Minjiang Chen

This case exemplifies stepwise histological transformations of an initially EGFR‐mutant lung adenocarcinoma driven by tumor lineage plasticity under therapeutic pressure. Initial resistance to osimertinib manifested as transformation to combined small‐cell lung carcinoma, associated with concurrent TP53/RB1 co‐inactivation and the acquisition of an epidermal growth factor receptor (EGFR) C797S mutation. Subsequent progression after chemotherapy featured a rare sarcomatoid transformation, with the tumor retaining the original EGFR Exon 19 deletion, supporting clonal evolution. This phenotypic shift, indicative of epithelial‐to‐mesenchymal transition (EMT), may have been associated with PTEN loss and potential activation of the PI3K/AKT/mTOR pathway. The serial emergence of neuroendocrine and sarcomatoid phenotypes underscores the critical need for rebiopsy to guide therapy and highlights the profound adaptability of EGFR‐mutant tumors, which remain a major therapeutic challenge.

Introduction: Leptomeningeal metastasis (LM) is a devastating complication of lung cancer. We investigated the clinical and molecular evolution of LM in the modern targeted‐therapy era and factors associated with post‐LM survival. Methods: We retrospectively analyzed 201 patients with cytologically confirmed lung cancer LM diagnosed between November 2012 and May 2026. Patients were classified by LM diagnosis date (2012–2016 vs. 2017–2026). Intervals from lung cancer and Stage IV diagnosis to LM were compared using the Mann–Whitney U test. Paired primary tumor and cerebrospinal fluid (CSF) molecular profiles were assessed in 80 patients. Overall survival (OS) was evaluated using Kaplan–Meier and prespecified multivariable cox analyses. Results: Adenocarcinoma accounted for 93.0% of cases. The intervals from lung cancer and Stage IV diagnosis to LM were longer in the later cohort (23.7 vs. 13.8 months, p < 0.001; 17.4 vs. 10.4 months, p = 0.002). Unadjusted OS from LM diagnosis did not differ significantly between eras (9.8 vs. 11.3 months, p = 0.864). Tissue‐CSF driver discordance occurred in 7/80 patients (8.75%). In multivariable analysis, later diagnostic era, smoking, and ECOG PS ≥ 2 were associated with higher mortality (adjusted HR, 1.826, p = 0.014; 1.847, p = 0.014; and 1.674, p = 0.007, respectively), whereas post‐LM third‐generation EGFR‐TKI exposure was associated with lower mortality (adjusted HR, 0.385; p < 0.001). Conclusion: The later era was associated with a longer interval to LM diagnosis but no statistically significant improvement in unadjusted post‐LM OS. Adjusted associations require cautious interpretation because of residual confounding and post‐baseline treatment bias. CSF profiling may provide clinically relevant information beyond primary tumor genotyping.

In patients with small cell lung cancer (SCLC), nutritional status is a key determinant of disease progression, treatment tolerance, and prognosis. The prognostic nutritional index (PNI), reflecting both immune and nutritional conditions, is widely used to evaluate prognostic risk, but its longitudinal monitoring is often limited by incomplete clinical data in real‐world settings. This study aimed to propose a decision‐support framework for predicting future nutritional status and improving risk screening in SCLC patients with missing data. Using PNI values and related variables from the first four follow‐up time points to predict the PNI at the fifth time point (PNI5) and evaluated the impact of different missing data imputation strategies on predictive performance. Missing PNI values were imputed using mean imputation, multiple imputation (MI), Kalman filtering, k‐nearest neighbors (KNN), and XGBoost imputation. Predictive models were developed with two machine learning algorithms: random forest (RF) and XGBoost. The RF model demonstrated better overall performance, and MI combined with RF achieved the best predictive accuracy (MAE: 2.952; RMSE: 3.727). Predicted PNI values were further translated into risk categories using a predefined threshold (PNI = 45), with overall accuracy of 93.33%, PPV 95.24%, and NPV 92.59%. Importantly, the model enabled risk assessment in patients with incomplete laboratory data, covering previously unassessable cases and reducing monitoring gaps. This study highlights the importance of appropriate imputation strategies in and provides a practical tool for continuous nutritional risk assessment and early identification of high‐risk patients in SCLC.

Purpose: Neoadjuvant chemoimmunotherapy improves outcomes in resectable non–small cell lung cancer (NSCLC), yet the spatial immune features associated with treatment response remain unclear. Patients and Methods: In this single-arm phase II trial (NCT05383716), patients with resectable NSCLC received neoadjuvant pembrolizumab plus platinum-based chemotherapy, followed by surgery and adjuvant immunotherapy. The primary endpoint was major pathologic response (MPR). Digital spatial profiling was performed on resected tumors and paired draining lymph nodes from 22 patients, with additional tumor samples collected for validation. Results: Among 80 enrolled patients, 55 underwent surgery, achieving an MPR rate of 37.5% and a pathologic complete response rate of 26.3%. Grade 3 to 4 treatment-related adverse events occurred in 26.3% of patients. Spatial transcriptomics showed that MPR tumors were enriched for T- and B-cell activation pathways and infiltration of CD8+ T cells, B cells, plasma cells, and T follicular helper cells, whereas non-MPR tumors exhibited stress adaptation and immune suppression signatures. Two immune phenotypes were identified within MPR samples: myeloid-enriched (ME) and lymphoid-enriched (LE) subtypes. The LE subtype was associated with improved response and survival in validation cohorts, whereas higher ME scores showed a trend toward poorer survival. An 18-gene LE signature was developed as a potential biomarker for adjuvant immunotherapy benefit. Conclusions: Neoadjuvant pembrolizumab plus chemotherapy demonstrated encouraging efficacy and manageable safety in resectable NSCLC. Spatial profiling identified distinct immune phenotypes associated with response and may inform patient stratification for adjuvant therapy.

