Interleukin-6: A Masterplayer in the Cytokine Network.

Interleukin-6 (IL-6) is a member of the pro-inflammatory cytokine family, induces the expression of a variety of proteins responsible for acute inflammation, and plays an important role in the proliferation and differentiation of cells in humans. IL-6 signaling is mediated by building a complex of IL-6, the transmembrane IL-6 receptor (mIL-6R) or with soluble forms of IL-6R (sIL-6R), and the signal-transducing subunit molecule gp130. Therefore, three modes for IL-6 signaling may occur in which IL-6 is binding to mIL-6R (classic), to sIL-6R (trans-signaling), or is joined through IL-6R to gp130 on nearby located cells (trans-presentation). These pathways, and the fact that gp130 is ubiquitously expressed, lead to the pleiotropic functions of IL-6. The control of IL-6 signaling is regulated through the induction of suppressor molecules after activation of the IL-6 pathways as well as through the presence of sIL-6R and gp130 forms in the blood. Vice versa, an overproduction of IL-6 and dysregulation of the IL-6 signaling pathways can result in inflammatory and autoimmune disorders as well as cancer development suggesting that IL-6 plays a significant role in the human cytokine network. Several therapeutic agents have been evaluated for inhibiting the cytokine itself, the signaling via the IL-6 receptor, or target kinases (e.g., JAK/STAT) associated with the signaling pathways. Amongst others, tocilizumab (anti-IL-6R humanized antibody) has been approved for the treatment of rheumatoid arthritis, cytokine release syndrome, and idiopathic multicentric Castleman's disease (iMCD), whereas siltuximab (an IL-6 antagonist) received approval for iMCD only. Although not all IL-6-associated diseases respond to IL-6 blockade, a better understanding of the underlying mechanisms of the IL-6 pathways may, therefore, help to find the best treatment for IL-6-associated diseases in the near future.

Targeting SHP-1, 2 and SHIP Pathways: A Novel Strategy for Cancer Treatment?

Well-balanced levels of tyrosine phosphorylation, maintained by the reversible and coordinated actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), are critical for a wide range of cellular processes including growth, differentiation, metabolism, migration, and survival. Aberrant tyrosine phosphorylation, as a result of a perturbed balance between the activities of PTKs and PTPs, is linked to the pathogenesis of numerous human diseases, including cancer, suggesting that PTPs may be innovative molecular targets for cancer treatment. Two PTPs that have an important inhibitory role in haematopoietic cells are SHP-1 and SHP-2. SHP-1, 2 promote cell growth and act by both upregulating positive signaling pathways and by downregulating negative signaling pathways. SHIP is another inhibitory phosphatase that is specific for the inositol phospholipid phosphatidylinositol-3,4,5-trisphosphate (PIP3). SHIP acts as a negative regulator of immune response by hydrolysing PIP3, and SHIP deficiency results in myeloproliferation and B-cell lymphoma in mice. The validation of SHP-1, 2 and SHIP as oncology targets has generated interest in the development of inhibitors as potential therapeutic agents for cancers; however, SHP-1, 2 and SHIP have proven to be an extremely difficult target for drug discovery, primarily due to the highly conserved and positively charged nature of their PTP active site, and many PTP inhibitors lack either appro-priate selectivity or membrane permeability. To overcome these caveats, novel techniques have been employed to synthesise new inhibitors that specifically attenuate the PTP-dependent signaling inside the cell and amongst them; some are already in clinical development which are discussed in this review.

Targeting Developmental Pathways: The Achilles Heel of Cancer?

