Yan Xu

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.

Background: In patients receiving immune checkpoint inhibitors (ICIs), central nervous system (CNS) infections may mimic or coexist with neurological immune-related adverse events (irAEs). ICI-driven immune dysregulation has been proposed to amplify inflammation against latent pathogens (“immunotherapy infections due to dysregulated immunity”, ITI-DI), but this remains a hypothesis-generating framework rather than a validated diagnosis. Case Presentation: A 54-year-old man with stage IIIC lung adenocarcinoma developed a herpes zoster eruption and lumbosacral pain 7 days after the first infusion of pembrolizumab-containing chemoimmunotherapy, followed by rapidly progressive flaccid paraplegia, urinary incontinence, and declining consciousness. Intravenous acyclovir was not initiated until 20 days after rash onset. The first cerebrospinal fluid (CSF) sample was xanthochromic and coagulated spontaneously in the collection tube (Froin-like CSF), precluding protein measurement. A second lumbar puncture showed mild pleocytosis (8 cells/ μ L; 70% neutrophils) and undetectable glucose; varicella-zoster virus (VZV) DNA was detected in CSF by post-mortem targeted polymerase chain reaction. Spinal Magnetic resonance imaging (MRI) showed diffuse meningeal enhancement; follow-up cranial imaging showed acute hydrocephalus. Despite intravenous acyclovir, corticosteroids, and intravenous immunoglobulin, the patient died 43 days after pembrolizumab initiation. Conclusion: This case highlights VZV CNS infection as an important diagnostic consideration in ICI-treated patients who develop herpes zoster and neurological symptoms, because infection may mimic or coexist with a neurological irAE. The temporal relationship with pembrolizumab raises, but does not establish, the possibility that PD-1 blockade modified the inflammatory response. Prompt virological testing and adequately dosed antiviral therapy are central to management; the role of adjunctive immunomodulation remains uncertain and should be individualized.

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.

Background: Research on the efficacy of first-line osimertinib in non-small cell lung cancer (NSCLC) patients with different epidermal growth factor receptor (EGFR) exon 19 deletion (19del) mutation sites is limited. This study aimed to evaluate whether different EGFR 19del subtypes are associated with differential clinical outcomes in patients with EGFR-mutant NSCLC receiving first-line osimertinib therapy. Methods: This study included 106 NSCLC patients with stage IIIb–IV disease from the CAPTRA-Lung database, confirmed to have EGFR 19del mutations through next-generation sequencing (NGS) and receiving first-line osimertinib. Patients were categorized based on mutation frequencies (common E746_A750del mutation or other uncommon subtypes), the deletion start codon for the EGFR 19del (E746 or L747), and the number of deleted nucleotides (15-nucleotide deletion [15n-del] or non-15n-del). Clinical characteristics, objective response rate (ORR) and progression-free survival (PFS) were compared between these subgroups. Results: A total of 19 EGFR 19del mutation subtypes were identified. The most frequent mutation site for exon 19 deletion was E746_A750del, accounting for 56.6% of cases ( n = 60), followed by L747_P753delinsS (9.4%, n = 10), L747_T751delinsP (6.6%, n = 7), and L747_A750delinsP (4.7%, n = 5). Patients in the non-15n-del group had a higher prevalence of baseline brain metastases compared with those in the 15n-del group (41.7% vs. 22.9%; P = 0.044). No associations were found between ORR and PFS of first-line osimertinib treatment and mutation frequencies, the deletion start codon for the EGFR 19del, and the number of deleted nucleotides. However, certain subtypes, particularly L747_A750delinsP, showed a trend toward a shorter PFS compared with the common E746_A750del subtype, although these differences did not reach statistical significance (12.3 months vs. 24.3 months; P = 0.100). Conclusions: Overall, EGFR 19del subtypes showed comparable responses to first-line osimertinib. However, the trend toward poorer outcomes in the L747_A750delinsP subtype suggests potential heterogeneity that warrants confirmation in larger cohorts with longer follow-up.

