Purpose
The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS).

Patients and Methods
In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs).

Results
A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatmentrelated adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain.

Conclusion
Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations

Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer

Despite recent advances in the use of immunotherapy, only a minority of small cell lung cancer (SCLC) patients respond to immune checkpoint blockade (ICB). Here, we show that targeting DNA damage response (DDR) proteins, poly ADP-ribose polymerase (PARP) and checkpoint kinase 1 (CHK1) significantly increased protein and surface expression of PD-L1. PARP or CHK1 inhibition remarkably potentiated the anti-tumor effect of PD-L1 blockade and augmented cytotoxic T-cell infiltration in multiple immunocompetent SCLC in vivo models. CD8 depletion reversed the anti-tumor effect demonstrating the role of CD8+ T-cells in combined DDR-PD-L1 blockade in SCLC. We further demonstrate that DDR inhibition activated the STING/TBK1/IRF3 innate immune pathway, leading to increased levels of chemokines such as CXCL10 and CCL5 that induced activation and function of cytotoxic T-lymphocytes. Knockdown of cGAS and STING successfully reversed the anti-tumor effect of combined inhibition DDR and PD-L1. Our results define previously unrecognized innate immune pathway-mediated immunomodulatory functions of DDR proteins and provide a rationale for combining PARP/CHK1 inhibitors and immunotherapies in SCLC.

/pdf/targeting-dna-damage-response-promotes-antitumor-immunity-3sab8ih56y.pdf

Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer

A.i. in europe.

Advances in the enrichment and analysis of rare cells from the bloodstream have allowed for detection and characterization of circulating tumor cells (CTCs) from patients with cancer. The analysis of CTCs has provided significant insight into the metastatic process. Studies on the biology of CTCs have begun to elucidate the molecular mechanisms of CTC generation, intravasation, survival, interactions with components of the blood, extravasation, and colonization of distant organs. Additionally, the study of CTCs has exposed dramatic intrapatient and interpatient heterogeneity and their evolution over time. In this review, we focus on the current knowledge of CTC biology and the potential clinical implications.

/pdf/a-conduit-to-metastasis-circulating-tumor-cell-biology-54rny5ln5p.pdf

A conduit to metastasis: circulating tumor cell biology.

Background Explore markers to predict the clinical outcomes of checkpoint inhibitors have high unmet needs The following study investigates whether hematologic parameter such as systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) is associated with nivolumab efficacy in advanced non-small-cell lung cancer (NSCLC) Methods Advanced/metastatic NSCLC patients treated with nivolumab monotherapy for second-line or further-line treatment at Jilin Cancer Hospital between March 2016 and July 2018 were enrolled in this retrospective study The optimal cutoff values of SII, NLR, and PLR for predicting efficacy and prognosis were determined according to receiver operating characteristic (ROC) curve and the areas under the ROC curve Progression-free survival (PFS) and overall survival (OS) were calculated and compared using Kaplan-Meier method and log-rank test Prognostic values of each variable were evaluated with univariate and multivariate Cox proportional hazard regression (PHR) analyses Results A total of 44 patients with advanced NSCLC were included; the median age was 60 (range: 43-74) The optimal cutoff value of SII/NLR/PLR predicted PFS and OS was 6035, 307, and 144 Low SII, NLR, and PLR were associated with longer PFS (HR for SII = 034, 95%CI 015-076, P = 0006; HR for NLR = 046, 95%CI 022-099, P = 0048; HR for PLR = 039, 95%CI 017-094, P = 0025) and OS (HR for SII = 016, 95%CI 005-051, P = 0005; HR for NLR = 020, 95%CI 006-062, P = 0002; HR for PLR = 020, 95%CI 006-073, P = 0008) NLR ≤ 307, PLR ≤ 144, SII ≤ 6035 were independently associated with longer PFS and OS Conclusion The SII, NLR, and PLR are promising prognostic predictor for patients with metastatic NSCLC patients

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcla.22964

Systemic immune-inflammation index, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio can predict clinical outcomes in patients with metastatic non-small-cell lung cancer treated with nivolumab.

Aims: As data on the use of circulating tumor cells (CTCs) to predict patient outcomes in extensive-stage small-cell lung cancer (ES-SCLC) remain inconclusive, we investigated the clinical value of CTC determination in an open-label, multicenter study of 91 patients with newly diagnosed ES-SCLC. Materials & methods: Blood CTC counts were determined using the CellSearch® system at baseline, after the second cycle of chemotherapy, and on disease progression. Results & conclusion: Following the second cycle of treatment, CTC numbers and the change in CTCs were strong, significant and independent indicators for both progression-free survival and overall survival in ES-SCLC. The CTC change was associated with both refractory disease (response to initial therapy ≤3 months) and sensitive disease (response to initial therapy >3 months).

Circulating tumor cell counts/change for outcome prediction in patients with extensive-stage small-cell lung cancer.

