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.
Opinion Statement
The standard therapy for limited disease small cell lung cancer (LD-SCLC) is concurrent chemoradiotherapy and prophylactic cranial irradiation (PCI) for those who achieve complete ...remission (CR) or good partial response (PR) with initial therapy. On the other hand, the standard therapy for extensive disease (ED-SCLC) is chemotherapy only. After the two phase III study conducted by Slotman et al., PCI with/without thoracic radiotherapy (TRT) is also recommended in the treatment of ED-SCLC. However, a Japanese phase III study failed to confirm the benefit of PCI for patients with ED-SCLC. All studies have demonstrated the effectiveness of PCI for preventing brain metastasis, but PCI seems to have a limited influence on OS. In the 2014 edition of the
Guidelines for the Treatment of Lung Cancer
from the Japan Lung Cancer Society (JLCS), use of PCI for patients with ED-SCLC has been changed from “recommended” to “not recommended”. Appropriate selection of patients for PCI with/without TRT is very important. It is hoped that the characteristics of patients for whom PCI with/without TRT should be considered or avoided will be better defined in the future.
Lung cancer is one of the most aggressive tumour types. Targeted therapies stratified by oncogenic drivers have substantially improved therapeutic outcomes in patients with non-small-cell lung cancer ...(NSCLC)
. However, such oncogenic drivers are not found in 25-40% of cases of lung adenocarcinoma, the most common histological subtype of NSCLC
. Here we identify a novel fusion transcript of CLIP1 and LTK using whole-transcriptome sequencing in a multi-institutional genome screening platform (LC-SCRUM-Asia, UMIN000036871). The CLIP1-LTK fusion was present in 0.4% of NSCLCs and was mutually exclusive with other known oncogenic drivers. We show that kinase activity of the CLIP1-LTK fusion protein is constitutively activated and has transformation potential. Treatment of Ba/F3 cells expressing CLIP1-LTK with lorlatinib, an ALK inhibitor, inhibited CLIP1-LTK kinase activity, suppressed proliferation and induced apoptosis. One patient with NSCLC harbouring the CLIP1-LTK fusion showed a good clinical response to lorlatinib treatment. To our knowledge, this is the first description of LTK alterations with oncogenic activity in cancers. These results identify the CLIP1-LTK fusion as a target in NSCLC that could be treated with lorlatinib.
Liquid biopsy offers a potential alternative to tissue biopsy for detection of genetic alterations in cancer, and it has been introduced into clinical practice to detect the tyrosine kinase inhibitor ...(TKI) resistance‐conferring T790M mutation of epidermal growth factor receptor (EGFR) in patients with non‐small‐cell lung cancer (NSCLC). We prospectively collected tumor and plasma samples from 25 NSCLC patients who harbored activating mutations of EGFR and experienced failure of treatment with afatinib. The samples were analyzed by digital PCR (dPCR) and next‐generation sequencing (NGS). T790M was detected in plasma with a respective sensitivity and specificity of 83.3% and 70.0% by dPCR and 50.0% and 70.0% by NGS relative to analysis of corresponding tumor samples. Quantitation of T790M based on the ratio of the number of T790M alleles to that of activating mutation alleles (T/A ratio) improved the specificity of plasma analysis to 100% for both dPCR and NGS without a reduction in sensitivity. Although several afatinib resistance mechanisms other than T790M—including copy number gain of NRAS or MET—were identified in tumor samples, the corresponding genetic alterations were not detected in plasma. TP53 mutations were frequently identified in plasma and tumor samples, with most such mutations also having been detected before afatinib treatment. The presence of de novo TP53 mutations was associated with reduced progression‐free survival. Quantitation of T790M in plasma is thus a clinically relevant approach to determine the T790M status of tumors. In addition, genetic alterations coexisting with EGFR mutations can affect the efficacy of EGFR‐TKI treatment.
Quantitation of T790M in plasma is a clinically relevant approach to determine the T790M status of tumors.
