Treatment Options and Therapeutics for Non-small Cell Lung Cancer

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 38920

Special Issue Editor

Medizinische Universitat Wien, Vienna, Austria
Interests: preclinical drug development; lung cancer; targeted therapy; tyrosine kinase inhibitors

Special Issue Information

Dear Colleagues,

The treatment of non-small cell lung cancer (NSCLC) has heralded an era of precision medicine based on the detection of mutated driver kinases and the development of specific inhibitors targeting altered EGFR receptors, rearranged anaplastic lymphoma kinase (ALK), ROS1, MET, and a host of other minor oncogenic proteins. Knowledge of the 3D structure of the mutated kinases allowed for rational drug design fitting therapeutics mostly to the ATP binding pocket of the enzymes. Clinical administration of these tyrosine kinase inhibitors (TKIs) results in prolonged survival of up to several years of the subpopulation of patients expressing suitable molecular markers. However, drug resistance invariably develops and the affected patients have to be treated with new drugs targeting secondary mutations or bypass pathways. Accordingly, for mutated EGFR and rearranged ALK, several TKIs are approved and can be applied in sequence and a host of new compounds are in preclinical testing and early trials. The pipeline of new drugs comprises various multi-kinase inhibitors, inhibitors to oncogenic proteins that exhibit activating mutations, overexpression, gene amplification, and translocations, as well as novel agents directed to formerly “undruggable” targets such as KRAS, which is frequently mutated in NSCLC.

This Special Issue of Pharmaceuticals on “Treatment Options and Therapeutics for Non-Small Cell Lung Cancer” will include both regular articles and reviews focused on the most recent advances in the development of targeted pharmaceuticals active against NSCLC. Submissions should deal with the development and application of novel agents showing potential improvements in several aspects including broadened target profiles, overcoming resistance mechanisms, and lower toxicity for the treatment of NSCLC.

Prof. Gerhard Hamilton
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • non-small cell lung cancer
  • targeted therapy
  • oncogenes
  • tyrosine kinase inhibitors
  • drug resistance
  • crystal structure
  • drug combinations

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Published Papers (9 papers)

