Primary pulmonary lymphoepithelioma-like carcinoma (pLELC) is a relatively uncommon variant of primary non-small cell lung cancer, and its etiology is still largely unexplored. Objective: The aim of this study is to investigate the underlying mechanisms and potential therapeutic targets associated with pLELC. The patients diagnosed with advanced pLELC were retrospectively collected and subjected to proteomics and metabonomics analysis. Finally, a patient-derived xenograft (PDX) model of pLELC xenograft was constructed for validation. The results of the data-independent acquisition(DIA) quantitative analysis revealed that the expression of tissue factor (TF) protein was found to be upregulated in pLELC. Furthermore, it was observed that TF protein played a role in iron death, hypoxia-inducible factor-1 (HIF-1) signalling pathway, and leukocyte transendothelial migration. Untargeted metabonomics analysis revealed the presence of major metabolites, namely linoleic acid (LA), free fatty acid (16:0), and histidine. LA has been found to contribute to the progression of tumors by promoting the infiltration of M2 tumor-associated macrophages and inhibiting the infiltration of natural killer(NK) cells. However, this effect can be reversed by the TF inhibitor Tisotumab. LA enhances the expression of TF through peroxisome proliferator-activated receptor (PPAR)-α, and the malignancy caused by LA can be counteracted by TF inhibitors.The findings of this study suggest that LA has the ability to alter the tumor microenvironment in pLELC by upregulating TF expression through PPAR-α. These results indicate that TF could potentially serve as a therapeutic target for pLELC.

Compared to exon 19 deletions, the epidermal growth factor receptor (EGFR) exon 21 L858R (21L858R) mutation is associated with a poorer prognosis in non-small cell lung cancer (NSCLC), particularly in patients with brain metastases (BMs). However, there is a notable lack of prospective or retrospective clinical studies focusing on this specific population. This study aims to evaluate the efficacy of different first-line treatment strategies using EGFR-tyrosine kinase inhibitors (TKIs) in NSCLC patients harboring the 21L858R mutation and BMs while providing insights into concurrent mutations and resistance mechanisms. We analyzed clinical data from 331 patients diagnosed with the EGFR 21L858R mutation and BMs who received first-line EGFR-TKI treatment at Sun Yat-sen University Cancer Center between April 2014 and June 2023 (ID: GASTO-1027). The efficacy was evaluated through intracranial progression-free survival (iPFS), PFS, and overall survival (OS). Compared to the first-generation and second-generation cohorts, the third-generation EGFR-TKI cohort demonstrated significant improvements in iPFS (p = 0.002), PFS (p < 0.001), and OS (p = 0.016). Within the third-generation EGFR-TKI group, the combination chemotherapy cohort exhibited the most favorable outcomes, with marked extensions in both iPFS (p = 0.037) and PFS (p = 0.049). Multivariate analyses identified the treatment regimen of third-generation TKIs combined with chemotherapy as an independent prognostic factor for improved iPFS. Compared to treatment regimens containing first-generation or second-generation EGFR-TKIs, patients with TP53 mutations derived greater benefit from treatment regimens containing third-generation EGFR-TKIs. The combination of third-generation EGFR-TKIs with chemotherapy shows enhanced efficacy in patients with EGFR 21L858R mutations and BMs compared to other treatments. Future prospective clinical trials are essential to assess this combination's effects in this population.

The efficacy and prognosis of epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) patients with brain metastases (BMs) are poor. The third-generation EGFR-tyrosine kinase inhibitor proved to have better intracranial efficacy, which combined with anti-angiogenic drugs can further improve the efficacy. We conducted a single-arm, phase 2 clinical study (GASTO-1063) to explore the intracranial efficacy of aumolertinib plus anlotinib for NSCLC with BMs, with 87 patients enrolled. Median intracranial progression-free survival (PFS) was 30.2 months, median overall PFS was 22.5 months, and median overall survival was not reached. The intracranial objective response rate and intracranial disease control rate were 71.3% and 93.1%. Patients with exon 19 deletion or wild-type TP53 exhibited significantly longer intracranial PFS and PFS compared to those with exon 21 L858R mutation or mutated TP53. Aumolertinib plus anlotinib was effective and well-tolerated as first-line therapy in EGFR-mutant NSCLC patients with BMs. Trial Registration: ClinicalTrials.gov(identifier NCT04978753, registered July 20, 2021).