•The presence of tertiary lymphoid structures (TLS) was associated with significantly lower risk of recurrence.•TLS presence was not associated with PD-L1 expression.•Tumors with TLS have specific ...gene expression related to antitumor immune responses.
Tertiary lymphoid structures (TLS) are observed in several cancers and are associated with favorable prognosis. This study aimed to examine the clinicopathological, genetic, and gene expression profiles of lung adenocarcinoma patients with TLS.
A total of 112 patients with pathological stage IB lung adenocarcinoma who underwent complete resection between 2011 and 2015 were enrolled in this study. We investigated whether TLS correlated with prognosis and programmed death-ligand 1 (PD-L1) expression. Furthermore, the correlation of TLS with tumor mutation burden (TMB) and genetic mutations was evaluated in patients for whom whole-exon sequencing data were available. In addition, using the Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) dataset, gene expression analysis according to the TLS status was performed.
Among the 112 patients, 49 were TLS-positive (TLS+). TLS+ correlated with longer recurrence-free survival (RFS) than TLS-negative cases (TLS−) (hazard ratio HR, 0.47; 95 % confidence interval CI: 0.23–0.88, p = 0.02). In the multivariate analysis, TLS was a better independent prognostic factor for RFS (HR 0.37, 95 %CI 0.18–0.72, p < 0.01). PD-L1 expression was not significantly different between TLS+ and TLS− patients (p = 0.54). TMB in TLS+ was similar to that in TLS− patients (p = 0.39); however, it tended to be lower than that in TLS− especially among smokers (p = 0.07). In gene expression analysis, RNA expression of chemokines related to lymph node formation, such as CXCL13, CCL19 and CCL21, was significantly higher, and biological processes such as positive regulation of humoral immune response and regulation of antigen receptor-mediated signaling pathway were enhanced in TLS+.
TLS was a favorable prognostic factor and was not associated with PD-L1 expression in patients with lung adenocarcainoma. Moreover, gene expression analysis indicated that TLS is a site for the generation and regulation of antitumor immune responses.
We wanted to assess the efficacy of curative intent pulmonary resection for non-small cell lung cancer (NSCLC) patients with synchronous M1b-distant metastases in a single organ or lesion.
Between ...1995 and 2015, 23 consecutive synchronous M1b-cStage IV NSCLC patients who underwent any treatment for metastases and curative intent pulmonary resection were retrospectively analyzed.
Sixteen patients were men and 7 were women, with a median age of 56 years (range: 41 to 76 years). There were 17 adenocarcinoma, 4 large-cell carcinoma, 1 large-cell neuroendocrine cancer, and 1 carcinosarcoma. Thirteen patients had no lymph node metastasis. Fourteen patients received preoperative chemotherapy, and 10 received postoperative chemotherapy. The metastatic sites were the brain in 13 patients; bone in 3 patients; adrenal glands and extrathoracic lymph nodes in 2 patients each; and the liver, small intestine, and subcutaneous tissue in 1 patient each. Nineteen patients underwent lobectomy, and the other 4 patients underwent pneumonectomy. Seventeen patients experienced recurrence as follows: local recurrence in 3 patients, distant recurrence in 13 patients, and both in 1 patient. The 5-year progression-free survival rates in the 23 patients was14.5% (95% confidence interval: 0% to 30.6%), and the 5-year overall survival rate was 41.7% (95% confidence interval: 19.6% to 63.8%).
Some M1b-cStage IV NSCLC patients achieved longer survival than others with the same stage disease by using local treatment for distant metastases and curative intent pulmonary resection. Oligometastatic patients might have been inadvertently included in the present cohort. However, at present, the optimum method for patient selection remains unclear.