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Research

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15 pages, 949 KiB  
Article
Later-Line Treatment with Lorlatinib in ALK- and ROS1-Rearrangement-Positive NSCLC: A Retrospective, Multicenter Analysis
Pharmaceuticals 2020, 13(11), 371; https://doi.org/10.3390/ph13110371 - 07 Nov 2020
Cited by 18 | Viewed by 3028
Abstract
In clinical practice, patients with anaplastic lymphoma kinase (ALK)-rearrangement–positive non–small-cell lung cancer commonly receive sequential treatment with ALK tyrosine kinase inhibitors. The third-generation agent lorlatinib has been shown to inhibit a wide range of ALK resistance mutations and thus offers potential benefit [...] Read more.
In clinical practice, patients with anaplastic lymphoma kinase (ALK)-rearrangement–positive non–small-cell lung cancer commonly receive sequential treatment with ALK tyrosine kinase inhibitors. The third-generation agent lorlatinib has been shown to inhibit a wide range of ALK resistance mutations and thus offers potential benefit in later lines, although real-world data are lacking. This multicenter study retrospectively investigated later-line, real-world use of lorlatinib in patients with advanced ALK- or ROS1-positive lung cancer. Fifty-one patients registered in a compassionate use program in Austria, who received second- or later-line lorlatinib between January 2016 and May 2020, were included in this retrospective real-world data analysis. Median follow-up was 25.3 months. Median time of lorlatinib treatment was 4.4 months for ALK-positive and 12.2 months for ROS-positive patients. ALK-positive patients showed a response rate of 43.2%, while 85.7% percent of the ROS1-positive patients were considered responders. Median overall survival from lorlatinib initiation was 10.2 and 20.0 months for the ALK- and ROS1-positive groups, respectively. In the ALK-positive group, lorlatinib proved efficacy after both brigatinib and alectinib. Lorlatinib treatment was well tolerated. Later-line lorlatinib treatment can induce sustained responses in patients with advanced ALK- and ROS1-positive lung cancer. Full article
(This article belongs to the Special Issue Treatment Options and Therapeutics for Non-small Cell Lung Cancer)
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12 pages, 837 KiB  
Article
The Combination of Afatinib and Bevacizumab in Untreated EGFR-Mutated Advanced Lung Adenocarcinoma: A Multicenter Observational Study
Pharmaceuticals 2020, 13(11), 331; https://doi.org/10.3390/ph13110331 - 23 Oct 2020
Cited by 15 | Viewed by 2691
Abstract
The efficacy of afatinib in combination with bevacizumab in untreated advanced epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma is currently unclear. We sought to investigate the efficacy of this combination through a multicenter observational analysis. Data for 57 patients with advanced EGFR-mutated lung [...] Read more.
The efficacy of afatinib in combination with bevacizumab in untreated advanced epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma is currently unclear. We sought to investigate the efficacy of this combination through a multicenter observational analysis. Data for 57 patients with advanced EGFR-mutated lung adenocarcinoma who received afatinib combined with bevacizumab as first-line therapy at the Chang Gung Memorial Hospitals in Linkou and Kaohsiung and Taipei Tzu Chi Hospital from May 2015 to July 2019 were analyzed. The objective response rate and disease control rate of afatinib combined with bevacizumab therapy were 87.7% and 100%, respectively. In all patients, the median progression-free survival (PFS) and overall survival (OS) were 23.9 (95% confidence interval (CI) (17.56–29.17)) and 45.9 (95% CI (39.50–53.60)) months, respectively. No statistical significance between exon 19 deletion and L858R mutations was noted in PFS or OS. The most frequent adverse events (AEs) were diarrhea (98.2%) and dermatitis (96.5%), and most AEs were grade 2 or lower and manageable. The combination of afatinib and bevacizumab is an effective therapy for untreated advanced EGFR-mutated lung adenocarcinoma with acceptable safety. Future prospective studies focusing on this combination for untreated advanced EGFR-mutated lung adenocarcinoma are warranted. Full article
(This article belongs to the Special Issue Treatment Options and Therapeutics for Non-small Cell Lung Cancer)
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25 pages, 3196 KiB  
Review
MERTK Inhibition: Potential as a Treatment Strategy in EGFR Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer
Pharmaceuticals 2021, 14(2), 130; https://doi.org/10.3390/ph14020130 - 06 Feb 2021
Cited by 9 | Viewed by 6022
Abstract
Epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) are currently the most effective treatment for non-small cell lung cancer (NSCLC) patients, who carry primary EGFR mutations. However, the patients eventually develop drug resistance to EGFR-TKIs after approximately one year. In addition to the acquisition [...] Read more.
Epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) are currently the most effective treatment for non-small cell lung cancer (NSCLC) patients, who carry primary EGFR mutations. However, the patients eventually develop drug resistance to EGFR-TKIs after approximately one year. In addition to the acquisition of the EGFR T790M mutation, the activation of alternative receptor-mediated signaling pathways is a common mechanism for conferring the insensitivity of EGFR-TKI in NSCLC. Upregulation of the Mer receptor tyrosine kinase (MERTK), which is a member of the Tyro3-Axl-MERTK (TAM) family, is associated with a poor prognosis of many cancers. The binding of specific ligands, such as Gas6 and PROS1, to MERTK activates phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) cascades, which are the signaling pathways shared by EGFR. Therefore, the inhibition of MERTK can be considered a new therapeutic strategy for overcoming the resistance of NSCLC to EGFR-targeted agents. Although several small molecules and monoclonal antibodies targeting the TAM family are being developed and have been described to enhance the chemosensitivity and converse the resistance of EGFR-TKI, few have specifically been developed as MERTK inhibitors. The further development and investigation of biomarkers which can accurately predict MERTK activity and the response to MERTK inhibitors and MERTK-specific drugs are vitally important for obtaining appropriate patient stratification and increased benefits in clinical applications. Full article
(This article belongs to the Special Issue Treatment Options and Therapeutics for Non-small Cell Lung Cancer)
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17 pages, 1177 KiB  
Review
Therapeutic Sequencing in ALK+ NSCLC
Pharmaceuticals 2021, 14(2), 80; https://doi.org/10.3390/ph14020080 - 21 Jan 2021
Cited by 41 | Viewed by 7143
Abstract
Anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK+ NSCLC) is a model disease for the use of targeted pharmaceuticals in thoracic oncology. Due to higher systemic and intracranial efficacy, the second-generation ALK tyrosine kinase inhibitors (TKI) alectinib and brigatinib have irrevocably displaced crizotinib [...] Read more.
Anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK+ NSCLC) is a model disease for the use of targeted pharmaceuticals in thoracic oncology. Due to higher systemic and intracranial efficacy, the second-generation ALK tyrosine kinase inhibitors (TKI) alectinib and brigatinib have irrevocably displaced crizotinib as standard first-line treatment, based on the results of the ALEX and ALTA-1L trials. Besides, lorlatinib and brigatinib are the preferred second-line therapies for progression under second-generation TKI and crizotinib, respectively, based on the results of several phase II studies. Tissue or liquid rebiopsies at the time of disease progression, even though not mandated by the approval status of any ALK inhibitor, are gaining importance for individualization and optimization of patient management. Of particular interest are cases with off-target resistance, for example MET, HER2 or KRAS alterations, which require special therapeutic maneuvers, e.g., inclusion in early clinical trials or off-label administration of respectively targeted drugs. On the other hand, up to approximately half of the patients failing TKI, develop anatomically restricted progression, which can be initially tackled with local ablative measures without switch of systemic therapy. Among the overall biologically favorable ALK+ tumors, with a mean tumor mutational burden uniquely below 3 mutations per Mb and the longest survival among NSCLC currently, presence of the EML4-ALK fusion variant 3 and/or TP53 mutations identify high-risk cases with earlier treatment failure and a need for more aggressive surveillance and treatment strategies. The potential clinical utility of longitudinal ctDNA assays for earlier detection of disease progression and improved guidance of therapy in these patients is a currently a matter of intense investigation. Major pharmaceutical challenges for the field are the development of more potent, fourth-generation TKI and effective immuno-oncological interventions, especially ALK-directed cell therapies, which will be essential for further improving survival and achieving cure of ALK+ tumors. Full article
(This article belongs to the Special Issue Treatment Options and Therapeutics for Non-small Cell Lung Cancer)
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23 pages, 711 KiB  
Review
The Emerging Therapeutic Landscape of ALK Inhibitors in Non-Small Cell Lung Cancer