Neoadjuvant immunochemotherapy (nICT) has significantly improved the treatment of locally advanced esophageal cancer (EC), yet accurately identifying patients' response remains a major challenge. In this study, we introduce eSPARK, a multimodal framework designed to integrate routinely available clinical data for informed decision-making in nICT treatment for EC. The model is developed using 344 patients from three independent regions, each with pre-treatment-paired computed tomography (CT) imaging and pathological slides, and postoperative pathological complete response (pCR) outcomes. By incorporating cytological semantic information, eSPARK demonstrates superior generalizability, outperforming single-modality models and achieving robust predictive accuracy across multicenter datasets. Additionally, a multi-scale interpretability module identifies several biomarkers, including the neutrophil-to-lymphocyte ratio (NLR) in the tumor microenvironment, associated with nICT response. Our findings underscore the potential of eSPARK as a powerful tool for personalized therapeutic decision-making in locally advanced EC and its broader implications for advancing precision oncology through multidisciplinary data integration.

BackgroundPrimary pulmonary lymphoepithelioma-like carcinoma (pLELC) is a rare subtype of non-small cell lung cancer(NSCLC) with unclear etiological mechanisms. This study aimed to investigate the underlying molecular mechanisms and therapeutic targets for pLELC.MethodsRetrospectively collected samples from advanced pLELC patients underwent proteomic and metabolomic analyses, and patient-derived xenograft (PDX) models were established for validation. Data-independent acquisition (DIA) quantitative proteomics revealed upregulated tissue factor (TF) protein expression in pLELC, while untargeted metabolomics identified key metabolites such as linoleic acid (LA).ResultsResults demonstrated that LA promotes tumor progression by facilitating M2-type tumor-associated macrophage infiltration and suppressing natural killer (NK) cell activity, effects reversible by the TF inhibitor Tisotumab. Mechanistic studies indicated that LA enhances TF expression via peroxisome proliferator-activated receptor α (PPAR-α), and TF inhibitors effectively counteract LA-induced malignant phenotypes.ConclusionThis study reveals that LA remodels the pLELC tumor microenvironment through the PPAR-α/TF axis, suggesting TF as a potential therapeutic target for pLELC.

Optimal first-line treatment approaches for non-small cell lung cancer (NSCLC) with brain metastases (BMs) without driver gene alterations remain unclear. Recently, some studies preliminarily have suggested that immunotherapy plus chemotherapy (ICI+Chemo) may be superior to bevacizumab plus chemotherapy (Beva+Chemo). However, no study directly compares the effectiveness of two treatment approaches for NSCLC patients with BMs without driver gene alterations. NSCLC patients are retrospectively identified with BMs lacking sensitizing mutations, and patients are divided into ICI+Chemo and Beva+Chemo groups based on the front-line treatment approach. It is aimed to compare the efficacy for two treatments. All 155 eligible patients between March 2017 and May 2022 have been enrolled. Median intracranial progression-free survival (iPFS) and systemic PFS (sPFS) in ICI+Chemo group are 14.4 and 12.1 months compared with those in Beva+Chemo group (10.0 and 8.4 months) (hazard ratio (HR), 0.626; P = 0.035; and HR, 0.634; P = 0.022). The PFS benefit of ICI+Chemo over Beva+Chemo is significant in those with programmed cell death-ligand 1(PD-L1)-positive expression. Median overall survival (OS) is similar between the ICI+Chemo and Beva+Chemo groups (26.9 versus 23.1 months, HR, 0.790; P = 0.335). The objective response rates (ORR) are similar in both groups, and both of the regimens are well tolerated without newly reported adverse events (AEs). Sixty-three patients (40%) received locoregional therapy for BMs including radiotherapy or surgery throughout the course of treatment. The subsequent treatment is analyzed after progression and it is found that patients who receive immunotherapy throughout the course of treatment have significantly improved OS compared with those who are na & iuml;ve to immunotherapy (P < 0.001). OS is comparable in patients who receive immunotherapy compared with those who receive both immunotherapy and bevacizumab (P = 0.394). The ICI+Chemo significantly improves iPFS and sPFS for PD-L1-positive NSCLC patients with BMs lacking driver gene alterations. Immunotherapy provides the vital contribution to improving OS of NSCLC patients with BMs.