Patients with non‐small cell lung cancer (NSCLC) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) eventually acquire resistance to these drugs. The ...identification of various resistance mechanisms for determination of subsequent treatment for these patients will require a method for simultaneous detection of multiple genetic alterations with high sensitivity. We performed cancer personalized profiling by deep sequencing (CAPP‐Seq) with circulating tumor DNA obtained from patients with NSCLC who acquired resistance to first‐ or second‐generation EGFR‐TKIs. Plasma samples from 27 patients were analyzed, and 24 samples underwent CAPP‐Seq successfully. Original activating EGFR mutations were detected in 23 patients, with the remaining patient showing MET amplification. With regard to known mechanisms of EGFR‐TKI resistance, the T790M mutation of EGFR was detected in 17 of the 24 patients, MET amplification in 9 patients (6 of whom also harbored T790M), ERBB2 amplification in 2 patients (1 of whom also harbored T790M), and EGFR amplification in 4 patients (all of whom harbored T790M). Our results thus show that CAPP‐Seq is applicable to clinical samples for the identification of multiple somatic mutations in circulating tumor DNA obtained from patients with NSCLC at the time of disease progression during treatment with first‐ or second‐generation EGFR‐TKIs. Patients positive for the T790M mutation of EGFR were also found to constitute a molecularly heterogeneous population.
Key Points
CAPP‐Seq is applicable to clinical samples for the identification of multiple somatic mutations.
The T790M mutation of EGFR is associated with amplification of MET, ERBB2, or EGFR in NSCLC patients resistant to EGFR‐TKIs.
T790M‐positive patients are molecularly heterogeneous, and genetic alterations coexisting with T790M may differ between patients treated with first‐generation or second‐generation EGFR‐TKIs.
摘要
接受表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂 (TKI) 治疗的非小细胞肺癌 (NSCLC) 患者最终会对此类药物获得性耐药。为了确定这些患者的后续治疗，需要了解各种耐药机制，而这需要一种可以同时检测多种高灵敏度遗传变异情况的方法。研究从对第一代或第二代 EGFR‐TKI 获得性耐药的 NSCLC 患者中提取了循环肿瘤 DNA，然后通过深度测序 (CAPP‐Seq) 对肿瘤进行了个性化分析。分析 27 例患者血浆标本，其中 24 例最终进行了CAPP‐Seq 检测。23 例患者检测到 EGFR 原始激活突变，另一名患者出现 MET 扩增。关于已知的 EGFR‐TKI 耐药机制，在 24 例患者中，有 17 例出现了 EGFR 的 T790M 突变，9 例出现 MET 扩增(其中 6 例也存在 T790M)，2 例患者出现 ERBB2 扩增(其中 1 例还存在 T790M)，4 例患者出现 EGFR 扩增(所有患者都存在 T790M)。因此，研究结果表明，CAPP‐Seq 适用于临床样本，可用于确定疾病进展期间采用第一代或第二代 EGFR‐TKI 药物治疗的NSCLC患者体内循环肿瘤 DNA 中的多个体细胞突变。同时还发现，EGFR T790M 突变阳性患者存在分子异质性。
主要重点
• CAPP‐Seq 适用于临床样本，可用于确定多个体细胞突变。
• EGFR T790M 突变与对 EGFR‐TKI耐药的 NSCLC 患者出现 MET、ERBB2 或 EGFR扩增相关。
• T790M 阳性患者存在分子异质性，在采用第一代或第二代 EGFR‐TKI 治疗的患者中，与 T790M 共存的遗传变异可能有所不同。
This study performed cancer personalized profiling by deep sequencing (CAPP‐Seq) with circulating tumor DNA, a ctDNA‐based form of targeted next‐generation sequencing, to identify somatic mutations in patients with non‐small cell lung cancer (NSCLC) positive for activating mutations of the epidermal growth factor receptor (EGFR) gene at the time of disease progression during treatment with first‐generation (gefitinib or erlotinib) or second‐generation (afatinib) EGFR tyrosine kinase inhibitors.
