Real-world outcomes of immunotherapy-based neoadjuvant therapy in resectable non-small cell lung cancer.

Objectives: Recent clinical studies have demonstrated that immunotherapy-based neoadjuvant therapy have promising effectiveness for patients with resectable non-small cell lung cancer (NSCLC) in terms of pathologic response. Therefore, we performed this study to investigate whether immunotherapy-based neoadjuvant therapy is effective and safe for patients with resectable NSCLC. Materials and methods: This open-label observational two-arm clinical study was performed at Shanghai Chest Hospital in China with patients who had resectable NSCLC and received two to three cycles of immunotherapy-based neoadjuvant therapy or neoadjuvant chemotherapy alone, followed by surgical resection. The primary endpoint was a major pathologic response (MPR). The secondary endpoints include a complete pathological response (pCR), a radiologic response to neoadjuvant therapy (TRR), event-free survival (EFS), and overall survival (OS). Results: A total of 51 patients was included in this clinical study, of which 31 patients received immunotherapy-based neoadjuvant therapy and 20 patients received neoadjuvant chemotherapy alone. The percentage of patients achieving a major pathologic response was 41.9% with immunotherapy-based neoadjuvant therapy and 15.0% (95% CI, 0.008 to 0.468; P = 0.043) with neoadjuvant chemotherapy alone. The percentage of patients with pathologic complete response was 19.4% in the immunotherapy-based group and 5% (95% CI, -0.069 to 0.318; P = 0.223) in the chemotherapy group. The radiographic response rate was 71% after immunotherapy-based neoadjuvant therapy and 60% (95% CI, -0.143 to 0.359; P = 0.417) after neoadjuvant chemotherapy. At a median follow-up of 28 months, the median EFS and OS endpoints were not reached. Conclusions: Neoadjuvant immunotherapy offers a considerable advantage over chemotherapy alone for resectable NSCLC in terms of the major pathologic response. Moreover, it did not enhance the risk of adverse events or hinder surgical resection.

An open, observational clinical study of neoadjuvant therapy in resectable stage III non-small cell lung cancer.

Background: This open, observational clinical study aimed to investigate the efficacy, safety and survival outcomes of neoadjuvant chemotherapy, neoadjuvant immunotherapy with(out) chemotherapy and neoadjuvant targeted therapy among resectable stage III non-small cell lung cancer (NSCLC) patients (NCT04197076) in real world. 48 of the 57 evaluable patients were included in this interim analysis. Methods: This study was conducted at Shanghai Chest Hospital and included eligible NSCLC patients who were 18 years or older and had resectable clinical stage III disease. Surgical resection was conducted after neoadjuvant chemotherapy (13 patients), immunotherapy with(out) chemotherapy (26 patients), and targeted therapy (9 patients). Disease-free survival (DFS) was evaluated as the primary endpoint. The secondary endpoint was pathological complete response (pCR) rate. Clinical response rate (cRR), related adverse events (AEs), surgical feasibility and pathological features were also discussed in this study. Results: Significant differences in DFS were noted between chemotherapy and immunotherapy [7.7 months (range, 3.1 to 23.2 months) vs. 9.6 months (range, 4.0 to 47.9 months); P=0.032], and between chemotherapy and targeted therapy [7.7 months (range, 3.1 to 23.2 months) vs. 13.2 months (range, 7.5 to 32.2 months); P=0.015], but not between immunotherapy and targeted therapy (P=0.500). Subgroup analysis also favored neoadjuvant immunotherapy and targeted therapy. 5 patients achieved pathological complete response (pCR), all of whom were in the neoadjuvant immunotherapy arm, leading to a pCR rate of 19.2% in this arm. Treatment-emergent adverse events (TEAEs) of over grade 3 occurred in 11 patients (19.3%), with 5 (29.4%) in the chemotherapy arm, 5 (16.7%) in the immunotherapy arm and 1 (10.0%) in the targeted therapy arm. One grade 4 and one grade 2 surgery-related serious adverse event occurred in the neoadjuvant chemotherapy and immunotherapy arm, respectively. Conclusion: In patients diagnosed with resectable stage III NSCLC, neoadjuvant immunotherapy and neoadjuvant targeted therapy were associated with significantly longer disease-free survival compared with neoadjuvant chemotherapy. Clinical and pathological response rates were also higher in the immunotherapy and targeted therapy arm. Adverse events were found to be manageable and similar across all three groups, and surgical feasibility favored immunotherapy or targeted therapy rather than chemotherapy. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT04197076.

Analysis for discharge within 2 days after thoracoscopic anatomic lung cancer surgery.