Pharmaceuticals 2020, 13(12), 474; https://doi.org/10.3390/ph13120474 - 18 Dec 2020
Cited by 52 | Viewed by 6855
Abstract
The treatment of metastatic non-small cell lung cancer (NSCLC) has undergone a paradigm shift over the last decade. Better molecular characterization of the disease has led to the rapid improvement of personalized medicine and the prompt delivery of targeted therapies to patients with [...] Read more.
The treatment of metastatic non-small cell lung cancer (NSCLC) has undergone a paradigm shift over the last decade. Better molecular characterization of the disease has led to the rapid improvement of personalized medicine and the prompt delivery of targeted therapies to patients with NSCLC. The discovery of the EML4-ALK fusion gene in a limited subset of patients affected by NSCLC and the subsequent clinical development of crizotinib in 2011 has been an impressive milestone in lung cancer research. Unfortunately, acquired resistances regularly develop, hence disease progression occurs. Afterward, modern tyrosine kinase inhibitors (TKIs), such as ceritinib, alectinib, brigatinib, and lorlatinib, have been approved by the Food and Drug Administration (FDA) for the management of anaplastic lymphoma kinase (ALK)-positive NSCLCs. Several compounds are currently under investigation to achieve the optimal strategy of therapy. Additionally, the results of ongoing clinical trials with novel-generation TKI will provide more evidence on the best sequence in the treatment of ALK-positive NSCLC patients. In this review, we provide a comprehensive overview of the state-of-the-art targeted therapy options in ALK-positive NSCLCs. Resistance, potential therapeutic strategies to overcome drug resistance, and future perspectives for this subset of patients are critically analyzed and summarized. Full article
(This article belongs to the Special Issue Treatment Options and Therapeutics for Non-small Cell Lung Cancer)
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25 pages, 815 KiB  
Review
Serum and Glucocorticoid-Inducible Kinase 1 (SGK1) in NSCLC Therapy
Pharmaceuticals 2020, 13(11), 413; https://doi.org/10.3390/ph13110413 - 22 Nov 2020
Cited by 8 | Viewed by 3968
Abstract
Non-small cell lung cancer (NSCLC) remains the most prevalent and one of the deadliest cancers worldwide. Despite recent success, there is still an urgent need for new therapeutic strategies. It is also becoming increasingly evident that combinatorial approaches are more effective than single [...] Read more.
Non-small cell lung cancer (NSCLC) remains the most prevalent and one of the deadliest cancers worldwide. Despite recent success, there is still an urgent need for new therapeutic strategies. It is also becoming increasingly evident that combinatorial approaches are more effective than single modality treatments. This review proposes that the serum and glucocorticoid-inducible kinase 1 (SGK1) may represent an attractive target for therapy of NSCLC. Although ubiquitously expressed, SGK1 deletion in mice causes only mild defects of ion physiology. The frequent overexpression of SGK1 in tumors is likely stress-induced and provides a therapeutic window to spare normal tissues. SGK1 appears to promote oncogenic signaling aimed at preserving the survival and fitness of cancer cells. Most importantly, recent investigations have revealed the ability of SGK1 to skew immune-cell differentiation toward pro-tumorigenic phenotypes. Future studies are needed to fully evaluate the potential of SGK1 as a therapeutic target in combinatorial treatments of NSCLC. However, based on what is currently known, SGK1 inactivation can result in anti-oncogenic effects both on tumor cells and on the immune microenvironment. A first generation of small molecules to inactivate SGK1 has already been already produced. Full article
(This article belongs to the Special Issue Treatment Options and Therapeutics for Non-small Cell Lung Cancer)
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12 pages, 1824 KiB  
Review
Beyond LKB1 Mutations in Non-Small Cell Lung Cancer: Defining LKB1less Phenotype to Optimize Patient Selection and Treatment
Pharmaceuticals 2020, 13(11), 385; https://doi.org/10.3390/ph13110385 - 13 Nov 2020
Cited by 5 | Viewed by 2093
Abstract
LKB1 is frequently mutated in non-small cell lung cancer (NSCLC). LKB1-mutated NSCLCs often have a dismal prognosis and receive lower benefit from the currently available therapies. LKB1 acts as a cell emergency brake in low-energy conditions, by modulating the activity of crucial anabolic [...] Read more.