Background:Brain metastases (BM) are highly prevalent and associated with a poor prognosis in patients with small cell lung cancer (SCLC). However, the evidence regarding the efficacy of immune checkpoint inhibitors (ICIs) in combination with chemotherapy for patients with SCLC and BM remains limited. Therefore, the objective of this study is to evaluate whether the addition of ICIs confers survival benefits for patients with SCLC and BM. Methods:This retrospective study enrolled patients with SCLC and BM at the Sun Yat-sen University Cancer Center between January 2018 and December 2022. Clinical characteristics were extracted from medical records. Depending on whether ICIs were added to the first-line treatment, the patients were categorized into the chemotherapy group and the chemoimmunotherapy group. The efficacy of these two treatment approaches was analyzed and compared. Results:A total of 165 patients were enrolled, with 85 in the chemotherapy group and 80 in the chemoimmunotherapy group. The chemoimmunotherapy group showed a tendency towards prolonged intracranial [6.6 vs. 5.9 months, hazard ratio (HR) =0.77; P=0.14] and extracranial (6.9 vs. 6.5 months, HR =0.73; P=0.12) progression-free survival (PFS) and overall survival (OS) (15.6 vs. 14.5 months, HR =0.98; P=0.93) compared to the chemotherapy group. Cox regression analysis identified liver metastases and local treatment for BM as independent prognostic factors for OS in patients. Furthermore, the chemotherapy group and the chemoimmunotherapy group demonstrated similar patterns of initial disease progression. Conclusions:Adding ICIs to chemotherapy confers modest survival benefits in patients with SCLC and BM.

INTRODUCTION:Small cell lung cancer (SCLC) is a highly malignant tumor with an extremely poor prognosis. In the currentera of immunotherapy, the role of immune checkpoint inhibitors (ICIs) in the second-line treatment of patients with extensive-stage SCLC (ES-SCLC) who have progressed to initial chemoimmunotherapy remains unclear. METHODS:A multicenter retrospective study were conducted, involving patients with ES-SCLC who received second-line (2L) therapy after progression to first-line chemoimmunotherapy. Patients were divided into 2L-ICIs group and 2L-non-ICIs group according to whether ICIs were added to the 2L treatment. The efficacy and adverse events of the two groups were analyzed and compared. RESULTS:A total of 103 patients were included in this study, with 53 in the 2L-ICIs group and 50 in the 2L-non-ICIs group. The 2L-ICIs group demonstrated a longer median progression-free survival (PFS) compared to the 2L-non-ICIs group (4.4 months vs 3.9 months, HR = 0.45, p = 0.001). Similarly, median overall survival was also prolonged in the 2L-ICIs group (10.0 months vs 6.9 months, HR = 0.56, p = 0.015). Cox regression analysis revealed that the addition of ICIs to 2L treatment was an independent prognostic factor for both PFS and OS in ES-SCLC patients. Subgroup analysis indicated that patients with a first-line PFS of ≥6 months could potentially benefit more from 2L ICIs. Furthermore, the occurrence of adverse events in the two groups exhibited a similar pattern. CONCLUSION:For ES-SCLC patients who have progressed to first-line chemoimmunotherapy, adding ICIs to second-line treatment may be considered as an option with limited benefit but manageable adverse effects.

Thymic carcinoma (TC) is a rare malignant tumor with a poor prognosis, and there is currently limited data on the use of immunotherapy in patients with unresectable TC. In this study, data of patients with unresectable TC diagnosed from January 2017 were retrospectively collected from multiple centers. Treatment response, progression-free survival (PFS), overall survival (OS), survival-independent prognostic factor, and adverse events (AEs) were further analyzed. As a result, a total of 93 patients with unresectable TC were enrolled, of which 54 received first-line chemotherapy, and 39 received chemotherapy plus immune checkpoint inhibitors (ICIs). The objective response rate was 50% (27/54) in the chemotherapy group and 76.9% (30/39) in the chemotherapy plus ICIs group. The chemotherapy plus ICIs group achieved significant median PFS benefit (8.8 vs. 34.9 months, p < .001) and median OS benefit (41.8 months vs. not reached, p = .025). Multivariate analysis showed that ICIs and local therapy were independent prognostic factors for PFS. In addition, 17 patients developed immune-related AEs (IRAEs), of which 15 (38.5%) had Grade 1 or 2 IRAEs and 2 (5.1%) had Grade 3 IRAEs in the chemotherapy plus ICIs group. In conclusion, the efficacy of chemotherapy plus ICIs is superior to chemotherapy, and the adverse effects are manageable in patients with unresectable TC.

