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Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments
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Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Pulmonology".

Deadline for manuscript submissions: closed (1 December 2020) | Viewed by 61468

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Junji Uchino

E-Mail Website
Guest Editor
1. Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
2. Bannan Central Hospital, Hamamatsu, Shizuoka 438-0814, Japan
Interests: lung cancer; chemotherapy; clinical trial
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Conventional lung cancer treatments were once limited to surgery, radiation, and chemotherapy. However, gefitinib, a targeted drug, was launched in 2004, and the situation changed. Cancer cases that were highly responsive to gefitinib were later discovered to have epithelial growth factor receptor (EGFR) mutations. This discovery opened the door for biomarker-based treatment strategies. Subsequently, several EGFR-tyrosine kinase inhibitors (TKI) were developed, and they became a new mainstay of treatment for non-small cell lung cancer. In recent years, many mechanisms of resistance to EGFR-TKI have been elucidated; a mutation in the T790M gene at exon 20 is found in half of the resistant cases. Hence, osimertinib, which specifically inhibits EGFR despite this T790M gene mutation, was developed to achieve long-term progression-free survival. Other driver mutations that are similar to the EGFR mutation were discovered, including the EML4-ALK fusion gene (discovered in 2007), ROS1 gene, and BRAF gene mutations. The TKIs for each of these fusion genes were developed and are used as therapeutic agents.

Another advancement in advanced non-small cell lung cancer is the development of immune checkpoint inhibitors. Four PD-1/PD-L1 inhibitors, including nivolumab, are currently available for treatment of lung cancer. These drugs prevent an escape from the cancer immunity cycle. This ensures that cancer cells will express cancer antigens, causing an anticancer immune response. Due to cancer immunotherapy, long-term survival is possible. The biomarker development for cancer immunotherapy and its side effects are actively being studied.

This Special Issue on “Non-Small Cell Lung Cancer: Current Therapies and New Targeted Treatments” aims to update researchers and clinicians by summarizing the remarkable progress made recently in the field of targeted therapy, immunotherapy, and cancer biology for non-small cell lung cancer.

Dr. Junji Uchino
Guest Editor

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Keywords

  • NSCLC
  • Chemotherapy
  • targeted therapy
  • immunotherapy
  • biomarkers
  • cancer biology
  • drug resistance
  • combination therapy
  • radiation therapy.

Published Papers (20 papers)

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13 pages, 3891 KiB  
Article
Negative Effect of Reduced NME1 Expression on Recurrence-Free Survival in Early Stage Non-Small Cell Lung Cancer
by Dohun Kim, Yujin Kim, Bo Bin Lee, Dongho Kim, Ok-Jun Lee, Pildu Jeong, Wun-Jae Kim, Eun Yoon Cho, Joungho Han, Young Mog Shim and Duk-Hwan Kim
J. Clin. Med. 2020, 9(10), 3067; https://doi.org/10.3390/jcm9103067 - 23 Sep 2020
Cited by 3 | Viewed by 1861
Abstract
This study aimed to understand whether the effect of non-metastatic cells 1 (NME1) on recurrence-free survival (RFS) in early stage non-small cell lung cancer (NSCLC) can be modified by β-catenin overexpression and cisplatin-based adjuvant chemotherapy. Expression levels of NME1 and β-catenin were analyzed [...] Read more.
This study aimed to understand whether the effect of non-metastatic cells 1 (NME1) on recurrence-free survival (RFS) in early stage non-small cell lung cancer (NSCLC) can be modified by β-catenin overexpression and cisplatin-based adjuvant chemotherapy. Expression levels of NME1 and β-catenin were analyzed using immunohistochemistry in formalin-fixed paraffin-embedded tissues from 425 early stage NSCLC patients. Reduced NME1 expression was found in 39% of samples. The median duration of follow-up was 56 months, and recurrence was found in 186 (44%) of 425 patients. The negative effect of reduced NME1 expression on RFS was worsened by cisplatin-based adjuvant chemotherapy (adjusted hazard ratio = 3.26, 95% CI = 1.16–9.17, p = 0.03). β-catenin overexpression exacerbated the effect of reduced NME1 expression on RFS and the negative effect was greater when receiving cisplatin-based adjuvant chemotherapy: among patients treated with cisplatin-based adjuvant chemotherapy, hazard ratios of patients with reduced NME1 expression increased from 5.59 (95% confidence interval (CI) = 0.62–50.91, p = 0.13) to 15.52 (95% CI = 2.94–82.38, p = 0.001) by β-catenin overexpression, after adjusting for confounding factors. In conclusion, the present study suggests that cisplatin-based adjuvant chemotherapy needs to be carefully applied to early stage NSCLC patients with overexpressed β-catenin in combination with reduced NME1 expression. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments)
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10 pages, 5621 KiB  
Article
Predicting the Role of DNA Polymerase β Alone or with KRAS Mutations in Advanced NSCLC Patients Receiving Platinum-Based Chemotherapy
by Maria Francesca Alvisi, Monica Ganzinelli, Helena Linardou, Elisa Caiola, Giuseppe Lo Russo, Fabiana Letizia Cecere, Anna Cecilia Bettini, Amanda Psyrri, Michele Milella, Eliana Rulli, Alessandra Fabbri, Marcella De Maglie, Pierpaolo Romanelli, Samuel Murray, Gloriana Ndembe, Massimo Broggini, Marina Chiara Garassino and Mirko Marabese
J. Clin. Med. 2020, 9(8), 2438; https://doi.org/10.3390/jcm9082438 - 30 Jul 2020
Cited by 2 | Viewed by 1918
Abstract
Clinical data suggest that only a subgroup of non-small cell lung cancer (NSCLC) patients has long-term benefits after front-line platinum-based therapy. We prospectively investigate whether KRAS status and DNA polymerase β expression could help identify patients responding to platinum compounds. Prospectively enrolled, advanced [...] Read more.
