Chemotherapy versus chemotherapy plus immune checkpoint inhibitors for the first-line treatment of unresectable thymic carcinoma: A multicenter retrospective study.

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.

Prognostic Nutritional Index Predicts Efficacy and Immune-Related Adverse Events of First-Line Chemoimmunotherapy in Patients with Extensive-Stage Small-Cell Lung Cancer.

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.

Cerebrospinal fluid immunological cytokines predict intracranial tumor response to immunotherapy in non-small cell lung cancer patients with brain metastases.

Background: Immunotherapy has shown intracranial efficacy in non-small cell lung cancer (NSCLC) patients with brain metastases. However, predictive biomarkers for intracranial response to immunotherapy are lacking. This post-hoc analysis aimed to explore the potential of immunological cytokines in cerebrospinal fluid (CSF) to predict intracranial tumor response to immunotherapy in patients with brain metastases. Methods: Treatment-naive NSCLC patients with brain metastases who received camrelizumab plus chemotherapy were enrolled. Paired plasma and CSF samples were prospectively collected at baseline and the first treatment assessment. All samples were analyzed for 92 immuno-oncology cytokines using Olink's panels. Results: A total of 28 patients were included in this analysis. At baseline, most immunological cytokines were significantly lower in CSF than in plasma, whereas a subset comprising CD83, PTN, TNFRSF21, TWEAK, ICOSLG, DCN, IL-8, and MCP-1, was increased in CSF. Baseline CSF levels of LAMP3 were significantly higher in patients with intracranial tumor response, while the levels of CXCL10, IL-12, CXCL11, IL-18, TIE2, HGF, and PDCD1 were significantly lower. Furthermore, the CXCL10, CXCL11, TIE2, PDCD1, IL-18, HGF, and LAMP3 in CSF were also significantly associated with intracranial progression-free survival for immunotherapy. The identified cytokines in CSF were decreased at the first treatment evaluation in patients with intracranial tumor response. The logistic CSF immuno-cytokine model yielded an AUC of 0.91, as compared to PD-L1 expression (AUC of 0.72). Conclusions: Immunological cytokines in CSF could predict intracranial tumor response to immunotherapy in NSCLC patients with brain metastases, and the findings warrant validation in a larger prospective cohort study. Trial registration: ClinicalTrials.gov identifier: NCT04211090.

Clinical efficacy and safety of individualized pembrolizumab administration based on pharmacokinetic in advanced non-small cell lung cancer: A prospective exploratory clinical trial.

INTRODUCTION: Pembrolizumab is recommended with a fixed dose of 200 mg 3-weekly. We performed this study to explore the clinical efficacy and safety of pharmacokinetic (PK)-guided pembrolizumab administration in advanced non-small cell lung cancer (NSCLC). METHODS: In this prospective exploratory study, we enrolled advanced NSCLC patients in Sun Yat-Sen University Cancer Center. Eligible patients received pembrolizumab 200 mg 3-weekly with or without chemotherapy for four cycles, then for patients without progressive disease (PD), pembrolizumab was administrated in new dose-intervals according to steady state plasma-concentration (Css) of pembrolizumab until PD. We set the effective concentration (Ce) at 15 µg/ml and new dose-intervals (T) was calculated according to Css of pembrolizumab using following equation: Css × 21D = Ce (15 µg/ml) × T. Primary endpoint was the progression-free survival (PFS), secondary endpoints were objective response rate (ORR) and safety. Besides, advanced NSCLC patients received pembrolizumab 200 mg 3-weekly and more than four cycles in our center were defined as the history-controlled cohort. Patients with Css of pembrolizumab underwent genetic polymorphism analysis of variable number of tandem repeats (VNTR) region in neonatal Fc receptor (FcRn). The study was registered at ClinicalTrials.gov, NCT05226728. RESULTS: A total 33 patients received pembrolizumab in new adjusted dose-intervals. The Css of pembrolizumab ranged from 11.01 to 61.21 µg/ml, 30 patients need prolonged intervals (22-80d) and 3 shortened intervals (15-20 d). In PK-guided cohort, the median PFS was 15.1 months and ORR 57.6 %, whereas in history-controlled cohort was 7.7 months and ORR 48.2 %. The immune-related adverse events were 15.2 % and 17.9 % between two 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. Meanwhile less frequent dosing of pembrolizumab by PK-guided could reduce financial toxicity potentially. This provided an alternative rational therapeutic strategy of pembrolizumab in advanced NSCLC.

Gefitinib Plus Chemotherapy vs Gefitinib Alone in Untreated EGFR-Mutant Non-Small Cell Lung Cancer in Patients With Brain Metastases: The GAP BRAIN Open-Label, Randomized, Multicenter, Phase 3 Study.

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 < .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 < .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.

Anti-angiogenic therapy for advanced primary pulmonary lymphoepithelioma-like carcinoma: a retrospective multicenter study.

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.