Purpose:Tislelizumab, an anti–PD-1 monoclonal antibody, is approved for various indications intravenously. Subcutaneous delivery offers potential advantages in convenience and resource utilization. BGB-A317-103 assessed pharmacokinetics, safety, and efficacy of subcutaneous tislelizumab in treatment-naïve patients with advanced or metastatic non–small cell lung cancer.Patients and Methods:BGB-A317-103 is an open-label, multicenter, phase I study. In part 1 (dose/injection site exploration), patients received subcutaneous tislelizumab (abdomen or thigh injections; 300 mg) in two of the first three cycles and intravenous tislelizumab (200 mg) in the remaining cycle, followed by intravenous tislelizumab thereafter. In part 2 (dose expansion), patients received 300 mg of subcutaneous tislelizumab in the thigh in all cycles. Both parts included chemotherapy during the first four to six cycles. Pharmacokinetics, bioavailability, efficacy, immunogenicity, and safety were assessed.Results:At data cutoff (December 6, 2024), in part 1 (N = 39), subcutaneous administration yielded higher trough concentrations than intravenous [geometric means: 23.1 μg/mL (thigh), 19.5 μg/mL (abdomen), and 14.8 μg/mL (intravenously)]. Estimated bioavailability was 85.6% for thigh and 72.4% for abdomen. In part 2 (N = 22), subcutaneous tislelizumab in the thigh showed consistent pharmacokinetics with part 1. Preliminary analysis showed an overall response rate of 44.4%; the median duration of response and median progression-free survival were not reached. Tislelizumab’s safety profile was consistent with previous studies, with no new signals or injection-site reactions.Conclusions:Subcutaneous tislelizumab demonstrated high bioavailability after thigh and abdomen injections. Safety and efficacy were consistent with previous tislelizumab plus chemotherapy studies, warranting further investigation of subcutaneous tislelizumab.

Purpose: Tislelizumab, an anti–PD-1 monoclonal antibody, is approved for various indications intravenously. Subcutaneous delivery offers potential advantages in convenience and resource utilization. BGB-A317-103 assessed pharmacokinetics, safety, and efficacy of subcutaneous tislelizumab in treatment-naïve patients with advanced or metastatic non–small cell lung cancer. Patients and Methods: BGB-A317-103 is an open-label, multicenter, phase I study. In part 1 (dose/injection site exploration), patients received subcutaneous tislelizumab (abdomen or thigh injections; 300 mg) in two of the first three cycles and intravenous tislelizumab (200 mg) in the remaining cycle, followed by intravenous tislelizumab thereafter. In part 2 (dose expansion), patients received 300 mg of subcutaneous tislelizumab in the thigh in all cycles. Both parts included chemotherapy during the first four to six cycles. Pharmacokinetics, bioavailability, efficacy, immunogenicity, and safety were assessed. Results: At data cutoff (December 6, 2024), in part 1 (N = 39), subcutaneous administration yielded higher trough concentrations than intravenous [geometric means: 23.1 μg/mL (thigh), 19.5 μg/mL (abdomen), and 14.8 μg/mL (intravenously)]. Estimated bioavailability was 85.6% for thigh and 72.4% for abdomen. In part 2 (N = 22), subcutaneous tislelizumab in the thigh showed consistent pharmacokinetics with part 1. Preliminary analysis showed an overall response rate of 44.4%; the median duration of response and median progression-free survival were not reached. Tislelizumab’s safety profile was consistent with previous studies, with no new signals or injection-site reactions. Conclusions: Subcutaneous tislelizumab demonstrated high bioavailability after thigh and abdomen injections. Safety and efficacy were consistent with previous tislelizumab plus chemotherapy studies, warranting further investigation of subcutaneous tislelizumab.

Brain metastases (BMs) are common in patients with non-small-cell lung cancer (NSCLC) and remain a major therapeutic challenge. While immune checkpoint inh

Epidermal growth factor receptor (EGFR) exon 20 mutations represent a rare subset of genetic alterations in non-small cell lung cancer (NSCLC). Among them, the complex mutation H773_V774delinsLM is exceedingly uncommon, accounting for only 0.2%-1% of all EGFR mutations. It is currently believed that rare EGFR mutations are generally resistant to the first- and second-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Although the third-generation EGFR-TKIs have shown some efficacy in certain rare mutations, clinical evidence regarding their use in NSCLC patients with the H773_V774delinsLM mutation remains sparse, and their efficacy and safety are yet to be clarified. Here, we present the first documented case of a patient with EGFR H773_V774delinsLM-mutant lung adenocarcinoma who experienced remarkable tumor regression following treatment with furmonertinib. This case highlights the potential utility of furmonertinib in treating patients with this rare EGFR mutation and may provide valuable insight into emerging treatment strategies for similarly affected patients. .