Clinical data suggest that only a subgroup of non-small cell lung cancer (NSCLC) patients has long-term benefits after front-line platinum-based therapy. We prospectively investigate whether KRAS status and DNA polymerase β expression could help identify patients responding to platinum compounds. Prospectively enrolled, advanced NSCLC patients treated with a first-line regimen containing platinum were genotyped for KRAS and centrally evaluated for DNA polymerase β expression. Overall survival (OS), progression-free survival (PFS), and the objective response rate (ORR) were recorded. Patients with KRAS mutations had worse OS (hazard ratio (HR): 1.37, 95% confidence interval (95% CI): 0.70–2.27). Negative DNA polymerase β staining identified a subgroup with worse OS than patients expressing the protein (HR: 1.43, 95% CI: 0.57–3.57). The addition of KRAS to the analyses further worsened the prognosis of patients with negative DNA polymerase β staining (HR: 1.67, 95% CI: 0.52–5.56). DNA polymerase β did not influence PFS and ORR. KRAS may have a negative role in platinum-based therapy responses in NSCLC, but its impact is limited. DNA polymerase β, when not expressed, might indicate a group of patients with poor outcomes. KRAS mutations in tumors not expressing DNA polymerase β further worsens survival. Therefore, these two biomarkers together might well identify patients for whom alternatives to platinum-based chemotherapy should be used. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments)
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12 pages, 714 KiB  
Article
Final Results from a Phase II Trial of Osimertinib for Elderly Patients with Epidermal Growth Factor Receptor t790m-Positive Non-Small Cell Lung Cancer That Progressed during Previous Treatment
by Akira Nakao, Osamu Hiranuma, Junji Uchino, Chikara Sakaguchi, Tomoyuki Araya, Noriya Hiraoka, Tamotsu Ishizuka, Takayuki Takeda, Masayuki Kawasaki, Yasuhiro Goto, Hisao Imai, Noboru Hattori, Keita Nakatomi, Hidetaka Uramoto, Kiyoaki Uryu, Minoru Fukuda, Yasuki Uchida, Toshihide Yokoyama, Masaya Akai, Tadashi Mio, Seiji Nagashima, Yusuke Chihara, Nobuyo Tamiya, Yoshiko Kaneko, Takako Mouri, Tadaaki Yamada, Kenichi Yoshimura, Masaki Fujita and Koichi Takayamaadd Show full author list remove Hide full author list
J. Clin. Med. 2020, 9(6), 1762; https://doi.org/10.3390/jcm9061762 - 5 Jun 2020
Cited by 10 | Viewed by 3150
Abstract
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used for treating EGFR-mutated lung cancer, and osimertinib is effective in cases that acquired T790M mutations after treatment with the first- and second-generation EGFR-TKIs. However, no study has evaluated its safety and efficacy in [...] Read more.
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used for treating EGFR-mutated lung cancer, and osimertinib is effective in cases that acquired T790M mutations after treatment with the first- and second-generation EGFR-TKIs. However, no study has evaluated its safety and efficacy in older patients. This phase II trial (jRCTs071180002) evaluated osimertinib in T790M mutation-positive Japanese patients who were ≥75 years old and had experienced relapse or progression after previous EGFR-TKI treatment. Our previous report that enrolled 36 patients showed the overall response rate (58.3%) and disease control rate (97.2%), while this report describes the results for the progression-free survival (PFS), overall survival (OS), and safety analyses. The median PFS was 11.9 months (95% confidence interval (CI): 7.9–17.5), and the median OS was 22.0 months (95% CI: 16.0 months–not reached). The most frequent adverse events were anemia/hypoalbuminemia (27 patients, 75.0%), thrombocytopenia (21 patients, 58.3%), and paronychia/anorexia/diarrhea/neutropenia (15 patients, 41.7%). Pneumonitis was observed in four patients (11.1%), including two patients (5.6%) with Grade 3–4 pneumonitis. These results suggest that osimertinib was relatively safe and effective for non-small cell lung cancer that acquired T790M mutations after previous EGFR-TKI treatment, even among patients who were ≥75 years old. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments)
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13 pages, 2207 KiB  
Article
Clinicopathological Significance of RUNX1 in Non-Small Cell Lung Cancer
by Yujin Kim, Bo Bin Lee, Dongho Kim, Sangwon Um, Eun Yoon Cho, Joungho Han, Young Mog Shim and Duk-Hwan Kim
J. Clin. Med. 2020, 9(6), 1694; https://doi.org/10.3390/jcm9061694 - 2 Jun 2020
Cited by 15 | Viewed by 2145
Abstract
This study aimed to understand the clinicopathological significance of runt-related transcription factor 1 (RUNX1) in non-small cell lung cancer (NSCLC). The methylation and mRNA levels of RUNX1 in NSCLC were determined using the Infinium HumanMethylation450 BeadChip and the HumanHT-12 expression BeadChip. [...] Read more.
This study aimed to understand the clinicopathological significance of runt-related transcription factor 1 (RUNX1) in non-small cell lung cancer (NSCLC). The methylation and mRNA levels of RUNX1 in NSCLC were determined using the Infinium HumanMethylation450 BeadChip and the HumanHT-12 expression BeadChip. RUNX1 protein levels were analyzed using immunohistochemistry of formalin-fixed paraffin-embedded tissues from 409 NSCLC patients. Three CpGs (cg04228935, cg11498607, and cg05000748) in the CpG island of RUNX1 showed significantly different methylation levels (Bonferroni corrected p < 0.05) between tumor and matched normal tissues obtained from 42 NSCLC patients. Methylation levels of the CpGs in the tumor tissues were inversely related to mRNA levels of RUNX1. A logistic regression model based on cg04228935 showed the best performance in predicting NSCLCs in a test dataset (N = 28) with the area under the receiver operating characteristic (ROC) curve (AUC) of 0.96 (95% confidence interval (CI) = 0.81–0.99). The expression of RUNX1 was reduced in 125 (31%) of 409 patients. Adenocarcinoma patients with reduced RUNX1 expression showed 1.97-fold (95% confidence interval = 1.16–3.44, p = 0.01) higher hazard ratio for death than those without. In conclusion, the present study suggests that abnormal methylation of RUNX1 may be a valuable biomarker for detection of NSCLC regardless of race. And, reduced RUNX1 expression may be a prognostic indicator of poor overall survival in lung adenocarcinoma. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments)
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12 pages, 2433 KiB  
Article
HIP1R Expression and Its Association with PD-1 Pathway Blockade Response in Refractory Advanced NonSmall Cell Lung Cancer: A Gene Set Enrichment Analysis
by Young Wha Koh, Jae-Ho Han, Seokjin Haam and Hyun Woo Lee
J. Clin. Med. 2020, 9(5), 1425; https://doi.org/10.3390/jcm9051425 - 11 May 2020
Cited by 6 | Viewed by 2579
Abstract
Huntingtin-interacting protein 1-related protein (HIP1R) plays an important role in the regulation of programmed death-ligand 1 (PD-L1). The aim of this study was to investigate the expression of HIP1R and confirm its predictive or prognostic roles in anti-PD-1 therapy in nonsmall cell lung [...] Read more.
