Gut microbiota serves an important role in shaping systemic immune responses. Antibiotics cause changes in the gut microbiota that may influence the efficacy of cancer immunotherapy. In the present ...study, a retrospective analysis of the data from 90 patients treated with nivolumab for non-small cell lung cancer (NSCLC) was conducted. A total of 13 patients were treated with antibiotics prior to nivolumab therapy. The median progression-free survival time in patients treated with antibiotics was 1.2 months 95% confidence interval (CI), 0.5-5.8, while the time for patients who were not treated with antibiotics was 4.4 months (95% CI, 2.5-7.4). The median overall survival time in patients treated with antibiotics was 8.8 months, while it was not reached in those not treated with antibiotics, respectively. The differences between the survival curves with regard to PFS and OS were statistically significant (P=0.04 and P=0.037, respectively). However, in multivariate analysis, no statistically significant association was indicated between survival and prior antibiotic use, although a certain trend concerning the negative influence of antibiotic use was conveyed.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objectives
Although liver metastasis has been known to be associated with poor prognosis, only a few studies have shown an association between liver metastasis and treatment outcomes with immune ...checkpoint inhibitors (ICI). Furthermore, factors associated with prognosis have remained unclear. The present study therefore evaluates the efficacy of nivolumab, pembrolizumab, and atezolizumab among patients with non-small cell lung cancer (NSCLC) who had liver metastasis and identifies factors correlated with prognosis.
Materials and methods
A total of 215 patients with advanced and recurrent NSCLC who received ICI therapy at a single center were retrospectively reviewed. A total of 41 patients (19.1%) had liver metastasis upon initiation of ICI therapy. Overall, 125, 64, and 26 patients were treated with nivolumab, pembrolizumab, and atezolizumab, respectively.
Results
Among the included patients, those with liver metastasis had shorter overall survival (OS) hazard ratio (HR), 2.04; 95% CI 1.33–3.13 and progression-free survival (PFS) (HR, 1.89; 95% CI 1.29–1.71) compared to those without the same. Patients with liver metastasis had a response rate (RR) of 22.5%. Among patients with liver metastasis, inferior OS was associated with low albumin, poor Eastern Cooperative Oncology Group performance status, driver mutation, and number of liver metastasis (≥ 5). Moreover, patients with liver metastasis who had good Royal Marsden Hospital (0–1) and Gustave Roussy Immune (0–1) scores showed significantly longer OS and PFS.
Conclusion
Despite the poor outcomes with ICI treatment in patients with advanced and recurrent NSCLC who had liver metastasis, some characteristics among patients with liver metastasis may be associated with prognosis.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The identification of epidermal growth factor receptor (
) mutations and development of
tyrosine kinase inhibitors (EGFR-TKIs) have dramatically improved the prognosis of advanced EGFR-mutated ...non-small cell lung cancer (NSCLC), setting a landmark in precision oncology. Exon 19 deletions and exon 21 L858R substitutions, which comprise the majority of common
mutations, are predictors of good sensitivity to EGFR-TKIs. However, not all cancers harboring
mutations are sensitive to EGFR-TKIs. Most patients harboring uncommon
mutations demonstrate a poorer clinical response than those harboring common
mutations. For example, cancers harboring exon 20 insertions, which represent approximately 4-12% of
mutations, are generally insensitive to first- and second-generation EGFR-TKIs. Although understanding the biology of uncommon
mutations is essential for developing treatment strategies, there is little clinical data because of their rarity. Moreover, clarifying the acquired resistance of
-mutated NSCLC may lead to more precise treatments. Sequencing and structure-based analyses of EGFRmutated NSCLC have revealed resistance mechanisms and drug sensitivity. In this review, we discuss the strategies in development for treating NSCLC harboring common and uncommon
mutations. We will also focus on EGFR-TKI sensitivity in patients harboring
mutations based on the structural features.
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IMpower132 explored the safety and efficacy of atezolizumab plus pemetrexed and platinum‐based chemotherapy as first‐line treatment for advanced non‐small‐cell lung cancer (NSCLC). Key eligibility ...criteria for the phase 3, open‐label, IMpower132 study included age ≥18 y, histologically or cytologically confirmed advanced non‐squamous NSCLC per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status of 0/1, and no prior systemic treatment for stage IV NSCLC. Patients received atezolizumab (1200 mg) plus pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) or carboplatin (area under the concentration curve, 6 mg/mL/min) (APP arm) or chemotherapy alone (PP arm). The co‐primary study endpoints were overall survival (OS) and investigator‐assessed progression‐free survival (PFS) per RECIST 1.1 in the intention‐to‐treat population. A subgroup analysis was conducted in Japanese patients. In the Japanese subgroup (n = 101), median OS was 30.8 (95% CI, 24.3 to not estimable) mo in the APP arm (n = 48) and 22.2 (95% CI, 15.7‐30.8) mo in the PP arm (n = 53; hazard ratio HR, 0.63 95% CI, 0.36‐1.14). PFS was 12.8 (95% CI, 8.6‐16.6) mo in the APP arm vs 4.5 (95% CI, 4.1‐6.7) mo in the PP arm (HR, 0.33 95% CI, 0.21‐0.58). Grade 3/4 treatment‐related adverse events (TRAEs) occurred in 68.8% of APP arm patients and 44.2% of PP arm patients. Consistent with global study results, atezolizumab plus pemetrexed and platinum‐based chemotherapy improved efficacy and was well tolerated in Japanese patients with advanced NSCLC despite a higher incidence of grade 3/4 TRAEs.