This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without ...EGFR/ALK alterations and a programmed death ligand 1 (PD‐L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum‐based chemotherapy (four to six cycles). The primary end‐point was progression‐free survival; secondary end‐points included overall survival and safety. Of 305 patients randomized in KEYNOTE‐024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression‐free survival was 41.4 (95% confidence interval CI, 4.2‐42.5) months with pembrolizumab and 4.1 (95% CI, 2.8‐8.3) months with chemotherapy (hazard ratio HR, 0.27 95% CI, 0.11‐0.65; one‐sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9‒NR) and 21.5 (95% CI, 5.2‐35.0) months, respectively (HR, 0.39 95% CI, 0.17‐0.91; one‐sided, nominal P = .012). Treatment‐related adverse events occurred in 21/21 (100%) pembrolizumab‐treated and 18/19 (95%) chemotherapy‐treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3‐5 events. Immune‐mediated adverse events and infusion reactions occurred in 11 pembrolizumab‐treated patients (52%) and four chemotherapy‐treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3‐5 events. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: NCT02142738.
This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among 40 Japanese patients in the study.
Background
It has recently been suggested that concomitant medication may affect the clinical outcome of patients treated with immune checkpoint inhibitors (ICIs). However, only a few studies on the ...impact of concomitant medication on immune‐related adverse events (irAEs) have previously been reported. Here, we aimed to determine the impact of concomitant medication on the efficacy and safety of ICIs.
Methods
We retrospectively analyzed the data of 300 patients treated with nivolumab or pembrolizumab for advanced non‐small cell lung cancer (NSCLC) between January 2016 and July 2018. Multivariate logistic regression analysis was used to assess the effect of concomitant medication on treatment response or irAEs. A multivariate Cox proportional hazards model was used to evaluate concomitant medication‐related factors associated with time‐to‐treatment failure or overall survival (OS).
Results
A total of 70 patients responded to treatment and 137 experienced irAEs. The response rate and incidence of irAEs in patients treated with ICIs were not significantly associated with concomitant medication. Multivariate analysis showed that the use of opioids was an independent factor (time‐to‐treatment failure: hazard ratio 1.39, p = 0.021, OS: hazard ratio 1.54, p = 0.007).
Conclusions
The efficacy and safety of nivolumab or pembrolizumab in the treatment of patients with advanced NSCLC were not significantly influenced by concomitant medication. However, opioid usage might be associated with shorter OS in patients treated with these ICIs. Further mechanistic investigations should explore whether these associations are purely prognostic or contribute to ICI resistance.
Concomitant medication had no significant effect on the efficacy and safety of immune checkpoint inhibitors. Opioid use was associated with shorter overall survival and further study of this possible effect is required. This study is the first to demonstrate the impact of angiotensin receptor blockers or vitamin D on ICI treatment in patients with non‐small cell lung cancer.
This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without ...EGFR/ALK alterations and a programmed death‐ligand 1 (PD‐L1) tumor proportion score of 50% or greater evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum‐based chemotherapy (four to six cycles). The primary end‐point was progression‐free survival; secondary end‐points included overall survival and safety. Of 305 patients randomized in KEYNOTE‐024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). The hazard ratio (HR) for progression‐free survival by independent central review (data cut‐off date, 10 July 2017) was 0.25 (95% confidence interval CI, 0.10‐0.64; one‐sided, nominal P = .001). The HR for overall survival (data cut‐off date, 15 February 2019) was 0.39 (95% CI, 0.17‐0.91; one‐sided, nominal P = .012). Treatment‐related adverse events occurred in 21/21 (100%) pembrolizumab‐treated and 18/19 (95%) chemotherapy‐treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3‐5 events. Immune‐mediated adverse events and infusion reactions occurred in 11 patients (52%) and four patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3‐5 events. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or greater. The trial is registered with ClinicalTrials.gov: NCT02142738.
This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE‐024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non‐small‐cell lung cancer without EGFR/ALK alterations and a PD‐L1 tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Consistent with results from KEYNOTE‐024 overall, first‐line pembrolizumab improved progression‐free survival and overall survival vs chemotherapy with manageable safety among 40 Japanese patients in the study.
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