Huntingtin-interacting protein 1-related protein (HIP1R) plays an important role in the regulation of programmed death-ligand 1 (PD-L1). The aim of this study was to investigate the expression of HIP1R and confirm its predictive or prognostic roles in anti-PD-1 therapy in nonsmall cell lung cancer (NSCLC) patients. HIP1R and PD-L1 immunohistochemical expression was examined in 52 refractory advanced NSCLC patients treated with anti-PD-1 inhibitors. We performed gene set enrichment analysis (GSEA) to detect HIP1R-specific gene sets. Patients in the PD-1 inhibitor responder group had lower HIP1R expression by univariate logistic regression analysis (odds ratio (OR) = 0.235, p = 0.015) and multivariate logistic regression analysis (OR = 0.209, p = 0.014). Patients with high HIP1R expression had poorer progression-free survival (PFS) than patients with low HIP1R expression in univariate analysis (p = 0.037) and multivariate Cox analysis (hazard ratio = 2.098, p = 0.019). The web-based mRNA dataset also showed that high HIP1R expression correlated with inferior overall survival in lung adenocarcinoma (p = 0.026). GSEA revealed that HIP1R levels correlate with a set of genes that reflect PD-L1-related immune pathways. HIP1R expression may be a promising predictor for determination of patient responses to anti-PD-1 treatment. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments)
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10 pages, 511 KiB  
Article
Prognostic Value of Tumor Size in Resected Stage IIIA-N2 Non-Small-Cell Lung Cancer
by Chih-Yu Chen, Bing-Ru Wu, Chia-Hung Chen, Wen-Chien Cheng, Wei-Chun Chen, Wei-Chih Liao, Chih-Yi Chen, Te-Chun Hsia and Chih-Yen Tu
J. Clin. Med. 2020, 9(5), 1307; https://doi.org/10.3390/jcm9051307 - 1 May 2020
Cited by 6 | Viewed by 2107
Abstract
The eighth edition of the American Joint Committee on Cancer (AJCC) staging system for lung cancer was introduced in 2017 and included major revisions, especially of stage III. For the subgroup stage IIIA-N2 non-small-cell lung cancer (NSCLC), surgical resection remains controversial due to [...] Read more.
The eighth edition of the American Joint Committee on Cancer (AJCC) staging system for lung cancer was introduced in 2017 and included major revisions, especially of stage III. For the subgroup stage IIIA-N2 non-small-cell lung cancer (NSCLC), surgical resection remains controversial due to heterogeneous disease entity. The aim of this study was to evaluate the clinicopathologic features and prognostic factors of patients with completely resected stage IIIA-N2 NSCLC. We retrospectively evaluated 77 consecutive patients with pathologic stage IIIA-N2 NSCLC (AJCC eighth edition) who underwent surgical resection with curative intent in China Medical University Hospital between 2006 and 2014. Survival analysis was conducted, using the Kaplan–Meier method. Prognostic factors predicting overall survival (OS) and disease-free survival (DFS) were analyzed, using log-rank tests and multivariate Cox proportional hazards models. Of the 77 patients with pathologic stage IIIA-N2 NSCLC examined, 35 (45.5%) were diagnosed before surgery and 42 (54.5%) were diagnosed unexpectedly during surgery. The mean age of patients was 59 years, and the mean length of follow-up was 38.1 months. The overall one-, three-, and five-year OS rates were 91.9%, 61.3%, and 33.5%, respectively. Multivariate analysis showed that tumor size <3 cm (hazards ratio (HR): 0.373, p = 0.003) and video-assisted thoracoscopic surgery (VATS) approach (HR: 0.383, p = 0.014) were significant predictors for improved OS. For patients with surgically treated, pathologic stage IIIA-N2 NSCLC, tumor size <3 cm and the VATS approach seemed to be associated with better prognosis. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments)
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11 pages, 1238 KiB  
Article
Comparative Efficacy of Targeted Therapies in Patients with Non-Small Cell Lung Cancer: A Network Meta-Analysis of Clinical Trials
by Tung Hoang, Seung-Kwon Myung, Thu Thi Pham, Jeongseon Kim and Woong Ju
J. Clin. Med. 2020, 9(4), 1063; https://doi.org/10.3390/jcm9041063 - 9 Apr 2020
Cited by 7 | Viewed by 3506
Abstract
This study aims to investigate the efficacy of targeted therapies in the treatment of non-small cell lung cancer (NSCLC) by using a network meta-analysis of clinical trials. PubMed, EMBASE, Cochrane Library, and Clinicaltrials.gov were searched by using keywords related to the topic on [...] Read more.