The global phase 3 IMpower132 study evaluated atezolizumab plus pemetrexed and platinum‐based chemotherapy vs chemotherapy alone for first‐line treatment of advanced non‐squamous NSCLC. A subgroup analysis of 101 Japanese patients showed that atezolizumab plus chemotherapy was well tolerated in these patients and provided overall treatment benefit vs chemotherapy alone. These results are consistent with the global study.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
According to rapid development of chemotherapy in advanced non-small cell lung cancer (NSCLC), the Japan Lung Cancer Society has been updated its own guideline annually since 2010. In this latest ...version, all of the procedure was carried out in accordance with grading of recommendations assessment, development and evaluation (GRADE) system. It includes comprehensive literature search, systematic review, and determination of the recommendation by multidisciplinary expert panel which consisted of medical doctors, pharmacists, nurses, statisticians, and patients from patient advocacy group. Recently, we have had various types of chemotherapeutic drugs like kinase inhibitors or immune-checkpoint inhibitors. Thus, the guideline proposes to categorize patients into three entities: (1) driver oncogene-positive, (2) PD-L1 ≥ 50%, and (3) others. Based on this subgroup, 31 clinical questions were described. We believe that this attempt enables clinicians to choose appropriate treatment easier. Here, we report an English version of the Japan Lung Cancer Society Guidelines 2018 for NSCLC, stages IV.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Thymic carcinoma is a rare cancer that arises from thymic epithelial cells. Its nature and pathology differ from that of benign thymoma, presenting a poorer prognosis. If surgically resectable, ...surgery alone or surgery followed by chemoradiotherapy or radiotherapy is recommended by the National Comprehensive Cancer Network Guidelines. Metastatic and refractory thymic carcinomas require systemic pharmacotherapy. Combined carboplatin and paclitaxel, and cisplatin and anthracycline-based regimens have been shown a fair response rate and survival to provide a de facto standard of care when compared with other drugs employed as first-line chemotherapy. Cytotoxic agents have been pivotal for treating thymic carcinoma, as little is known regarding its tumorigenesis. In addition, genetic alterations, including driver mutations, which play an important role in treatments, have not yet been discovered. However, molecular pathways and biomarker studies assessing thymic epithelial tumors have been reported recently, resulting in the development of new agents, such as molecular targeted agents and immune checkpoint inhibitors. As treatment options are currently limited and the prognosis remains poor in metastases and recurrent thymic carcinoma, genetic alterations need to be assessed. In the present review, we focused on the current role of targeted therapies and immune checkpoint inhibitors in treating thymic carcinoma.
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The pathological diagnosis of lung cancer has largely been based on the morphological features observed microscopically. Recent innovations in molecular and genetic technology enable us to compare ...conventional histological classifications, protein expression status, and gene abnormalities. The introduction of The Cancer Genome Atlas (TCGA) project along with the widespread use of the next-generation sequencer (NGS) have facilitated access to enormous data regarding the molecular profiles of lung cancer. The World Health Organization classification of lung cancer, which was revised in 2015, is based on this progress in molecular pathology; moreover, immunohistochemistry has come to play a larger role in diagnosis. In this article, we focused on genetic and epigenetic abnormalities in non-small cell carcinoma (adenocarcinoma and squamous cell carcinoma), neuroendocrine tumor (including carcinoids, small cell carcinoma, and large cell neuroendocrine carcinoma), and carcinoma with rare histological subtypes. In addition, we summarize the therapeutic targeted reagents that are currently available and undergoing clinical trials. A good understanding of the morphological and molecular profiles will be necessary in routine practice when the NGS platform is widely used.
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Biomarkers for predicting the effect of anti–programmed cell death 1 monoclonal antibody therapy against non–small-cell lung cancer (NSCLC) are urgently required. We prospectively studied the ...baseline plasma soluble programmed cell death ligand 1 (sPD-L1) levels from 39 NSCLC patients as a predictive marker of nivolumab therapy. The clinical benefit from nivolumab therapy was significantly associated with the baseline plasma sPD-L1 levels. Plasma sPD-L1 levels could represent a novel predictive marker for nivolumab therapy against NSCLC.