Developmental pathways (e.g., Notch, Hippo, Hedgehog, Wnt, and TGF-ß/BMP/FGF) are networks of genes that act co-ordinately to establish the body plan, and disruptions of genes in one pathway can have effects in related pathways and may result in serious dysmorphogenesis or cancer. Interestingly, all developmental pathways are highly conserved cell signalling systems present in almost all multicellular organisms. In addition, they have a crucial role in cell proliferation, apoptosis, differentiation, and finally in organ development. Of note, almost all of these pathways promote oncogenesis through synergistic associations with the Hippo signalling pathway, and several lines of evidence have also indicated that these pathways (e.g., Wnt/ß-catenin) may be implicated in checkpoint inhibitor resistance (e.g., CTLA-4, PD-1, and PD-L1). Since Notch inhibition in vivo results in partial loss of its stemness features such as self-renewal, chemoresistance, invasive and migratory potential, and tumorigenesis, these highly conserved developmental pathways are regarded as being critical for regulation of self-renewal in both embryonic and adult stem cells and hence are likely to be implicated in the maintenance of cancer stem cells. Many small molecules are currently in preclinical and early clinical development, and only two compounds are approved for treatment of advanced or metastatic basal cell carcinoma (vismodegib and sonidegib). Furthermore, therapeutic targeting of cancer stem cells using drugs that disrupt activated developmental pathways may also represent an attractive strategy that is potentially relevant to many types of malignancy, notably blood cancers, where the evidence for leukaemia stem cells is well established. Future work will hopefully pave the way for the development of new strategies for targeting these pervasive oncogenic pathways.

Somatic KMT2D loss-of-function mutations in lung squamous cell carcinoma: a single-center cohort study.

Background: The significant progress has been made in targeted therapy for lung adenocarcinoma (LUAD) in the past decade. Only few targeted therapeutics have yet been approved for the treatment of lung squamous cell carcinoma (LUSC). Several higher frequency of gene alterations are identified as potentially actionable in LUSC. Our work aimed to explore the complex interplay of multiple genetic alterations and pathways contributing to the pathogenesis of LUSC, with a very low frequency of a single driver molecular alterations to develop more effective therapeutic strategies in the future. Methods: We retrospectively analyzed the targeted next-generation sequencing (NGS) data (approximately 600 genes) of 335 patients initially diagnosed with non-small cell lung cancer (NSCLC) at our institution between January 2019 and March 2023 and explored the somatic genome alteration difference between LUSC and LUAD. Results: We analyzed that the presence of loss-of-function (LoF) mutations (nonsense, frameshift, and splice-site variants) in histone-lysine N-methyltransferase 2D (KMT2D) was much more prevalent in LUSC (11/53, 20.8%) than in LUAD (6/282, 2.1%). Moreover, our data indicated TP53 co-mutated with KMT2D LoF in 90.9% (10/11) LUSC and 33.3% (2/6) LUAD. Notably, the mutation allele fraction (MAF) of KMT2D was very similar to that of TP53 in the co-mutated cases. Genomic profiling of driver gene mutations of NSCLC showed that 81.8% (9/11) of the patients with LUSC with KMT2D LoF mutations had PIK3CA amplification and/or FGFR1 amplification. Conclusions: Our results prompted that somatic LoF mutations of KMT2D occur frequently in LUSC, but are less frequent in LUAD and therefore may potentially contribute to the pathogenesis of LUSC. Concurrent TP53 mutations, FGFR1 amplification, and PIK3CA amplification are very common in LUSC cases with KMT2D LoF mutations. It needs more deeper investigation on the interplay of the genes and pathways and uses larger cohorts in the future.

Targeting the undruggable: menin inhibitors ante portas.