Background:Currently, there is a lack of well-established markers to predict the efficacy of chemoimmunotherapy in small-cell lung cancer (SCLC). Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), advanced lung cancer inflammation index (ALI) and prognostic nutritional index (PNI) are associated with prognosis in several tumors, whereas their predictive role in SCLC remains unclear.Methods:A retrospective study was conducted at Sun Yat-sen University Cancer Center, involving extensive-stage SCLC (ES-SCLC) patients who received first-line chemoimmunotherapy between January 2020 and December 2021. Peripheral blood biomarkers were extracted from medical records and their correlation with prognosis and immune-related adverse events (IRAEs) was analyzed.Results:A total of 114 patients were included. Patients with a low PLR, high ALI and high PNI had prolonged progression-free survival (PFS) compared to those with a high PLR, low ALI and low PNI. Patients with a low NLR, low PLR, high ALI and high PNI had prolonged overall survival (OS) compared to those with a high NLR, high PLR, low ALI and low PNI. Cox regression model showed that PNI was an independent risk factor for both PFS and OS. ROC curve showed that PNI outperforms NLR, PLR and ALI in predicting both PFS and OS. The PNI-based nomogram demonstrated strong predictive capability for both PFS and OS. In addition, there was a significant correlation between PNI and IRAEs.Conclusion:A high baseline PNI might be associated with improved prognosis and the occurrence of IRAEs in ES-SCLC patients treated with first-line chemoimmunotherapy.

Abstract Background Due to the blood-brain barrier, plasma is not an ideal source to evaluate the genetic characteristics of central nervous system tumors. Thus, cerebrospinal fluid (CSF) is becoming an alternative biopsy type to evaluate the genetic landscape of intracranial tumors. We aimed to explore the genetic profiles of CSF-derived circulating tumor DNA (ctDNA) to predict intracranial tumor responses and monitor mutational evolution during the treatment of non-small cell lung cancer (NSCLC) patients with brain metastases. Methods We conducted a prospective study of 92 newly diagnosed NSCLC patients with brain metastases. Paired CSF and plasma samples were collected at baseline, 8 weeks after treatment initiation, and disease progression. All samples underwent next-generation sequencing of 425 cancer-related genes. Results At baseline, the positive detection rates of ctDNA in CSF, plasma, and extracranial tumors were 63.7% (58/91), 91.1% (82/90), and 100% (58/58), respectively. A high level of genetic heterogeneity was observed between paired CSF and plasma, while concordance in driver mutations was also observed. A higher number of unique copy number variations was detected in CSF-ctDNA than in plasma. ctDNA positivity of CSF samples at baseline was associated with poor outcomes (HR=2.565, P=0.003). Moreover, patients with ≥ 50% reductions in the concentrations of CSF ctDNA after 8 weeks of treatment had significantly longer intracranial progression-free survivals (PFS) than patients with < 50% reductions in CSF ctDNA concentrations (13.27 months vs 6.13 months, HR=0.308, P=0.017). A ≥ 50% reduction in CSF ctDNA concentrations had better concordance with radiographic intracranial tumor responses than plasma. A ≥ 50% reduction in plasma ctDNA concentrations was also associated with longer extracranial PFS (11.57 months vs 6.20 months, HR=0.406, P=0.033). Based on clonal evolution analyses, the accumulation of subclonal mutations in CSF ctDNA was observed after 8 weeks of treatment. The clonal mutations that remained in more than 80% in CSF after 8 weeks also predicted shorter intracranial PFS (HR=3.785, P=0.039). Conclusions CSF ctDNA exhibited unique genetic profiles of brain metastases, and dynamic changes in CSF ctDNA could better predict intracranial tumor responses and track clonal evolution during treatment in NSCLC patients with brain metastases. Trial registration ClinicalTrials.gov identifier: NCT 03257735.