This study aims to investigate the efficacy of targeted therapies in the treatment of non-small cell lung cancer (NSCLC) by using a network meta-analysis of clinical trials. PubMed, EMBASE, Cochrane Library, and Clinicaltrials.gov were searched by using keywords related to the topic on 19 September 2018. Two investigators independently selected relevant trials by pre-determined criteria. A pooled response ratio (RR) for overall response rate (ORR) and a hazard ratio (HR) for progression-free survival (PFS) were calculated based on both the Bayesian and frequentist approaches. A total of 128 clinical trials with 39,501 participants were included in the final analysis of 14 therapeutic groups. Compared with chemotherapy, both ORR and PFS were significantly improved for afatinib, alectinib, and crizotinib, while only PFS was significantly improved for cabozantinib, ceritinib, gefitinib, and osimertinib. Consistency was observed between the direct and indirect comparisons based on the Bayesian approach statistically and the frequentist approach visually. Cabozantinib and alectinib showed the highest probability for the first-line treatment ranking in ORR (62.5%) and PFS (87.5%), respectively. The current network meta-analysis showed the comprehensive evidence-based comparative efficacy of different types of targeted therapies, which would help clinicians use targeted therapies in clinical practice. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments)
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12 pages, 1055 KiB  
Article
Concomitant TP53 Mutation Confers Worse Prognosis in EGFR-Mutated Non-Small Cell Lung Cancer Patients Treated with TKIs
by Matteo Canale, Elisabetta Petracci, Angelo Delmonte, Giuseppe Bronte, Elisa Chiadini, Vienna Ludovini, Alessandra Dubini, Maximilian Papi, Sara Baglivo, Nicoletta De Luigi, Alberto Verlicchi, Rita Chiari, Lorenza Landi, Giulio Metro, Marco Angelo Burgio, Lucio Crinò and Paola Ulivi
J. Clin. Med. 2020, 9(4), 1047; https://doi.org/10.3390/jcm9041047 - 7 Apr 2020
Cited by 48 | Viewed by 3494
Abstract
Background: Non-small cell lung cancer (NSCLC) is the primary cause of cancer-related deaths worldwide. Epidermal Growth Factor Receptor (EGFR)-mutated patients usually benefit from TKIs treatment, but a significant portion show unresponsiveness due to primary resistance mechanisms. We investigated the role of [...] Read more.
Background: Non-small cell lung cancer (NSCLC) is the primary cause of cancer-related deaths worldwide. Epidermal Growth Factor Receptor (EGFR)-mutated patients usually benefit from TKIs treatment, but a significant portion show unresponsiveness due to primary resistance mechanisms. We investigated the role of TP53 mutations in predicting survival and response to EGFR-TKIs in EGFR-mutated NSCLC patients, to confirm, on an independent case series, our previous results. Methods: An independent retrospective cohort study was conducted, on a case series of 136 EGFR-mutated NSCLC patients receiving first or second generation TKIs as a first line therapy, and a smaller fraction of patients who acquired the T790M resistance mutation and were treated with third generation TKIs in the second or further line of treatment. TP53 mutations were evaluated in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) of the patients. Results: Forty-two patients (30.9%) showed a TP53 mutation. Considered together, TP53 mutations had no significant impact on time-to-event endpoints. Considering the different TP53 mutations separately, exon 8 mutations confirmed their negative effect on PFS (HR 3.16, 95% 1.59–6.28, p = 0.001). In patients who developed the T790M resistance mutation, treated with third generation TKIs, the TP53 exon 8 mutations predicted worse PFS (even though not statistically significant), and OS (HR 4.86, 95% CI: 1.25–18.90, p = 0.023). Conclusions: TP53 exon 8 mutations confirmed their negative prognostic impact in patients treated with first and second generation TKIs and demonstrated a role in affecting clinical outcome in patients treated with third generation TKIs. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments)
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11 pages, 1509 KiB  
Article
Prediction of Anti-Cancer Drug-Induced Pneumonia in Lung Cancer Patients: Novel High-Resolution Computed Tomography Fibrosis Scoring
by Hiroshi Gyotoku, Hiroyuki Yamaguchi, Hiroshi Ishimoto, Shuntaro Sato, Hirokazu Taniguchi, Hiroaki Senju, Tomoyuki Kakugawa, Katsumi Nakatomi, Noriho Sakamoto, Minoru Fukuda, Yasushi Obase, Hiroshi Soda, Kazuto Ashizawa and Hiroshi Mukae
J. Clin. Med. 2020, 9(4), 1045; https://doi.org/10.3390/jcm9041045 - 7 Apr 2020
Cited by 2 | Viewed by 2681
Abstract
Background and objective: Pre-existing interstitial lung disease (ILD) in lung cancer patients is considered a risk factor for anti-cancer drug-induced pneumonia; however, a method for evaluating ILD, including mild cases, has not yet been established. We aimed to elucidate whether the quantitative high-resolution [...] Read more.
Background and objective: Pre-existing interstitial lung disease (ILD) in lung cancer patients is considered a risk factor for anti-cancer drug-induced pneumonia; however, a method for evaluating ILD, including mild cases, has not yet been established. We aimed to elucidate whether the quantitative high-resolution computed tomography fibrosis score (HFS) is correlated with the risk of anti-cancer drug-induced pneumonia in lung cancer patients, even in those with mild pre-existing ILD. Methods: The retrospective single-institute study cohort comprised 214 lung cancer patients who underwent chemotherapy between April 2013 and March 2016. The HFS quantitatively evaluated the grade of pre-existing ILD. We extracted data regarding age, sex, smoking history, and coexisting factors that could affect the incidence of anti-cancer drug-induced pneumonia. Cox proportional hazard models were used to analyze the effects of the HFS and other factors on the risk of anti-cancer drug-induced pneumonia. Results: Pre-existing ILD was detected in 61 (29%) of 214 patients, while honeycombing and traction bronchiectasis were observed in only 15 (7.0%) and 10 (4.7%) patients, respectively. Anti-cancer drug-induced pneumonia developed in 19 (8.9%) patients. The risk of anti-cancer drug-induced pneumonia increased in proportion to the HFS (hazard ratio, 1.16 per point; 95% confidence interval, 1.09–1.22; p < 0.0001). Conclusions: The quantitative HFS was correlated with the risk of developing anti-cancer drug-induced pneumonia in lung cancer patients, even in the absence of honeycombing or traction bronchiectasis. The quantitative HFS may lead to better management of lung cancer patients with pre-existing ILD. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments)
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12 pages, 1666 KiB  
Article
RAD51Bme Levels as a Potential Predictive Biomarker for PD-1 Blockade Response in Non-Small Cell Lung Cancer
by Inês Maria Guerreiro, Daniela Barros-Silva, Paula Lopes, Mariana Cantante, Ana Luísa Cunha, João Lobo, Luís Antunes, Ana Rodrigues, Marta Soares, Rui Henrique and Carmen Jerónimo
J. Clin. Med. 2020, 9(4), 1000; https://doi.org/10.3390/jcm9041000 - 2 Apr 2020
Cited by 7 | Viewed by 2395
Abstract
Lung cancer (LC) cells frequently express high levels of programmed death-ligand 1 (PD-L1). Although these levels grossly correlate with the likelihood of response to specific checkpoint inhibitors, the response prediction is rather imperfect, and more accurate predictive biomarkers are mandatory. We examined the [...] Read more.