Acute myeloid leukaemias harbouring a rearrangement of the mixed lineage leukaemia gene (MLL) are aggressive haematopoietic malignancies that relapse early and have a poor prognosis (event-free survival less than 50%). Menin is a tumour suppressor, however, in MLL-rearranged leukaemias it functions as a co-factor which is mandatory for the leukaemic transformation by interaction with the N-terminal part of MLL, which is maintained in all MLL-fusion proteins. Inhibition of menin blocks leukaemogenesis and leads to differentiation and, in turn, to apoptosis of leukaemic blasts. Furthermore, nucleophosmin 1 (NPM1) binds to specific chromatin targets, which are co-occupied by MLL, and menin inhibition has been shown to trigger degradation of mNPM1 resulting in a rapid decrease in gene expression and activating histone modifications. Therefore, disruption of the menin-MLL axis blocks leukaemias driven by NPM1 mutations for which the expression of menin-MLL target genes (e.g., MEIS1, HOX etc.) is essential. To date at least six different menin-MLL inhibitors are undergoing clinical evaluation as first- and second-line monotherapy in acute leukaemias: DS-1594, BMF-219, JNJ-75276617, DSP-5336, revumenib, and ziftomenib, however, only for revumenib and ziftomenib early clinical data have been reported. In the revumenib phase I/II AUGMENT-101 trial (N = 68) with very heavily pretreated AML patients the ORR was 53% with a CR rate of 20%. The ORR in patients harbouring MLL rearrangement of mNPM1 was 59%. Patients who achieved a response had a mOS of 7 months. Similar results have been reported for ziftomenib in the phase I/II COMET-001 trial. ORR was 40% and CRc was 35% in AML patients with mNPM1. However, outcome was worse in AML patients with a MLL rearrangement (ORR 16.7%, CRc 11%). Differentiation syndrome was a notable adverse event. The clinical development of novel menin-MLL inhibitors is well in line with the currently ongoing paradigm shift towards targeted therapies seen in the AML treatment landscape. Moreover, the clinical assessment of combinations of these inhibitors with established therapy options in AML could be the fuel for an improved outcome of MLL/NPM1 patients.

Anthracycline-induced cardiotoxicity - are we about to clear this hurdle?

Anthracyclines have contributed significantly to remarkable improvements in overall survival and are regarded as the most effective cytostatic drug for cancer treatment in various malignancies. However, anthracyclines are a significant cause of acute and chronic cardiotoxicity in cancer patients, and long-term cardiotoxicity can lead to death in about one-third of patients. Several molecular pathways have been implicated in the development of anthracycline-induced cardiotoxicity, although the underlying mechanisms of some molecular pathways are not fully elucidated. It is now generally believed that anthracycline-induced reactive oxygen species (resulting from intracellular metabolism of anthracyclines) and drug-induced inhibition of topoisomerase II beta are the key mechanisms responsible for the cardiotoxicity. To prevent cardiotoxicity, several strategies are being followed: (i) angiotensin-converting enzyme inhibitors, sartans, beta-blockers, aldosterone antagonists, and statins; (ii) iron chelators; and (iii) by development of new anthracycline derivatives with little or no cardiotoxicity. This review will discuss clinically evaluated doxorubicin analogues that were developed as potentially non-cardiotoxic anticancer agents and include recent development of a novel liposomal anthracycline (L-Annamycin) for the treatment of soft-tissue sarcoma metastatic to the lung and acute myelogenous leukaemia.

Efficacy evaluation of surgery combined with chemotherapy for stage IIIA small cell lung cancer patients: a retrospective analysis.