2040 Background: Immunotherapy has been the standard first-line therapy in patients with advanced non-small cell lung cancer (NSCLC), and shown a certain efficacy for patients with brain metastases. however, the appropriate predictive biomarkers for intracranial tumor response to immunotherapy are unclear. We conducted this prospective study to explore the immunological cytokines in cerebrospinal fluid (CSF) to predict intracranial tumor response to immunotherapy in NSCLC patients with brain metastases. Methods: We prospectively enrolled treatment-naive, EGFR/ALK wild-type NSCLC patients with brain metastases in this study. Patients received chemotherapy plus camrelizumab (a humanized anti-PD-1 monoclonal antibody) as first-line treatment, and paired plasma and cerebrospinal fluid (CSF) samples were collected at baseline and first treatment evaluation (8-week). All samples were detected for 92 Immuno-Oncology cytokines using the Olink panels, and were explored for predictive biomarkers to immunotherapy. The Mann-Whitney U test was performed to compare the immunological cytokine expression between intracranial response and non-response groups. And logistic LASSO regression model was used to variate selection and develop a CSF immuno-cytokine model to predict intracranial tumor response. Results: Between April 2020 and May 2022, a total of 28 patients were enrolled this study.At baseline, most immunological cytokines were significantly lower in paired CSF than in plasma, whereas a subset including CD83, PTN, TNFRSF21, TWEAK, ICOSLG, DCN, IL-18 and MCP-1 were increasing expressed in CSF samples. For patients with objective intracranial tumor response compared to patients with non-response, the baseline CSF levels of LAMP3 were significantly higher, whereas the CXCL10, IL-12, CXCL11, IL-18, TIE2, HGF and PDCD1 levels were significantly lower. And patients with lower HGF, IL-18 or PDCD1 levels had significantly longer intracranial progression-free survival to immunotherapy. The above CSF immunological cytokines were significantly decreased at first treatment evaluation in patients with intracranial tumor response. Our logistic CSF immuno-cytokine model selected TIE2, IL-18, LAMP3, PDCD1 and IL-12 that were significantly associated with intracranial tumor response, and yielded a mean AUC of 0.91, compared to PD-L1 expression (mean AUC of 0.72). Conclusions: Immunological cytokines in CSF could predict intracranial tumor response to immunotherapy in NSCLC patients with brain metastases, and findings require validation in a larger prospective cohort.

9095 Background: Combination of tyrosine kinase inhibitor (TKI) and chemotherapy has shown improved clinical outcomes in advanced epidermal growth factor receptor ( EGFR) mutated non-small cell lung cancer (NSCLC) patients. We conducted this phase 3, randomized, controlled trial to further investigate the clinical efficacy and safety of gefitinib combined with chemotherapy in EGFR mutated NSCLC patients with brain metastases. Methods: Treatment-naïve, confirmed brain metastases and EGFR sensitive mutated NSCLC patients were screened from six centers in China. The eligible patients were randomly assigned (1:1) to receive gefitinib alone or gefitinib plus pemetrexed-platinum chemotherapy until intracranial progressive diseases, unacceptable adverse, or any cause of death. Theprimary endpoint was intracranial progression-free survival (iPFS), secondary endpoints were PFS, overall survival, intracranial objective response rate, overall objective response rate, and safety. This study is registered at ClinicalTrials. gov, number NCT01951469. Results: From January 2017 to June 2021, 161 patients were randomly assigned to receive gefitinib (n = 81) or gefitinib plus pemetrexed-platinum chemotherapy (n = 80), the median follow-up time was 18.2 (IQR 11.8-29.7) months. The median intracranial PFS was 15.6 (14.3-16.9) months in gefitinib plus chemotherapy group versus 9.1 (8.0-10.2) months in gefitinib group (HR = 0.36, 95% CI, 0.25-0.53, P < 0.001). Similarly, the median PFS was also significantly longer in gefitinib plus chemotherapy than gefitinib alone (16.3 months vs 9.5 months, P < 0.001). In addition, gefitinib plus chemotherapy had better intracranial objective response rate (85.0% versus 63.0%, P = 0.002) and overall objective response rate (80.0% versus 64.2%, P = 0.035) than gefitinib alone. At the data cutoff, 50.3% of patients (35 patients in gefitinib plus chemotherapy group and 46 patients in gefitinib group) had died. The 3-year OS rate was significantly higher in gefitinib plus chemotherapy group (47.4%, 95% CI 36.3-58.7) than in gefitinib group (24.9%, 95% CI 15.1-34.3, P = 0.003). And median overall survival was 35.0 months (95% CI, 28.8-41.3 months) in gefitinib plus chemotherapy group versus 28.9 months (95% CI, 23.4-34.4 months) in gefitinib group (HR = 0.66, 95% CI, 0.42-1.03, P = 0.065). Grade 3 or worse adverse events were more common in gefitinib plus chemotherapy group (40.0% versus 21.0%, P = 0.010), but most of them were manageable. Conclusions: Inuntreated EGFR mutated NSCLC patients with brain metastases, gefitinib plus chemotherapy significantly improved intracranial PFS, PFS and a tendency of OS than gefitinib alone, and could be the optional first-line treatment. Clinical trial information: NCT01951469.