OBJECTIVES: The risk and beneficial factors of early discharge after thoracoscopic anatomic lung cancer surgery are unknown, and this study aims to investigate predictors and associated 30-day readmission for early discharge. METHODS: We performed a single-center retrospective analysis of 10,834 consecutive patients who underwent thoracoscopic anatomic lung cancer surgery. Two groups were determined based on discharge date: "discharged by postoperative Day 2" and "discharged after postoperative Day 2." Univariable and multivariable analysis were conducted to identify predictors for discharge. Using propensity score matching (PSM) to compare 30-day readmission rate between two cohorts. RESULTS: A total of 1911 patients were discharged by postoperative Day 2. Multivariable analysis identified older age (odds ratio (OR) = 1.014, p < 0.001), male sex (OR = 1.183, p = 0.003), larger tumor size (OR = 1.248, p < 0.001), pleural adhesions (OR = 1.638, p = 0.043), lymph nodes calcification (OR = 1.443, p = 0.009), advanced clinical T stage (vs. T < 2, OR = 1.470, p = 0.010), lobectomy resection (vs. segmentectomy resection, OR = 2.145, p < 0.001) and prolonged operative time (OR = 1.011, p < 0.001) as independent risk factors for discharge after postoperative Day 2. Three adjustable variables including higher FEV1 /FVC (OR = 0.989, p = 0.001), general anesthesia (GA) plus thoracic paravertebral blockade (vs. GA alone, OR = 0.823, p = 0.006) and uni-portal thoracoscopic surgery (vs. multi-portal, OR = 0.349, p < 0.001) were associated with a decreased likelihood of discharge after postoperative Day 2. Before and after a 1:1 PSM, discharged by postoperative Day 2 did not increase the risk of 30-day readmission compared to counterparts. CONCLUSIONS: Carefully selected patients can be safely discharged within 2 days after thoracoscopic anatomic lung cancer surgery. Three modifiable variables may be favorable for promoting discharge by postoperative Day 2.

An open, observational, three-arm clinical study of 2-3 cycles of treatment as neoadjuvant therapy in operable locally advanced non-small cell lung cancer: An interim analysis.

Background: An open, observational, three-arm clinical study aimed at investigating the efficacy of different neoadjuvant therapies (neoadjuvant immunotherapy with(out) chemotherapy, neoadjuvant chemotherapy, and neoadjuvant targeted therapy) in operable locally advanced non-small cell lung cancer (NSCLC) was conducted (NCT04197076). We report an interim analysis of 49 of 53 evaluable patients. Methods: This study was conducted at Shanghai Chest Hospital and included eligible NSCLC patients who were 18 years old and had clinical stage IIB-IIIB disease. All 49 patients had surgical resection within 4-6 weeks after 2-3 cycles of neoadjuvant treatment consisting of immunotherapy (24 patients), chemotherapy (16 patients), and a targeted therapy (9 patients) regimen starting on the first day of each 21-day cycle. Pathologic complete response (pCR) was evaluated as the primary endpoint. Major pathological response (MPR) and tumor regression rate (TRR) were also evaluated. Results: An improved pathologic complete response was achieved in the neoadjuvant immunotherapy arm compared with the neoadjuvant chemotherapy arm and neoadjuvant targeted therapy arm [20.8% (5/24) vs. 6.3% (1/16) vs. 0.0% (0/9); P = 0.089, 95% CI 0.138-0.151]. More importantly, we found that the curative effect of the neoadjuvant immunotherapy arm in pCR+MPR was better than that of the neoadjuvant chemotherapy arm and neoadjuvant targeted therapy arm [45.8% (11/24) vs. 18.8% (3/16) vs. 0.0% (0/9); P = 0.006, 95% confidence interval, 0.008-0.012]. Different neoadjuvant therapies had a statistically significant effect on postoperative pathological tumor downstaging (P = 0.017). Conclusions: Neoadjuvant immunotherapy was associated with a trend toward better pCR than the neoadjuvant chemotherapy arm and neoadjuvant targeted therapy. Curative effect (pCR + MPR) was significantly better with neoadjuvant immunotherapy (P = 0.006, 95% confidence interval, 0.008-0.012). Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04197076?recrs=a&cond=NCT04197076&draw=2&rank=1.

Early-like differentiation status of systemic PD-1+CD8+ T cells predicts PD-1 blockade outcome in non-small cell lung cancer.