Background: The efficacy of surgery in combination of chemotherapy for stage IIIA small cell lung cancer (IIIA-SCLC) is controversial. The aim of the present study was to analyze the efficacy of surgery combined with chemotherapy, especially in the setting of neoadjuvant chemotherapy (NAC) followed by surgery for IIIA-SCLC. Methods: Between 2004 and 2015, we reviewed 2,199 chemotherapy-treated stage IIIA (N1/2) SCLC cases in the Surveillance, Epidemiology, and End Results (SEER) database, and 32 NAC + intentional radical resection-treated, centrally-located IIIA-SCLC cases at Shanghai Pulmonary Hospital (SPH). Outcomes were compared between surgically and non-surgically treated patients from the SEER database after propensity score matching (PSM), and comparing lobectomy/bi-lobectomy and pneumonectomy patients from SPH. Prognostic factors were evaluated by Kaplan-Meier method and the Cox proportional hazards regression model. Results: There was significantly higher overall survival (OS) in surgically treated IIIA-SCLC patients (OS, 44.8 vs. 21.2 months, P=0.048), and similar efficacy was observed between sub-lobectomy and lobectomy/bi-lobectomy patients (OS: 55.6 vs. 30.3 months, P=0.167) in SEER database. At SPH, significantly higher OS was associated with T1 stage (before NAC: T1 vs. T2-4, 48.7 vs. 32.2 months, P=0.025; after NAC: T1 vs. T2-4, 42.7 vs. 21.3 months, P=0.048). Female sex [hazard ratio (HR): 0.078, P=0.009], T1 stage (HR: 13.048, P=0.026), and pneumonectomy (HR: 0.095, P=0.009) were independent prognostic factors for IIIA-SCLC patients who received NAC + intentional radical resection. Conclusions: For stage IIIA SCLC patients, complete resection combined with chemotherapy might improve the prognosis than patients without surgery. Post-NAC lobectomy was not found to be superior to sub-lobectomy, while pneumonectomy was considered suitable for central-type IIIA-SCLC patients after NAC treatment.

Has programmed cell death ligand-1 MET an accomplice in non-small cell lung cancer?-a narrative review.

Recently approved and highly specific small-molecule inhibitors of c-MET exon 14 skipping mutations (e.g., capmatinib, tepotinib) are a new and important therapeutic option for the treatment of non-small cell lung cancer (NSCLC) patients harbouring c-MET alterations. Several experimental studies have provided compelling evidence that c-MET is involved in the regulation of the immune response by up-regulating inhibitory molecules (e.g., PD-L1) and down-regulating of immune stimulators (e.g., CD137, CD252, CD70, etc.). In addition, c-MET was found to be implicated in the regulation of the inflamed tumour microenvironment (TME) and thereby contributing to an increased immune escape of tumour cells from T cell killing. Moreover, it is a major resistance mechanism following treatment of epidermal growth factor receptor mutations (EGFRmut) with tyrosine kinase receptor inhibitors (TKIs). In line with these findings c-MET alterations have also been shown to be associated with a worse clinical outcome and a poorer prognosis in NSCLC patients. However, the underlying mechanisms for these experimental observations are neither fully evaluated nor conclusive, but clearly multifactorial and most likely tumour-specific. In this regard the clinical efficacy of checkpoint inhibitors (CPIs) and TKIs against EGFRmut in NSCLC patients harbouring c-MET alterations is also not yet established, and further research will certainly provide some guidance as to optimally utilise CPIs and c-MET inhibitors in the future.

KEAP1/NRF2 (NFE2L2) mutations in NSCLC - Fuel for a superresistant phenotype?

The transcription factor NRF2 (nuclear factor E2-related factor 2) (also known as nuclear factor, erythroid 2 like 2 [NFE2L2]) is the master regulator of cellular antioxidant responses. NRF2 is repressed by interaction with a redox-sensitive protein KEAP1 (Kelch-like ECH-associated protein 1). Dysregulation of KEAP1/NRF2 transcriptional activity has been associated with the pathogenesis of multiple diseases, and the KEAP1/NRF2 axis has emerged to be the most important modulator of cellular homeostasis. Oxidative stress plays an important role in the initiation and progression of many chronic diseases, including diabetes, cancer, and neurodegenerative diseases. Although its role in immunotherapy is still somewhat controversial, it is well documented from clinical studies that KEAP1/NRF2 mutations in NSCLCs are associated with resistance to various cancer treatments including chemotherapy, X-irradiation, TKI treatment, and a shorter OS and currently available results from clinical trials suggest that KEAP1/NRF2 mutations can be used as a prognostic biomarker (poorer prognosis) for determining prognosis following immunotherapy and a predictive marker for chemo-, radio-, immunotherapy- and TKI-resistance. Despite overwhelming enthusiasm about the various KEAP1/NRF2 inhibitors that have been described during the last decades, none of these inhibitors are currently explored in clinical trials or in clinical applications which clearly add weight to the proposal that the development of these inhibitors remains challenging, but will be beneficial for novel treatment approaches in NSCLC in the near future. In this review we highlight the molecular features, the key components, and possible inhibitors of the KEAP1/NRF2 pathway, its role as prognostic and predictive biomarker, and the resulting clinical implications in NSCLC patients.