Lung cancer (LC) cells frequently express high levels of programmed death-ligand 1 (PD-L1). Although these levels grossly correlate with the likelihood of response to specific checkpoint inhibitors, the response prediction is rather imperfect, and more accurate predictive biomarkers are mandatory. We examined the methylation profile of RAD51B (RAD51Bme) as a candidate predictive biomarker for anti-PD-1 therapy efficacy in non-small cell lung cancer (NSCLC), correlating with patients’ outcome. PD-L1 immunoexpression and RAD51Bme levels were analysed in NSCLC samples obtained from patients not treated with anti-PD-1 (Untreated Cohort (#1)) and patients treated with PD-1 blockade (Treated Cohort (#2)). Of a total of 127 patients assessed, 58.3% depicted PD-L1 positivity (PD-L1+). RAD51Bme levels were significantly associated with PD-L1 immunoexpression. Patients with PD-1 blockade clinical benefit disclosed higher RAD51Bme levels (p = 0.0390) and significantly lower risk of disease progression (HR 0.37; 95% CI: 0.15–0.88; p = 0.025). Combining RAD51Bme+ with PD-L1+ improved the sensitivity of the test to predict immunotherapy response. PD-L1+ was also associated with lower risk of death (HR 0.35; 95% CI: 0.15–0.81; p = 0.014). Thus, RAD51Bme levels might be combined with validated predictive biomarker PD-L1 immunostaining to select patients who will most likely experience clinical benefit from PD-1 blockade. The predictive value of RAD51Bme should be confirmed in prospective studies. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments)
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10 pages, 1528 KiB  
Article
Potential of FDG-PET as Prognostic Significance after anti-PD-1 Antibody against Patients with Previously Treated Non-Small Cell Lung Cancer
by Kosuke Hashimoto, Kyoichi Kaira, Ou Yamaguchi, Atsuto Mouri, Ayako Shiono, Yu Miura, Yoshitake Murayama, Kunihiko Kobayashi, Hiroshi Kagamu and Ichiei Kuji
J. Clin. Med. 2020, 9(3), 725; https://doi.org/10.3390/jcm9030725 - 7 Mar 2020
Cited by 46 | Viewed by 3903
Abstract
It remains unclear whether the accumulation of 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) before the initiation of anti-programmed death-1 (PD-1) antibody can predict the outcome after its treatment. The aim of this study is to retrospectively examine the prognostic significance of [...] Read more.
It remains unclear whether the accumulation of 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) before the initiation of anti-programmed death-1 (PD-1) antibody can predict the outcome after its treatment. The aim of this study is to retrospectively examine the prognostic significance of 18F-FDG uptake as a predictive marker of anti-PD-1 antibody. Eighty-five patients with previously treated non-small cell lung cancer (NSCLC) who underwent 18F-FDG-positron emission tomography (PET) just before administration of nivolumab or pembrolizumab monotherapy were eligible in our study, and metabolic tumor volume (MTV), total lesion glycolysis (TLG) and the maximum of standardized under value (SUVmax) on 18F-FDG uptake were assessed. Objective response rate, median progression-free survival and median overall survival were 36.6%, 161 days and 716 days, respectively. The frequency of any immune-related adverse events was significantly higher in patients with low 18F-FDG uptake on PET than in those with high uptake. By multivariate analysis, the tumor metabolic activity by TLG and MTV was identified as an independent prognostic factor for predicting outcome after anti-PD-1 antibody therapy, but not SUVmax, predominantly in patients with adenocarcinoma. Metabolic tumor indices as TLG and MTV on 18F-FDG uptake could predict the prognosis after anti-PD-1 antibodies in patients with previously treated NSCLC. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments)
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16 pages, 7319 KiB  
Article
Identification of Clonality through Genomic Profile Analysis in Multiple Lung Cancers
by Rumi Higuchi, Takahiro Nakagomi, Taichiro Goto, Yosuke Hirotsu, Daichi Shikata, Yujiro Yokoyama, Sotaro Otake, Kenji Amemiya, Toshio Oyama, Hitoshi Mochizuki and Masao Omata
J. Clin. Med. 2020, 9(2), 573; https://doi.org/10.3390/jcm9020573 - 20 Feb 2020
Cited by 27 | Viewed by 2501
Abstract
In cases of multiple lung cancers, individual tumors may represent either a primary lung cancer or both primary and metastatic lung cancers. In this study, we investigated the differences between clinical/histopathological and genomic diagnoses to determine whether they are primary or metastatic. 37 [...] Read more.