Biomarkers for predicting the effect of anti–programmed cell death 1 (PD-1) monoclonal antibody against non–small-cell lung cancer (NSCLC) are urgently required. Although it is known that the blood levels of soluble programmed cell death ligand 1 (sPD-L1) are elevated in various malignancies, the nature of sPD-L1 has not been thoroughly elucidated. We investigated the significance of plasma sPD-L1 levels as a biomarker for anti–PD-1 monoclonal antibody, nivolumab therapy.
The present prospective study included 39 NSCLC patients. The patients were treated with nivolumab at the dose of 3 mg/kg every 2 weeks, and the effects of nivolumab on NSCLC were assessed according to the change in tumor size, time to treatment failure (TTF), and overall survival (OS). The baseline plasma sPD-L1 concentration was determined using an enzyme-linked immunosorbent assay.
The area under the curve of the receiver operating characteristic curve was 0.761. The calculated optimal cutoff point for sPD-L1 in the plasma samples was 3.357 ng/mL. Of the 39 patients, 59% with low plasma sPD-L1 levels achieved a complete response or partial response and 25% of those with high plasma sPD-L1 levels did so. In addition, 22% of the patients with low plasma sPD-L1 levels developed progressive disease compared with 75% of those with high plasma sPD-L1 levels. The TTF and OS were significantly longer for those patients with low plasma sPD-L1 levels compared with the TTF and OS for those with high plasma sPD-L1 levels.
The clinical benefit from nivolumab therapy was significantly associated with the baseline plasma sPD-L1 levels. Plasma sPD-L1 levels might represent a novel biomarker for the prediction of the efficacy of nivolumab therapy against NSCLC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
For non‐small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, the initial therapeutic interventions will have crucial impacts on their clinical outcomes. ...Drug tolerant factors reportedly have an impact on EGFR‐tyrosine kinase inhibitor sensitivity. This prospective study investigated the impacts of drug tolerant‐related protein expression in tumors based on the efficacy of osimertinib in the first‐setting of EGFR‐mutated advanced NSCLC patients. A total of 92 patients with EGFR‐mutated advanced or postoperative recurrent NSCLC were analyzed and treated with osimertinib at 14 institutions in Japan. AXL, p53, and programmed death‐ligand 1 (PD‐L1) expression in patient tumors was determined using immunohistochemistry. The AXL signaling pathway was investigated using a cell line‐based assay and AXL‐related gene expression in The Cancer Genome Atlas (TCGA) database. High levels of AXL and positive‐p53 expression were detected in 26.1% and 53.3% of the pretreatment EGFR‐mutated NSCLC tumors, respectively. High AXL expression levels were significantly associated with a shorter progression‐free survival compared with low AXL expression levels, irrespective of the EGFR activating mutation status (p = 0.026). Cell line‐based assays indicated that the overexpression of AXL protein accelerated PD‐L1 expression, which induced insensitivity to osimertinib. In the TCGA database, AXL RNA levels were positively correlated with PD‐L1 expression in the lung adenocarcinoma cohort. The results show that high AXL expression levels in tumors impact clinical predictions when using osimertinib to treat EGFR‐mutated NSCLC patients. Trial Registration: UMIN000043942.
High levels of AXL and PD‐L1 expression predicts poor PFS with osimertinib. AXL protein overexpression induces PD‐L1 expression and osimertinib insensitivity. AXL expression in tumors impacts clinical predictions when using osimertinib.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Epidermal growth factor receptor (EGFR) exon 20 insertion mutations (Exon20ins) account for 4-12% of all EGFR mutations in non-small cell lung cancer (NSCLC) patients. Data on the differences in ...clinical characteristics between patients with Exon20ins and major mutations (M-mut) such as exon 19 deletion and L858R are limited. We retrospectively reviewed advanced NSCLC patients with EGFR mutations, who were treated with systemic therapy between January 2011 and December 2019. We identified 23 patients with Exon20ins and 534 patients with M-mut. In Exon20ins patients, the median age was 60 (range 27-88) years, and females and never-smokers were predominant. Clinical characteristics were similar in the two groups. In Exon20ins patients, 17 patients received platinum doublet as first-line therapy, and the overall response rate (ORR) and median progression-free survival (mPFS) were 11.8% and 8.9 months. Additionally, seven patients received conventional EGFR-tyrosine kinase inhibitors (TKIs), and eight patients anti-PD-1 antibodies in any-line therapy. ORR and mPFS of EGFR-TKIs and anti-PD-1 antibodies were 0%, 2.2 months and 25%, 3.1 months, respectively. Overall survival was significantly shorter in Exon20ins patients than in M-mut patients (29.3 vs. 43.4 months, p = 0.04). The clinical outcomes in Exon20ins patients were not satisfactory compared to M-mut patients.
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