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• We report prespecified exploratory analyses of an mNSCLC cohort in China (NEPTUNE). 85 chars. • First-line durvalumab + tremelimumab showed a trend of improved OS vs chemotherapy. 85 chars. • This trend was observed in all patients and those with low tumor PD-L1 expression. 84 chars. • 24-month OS and 12-month PFS rates indicated benefit in the survival curve tails. 83 chars. • Durvalumab + tremelimumab was well tolerated with no new safety signals. 74 chars. The phase 3 NEPTUNE study (NCT02542293) evaluated first-line durvalumab plus tremelimumab (DT) versus chemotherapy for metastatic NSCLC. Prespecified exploratory analyses were conducted in an extended cohort enrolled in China. Patients were randomized (1:1) to DT or standard chemotherapy, stratified by PD-L1 tumor cell (TC) expression (≥25 % vs < 25 %), histology, and smoking history. The primary analysis for this cohort was overall survival (OS) in patients with PD-L1 TC < 1 %. Secondary analyses included OS and progression-free survival (PFS) in the ITT population and PD-L1 subgroups, and safety. No alpha was allocated to these cohort analyses (data cut-off, 21-September-2020). 78 and 82 patients were randomized to DT and chemotherapy, respectively; 26 and 29 had PD-L1 TC < 1 % (median follow-up, 31.2 and 29.7 months [censored patients]). Among patients with PD-L1 TC < 1 %, OS favored DT versus chemotherapy (HR 0.60; 95 % CI, 0.32–1.11), with medians of 15.0 months (95 % CI, 10.5–27.4) and 11.7 months (95 % CI, 8.6–20.5), respectively; 24-month rates were 36.0 % (95 % CI, 18.2–54.2) and 17.9 % (95 % CI, 6.5–33.7). In the ITT population, OS was prolonged with DT versus chemotherapy (HR 0.70; 95 % CI, 0.48–1.02); medians were 20.0 and 14.1 months and 24-month rates were 44.2 % and 30.4 %. PFS was similar in the PD-L1 TC < 1 % (HR 1.13; 95 % CI, 0.59–2.14) and ITT (HR 0.95; 95 % CI, 0.66–1.36) populations; 12-month rates were 15.6 % versus 11.3 % and 23.9 % versus 16.6 %. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 31.2 % with DT and 52.6 % with chemotherapy; 3.9 % versus 10.3 % discontinued due to TRAEs. In exploratory analyses, first-line DT showed a trend towards improved OS versus chemotherapy among Chinese patients in the PD-L1 TC < 1 % population and ITT population, with 24-month OS and 12-month PFS rates indicating benefit in survival curve tails. DT was well tolerated with no new safety signals. [ABSTRACT FROM AUTHOR]

• The genomic characteristics and mutations in Notch signaling pathway-related genes of SCLC patients were clarified. • The relationship of Notch signaling pathway mutations with tumor immune microenvironment were analyzed. • There was a significant negative correlation between NOTCH 1 gene mutation status and PD-L1 protein expression level. • Patients with positive DLL3 expression and no NOTCH 1 gene mutation had higher PD-L1 expression and may be more likely to benefit from PD-1/PD-L1 ICIs treatment. To explore the characteristics of Notch pathway in small cell lung cancer (SCLC), clarify the expression of delta-like protein 3 (DLL3) in SCLC patients undergoing surgical treatment, and explore the correlation between DLL3 expression and clinicopathological features, prognosis, and immune microenvironment. A total of 134 patients who received surgical treatment and were diagnosed as SCLC by postoperative histopathology were enrolled. All exon gene sequencing was performed in tumor tissues and adjacent normal tissues of 28 patients to clarify the genomic characteristics of SCLC. The expressions of DLL3 and programmed cell death 1 ligand 1 (PDL1) were detected by immunohistochemistry (IHC) in 101 postoperative pathological specimens. Notch receptor mutations are common, but the overall mutation rate of Notch ligand family is not high and mutually exclusive. The mutation status of Notch and Notch1 gene were not related to the prognosis. Notch1 gene mutation was significantly negatively correlated with the expression of PD-L1. DLL3 was highly expressed in SCLC and had no significant correlation with prognosis. There was a positive correlation between DLL3 expression and PD-L1 expression. Patients with positive DLL3 expression and no NOTCH 1 gene mutation had higher PD-L1 expression. SCLC patients with such characteristics may be more likely to benefit from immunotherapy. This study preliminarily explored the genomic characteristics and immune microenvironment of surgical resection of SCLC in China, and found the correlation between Notch gene mutation, DLL3 expression and PD-L1 expression, which provided a new idea for selecting appropriate treatment strategies for SCLC in the future. [ABSTRACT FROM AUTHOR]