In cases of multiple lung cancers, individual tumors may represent either a primary lung cancer or both primary and metastatic lung cancers. In this study, we investigated the differences between clinical/histopathological and genomic diagnoses to determine whether they are primary or metastatic. 37 patients with multiple lung cancers were enrolled in this study. Tumor cells were selected from tissue samples using laser capture microdissection. DNA was extracted from those cells and subjected to targeted deep sequencing. In multicentric primary lung cancers, the driver mutation profile was mutually exclusive among the individual tumors, while it was consistent between metastasized tumors and the primary lesion. In 11 patients (29.7%), discrepancies were observed between genomic and clinical/histopathological diagnoses. For the lymph node metastatic lesions, the mutation profile was consistent with only one of the two primary lesions. In three of five cases with lymph node metastases, the lymph node metastatic route detected by genomic diagnosis differed from the clinical and/or pathological diagnoses. In conclusion, in patients with multiple primary lung cancers, cancer-specific mutations can serve as clonal markers, affording a more accurate understanding of the pathology of multiple lung cancers and their lymphatic metastases and thus improving both the treatment selection and outcome. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments)
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13 pages, 3294 KiB  
Article
Prognostic Significance of Glucose Metabolism as GLUT1 in Patients with Pulmonary Pleomorphic Carcinoma
by Hisao Imai, Kyoichi Kaira, Hideki Endoh, Kazuyoshi Imaizumi, Yasuhiro Goto, Mitsuhiro Kamiyoshihara, Takayuki Kosaka, Toshiki Yajima, Yoichi Ohtaki, Takashi Osaki, Yoshihito Kogure, Shigebumi Tanaka, Atsushi Fujita, Tetsunari Oyama, Koichi Minato, Takayuki Asao and Ken Shirabe
J. Clin. Med. 2020, 9(2), 413; https://doi.org/10.3390/jcm9020413 - 3 Feb 2020
Cited by 6 | Viewed by 1933
Abstract
Glucose metabolism is necessary for tumor progression, metastasis, and survival in various human cancers. Glucose transporter 1 (GLUT1), in particular, plays an important role in the mechanism of ¹⁸F-FDG (2-[¹⁸F]-fluoro-2-deoxy-d-glucose) within tumor cells. However, little is known about the clinicopathological significance of GLUT1 [...] Read more.
Glucose metabolism is necessary for tumor progression, metastasis, and survival in various human cancers. Glucose transporter 1 (GLUT1), in particular, plays an important role in the mechanism of ¹⁸F-FDG (2-[¹⁸F]-fluoro-2-deoxy-d-glucose) within tumor cells. However, little is known about the clinicopathological significance of GLUT1 in patients with pulmonary pleomorphic carcinoma (PPC). Adenocarcinoma, squamous cell carcinoma, adenosquamous cell carcinoma, poorly differentiated carcinoma, large cell carcinoma, and others were identified as epithelial components, and spindle-cell type, giant-cell type, and both spindle- and giant-cell types were identified as sarcomatous components. This study was performed to determine the prognostic impact of GLUT1 expression in PPC. Patients with surgically resected PPC (n = 104) were evaluated by immunohistochemistry analysis to detect GLUT1 expression and determine the Ki-67 labeling index using specimens of the resected tumors. GLUT1 was highly expressed in 48% (50/104) of all patients, 42% (20/48) of the patients with an adenocarcinoma component, and 53% (30/56) of the patients with a nonadenocarcinoma component. High expression of GLUT1 was significantly associated with advanced stage, vascular invasion, pleural invasion, and tumor cell proliferation as determined by Ki-67 labeling. GLUT1 expression and tumor cell proliferation were significantly correlated according to the Ki-67 labeling in all patients (Spearman’s rank; r = 0.25, p < 0.01). In multivariate analysis, GLUT1 was identified as a significant independent marker for predicting a poor prognosis. GLUT1 is an independent prognostic factor for predicting the poor prognosis of patients with surgically resected PPC. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments)
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10 pages, 1144 KiB  
Article
Retrospective Efficacy Analysis of Immune Checkpoint Inhibitor Rechallenge in Patients with Non-Small Cell Lung Cancer
by Yuki Katayama, Takayuki Shimamoto, Tadaaki Yamada, Takayuki Takeda, Takahiro Yamada, Shinsuke Shiotsu, Yusuke Chihara, Osamu Hiranuma, Masahiro Iwasaku, Yoshiko Kaneko, Junji Uchino and Koichi Takayama
J. Clin. Med. 2020, 9(1), 102; https://doi.org/10.3390/jcm9010102 - 31 Dec 2019
Cited by 42 | Viewed by 5118
Abstract
Little is known regarding the effectiveness and tolerability of immune checkpoint inhibitor (ICI) rechallenge after disease progression following initial ICI treatments. To identify eligible patients for ICI rechallenge, we retrospectively analyzed the relationship between clinical profiles and the effect of ICI rechallenge in [...] Read more.
Little is known regarding the effectiveness and tolerability of immune checkpoint inhibitor (ICI) rechallenge after disease progression following initial ICI treatments. To identify eligible patients for ICI rechallenge, we retrospectively analyzed the relationship between clinical profiles and the effect of ICI rechallenge in patients with non-small cell lung cancer (NSCLC). We enrolled 35 NSCLC patients at six different institutions who were retreated with ICIs after discontinued initial ICI treatments due to disease progression. Cox proportional hazards models were used to assess the impact of clinical profiles on overall survival (OS) and progression-free survival (PFS). Median PFS and OS were 81 d (95% confidence interval, CI, 41–112 d) and 225 d (95% CI 106–361 d), respectively. The objective response rate was 2.9%, and the disease control rate was 42.9%. Multivariate analysis demonstrated that Eastern Cooperative Oncology Group Performance Score (ECOG-PS) ≥ 2 (hazard ratio, HR, 2.38; 95% CI 1.03–5.52; p = 0.043) and body mass index (BMI) > 20 (HR 0.43, 95% CI 0.19–0.95, p = 0.036) were significantly associated with PFS of ICI rechallenge. Our observations suggest that poor ECOG-PS and low BMI at intervention with ICI rechallenge may be negative predictors for ICI rechallenge treatment in patients with NSCLC. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments)
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9 pages, 619 KiB  
Article
Phase I/II Study of Docetaxel and S-1 in Previously-Treated Patients with Advanced Non-Small Cell Lung Cancer: LOGIK0408
by Koichi Takayama, Junji Uchino, Masaki Fujita, Shoji Tokunaga, Tomotoshi Imanaga, Ryotaro Morinaga, Noriyuki Ebi, Sho Saeki, Kazuya Matsukizono, Hiroshi Wataya, Tadaaki Yamada and Yoichi Nakanishi
J. Clin. Med. 2019, 8(12), 2196; https://doi.org/10.3390/jcm8122196 - 12 Dec 2019
Cited by 2 | Viewed by 2079
Abstract
Background: As docetaxel plus S-1 may be feasible for cancer treatment, we conducted a phase I/II trial to determine the recommended docetaxel dose and the fixed S-1 dose (phase I), as well as confirm the regimen’s efficacy and safety (phase II) for previously-treated [...] Read more.