Dynamic monitoring of cerebrospinal fluid circulating tumor DNA to identify unique genetic profiles of brain metastatic tumors and better predict intracranial tumor responses in non-small cell lung cancer patients with brain metastases: a prospective cohort study (GASTO 1028).

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: NCT03257735.

Immune suppressive microenvironment in brain metastatic non-small cell lung cancer: comprehensive immune microenvironment profiling of brain metastases versus paired primary lung tumors (GASTO 1060).

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.

Efficacy of adjuvant EGFR inhibitors and impact of clinical factors in resected EGFR-mutated non-small-cell lung cancer: a meta-analysis.

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.

For lung cancer patients who undergo radical surgery and whose tumors have EGFR mutation (a specific gene alteration in the tumor tissue), the optimal treatment following surgery is unclear. We summarized the available studies to compare the efficacy of anti-EGFR targeted therapies (EGFR inhibitors) with chemotherapy in patients after surgery. We found patients who received EGFR inhibitors after surgery had longer survival without disease recurrence, and a tendency toward longer overall survival than patients who received chemotherapy or no further therapy. The different treatment regimes, treatment duration, tumor stage and EGFR mutation type may impact the efficacy of EGFR inhibitors in these patients after undergoing surgery.

ALK fusion variant 3a/b, concomitant mutations, and high PD-L1 expression were associated with unfavorable clinical response to second-generation ALK TKIs in patients with advanced ALK-rearranged non-small cell lung cancer (GASTO 1061).

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.

[USP33 suppresses lung adenocarcinoma lung cell invasion and metastasis by down-regulating SLIT2/ROBO1 signaling pathway].

OBJECTIVE: To investigate the role of USP33 as an independent prognostic marker in the regulation of SLIT2/ROBO1 signaling pathway to inhibit lung adenocarcinoma invasion and metastasis. METHODS: The expression of USP33 in 20 lung adenocarcinoma specimens was detected by qPCR and immunohistochemistry. A549 and SPC-A-1 cells with small interfering RNA (siRNA)-mediated USP33 silencing were examined for changes in invasion and metastasis abilities using scratch assay and Matrigel assay. Western blotting was used to detect the expression of SLIT2 and ROBO1 in the cells after USP33 silencing and the expression of USP33 after interleukin-6 (IL-6) stimulation. RESULTS: qPCR and immunohistochemistry showed that USP33 was significantly decreased in lung adenocarcinoma tissues as compared with the adjacent tissues. USP33 silencing in A549 and SPC-A-1 cells significantly promoted the cell migration, invasion and metastasis and obviously down-regulated the expressions of SLIT2 and ROBO1. IL-6 stimulation of the cells obviously enhanced the expression of USP33. CONCLUSIONS: USP33 silencing can promote the migration, invasion and metastasis of lung adenocarcinoma cells in vitro, and the mechanism may involve IL-6 and SLIT2/ROBO1 signaling pathways.

MicroRNA-365 promotes lung carcinogenesis by downregulating the USP33/SLIT2/ROBO1 signalling pathway.

BACKGROUND: Abnormal microRNA expression is closely related to cancer occurrence and development. miR-365a-3p plays an oncogenic role in skin cancer, but its role in lung cancer remains unclear. In this study, we aimed to investigate its role and underlying molecular mechanisms in lung cancer. METHODS: Western blot and real-time quantitative PCR (qPCR) were used to detect the expression of miR-365a-3p in lung adenocarcinoma and lung cancer cell lines. The effects of miR-365a-3p on lung cancer cell proliferation, migration, and invasion were also explored in vitro. The potential miR-365a-3p that targets USP33 was determined by dual luciferase reporter assay and verified by qPCR and western blot analysis. miR-365a-3p acts as an oncogene by promoting lung carcinogenesis via the downregulation of the miR-365a/USP33/SLIT2/ROBO1 axis based on western blot analysis. Subcutaneous tumourigenesis further demonstrated that miR-365a-3p promotes tumour formation in vivo. RESULTS: miR-365a-3p was upregulated in lung adenocarcinoma and lung cancer cell lines. Overexpression of miR-365a-3p promoted and inhibition of miR-365a-3p suppressed the proliferation, migration, and invasion of lung cancer cells. We identified USP33 as the downstream target of miR-365a-3p and observed a negative correlation between miR-365a-3p and USP33 expression in lung adenocarcinoma patients. The miR-365/USP33/SLIT2/ROBO1 axis, a new mechanism, was reported to inhibit the invasion and metastasis of lung cancer. A nude mouse model of lung cancer further verified these findings. CONCLUSIONS: In summary, miR-365a-3p acts as an oncogene by promoting lung carcinogenesis via the downregulation of the USP33/SLIT2/ROBO1 signalling pathway, making the miR-365/USP33/SLIT2/ROBO1 axis a new mechanism of lung cancer promotion and a novel therapeutic target for predicting prognosis and response to gene therapy.