BCKDK alters the metabolism of non-small cell lung cancer.

BACKGROUND: Metabolic reprogramming is a major feature of many tumors including non-small cell lung cancer (NSCLC). Branched-chain α-keto acid dehydrogenase kinase (BCKDK) plays an important role in diabetes, obesity, and other diseases. However, the function of BCKDK in NSCLC is unclear. This study aimed to explore the function of BCKDK in NSCLC. METHODS: Metabolites in the serum of patients with NSCLC and the supernatant of NSCLC cell cultures were detected using nuclear magnetic resonance (NMR) spectroscopy. Colony formation, cell proliferation, and cell apoptosis were assessed to investigate the function of BCKDK in the progression of NSCLC. Glucose uptake, lactate production, cellular oxygen consumption rate, extracellular acidification rate, and reactive oxygen species (ROS) were measured to examine the function of BCKDK in glucose metabolism. The expression of BCKDK was measured using reverse transcriptase-polymerase chain reaction, western blot, and immunohistochemical assay. RESULTS: Compared with healthy controls and postoperative NSCLC patients, increased branched-chain amino acid (BCAA) and decreased citrate were identified in the serum of preoperative NSCLC patients. Upregulation of BCKDK affected the metabolism of BCAAs and citrate in NSCLC cells. Knockout of BCKDK decreased the proliferation and exacerbated apoptosis of NSCLC cells ex vivo, while increased oxidative phosphorylation and, ROS levels, and inhibited glycolysis. CONCLUSIONS: BCKDK may influence glycolysis and oxidative phosphorylation by regulating the degradation of BCAA and citrate, thereby affecting the progression of NSCLC.

Efficacy and Safety of Approved First-Line Tyrosine Kinase Inhibitor Treatments in Metastatic Renal Cell Carcinoma: A Network Meta-Analysis.

INTRODUCTION: This network meta-analysis aims to deliver an up-to-date, comprehensive efficacy and toxicity comparison of the approved first-line tyrosine kinase inhibitors (TKIs) for metastatic renal cell carcinoma (mRCC) in order to provide support for evidence-based treatment decisions. Previous NMAs of first-line mRCC treatments either predate the approval of all the first-line TKIs currently available or do not include evaluation of safety data for all treatments. METHODS: We performed a systematic literature review and network meta-analysis of phase II/III randomised controlled trials (RCTs) assessing approved first-line TKI therapies for mRCC. A random effects model with a frequentist approach was computed for progression-free survival (PFS) data and for the proportion of patients experiencing a maximum of grade 3 or 4 adverse events (AEs). RESULTS: The network meta-analysis of PFS demonstrated no significant differences between cabozantinib and either sunitinib (50 mg 4/2), pazopanib or tivozanib. The network meta-analysis indicated that in terms of grade 3 and 4 AEs, tivozanib had the most favourable safety profile and was associated with significantly less risk of toxicity than the other TKIs. CONCLUSION: These network meta-analysis data demonstrate that cabozantinib, sunitinib, pazopanib and tivozanib do not significantly differ in their efficacy, but tivozanib is associated with a more favourable safety profile in terms of grade 3 or 4 toxicities. Consequently, the relative toxicity of these first-line TKIs may play a more significant role than efficacy comparisons in treatment decisions and in planning future RCTs.

Programmed cell death ligand-1 (PD-L1) as a biomarker for non-small cell lung cancer (NSCLC) treatment-are we barking up the wrong tree?