LKB1 is frequently mutated in non-small cell lung cancer (NSCLC). LKB1-mutated NSCLCs often have a dismal prognosis and receive lower benefit from the currently available therapies. LKB1 acts as a cell emergency brake in low-energy conditions, by modulating the activity of crucial anabolic enzymes. Thus, loss of LKB1 activity leads to the enhancement of tumor cell proliferation also under conditions of energy shortage. This unrestrained growth may be exploited as an Achilles heel in NSCLC, i.e., by inhibiting mitochondrial respiration. Recently, clinical trials have started to investigate the efficacy of metabolism-based treatments in NSCLCs. To date, enrollment of patients within these trials is based on LKB1 loss of function status, defined by mutation in the gene or by complete absence of immunohistochemical staining. However, LKB1 impairment could be the consequence of epigenetic regulations that partially or completely abrogate protein expression. These epigenetic regulations result in LKB1 wild-type tumors with aggressiveness and vulnerabilities similar to those of LKB1-mutated ones. In this review, we introduced the definition of the “LKB1less phenotype”, and we summarized all currently known features linked to this status, in order to optimize selection and treatment of NSCLC patients with impaired LKB1 function. Full article
(This article belongs to the Special Issue Treatment Options and Therapeutics for Non-small Cell Lung Cancer)
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14 pages, 237 KiB  
Review
Current Targeted Therapies for the Fight against Non-Small Cell Lung Cancer
Pharmaceuticals 2020, 13(11), 374; https://doi.org/10.3390/ph13110374 - 09 Nov 2020
Cited by 14 | Viewed by 2129
Abstract
Lung cancers contribute to the greatest number of cancer-related deaths worldwide and still pose challenges in response to current treatment strategies. Non-small cell lung cancer (NSCLC) accounts for over 85% of lung cancers diagnosed in the United States and novel therapeutics are needed [...] Read more.
Lung cancers contribute to the greatest number of cancer-related deaths worldwide and still pose challenges in response to current treatment strategies. Non-small cell lung cancer (NSCLC) accounts for over 85% of lung cancers diagnosed in the United States and novel therapeutics are needed for the treatment of this disease. First and second generation targeted therapies against specific mutated or rearranged oncogenes in NSCLCs show anti-tumor activity and also increase survival. However, many NSCLC patients eventually develop resistance to these therapies or do not properly respond if they have central nervous system metastases. Thus, this review summarizes recent developments and findings related to the generation of novel targeted therapies recently or currently being developed to tackle hurdles that prior therapies were not able to overcome. Full article
(This article belongs to the Special Issue Treatment Options and Therapeutics for Non-small Cell Lung Cancer)
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15 pages, 299 KiB  
Review
Epidermal Growth Factor Receptor (EGFR)-Mutated Non-Small-Cell Lung Cancer (NSCLC)
Pharmaceuticals 2020, 13(10), 273; https://doi.org/10.3390/ph13100273 - 25 Sep 2020
Cited by 26 | Viewed by 4305
Abstract
Epidermal growth factor receptor (EGFR) mutations are the most common oncogenic drivers in non-small-cell lung cancer (NSCLC). Significant developments have taken place which highlight the differences in tumor biology that exist between the mutant and wild-type subtypes of NSCLC. Patients with advanced EGFR-mutant [...] Read more.
Epidermal growth factor receptor (EGFR) mutations are the most common oncogenic drivers in non-small-cell lung cancer (NSCLC). Significant developments have taken place which highlight the differences in tumor biology that exist between the mutant and wild-type subtypes of NSCLC. Patients with advanced EGFR-mutant NSCLC have a variety of EGFR-targeting agents available proven to treat their disease. This has led to superior patient outcomes when used as a monotherapy over traditional cytotoxic systemic therapy. Attempts at combining EGFR agents with other anticancer systemic treatment options, such as chemotherapy, antiangiogenic agents, and immunotherapy, have shown varied outcomes. Currently, no specific combination stands out to cause a shift away from the use of single-agent EGFR inhibitors in the first-line setting. Similarly, adjuvant EGFR inhibitors, are yet to significantly add to patient overall survival if used at earlier timepoints in the disease course. Liquid biopsy is an evolving technology with potential promise of being incorporated into the management paradigm of this disease. Data are emerging to suggest that this technique may be capable of identifying early resistance mechanisms and consequential disease progression on the basis of the analysis of blood-based circulating tumor cells. Full article
(This article belongs to the Special Issue Treatment Options and Therapeutics for Non-small Cell Lung Cancer)
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