71/2021). FINDINGS: A total of 27 participants were included. A theoretical model of nursing staff adherence to professional ethics was constructed. The main core was adherence to professional ethics and the other cores were (1) causal conditions: professional ethics code, individual conscience; (2) intervening conditions: personal growth, social support system, matching career compensation, prediction of adverse consequences; (3) action strategies: sticking to professional values, self-regulation, flexible response, post-event improvement; and (4) outcomes: self-harmony, reduced medical disputes. CONCLUSIONS: This study provides an interpretive understanding of why clinical nurses adhere to professional ethics in China and describes the challenges and issues posed by nurses' use of strategies to cope with ethical adversity. The findings can be used to develop future complex studies.

Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial.

BACKGROUND: A substantial proportion of patients with unresectable stage III non-small-cell lung cancer (NSCLC) cannot either tolerate or access concurrent chemoradiotherapy, so sequential chemoradiotherapy is commonly used. We assessed the efficacy and safety of sugemalimab, an anti-PD-L1 antibody, in patients with stage III NSCLC whose disease had not progressed after concurrent or sequential chemoradiotherapy. METHODS: GEMSTONE-301 is a randomised, double-blind, placebo-controlled, phase 3 trial in patients with locally advanced, unresectable, stage III NSCLC, done at 50 hospitals or academic research centres in China. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 who had not progressed after concurrent or sequential chemoradiotherapy. We randomly assigned patients (2:1, using an interactive voice-web response system) to receive sugemalimab 1200 mg or matching placebo, intravenously every 3 weeks for up to 24 months. Stratification factors were ECOG performance status, previous chemoradiotherapy, and total radiotherapy dose. The investigators, trial coordination staff, patients, and study sponsor were masked to treatment allocation. The primary endpoint was progression-free survival as assessed by blinded independent central review (BICR) in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of assigned study treatment. The study has completed enrolment and the results of a preplanned analysis of the primary endpoint are reported here. The trial is registered with ClinicalTrials.gov, NCT03728556. FINDINGS: Between Aug 30, 2018 and Dec 30, 2020, we screened 564 patients of whom 381 were eligible. Study treatment was received by all patients randomly assigned to sugemalimab (n=255) and to placebo (n=126). At data cutoff (March 8, 2021), median follow-up was 14·3 months (IQR 6·4-19·4) for patients in the sugemalimab group and 13·7 months (7·1-18·4) for patients in the placebo group. Progression-free survival assessed by BICR was significantly longer with sugemalimab than with placebo (median 9·0 months [95% CI 8·1-14·1] vs 5·8 months [95% CI 4·2-6·6]; stratified hazard ratio 0·64 [95% CI 0·48-0·85], p=0·0026). Grade 3 or 4 treatment-related adverse events occurred in 22 (9%) of 255 patients in the sugemalimab group versus seven (6%) of 126 patients in the placebo group, the most common being pneumonitis or immune-mediated pneumonitis (seven [3%] of 255 patients in the sugemalimab group vs one [<1%] of 126 in the placebo group). Treatment-related serious adverse events occurred in 38 (15%) patients in the sugemalimab group and 12 (10%) in the placebo group. Treatment-related deaths were reported in four (2%) of 255 patients (pneumonia in two patients, pneumonia with immune-mediated pneumonitis in one patient, and acute hepatic failure in one patient) in the sugemalimab group and none in the placebo group. INTERPRETATION: Sugemalimab after definitive concurrent or sequential chemoradiotherapy could be an effective consolidation therapy for patients with stage III NSCLC whose disease has not progressed after sequential or concurrent chemoradiotherapy. Longer follow-up is needed to confirm this conclusion. FUNDING: CStone Pharmaceuticals and the National Key Research and Development Program of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Safety, antitumor activity and biomarkers of sugemalimab in Chinese patients with advanced solid tumors or lymphomas: results from the first-in-human phase 1 trial.

BACKGROUND: This first-in-human phase 1 trial is to evaluate the safety, pharmacokinetics, preliminary efficacy, and biomarkers of sugemalimab, a full-length, fully human anti-PD-L1 monoclonal antibody, in Chinese patients with advanced malignancies. METHODS: Eligible patients with unresectable advanced or metastatic solid tumors or lymphomas were enrolled in phase 1a to receive sugemalimab following a modified 3 + 3 design. The primary endpoints included safety, tolerability, and the recommended Phase 2 dose (RP2D). In phase 1b, patients with 7 selected types of tumor received sugemalimab at the RP2D alone (monotherapy cohorts) or in combination with standard-of-care (SOC) chemotherapy (combination cohorts). The primary endpoint of phase 1b was investigator-assessed objective response rate (ORR). RESULTS: As of 19 February 2020, 29 and 178 patients were treated in phase 1a and 1b, respectively. No dose-limiting toxicities were observed in phase 1a, and the RP2D of sugemalimab was determined as 1200 mg fixed dose once every 3 weeks. Sugemalimab-related adverse events (AEs) were mostly (75.9%) grade 1-2 in phase 1a. Antitumor activity was observed across dose levels with an ORR of 24.1%. In phase 1b, 15.9% and 40.4% of patients in the monotherapy and combination cohorts, respectively, reported grade 3-5 sugemalimab-related AEs. Promising efficacy was observed in all combination cohorts, with ORRs ranging from 47.6 to 75.0%. Exploratory biomarker analysis did not indicate significant differences in responses at different PD-L1 expression/tumor mutation burden levels. CONCLUSIONS: Sugemalimab was well-tolerated and showed promising antitumor activity as monotherapy or in combination with SOC chemotherapy in advanced malignancies. This trial was registered with ClinicalTrials.gov on Oct 18, 2017, number NCT03312842.