Importance Use of tyrosine kinase inhibitors (TKIs) is the standard therapy for epidermal growth factor receptor ( EGFR )–mutated non–small cell lung cancer (NSCLC) with brain metastases. Several studies have shown that adding chemotherapy to EGFR-TKIs could improve progression-free survival (PFS) in patients with EGFR -mutant advanced NSCLC; however, the efficacy of these agents in patients with brain metastases remains unclear. Objective To investigate the efficacy and safety of gefitinib plus chemotherapy (pemetrexed with platinum) compared with gefitinib alone in patients with untreated EGFR- mutant NSCLC brain metastases. Design, Setting, and Participants This open-label prospective, multicenter, phase 3 randomized clinical trial was conducted in 6 centers in China from January 13, 2016, to August 27, 2021. The median follow-up time was 21.1 months (IQR, 13.5-31.8 months). Patients with untreated confirmed brain metastases and EGFR -sensitive mutated NSCLC were enrolled. Interventions The eligible patients were randomly assigned (1:1) to receive gefitinib plus chemotherapy or gefitinib alone. Main Outcomes and Measures The primary end point was intracranial PFS; secondary end points included PFS, overall survival (OS), intracranial objective response rate, overall objective response rate, and safety. Intention-to-treat analysis was performed. Results A total of 161 patients (87 [54.0%] women; mean [SD] age, 55 [9.8] years; range, 26-80 years) were enrolled and randomized to receive gefitinib (n = 81) or gefitinib plus chemotherapy (n = 80). The median intracranial PFS was 15.6 months (95% CI, 14.3-16.9 months) in the gefitinib plus chemotherapy group vs 9.1 months (95% CI, 8.0-10.2 months) in the gefitinib group (hazard ratio, 0.36; 95% CI, 0.25-0.53; P &lt; .001). Similarly, the median PFS was significantly longer with gefitinib plus chemotherapy than gefitinib alone (16.3; 95% CI, 14.4-18.2 months vs 9.5; 95% CI, 8.3-10.8 months; P &lt; .001). Gefitinib plus chemotherapy had a better intracranial objective response rate (85.0%; 95% CI, 77.0%-93.0% vs 63.0%; 95% CI, 52.2%-73.7%; P = .002) and overall objective response rate (80.0%; 95% CI, 71.0%-89.0% vs 64.2%; 95% CI, 53.5%-74.9%; P = .03) than gefitinib alone. At data cutoff, the median OS was also significantly longer in the gefitinib plus chemotherapy group vs the gefitinib group (35.0 vs 28.9 months; hazard ratio, 0.65; 95% CI, 0.43-0.99; P = .04). Grade 3 or worse adverse events were more common with gefitinib plus chemotherapy, most of which were manageable. Conclusions and Relevance In this randomized clinical trial, gefitinib plus chemotherapy significantly improved intracranial PFS, PFS, and OS compared with gefitinib alone in patients with untreated EGFR- mutant NSCLC brain metastases and could be an optional first-line treatment for these patients. Trial Registration ClinicalTrials.gov Identifier: NCT01951469