Objectives: Despite remarkable advances in the treatment of non-small cell lung cancer (NSCLC) with anti-programmed death (PD)-1 therapy; only a fraction of patients derives durable clinical benefit. In this study, we investigated whether the differentiation status of systemic CD8+ T cells predicts the outcome of PD-1 blockade in NSCLC. Methods: We carried out a prospective study on a total of 77 NSCLC patients receiving anti-PD-1 blockers, among which 47 patients were assigned as a discovery cohort and 30 patients as a validation cohort. Peripheral blood samples were obtained at baseline and upon multiple therapy cycles and analyzed by multi-parameter flow cytometry. Results: We found that a higher baseline ratio of PD-1+ early effector memory CD8+ T cells (CD28+CD27-CD45RO+, TEEM) to PD-1+ effector CD8+ T cells (CD28-CD27-CD45RO-, TE) delineated responders to PD-1 blockade from progressors and was associated with prolonged progression-free survival (PFS) and durable clinical benefit. Moreover, PD-1+CD8 TEEM cells exhibited early responses after anti-PD-1 therapy and was the major fraction of cycling PD-1+Ki67+CD8+ T cells to expand specifically with positive impact on PFS. Conclusion: These findings provide insights into how the baseline differentiation status of the peripheral immune system determines responses to PD-1-targeted therapies.

Convergent alteration of lung tissue microbiota and tumor cells in lung cancer.

Microbiota-host interaction plays an important role in cancer predisposing, initiation, progression, and response to therapy. Here, we explored the composition of lung tissue microbiota in 143 Chinese patients through conducting 16S rRNA gene sequencing, while TP53 mutation in tumor cells was assessed simultaneously. We found PAH-degrading microbes were more abundant in lung tumor microbiota from smokers. Furthermore, TP53 mutation was more prevalent in smokers, and TP53-mutated tumor harbored more Massilia, as well as Acidovorax that was also capable of degrading PAH. Further analysis showed DNA recombination and repair pathway was enriched in microbiota of smokers, which was convergent to the alteration occurred in tumor cells. Meanwhile, the microbiota of TP53-mutated tumor also exhibited dysregulation of p53 signaling pathway. Our results provided insights into the association of lung commensal microbes with tobacco exposure and host gene mutation, suggesting microbiota and tumor cells might undergo convergent alteration and mutually benefit each other.

Predictable Roles of Peripheral IgM Memory B Cells for the Responses to Anti-PD-1 Monotherapy Against Advanced Non-Small Cell Lung Cancer.

Tumor-infiltrating B cells and tertiary lymphoid structures have been identified to predict the responses to immune checkpoint inhibitors (ICIs) in cancer immunotherapy. Considering the feasibility of sample collection, whether peripheral B cell signatures are associated with the responses to ICI therapy remains unclear. Herein, we have defined peripheral B cell signatures in advanced non-small cell lung cancer (NSCLC) patients receiving anti-PD-1 monotherapy and investigated their associations with clinical efficacy. It was found that the percentages of B cells before the treatment (baseline) were significantly higher (P = 0.004) in responder (R, n = 17) than those in non-responder (NonR, n = 33) NSCLC patients in a discovery cohort. Moreover, the percentages of baseline IgM+ memory B cells were higher (P < 0.001) in R group than those in NonR group, and associated with a longer progression free survival (PFS) (P = 0.003). By logistic regression analysis peripheral baseline IgM+ memory B cells were identified as an independent prognostic factor (P = 0.002) for the prediction of the responses to anti-PD-1 monotherapy with the AUC value of 0.791, which was further validated in another anti-PD-1 monotherapy cohort (P = 0.011, n = 70) whereas no significance was observed in patients receiving anti-PD-L1 monotherapy (P = 0.135, n = 30). Therefore, our data suggest the roles of peripheral IgM+ memory B cells in predicting the responses to anti-PD-1 treatment in Chinese advanced NSCLC patients.

Serum Metabolite Biomarkers Predictive of Response to PD-1 Blockade Therapy in Non-Small Cell Lung Cancer.