Background: Numerous ongoing trials are testing anti-PD-1-based or anti-PD-L1-based cancer treatment combinations. Understanding the toxicity profiles of treatment-related adverse events is essential. The aim of this study was to comprehensively investigate the incidences and profiles of treatment-related adverse events across different combination therapies.Methods: We did a systematic review and meta-analysis comparing different chemotherapy, targeted therapy, immunotherapy, and radiotherapy combinations with PD-1 or PD-L1 inhibitors. We searched Pubmed, Embase, and Cochrane databases for articles published in English between Jan 1, 2000, and May 21, 2020, investigating globally approved PD-1 or PD-L1 inhibitor-based combination therapies. Only prospective trials reporting overall incidence or tabulated data of treatment-related adverse events were included. Trials investigating sequential therapies, comprising three or more classes of therapies, and enrolling less than ten patients were excluded. The primary outcomes were overall incidences and profiles for all-grade and grade 3 or higher treatment-related adverse events by random-effect models. Heterogeneity between studies was assessed with I2 statistics. The summary measures for main outcomes are incidences (95% CI). The 95% CI were calculated together with the incidence through a random-effects model with a logit transformation. The protocol is registered with PROSPERO (CRD42020189617).Findings: We identified 2540 records, of which 161 studies (17 197 patients) met the inclusion criteria. The overall incidence of treatment-related adverse events in the chemotherapy combination was 97·7% (95% CI 96·4-98·5; I2=75%) for all-grade adverse events and 68·3% (60·7-75·0; I2=93%) for grade 3 or higher adverse events; in the targeted therapy combination was 94·5% (90·7-96·8; I2=86%) for all-grade adverse events and 47·3% (37·3-57·5; I2=93%) for grade 3 or higher adverse events; in the immunotherapy combination was 86·8% (80·9-91·1; I2=94%) for all-grade adverse events and 35·9% (29·5-42·9; I2=92%) for grade 3 or higher adverse events; and in the radiotherapy combination was 89·4% (69·0-96·9; I2=74%) for all-grade adverse events and 12·4% (4·4-30·6; I2=73%) for grade 3 or higher adverse events. For these four combination therapies, the most common all-grade adverse events were anaemia (45.4% [95% CI 32·4-59·1]), fatigue (34·3% [27·5-41·9]), fatigue (26·4% [19·2-35·2]), and dysphagia (30·0% [18·7-44·5]), respectively, and the most common grade 3 or higher adverse events were neutropenia (19·6% [13·5-27·7]), hypertension (9·3% [5·7-14·9]), lipase increased (7·2% [5·2-9·9]), and lymphopenia (10·3% [4·5-21·8]). All included randomised controlled trials had a low risk of bias.Interpretation: Our study provides comprehensive data on treatment-related adverse events of different PD-1 or PD-L1 inhibitor-based combination therapies. Our results provide an essential reference of toxicity profiles of PD-1 or PD-L1 inhibitor-based combination therapies for clinicians in routine practice of cancer care.Funding: National Key Research and Development Programme, National Natural Science Foundation of China key program, National Natural Science Foundation of China general program, Chinese Academy of Medical Sciences Initiative for Innovative Medicine, Beijing Municipal Science and Technology Commission, Non-profit Central Research Institute Fund. [ABSTRACT FROM AUTHOR]