Immunotherapy with monoclonal antibodies targeting programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) has become a standard of care treatment for patients with advanced or metastatic non-small cell lung cancer (NSCLC) in first and later treatment lines with durable responses seen in approximately 10-20% of patients treated. However, the optimal selection of eligible patients who will benefit most, is far from being clear and the best biomarker has not yet been established. PD-L1 expression as a predictive biomarker for immunotherapy in NSCLC patients has shown some value for predicting response to immune checkpoint inhibitors in some studies, but not in others, and its use has been complicated by a number of factors which has prompted many researchers to establish better predictive biomarkers for immunotherapy of NSCLC. Most recently, two phase III first-line NSCLC studies have provided evidence that tumour mutational burden (TMB) correlates with the clinical response to the combination of nivolumab and ipilimumab (CheckMate-227; NCT02477826), whereas atezolizumab response was correlated with T effector gene signature expression (IMPower 150; NCT02366143). Both studies demonstrated a significant primary endpoint [progression-free survival (PFS)] benefit in the TMB group and in the group of patients expressing a T effector cell signature, respectively. However, PFS benefit in both studies was seen regardless of the PD-L1 status of all patients suggesting that TMB and T effector cell signatures may be more robust to predict clinical response following treatment with checkpoint inhibitors. The role of putative novel predictive biomarkers evaluated in the CheckMate-227 and the IMPower 150 trials may, if confirmed in future prospective studies, offer a new perspective for predicting immunotherapy treatment outcomes of NSCLC patients in the near future.

Second- and third-generation drugs for immuno-oncology treatment-The more the better?

Recent success in cancer immunotherapy (anti-CTLA-4, anti-PD1/PD-L1) has confirmed the hypothesis that the immune system can control many cancers across various histologies, in some cases producing durable responses in a way not seen with many small-molecule drugs. However, only less than 25% of all patients do respond to immuno-oncology drugs and several resistance mechanisms have been identified (e.g. T-cell exhaustion, overexpression of caspase-8 and ß-catenin, PD-1/PD-L1 gene amplification, MHC-I/II mutations). To improve response rates and to overcome resistance, novel second- and third-generation immuno-oncology drugs are currently evaluated in ongoing phase I/II trials (either alone or in combination) including novel inhibitory compounds (e.g. TIM-3, VISTA, LAG-3, IDO, KIR) and newly developed co-stimulatory antibodies (e.g. CD40, GITR, OX40, CD137, ICOS). It is important to note that co-stimulatory agents strikingly differ in their proposed mechanism of action compared with monoclonal antibodies that accomplish immune activation by blocking negative checkpoint molecules such as CTLA-4 or PD-1/PD-1 or others. Indeed, the prospect of combining agonistic with antagonistic agents is enticing and represents a real immunologic opportunity to 'step on the gas' while 'cutting the brakes', although this strategy as a novel cancer therapy has not been universally endorsed so far. Concerns include the prospect of triggering cytokine-release syndromes, autoimmune reactions and hyper immune stimulation leading to activation-induced cell death or tolerance, however, toxicity has not been a major issue in the clinical trials reported so far. Although initial phase I/II clinical trials of agonistic and novel antagonistic drugs have shown highly promising results in the absence of disabling toxicity, both in single-agent studies and in combination with chemotherapy or other immune system targeting drugs; however, numerous questions remain about dose, schedule, route of administration and formulation as well as identifying the appropriate patient populations. In our view, with such a wealth of potential mechanisms of action and with the ability to fine-tune monoclonal antibody structure and function to suit particular requirements, the second and third wave of immuno-oncology drugs are likely to provide rapid advances with new combinations of novel immunotherapy (especially co-stimulatory antibodies). Here, we will review the mechanisms of action and the clinical data of these new antibodies and discuss the major issues facing this rapidly evolving field.

Overall survival in non-small cell lung cancer-what is clinically meaningful?