e21161 Background: Pembrolizumab with or without chemotherapy has become the standard therapy in advanced non-small cell lung cancer (NSCLC), with a fixed dose of 200mg every 3 weeks. We performed this study to explore the clinical efficacy and safety of pharmacokinetic (PK)-guided pembrolizumab administration in advanced NSCLC. Methods: In this prospective, open-label, single-arm exploratory study, we enrolled advanced NSCLC patients without sensitizing EGFR or ALK mutation in Sun Yat-Sen University Cancer Center. Eligible patients received pembrolizumab 200mg every 3 weeks with or without chemotherapy for four cycles, then for patients without progressive disease, pembrolizumab was administrated in new dose-intervals (T) until disease progression. We set the effective concentration (Ce) at 15μg/ml and new dose-intervals (T) was calculated according to steady state plasma-concentration (Css) of pembrolizumab using following equation: Css × 21D = Ce (15μg/ml) ×T. Primary endpoint was the progression-free survival (PFS), secondary endpoints were objective response rate (ORR), and safety. Besides, advanced NSCLC patients who regularly received pembrolizumab 200mg 3-weekly until disease progression and more than four cycles in our center were respectively enrolled as the history-controlled cohort. Patients with Css of pembrolizumab also underwent genetic polymorphism analysis of variable number of tandem repeats region (VNTR) in neonatal Fc receptor (FcRn). This study is registered at Clinicaltrials. gov, NCT05226728. Results: Between Nov 2019 and Dec 2020, total 58 patients were enrolled and received pembrolizumab 200mg every 3 weeks with or without chemotherapy, and 33 patients further received pembrolizumab in new adjusted dose-intervals according to Css after four cycles. The Css of pembrolizumab ranged from 11.01 to 61.21 μg/ml, 30 patients need prolonged intervals (22-80d) and 3 shortened intervals (15-20d). In PK-guided cohort, the median PFS was 15.1 months (95%CI 10.2-20.0 months) and ORR 57.6%, whereas the median PFS in history-controlled cohort was 7.7 months (95% CI 5.1-10.2 months) and ORR 48.2%. The immune-related adverse events occurred in 15.2% of patients in PK-guided cohort and 17.9% of patients in history-controlled cohort. The VNTR3/VNTR3 genotype of FcRn had significantly higher Css of pembrolizumab than VNTR2/VNTR3 ( p= 0.005). Conclusions: PK-guided pembrolizumab administration showed promising clinical efficacy and manageable toxicity, which provided an alternative rational therapeutic strategy of pembrolizumab in advanced NSCLC. Clinical trial information: NCT05226728.

Background: The role of adjuvant EGFR tyrosine kinase inhibitors (TKIs) in resected EGFR-mutated non-small-cell lung cancer (NSCLC) remains unclear. Materials & methods: We evaluated pooled hazard ratio and 95% CI for disease-free survival, overall survival and prespecified subgroups. Results: Seven prospective studies with 1288 patients were included in the meta-analysis. Adjuvant EGFR TKIs significantly improved disease-free survival in EGFR-mutated resected NSCLC (HR: 0.41; 95% CI: 0.24-0.70) and in all subgroups. However, the overall survival benefit was not significant (HR: 0.65; 95% CI: 0.36-1.17). The benefit of adjuvant TKIs may be associated with TKI regimens, treatment duration, pathological stage and EGFR mutation type. Conclusion: Adjuvant EGFR TKIs significantly improved disease-free survival and nonsignificantly improved overall survival in resected EGFR-mutated NSCLC.

Lung cancer is one of the most common causes of brain metastases and is always associated with poor prognosis. We investigated the immunophenotypes of primary lung tumors and paired brain metastases, as well as immunophenotypes in the synchronous group (patients with brain metastases upon initial diagnosis) and metachronous group (patients developed brain metastases during the course of their disease). RNA sequencing of eighty-six samples from primary lung tumors and paired brain metastases of 43 patients was conducted to analyze the tumor immune microenvironment. Our data revealed that matched brain metastases compared with primary lung tumors exhibited reduced tumor infiltrating lymphocytes (TILs), a higher fraction of neutrophils infiltration, decreased scores of immune-related signatures, and a lower proportion of tumor microenvironment immune type I (high PD-L1/high CD8A) tumors. Additionally, we found a poor correlation of PD-L1 expression between paired brain metastases and primary lung tumors. In addition, gene set enrichment analysis (GSEA) showed that some gene sets associated with the immune response were enriched in the metachronous group, while other gene sets associated with differentiation and metastasis were enriched in the synchronous group in the primary lung tumors. Moreover, the tumor immune microenvironment between paired brain metastases and primary lung tumors displayed more differences in the metachronous group than in the synchronous group. Our work illustrates that brain metastatic tumors are more immunosuppressed than primary lung tumors, which may help guide immunotherapeutic strategies for NSCLC brain metastases.