Objective: There is a need to explore multi-discipline general treatment modes to improve the survival period of patients with SCLC and brain metastases undergoing standard radiotherapy treatment.M...

A study on different therapies and prognosis-related factors for 101 patients with SCLC and brain metastases

Non-small cell lung cancer (NSCLC) accounts for ~85% of lung cancer cases worldwide. Current guidelines recommend the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors for patients with NSCLC. The EGF/EGFR signaling pathway has been demonstrated to activate nuclear factor (NF)-κB, which may inhibit tumor necrosis factor (TNF)-α induced cell apoptosis. The aim of the present study was to investigate whether inhibiting the EGF/EGFR signaling pathway sensitizes NSCLC cell lines to TNF-α-induced apoptosis. The resistance of NSCLC cell lines to TNF-α was evaluated by cell viability assay. The effect of nimotuzumab (Ni) on NSCLC cell sensitivity to TNF-α, as well as the role of NF-κB in mediating resistance to TNF-α-induced apoptosis, was explored by western blot analysis, cell viability assay, apoptosis assay and an NF-κB DNA binding assay. It was demonstrated that EGFR protein expression was markedly higher in the H292 and H1975 cell lines compared with H460 and H1299 cell lines. H292 and H1975 also exhibited significantly increased TNF-α resistance compared with H460 and H1299 cells. Low dose Ni treatment slightly reduced the viability of H292 and H1975 cells; however, combined treatment with low dose Ni and TNF-α significantly inhibited H292 and H1299 cell viability compared with H460 and H1299 cells by inducing cell apoptosis. NF-κB protein expression and activity were also inhibited by the combination treatment. TNF-α treatment alone induced apoptosis in NF-κB deficient H292 and H1975 cells, similar to the effect of combination treatment in wild type H292 and H1975 cells. The results of the present study suggest that Ni sensitizes NSCLC cell lines to TNF-α-induced cell death by inhibiting NF-κB protein expression and activation, indicating a novel mechanism by which Ni suppresses the development of NSCLC.

/pdf/nimotuzumab-enhances-the-sensitivity-of-non-small-cell-lung-1f3d9gi900.pdf

Nimotuzumab enhances the sensitivity of non-small cell lung cancer cells to tumor necrosis factor-α by inhibiting the nuclear factor-кB signaling pathway

Background and objective Epidermal growth factor receptor (EGFR)-based targeted therapy improves the survival of patients with advanced lung adenocarcinoma harboring EGFR mutations. However, factors including treatment or heterogeneity partly contribute to EGFR genetic status alteration between baseline and disease progresses (PD). The aim of this study is to compare difference of EGFR mutations between biopsy and rebiopsy in real world. Methods Data from 61 paired specimens performed EGFR testing in Jilin Provincial Cancer Hospital between January 2015 and December 2017 were collected and analyzed. The specimens were collected at baseline and PD, confirmed by histology or cytology and categorized as tumor tissue, malignant pleural effusion or plasma. All patients were naive and received chemotherapy or targeted therapy as first-line treatment. Amplification Refractory Mutation System (ARMS) was used to detect EGFR mutations. Results EGFR mutation rate in tumor tissue, pleural effusion or blood was 90.2% vs 88.5%, 6.6% vs 6.6% and 3.2% vs 4.9% at baseline or PD respectively and discrepancy was 72% and 36.3% for the same (n=50) or different (n=11) type of specimens. The EGFR mutation rate was 95.1% and 91.8% in patients before and after treatment, and the discrepancy was 63.9%, among which, 69.2% and 92.3% in chemotherapy-treated patients (n=13) with discrepancy to 46.1% (6/13), and 100.0% and 91.7% in EGFR-TKI-treated patients (n=48) with discrepancy to 70.8%. There were four types of alterations in terms of EGFR mutations: wild type turned into mutation (4.9%), mutation disappeared (8.2%), sensitive mutations transformed (1.6%), and new mutations appeared (49.1%). Conclusion In real world, the EGFR mutation status in advanced non-small cell lung cancer (NSCLC) patients altered significantly, due to tissue resources and therapeutic approaches, implying the importance of rebiopsy and real-time detection of EGFR mutation, in order to provide data to guide precise strategy in the following treatment. 
	
	DOI: 10.3779/j.issn.1009-3419.2018.11.03

Ying Liu

Papers

Systemic immune-inflammation index, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio can predict clinical outcomes in patients with metastatic non-small-cell lung cancer treated with nivolumab.

Circulating tumor cell counts/change for outcome prediction in patients with extensive-stage small-cell lung cancer.

A study on different therapies and prognosis-related factors for 101 patients with SCLC and brain metastases

Nimotuzumab enhances the sensitivity of non-small cell lung cancer cells to tumor necrosis factor-α by inhibiting the nuclear factor-кB signaling pathway

[Disparities of EGFR mutations between Biopsy and Rebiopsy in Non-small Cell Lung Cancer Patients].