The development of molecularly targeted therapies [tyrosine kinase inhibitors (TKIs) and monoclonal antibodies] has significantly improved outcomes for patients with advanced or metastatic non-small cell lung cancer (NSCLC) resulting in improved progression-free survival (PFS), overall survival (OS) and quality of life (QoL). In addition, targeting the immune axis (CTLA-4, PD-1/PD-L1) has also shown promising results. Major goals of almost all clinical trials based on histology and molecular markers for NSCLC patients are improvements of OS and QoL. However, in the majority of these trials only small incremental improvements in OS were seen. Food and Drug Administration (FDA) and other health authorities have recommended to consider OS to be the standard clinical benefit endpoint that should be used to establish the efficacy of a treatment for NSCLC patients, however, the question remains what is clinically meaningful and how can this outcome be measured. According to suggestions of the American Society of Clinical Oncology (ASCO) Cancer Research Committee a relative improvement in median OS of at least 20% (3-4 months) is regarded to define a clinically meaningful improvement in outcome of NSCLC patients. However, this should not diminish PFS as a valid endpoint since a PFS improvement can also result in a meaningful palliation (e.g., painful bone metastases). Other factors (e.g., QoL) may also be involved to measure and to define the clinical importance of a given trial result. Using the "Quality-adjusted Time Without Symptoms of Toxicity" (Q-TWiST) analysis method it has been demonstrated that a clinically important and meaningful difference for Q-TWiST is 10-15% of OS in a study. Trials that are designed with less ambitious goals, however, may still be of benefit to individual NSCLC patients if the trial endpoints are met. Since there is no single factor which will make a trial clinically meaningful, these recommendations, however, are not intended to set standards for regulatory approval or insurance coverage but rather to encourage patients and investigators to demand more from clinical trials.

Targeted Therapy for NSCLC--A Double-edged Sword?

Advanced or metastatic non-small cell lung cancer (NSCLC) is characterised by a poor prognosis and few second- or third-line treatments. First-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibition has paved the way for targeted therapies in lung cancer. Although these drugs result in excellent responses [and significantly improved progression-free survival (PFS)] in patients with activating EGFR mutations, only few studies revealed improved overall survival (OS), and resistance often develops. Bevacizumab, a monoclonal antibody which targets vascular endothelium growth factor (VEGF), has been fully developed in NSCLC, and small-molecule tyrosin kinase inhibitors (TKIs) have been approved as first-line therapy for patients with advanced and metastatic NSCLC harbouring EGFR mutations. In addition, crizotinib, a novel inhibitor of the anaplastic lymphoma kinase, has been approved for second-line treatment of NSCLC. Several new drugs targeting not only the EGFR pathways, but also signal transduction cascades involved in angiogenesis and the mitogene-activated extracellular signal-regulated kinase kinase pathways are currently evaluated in phase III clinical trials. Experimental monoclonal antibodies are also currently undergoing phase III clinical trials and have shown promising activity which might help to improve the therapeutic landscape of NSCLC. However, many other drugs prolonged PFS, but failed to demonstrate a significant improvement of OS. PFS is often used as a predictor for improved OS since it is independent of subsequent treatment, but OS is acknowledged as the key clinical outcome in the treatment of advanced NSCLC. Furthermore, since there are only very few trials that have shown a benefit from the addition of TKIs to chemotherapy, additional studies using this unselected approach are not recommended. Therefore, there is a definite need for an improved understanding of the complex mechanisms that are involved in TKI-mediated pathways, and for the development of validated predictive markers to allow a better treatment decision on the basis of the probability of response. This would certainly help to avoid the unnecessary use of potential toxic drugs in patients with known resistance and would facilitate the discovery of new targets and drugs on the basis of resistance mechanisms.

Improved overall survival following tyrosine kinase inhibitor treatment in advanced or metastatic non-small-cell lung cancer-the Holy Grail in cancer treatment?