Immunotherapies can substantially improve treatment efficacy, despite their high cost. A comprehensive overview of the cost-effectiveness analysis (CEA) of immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer based on different tumor proportion scores (TPSs) was conducted. PubMed, Embase, Cochrane Central Register of Controlled Trials, Health Technology Assessment Database, and NHS Economic Evaluation databases were searched from their inception until August 24, 2022. Data relevant to the CEA results were recorded, and quality assessments conducted based on the Quality of Health Economic Studies (QHES) process. Fifty-one original studies from seven countries were included. The mean QHES score was 77.0 (range: 53–95). Twenty-seven studies were classified as high-quality, and the rest as fair quality. Pembrolizumab, nivolumab, ipilimumab, atezolizumab, camrelizumab, cemiplimab, sintilimab, tislelizumab, and durvalumab were identified using three TPS categories. While nivolumab plus ipilimumab and pembrolizumab plus chemotherapy were unlikely to be cost-effective in China, the results for the US were uncertain. Atezolizumab combinations were not cost-effective in China or the US, and tislelizumab and sintilimab were cost-effective in China. For TPSs ≥ 50%, the pembrolizumab monotherapy could be cost-effective in some developed countries. Cemiplimab was more cost-effective than chemotherapy, pembrolizumab, and atezolizumab in the US. For TPSs ≥ 1%, the cost-effectiveness of pembrolizumab was controversial due to the different willingness-to-pay thresholds. None of the atezolizumab combination regimens were found to be cost-effective in any perspective of evaluations. Camrelizumab, tislelizumab, and sintilimab have lower ICERs compared to atezolizumab, pembrolizumab, and nivolumab in China. Cemiplimab may be a more affordable alternative to pembrolizumab or atezolizumab. However, it remains unclear which ICIs are the best choices for each country. Future CEAs are required to select comprehensive regimens alongside randomized trials and real-world studies to help verify the economics of ICIs in specific decision-making settings. [Display omitted] • A total of 51 studies related to nine ICIs, and 21 patient regimes were included. • None of the atezolizumab combination regimens were found to be cost-effective. • Camrelizumab/tislelizumab/sintilimab had lower ICERs than atezolizumab/pembrolizumab/nivolumab in China. • Cemiplimab may be a cheaper alternative to pembrolizumab or atezolizumab. • Country/PD-L1 levels dictate several immune checkpoint inhibitor cost-effectiveness. [ABSTRACT FROM AUTHOR]

To evaluate the cost-effectiveness of pembrolizumab versus chemotherapy as the first-line treatment for metastatic non-small cell lung cancer (NSCLC) with different tumor proportion scores (TPS), from perspective of payers in China. Conclusions Compared to standard chemotherapy, pembrolizumab is not a cost-effective choice for patients with locally advanced or metastatic NSCLC from the perspective of Chinese payer, regardless of TPS. [Extracted from the article]

The aim of this study was to research whether there was expression of PD-L1 in plasma exosome of NSCLC patients and whether its expression can partly represent PD-L1 expression of corresponding lung tumor tissues. Plasma was collected before and after surgery of NSCLC patients with stage II to stage III. Plasma of NSCLC patients with stage IV was also collected before and after anti-PD-1/PD-L1 therapy. Digital PCR was used to detect PD-L1 and β-actin mRNA expression of plasma exosomes. Expression of PD-L1 in tumor tissues was determined by immunohistochemical staining (22C3). Pearson correlation analysis and wilcoxon rank sum test was performed by SPSS 22.0. A total of 126 patients (54 patients with surgery and 72 patients with non-surgery therapy) were participated in this study. Exosomal PD-L1 expression can be detected in all plasma samples. Exosomal expression of PD-L1 calculated by both absolute quantification method and relative quantification method showed a positive correlation with PD-L1 expression of tumor tissues (absolute quantification method: r2=0.289, P = 0.001; relative quantification method: r2=0.547, P = 0.000). However, expression of exosomal PD-L1 calculated by relative quantification calculation showed higher correlation. Exosomal PD-L1 expression significantly decreased after surgery (P < 0.001) and three patients who showed good response (PR) to anti-PD-1/PD-L1 therapy also showed significantly decreasing exosomal PD-L1 expression after anti-PD-1/PD-L1 therapy (P < 0.001). Plasma exosomes of NSCLC patients contains substantial expression of PD-L1. Plasma exosomal PD-L1 expression showed high correlation with PD-L1 expression of tumor tissues. Exosomal PD-L1 expression could represent PD-L1 expression of tumor tissues and might be a potential predictive marker for anti-PD-1/PD-L1 therapy. Jifeng Feng. The National Natural Science Foundation of China. All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]