Background: As docetaxel plus S-1 may be feasible for cancer treatment, we conducted a phase I/II trial to determine the recommended docetaxel dose and the fixed S-1 dose (phase I), as well as confirm the regimen’s efficacy and safety (phase II) for previously-treated patients with advanced non-small cell lung cancer. Methods: Patients ≤75 years with performance status ≤1 and adequate organ function were treated at three-week intervals with docetaxel on day 1 and 80 mg/m2 oral S-1 from days 1–14. The starting docetaxel dose was 45 mg/m2 and this was escalated to a maximum of 70 mg/m2. In phase II, response rate, progression-free survival (PFS), overall survival (OS), and safety were assessed. Results: The recommended doses were 50 mg/m2 docetaxel (day 1) and 80 mg/m2 S-1 (days 1–14). Grades 3 and 4 leukocytopenia and neutropenia occurred in 44% and 67% of patients, respectively. Nonhematologic toxicities were generally mild. Overall response to chemotherapy was 7.7% (95% confidence interval (CI), 1.6–20.9%), and median PFS and OS were 18.0 weeks (95% CI; 11.3–22.9 weeks) and 53.0 weeks, respectively. Conclusion: Fifty mg/m2 docetaxel plus 80 mg/m2 oral S-1 had a lower response rate than anticipated; however, the survival data were encouraging. A further investigation is warranted to select the optimal patient population. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments)
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Review

Jump to: Research

9 pages, 386 KiB  
Review
Role of Surgical Intervention in Unresectable Non-Small Cell Lung Cancer
by Shigeki Suzuki and Taichiro Goto
J. Clin. Med. 2020, 9(12), 3881; https://doi.org/10.3390/jcm9123881 - 29 Nov 2020
Cited by 16 | Viewed by 2402
Abstract
With the development of systemic treatments with high response rates, including tyrosine kinase inhibitors and immune checkpoint inhibitors, some patients with unresectable lung cancer now have a chance to undergo radical resection after primary treatment. Although there is no general consensus regarding the [...] Read more.
With the development of systemic treatments with high response rates, including tyrosine kinase inhibitors and immune checkpoint inhibitors, some patients with unresectable lung cancer now have a chance to undergo radical resection after primary treatment. Although there is no general consensus regarding the definition of “unresectable” in lung cancer, the term “resectable” refers to technically resectable and indicates that resection can provide a favorable prognosis to some extent. Unresectable lung cancer is typically represented by stage III and IV disease. Stage III lung cancer is a heterogeneous disease, and in some patients with technically resectable non-small cell lung cancer (NSCLC), multimodality treatments, including induction chemoradiotherapy followed by surgery, are the treatments of choice. The representative surgical intervention for unresectable stage III/IV NSCLC is salvage surgery, which refers to surgical treatment for local residual/recurrent lesions after definitive non-surgical treatment. Surgical intervention is also used for an oligometastatic stage IV NSCLC. In this review, we highlight the role of surgical intervention in patients with unresectable NSCLC, for whom an initial complete resection is technically difficult. We further describe the history of and new findings on salvage surgery for unresectable NSCLC and surgery for oligometastatic NSCLC. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments)
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10 pages, 243 KiB  
Review
Nivolumab for Previously Treated Patients with Non-Small-Cell Lung Cancer—Daily Practice versus Clinical Trials
by Magdalena Knetki-Wróblewska, Dariusz M. Kowalski and Maciej Krzakowski
J. Clin. Med. 2020, 9(7), 2273; https://doi.org/10.3390/jcm9072273 - 17 Jul 2020
Cited by 4 | Viewed by 2074
Abstract
Based on the results of the CheckMate 017 and CheckMate 057 studies, nivolumab therapy has become a new standard treatment for both squamous and non-squamous non-small-cell lung cancer (NSCLC). However, due to the specific inclusion criteria of these clinical trials, the efficacy and [...] Read more.
Based on the results of the CheckMate 017 and CheckMate 057 studies, nivolumab therapy has become a new standard treatment for both squamous and non-squamous non-small-cell lung cancer (NSCLC). However, due to the specific inclusion criteria of these clinical trials, the efficacy and safety of nivolumab in real-world practice were not certain. In general, the real-world results of nivolumab treatment have been consistent with those obtained in clinical trials. Additional analyses of the real-world data have made the identification of prognostic factors possible. Good performance status is the most significant predictor of clinical benefit. Brain metastases, liver metastases, EGFR mutation, malignant pleural effusion, and a high number of metastatic sites were identified as negative prognostic factors. By contrast, a longer time to disease progression (>6 months) from the beginning of prior chemotherapy and an objective response to chemotherapy seem to have positive prognostic value in the case of nivolumab treatment. In terms of patient age, the data are inconclusive. Some blood biomarkers can also be considered significant prognostic factors. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments)
13 pages, 3982 KiB  
Review
PD-(L)1 Inhibitors in Combination with Chemotherapy as First-Line Treatment for Non-Small-Cell Lung Cancer: A Pairwise Meta-Analysis
by Jorge García-González, Juan Ruiz-Bañobre, Francisco J. Afonso-Afonso, Margarita Amenedo-Gancedo, María del Carmen Areses-Manrique, Begoña Campos-Balea, Joaquín Casal-Rubio, Natalia Fernández-Núñez, José Luis Fírvida Pérez, Martín Lázaro-Quintela, Diego Pérez Parente, Leonardo Crama, Pedro Ruiz-Gracia, Lucía Santomé-Couto and Luis León-Mateos
J. Clin. Med. 2020, 9(7), 2093; https://doi.org/10.3390/jcm9072093 - 3 Jul 2020
Cited by 15 | Viewed by 3188
Abstract
The combination of programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors with chemotherapy has emerged as a promising therapeutic option for advanced non-small-cell lung cancer (NSCLC). The aim of this meta-analysis was to evaluate the efficacy of the combined strategy in this setting. [...] Read more.