Background: Despite remarkable success of immunotherapies with checkpoint blockade antibodies targeting programmed cell death protein 1 (PD-1), the majority of patients with non-small-cell lung cancer (NSCLC) have yet to receive durable benefits. We used the metabolomic profiling of early on-treatment serum to explore predictors of clinical outcomes of anti-PD-1 treatment in patients with advanced NSCLC. Methods: We recruited 74 Chinese patients who had stage IIIB/IV NSCLC-proven tumor progression and were treated with PD-1 inhibitor. The study was comprised of a discovery cohort of patients treated with nivolumab and two validation cohorts of patients receiving tislelizumab or nivolumab. Serum samples were collected 2-3 weeks after the first infusion of PD-1 inhibitor. Metabolomic profiling of serum was performed using ultrahigh performance lipid chromatograph-mass spectrometry. The serum metabolite biomarkers were identified using an integral workflow of nontargeted metabolomic data analysis. Results: A serum metabolite panel consisting of hypoxanthine and histidine was identified and validated as a predictor of response to PD-1 blockade treatment in patients with advanced NSCLC. High levels of both hypoxanthine and histidine in early on-treatment serum were associated with improved progression-free survival [hazard ratio (HR) = 0.078, 95% confidence interval (CI), 0.027-0.221, p < 0.001] and overall survival (HR = 0.124, 95% CI, 0.039-0.397, p < 0.001) in the discovery cohort. The serum metabolite panel showed a high sensitivity and specificity in distinguishing responders and non-responders in the validation cohorts 1 and 2, with an area under the receiver-operating characteristic curve of 0.933 and 1.000, respectively. High levels of serum hypoxanthine and histidine were correlated with improved progression-free survival in the validation cohort 1 (HR = 0.137, 95% CI, 0.040-0.467, p = 0.001) and in the validation cohort 2 (HR = 0.084, 95% CI, 0.009-0.762, p = 0.028). Conclusion: Our results revealed that hypoxanthine and histidine in early on-treatment serum are predictive biomarkers of response to PD-1 blockade therapy in patients with advanced NSCLC. The serum biomarker panel would enable early identification of NSCLC patients who may benefit from PD-1 blockade therapy.

Peripheral CD4+ T cell signatures in predicting the responses to anti-PD-1/PD-L1 monotherapy for Chinese advanced non-small cell lung cancer.

Limited benefit population of immune checkpoint inhibitors makes it urgent to screen predictive biomarkers for stratifying the patients. Herein, we have investigated peripheral CD4+ T cell signatures in advanced non-small cell lung cancer (NSCLC) patients receiving anti-PD-1/PD-L1 treatments. It was found that the percentages of IFN-γ and IL-17A secreting naïve CD4+ T cells (Tn), and memory CD4+ T cells (Tm) expressing PD-1, PD-L1 and CTLA-4 were significantly higher in responder (R) than non-responder (NonR) NSCLC patients associated with a longer progression free survival (PFS). Logistic regression analysis revealed that the baseline IFN-γ-producing CD4+ Tn cells and PD-1+CD4+ Tm cells were the most significant signatures with the area under curve (AUC) value reaching 0.849. This was further validated in another anti-PD-1 monotherapy cohort. Conversely, high percentage of CTLA-4+CD4+ Tm cells was associated with a shorter PFS in patients receiving anti-PD-L1 monotherapy. Our study therefore elucidates the significance of functional CD4+ Tn and Tm subpopulations before the treatment in predicting the responses to anti-PD-1 treatment in Chinese NSCLC patients. The fact that there display distinct CD4+ T cell signatures in the prediction to anti-PD-1 and anti-PD-L1 monotherapy from our study provides preliminary evidence on the feasibility of anti-PD-1 and anti-PD-L1 combination therapy for advanced NSCLC patients.

An inter-correlation among chemokine (C-X-C motif) ligand (CXCL) 1, CXCL2 and CXCL8, and their diversified potential as biomarkers for tumor features and survival profiles in non-small cell lung cancer patients.

BACKGROUND: The aim was to explore the interaction among chemokine (C-X-C motif) ligand (CXCL) 1/2/8 expressions, and their associations with clinicopathologic features and survival profiles in non-small cell lung cancer (NSCLC) patients. METHODS: The tumor tissue specimens from 232 primary NSCLC patients with TNM stage I-IIIA underwent resection were obtained and the expressions of CXCL1, CXCL2 and CXCL8 were measured by immunohistochemical assay. Disease-free survival (DFS) and overall survival (OS) were calculated according to survival data. RESULTS: There were 117(50.4%) CXCL1 low expression patients versus (vs.) 115 (49.6%) CXCL1 high expression patients, 107(46.1%) CXCL2 low expression patients vs. 125 (53.9%) CXCL2 high expression patients, 93 (40.1%) CXCL8 low expression patients vs. 139 (59.9%) CXCL8 high expression patients. Meanwhile, CXCL1 expression was positively correlated with CXCL2 expression and CXCL8 expression; CXCL2 expression was also positively correlated with CXCL8 expression. For tumor features, CXCL1, CXCL2 and CXCL8 were positively correlated with lymph node (LYN) metastasis and TNM stage, but not correlated with differentiation, tumor size or carcinoembryonic antigen (CEA) level. For prognosis, CXCL1 high expression was associated with worse DFS and OS, so did CXCL2 high expression, while there was no correlation of CXCL8 with DFS or OS; Multivariate Cox's regression disclosed that high expression of CXCL1, but not CXCL2 or CXCL8, was an independent factor predicting shorter DFS and OS. CONCLUSIONS: An inter-correlation is observed among CXCL1, CXCL2 and CXCL8 expressions, and they show diversified potential as biomarkers for tumor features and survival profiles in NSCLC patients.