The efficacy of first-line immune checkpoint inhibitor (ICI)-based therapy remains to be established for patients with advanced non-small cell lung cancer (NSCLC) harboring specific driver mutations for which effective first-line targeted therapies are unavailable. This study aims to examine the outcomes of first-line ICIs for advanced NSCLC with gene alterations in China and explore predictive factors of survival in this cohort. This retrospective study analyzed pathologically diagnosed advanced NSCLC with KRAS, insensitive EGFR, HER2, MET, BRAF, RET, NTRK, or non-driver gene alterations that received first-line ICIs at Peking Union Medical College Hospital (PUMCH) in China between January 2017 and June 2023. Clinical, genomic, and serological information before first-line treatment was collected from an electronic medical database. Best overall response, progression-free survival (PFS), and overall survival (OS) were evaluated. There are 138 patients enrolled, including 96 with driver gene alterations and 42 with non-driver alterations. Driver gene alterations were insensitive EGFR (n=14), KRAS (n=45), HER2 (n=8), MET (n=2), BRAF (n=11), RET or NTRK (n=5), and concurrent driver genes (n=11). The objective response rate (ORR) was 44.9%, the median PFS was 11.3 months, and the median OS was 24.4 months. Survival was similar among different gene alteration subgroups. However, those with KRAS [14.6 months, 95% confidence interval (CI): 9.7–not reached (NR)] had longer PFS, while EGFR (7.97 months, 95% CI: 6.13–NR) and MET (7.4 months, 95% CI: not calculable) showed an inferior PFS. Programmed death ligand 1 (PD-L1) ≥50% was a consistent protective factor in univariate [hazard ratio (HR) 0.402, 95% CI: 0.196–0.827, P=0.01] and multivariate (HR 0.409, 95% CI: 0.186–0.903, P=0.03) Cox regression models, and PFS varied significantly among patients with PD-L1 <1%, 1–49%, and ≥50% (7.97 vs. 11.27 vs. 11.77 months, P=0.04). In KRAS mutant NSCLC, patients with KRAS G12C mutations exhibited longer PFS (19.9 vs. 10.3 months, P=0.71) and OS (NR vs. 14.2 months, P=0.36) compared to non-G12C mutations. Similarly, KRAS mutant patients with TP53 co-mutation had numerically prolonged PFS (25.9 vs. 10.5 months, P=0.16) and OS (NR vs. 20.4 months, P=0.06), compared to those without TP53 co-mutation. Among different gene alteration subgroups for advanced NSCLC, the efficacy of first-line ICIs did not differ with statistical significance, with high PD-L1 expression as a predictive factor for better survival. In KRAS mutant patients, KRAS G12C mutation or TP53 co-mutation might indicate improved survival.

Background: Clinical trials have demonstrated the efficacy of both alectinib and crizotinib in anaplastic lymphoma kinase (ALK) fusion (ALK-positive) non-small cell lung cancer (NSCLC). However, a critical question persists regarding their real-world comparative effectiveness in Chinese patients, especially in light of divergent overall survival (OS) results from Western and Asian trials. To address this uncertainty, this real-world study aimed to directly compare the efficacy of alectinib and crizotinib as first-line therapies in a Chinese clinical setting. Methods: Patients diagnosed with ALK-positive NSCLC from two centers in China were included in the study. Progression-free survival (PFS) was the primary endpoint, while OS, the disease control rate, the objective response rate, and safety were the secondary endpoints. Second-line therapy and prognostic factors were also investigated. Results: In total, 261 treatment-naïve patients were evaluated, of whom, 128 received crizotinib, and 133 received alectinib. Compared with crizotinib, alectinib demonstrated significant superiority in terms of PFS [45.5 vs. 16.6 months, hazard ratio (HR) =0.36, Pvs. 43.9 months, P=0.32). Similarly, the OS was comparable between the alectinib and crizotinib treatment groups (alectinib vs. crizotinib, not reached vs. 71.2 months, P=0.23). The alectinib treatment group also had a lower incidence of adverse events (AEs) than the crizotinib treatment group (34.6% vs. 50.0%, P=0.01). The occurrence rates of grade 3 or higher AEs were comparable between the two groups (alectinib vs. crizotinib, 4.5% vs. 5.5%). Further, receiving crizotinib instead of alectinib as the first-line therapy and the presence of bone and adrenal metastases at the baseline were independent risk factors for PFS. While the presence of bone, liver, and adrenal metastasis were independent risk factors for OS. Conclusions: Alectinib is recommended over crizotinib in the treatment of patients with ALK-positive NSCLC.

Background: In metastatic non‐small cell lung cancer (NSCLC) patients receiving first‐line immune checkpoint inhibitors (ICIs), the real‐world progression patterns and subsequent treatment outcomes remain controversial. Methods: We retrospectively analyzed patients with stage IV NSCLCs treated with first‐line immunotherapy between January 2017 and June 2023. Clinico‐demographic and treatment data were obtained from an electronic medical record system. Progression patterns were categorized by: (1) Progression in different organs; (2) Progression in existing or new lesions; and (3) Oligoprogression versus systemic progression. Survival was assessed using the Kaplan–Meier method and Cox proportional hazards models. Results: Among 157 patients, 67.5% experienced systemic progression, and 49.0% had progression in existing lesions. The most common organs with progression were the lung (81.5%), lymph nodes (35.0%), and pleural effusion (24.2%). Median post‐progression survival (PPS) was superior in oligoprogression versus systemic progression (22.4 vs. 10.9 months, p = 0.012). Patients with extrapulmonary progression (8.2 vs. 22.9 months, p < 0.001) or progression in new lesions (9.6 vs. 25.3 months, p = 0.029) showed decreased PPS. In multivariate Cox regression, ECOG PS of 2–4 (HR: 2.26, p = 0.003), tumor stage of IVB (HR: 1.74, p = 0.013), and extrapulmonary progression (HR: 2.05, p = 0.002) were associated with decreased PPS. Subsequent treatments containing ICIs improved survival compared to regimens without ICIs (29.0 vs. 11.3 months, p = 0.004), particularly in patients with systemic progression (19.3 vs. 9.2 months, p = 0.013). Conclusion: Most metastatic NSCLCs on first‐line immunotherapy experienced systemic progression. Oligoprogression and progression only in existing lesions showed better prognoses, whereas extrapulmonary progression indicated worse survival. Subsequent ICI‐containing treatments had improved survival.