The combination of programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors with chemotherapy has emerged as a promising therapeutic option for advanced non-small-cell lung cancer (NSCLC). The aim of this meta-analysis was to evaluate the efficacy of the combined strategy in this setting. For this purpose, we performed a literature search of randomized controlled trials comparing PD-(L)1 inhibitors plus platinum-based chemotherapy versus chemotherapy alone in stage IV NSCLC patients. Seven clinical trials with 4562 patients were included. In the intention-to-treat wildtype population, PD-(L)1 inhibitor plus chemotherapy was significantly associated with improved progression-free survival (PFS) (Hazard ratio (HR) = 0.61, 95% confidence interval (CI): 0.57–0.65, p < 0.001) and overall survival (OS) (HR = 0.76, 95% CI: 0.67–0.86; p < 0.001) compared to chemotherapy. A significantly higher overall response rate (ORR) was also observed with the combined strategy (Odds ratio (OR) = 2.12, 95% CI: 1.70–2.63, p < 0.001). Furthermore, in all the analyzed subgroups, addition of PD-(L)1 inhibitors to chemotherapy significantly improved efficacy endpoints. Specifically, stratification according to PD-L1 expression revealed a benefit across all patients, regardless of their PFS status. In conclusion, PD-(L)1 blockade added to standard platinum-based chemotherapy significantly improved PFS, OS, and ORR in the up-front treatment of advanced NSCLC. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments)
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12 pages, 386 KiB  
Review
Endocrinopathies Associated with Immune Checkpoint Inhibitor Cancer Treatment: A Review
by Naoko Okura, Mai Asano, Junji Uchino, Yoshie Morimoto, Masahiro Iwasaku, Yoshiko Kaneko, Tadaaki Yamada, Michiaki Fukui and Koichi Takayama
J. Clin. Med. 2020, 9(7), 2033; https://doi.org/10.3390/jcm9072033 - 29 Jun 2020
Cited by 13 | Viewed by 3768
Abstract
Treatment with immune checkpoint inhibitors has shown efficacy against a variety of cancer types. The effects of nivolumab and pembrolizumab on lung cancer have been reported, and further therapeutic advances are ongoing. The side effects of immune checkpoint inhibitors are very different from [...] Read more.
Treatment with immune checkpoint inhibitors has shown efficacy against a variety of cancer types. The effects of nivolumab and pembrolizumab on lung cancer have been reported, and further therapeutic advances are ongoing. The side effects of immune checkpoint inhibitors are very different from those of conventional cytocidal anticancer drugs and molecular targeted drugs, and they involve various organs such as the digestive and respiratory organs, thyroid and pituitary glands, and skin. The generic term for such adverse events is immune-related adverse events (irAEs). They are relatively infrequent, and, if mild, treatment with immune checkpoint inhibitors can be continued with careful control. However, early detection and appropriate treatment are critical, as moderate-to-severe irAEs are associated with markedly reduced organ function and quality of life, with fatal consequences in some cases. Of these, endocrinopathies caused by immune checkpoint inhibitors are sometimes difficult to distinguish from nonspecific symptoms in patients with advanced cancer and may have serious outcomes when the diagnosis is delayed. Therefore, it is necessary to anticipate and appropriately address the onset of endocrinopathies during treatment with immune checkpoint inhibitors. Here, we present a review of endocrine disorders caused by immune checkpoint inhibitor treatment. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments)
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16 pages, 622 KiB  
Review
Immune Checkpoint Inhibitors for Lung Cancer Treatment: A Review
by Keisuke Onoi, Yusuke Chihara, Junji Uchino, Takayuki Shimamoto, Yoshie Morimoto, Masahiro Iwasaku, Yoshiko Kaneko, Tadaaki Yamada and Koichi Takayama
J. Clin. Med. 2020, 9(5), 1362; https://doi.org/10.3390/jcm9051362 - 6 May 2020
Cited by 96 | Viewed by 7597
Abstract
The treatment of lung cancer has changed drastically in recent years owing to the advent of immune checkpoint inhibitors (ICIs). A 1992 study reported that programmed cell death-1 (PD-1), an immune checkpoint molecule, is upregulated during the induction of T cell death. Since [...] Read more.
The treatment of lung cancer has changed drastically in recent years owing to the advent of immune checkpoint inhibitors (ICIs). A 1992 study reported that programmed cell death-1 (PD-1), an immune checkpoint molecule, is upregulated during the induction of T cell death. Since then, various immunoregulatory mechanisms involving PD-1 have been clarified, and the successful use of PD-1 blockers in anticancer therapy eventually led to the development of the current generation of ICIs. Nivolumab was the first ICI approved for treating lung cancer in 2014. Since then, various ICIs such as pembrolizumab, atezolizumab, and durvalumab have been successively introduced into clinical medicine and have shown remarkable efficacy. The introduction of ICIs constituted a major advancement in lung cancer treatment, but disease prognosis continues to remain low. Therefore, new molecular-targeted therapies coupled with existing anticancer drugs and radiotherapy have recently been explored. This review encompasses the current status, challenges, and future perspectives of ICI treatment in lung cancer. Full article
(This article belongs to the Special Issue Non-small Cell Lung Cancer: Current Therapies and New Targeted Treatments)
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