Purpose Primary pulmonary lympho-epithelioma-like carcinoma (PPLELC) is a rare subtype of primary non-small cell lung cancer (NSCLC). Currently, there is still lack of research data on anti-angiogenic therapy of advanced PPLELC. The purpose of this study was to investigate the efficacy and safety of anti-angiogenic therapy combined with chemotherapy compared with traditional chemotherapy for these patients. Methods Advanced PPLELC patients admitted to six grade A hospitals from January 2013 to January 2021 were selected. The patients received anti-angiogenic therapy combined with chemotherapy (AT group) or chemotherapy (CT group) alone. Results A total of 65 patients were included in this study, including 31 patients in the AT group treated with anti-angiogenic therapy combined with chemotherapy and 34 patients in the CT group treated with chemotherapy alone. As of October 1, 2021, the median progression-free survival (PFS) in the AT group was 11.2 months [95% confidence interval (CI), 5.9–16.5]. The median PFS in the CT group was 7.0 months [95%CI, 5.1–8.9] [Hazard Ratio (HR), 0.49; 95%CI, 0.29–0.83; P = 0.008]. The 1-year PFS rates were 41.9% and 17.6%, respectively. The overall response rates (ORR) of two groups were 45.2% (95% CI, 0.27–0.64), 38.2% (95% CI, 0.21–0.56), ( P = 0.571). The disease control rates (DCR) of two groups were 93.5% (95% CI, 0.84–1.03), 88.2% (95% CI, 0.77–1.00), ( P = 0.756). Conclusion Among patients with advanced PPLELC, the PFS of patients with anti-angiogenic therapy combined with chemotherapy is better than that of patients with chemotherapy alone. Anti-angiogenic therapy combined with chemotherapy is an optional treatment scheme.

OBJECTIVES:Second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have significantly improved clinical outcomes in patients with advanced ALK-positive non-small cell lung cancer (NSCLC), but clinical responses vary widely. In this study, the impacts of ALK fusion variants, concomitant mutations, and PD-L1 expression on the clinical response were evaluated in patients receiving second-generation ALK TKIs. MATERIALS AND METHODS:We retrospectively enrolled 193 patients with ALK-rearranged advanced NSCLC who received second-generation ALK TKIs at Sun-yat Sen University Cancer Center from January 2015 to December 2020. The ALK fusion variants and concomitant mutations were identified with next-generation sequencing, while PD-L1 expression was assessed by immunohistochemistry. RESULTS:The median progression-free survival (PFS) was significantly shorter for variant 3a/b than for other variants (9.93 months vs 16.97 months, HR 1.941, P = 0.0014). Baseline concomitant mutations were significantly associated with shorter PFS while on ALK TKIs (median PFS, 10.87 months vs 22.47 months, HR 1.984, P = 0.002). A subset of 68 patients was analyzed for PD-L1 expression: TPS 0% in 32.4% (22/68) of the patients, 1-49% in 30.9% (21/68) of the patients, and ≥ 50% in 36.7% (25/68) of the patients. Expression of PD-L1 was significantly associated with variant 3a/b and concomitant mutations. Median PFS was shorter in patients with high PD-L1 expression (median PFS in patients with PD-L1 TPS of 0% vs 1-49% vs ≥ 50% were 27.43 months vs 30.63 months vs 9.50 months, respectively, P = 0.001). In multivariate analysis, PD-L1 expression (TPS ≥ 50%), concomitant mutations, and variant 3a/b remained negative prognostic factors for the clinical efficacy of second-generation ALK TKIs in ALK-rearranged non-small cell lung cancer. CONCLUSION:ALK fusion variant 3a/b, concomitant mutations, and high PD-L1 expression were associated with unfavorable clinical response to second-generation TKIs in ALK-rearranged NSCLC.