Advanced or metastatic non-small-cell lung cancer (NSCLC) is characterized by a poor prognosis and few second- or third-line treatments. First-generation epidermal growth factor receptor tyrosine kinase inhibition has paved the way for targeted therapies in lung cancer. Although these drugs result in excellent responses [and significantly improved progression-free survival (PFS)] in patients with activating EGFR mutations, none of these randomized studies has yet demonstrated a statistically significant improvement of overall survival (OS). PFS is often used as a predictor for improved OS since it is independent of subsequent treatment, but OS is acknowledged as the key clinical outcome in the treatment of advanced NSCLC. When effective treatment is given as post therapy, it will be difficult to distinguish the treatment effect of original and subsequent treatments because differences in OS are potentially confounded by crossover, and a relevant number of patients assigned to chemotherapy arms received tyrosine kinase inhibitors (TKIs) as second- or third-line treatment after disease progression. The high proportion of crossover may extend the benefit associated with the administration of TKIs to patients assigned to the control arm, and its "salvage"-effect may compensate for the relevant differences in PFS of first-line treatment consistently demonstrated in all TKI trials. Results for the INFORM trial (maintenance therapy with gefitinib following platinum-based chemotherapy) provided evidence that maintenance therapy with gefitinib significantly improved PFS, with greatest benefit in patients harboring EGFR mutation. Despite a high crossover rate (53%) final OS results of this study have now demonstrated a significant survival benefit for the gefitinib-treated EGFR mutation-positive patients (46.9 vs. 21.0 months, P=0.036). This is the first randomized clinical trial that showed a significant and clinical meaningful OS benefit in EGFR mutation-positive NSCLC patients following maintenance therapy with gefitinib as compared to placebo. It remains to be seen whether further exploration of this treatment strategy will confirm these promising results.

Immunotherapies for NSCLC: Are We Cutting the Gordian Helix?

Chemotherapy is currently the standard-of-care for non-oncogene-driven advanced non-small cell lung cancer (NSCLC). Due to improvements in chemotherapeutic choices and supportive care, patients currently typically undergo multiple lines of chemotherapy as their disease progresses. Although treatments have improved over recent years, limited benefits are seen, especially in patients receiving later-line chemotherapy, as response rates can be low, response duration short and survival poor. Molecular-targeted therapies have provided improvement in outcomes. However, these treatments only offer a clear benefit in subsets of tumors harbouring the appropriate genomic alteration (mutation, amplification, translocation). Recent advances in immunotherapy have highlighted the potential of immuno-oncology-based treatments for NSCLC, offering the potential to provide durable responses and outcomes regardless of histology or mutation status. Blocking inhibitory pathways such as the cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) checkpoint pathways with monoclonal antibodies has generated antitumor immune responses that are transforming cancer therapeutics. PD-1 and programmed cell death ligand-1(PD-L1) antibodies have shown durable responses in NSCLC, with a favourable safety profile and manageable side-effects. The activity of immune checkpoint inhibitors is currently been assessed in treatment-naïve patients with PD-L1-positive advanced NSCLC. Combinatorial approaches with other immune checkpoint inhibitors, chemotherapy, or targeted-agents are being explored in ongoing clinical trials, and may improve outcome in NSCLC. The emerging data not only offer the hope of a better cancer therapy but also provide evidence that changes our understanding on how the host immune system interacts with human cancer. It is therefore conceivable that agents blocking the CTLA-4/PD-1/PD-L1 axis will provide valuable additions to the growing armamentarium of targeted-agents.

Brain Metastases in NSCLC - are TKIs Changing the Treatment Strategy?

Non-small-cell lung cancer (NSCLC) ranks as a leading cause of cancer-related death globally. Brain metastases are a frequent complication of NSCLC, with 25-40% of patients developing brain metastases during the course of the disease, often within the first 2 years after diagnosis of the primary tumor. Improvements in neurological symptoms and performance status have been reported with whole-brain radiation therapy (WBRT) in combination with steroid therapy in NSCLC patients. In addition, a survival benefit has been reported for patients with a single brain metastasis treated with stereotactic radiosurgery, while the clinical outcome is improved with surgery followed by WBRT versus WBRT alone. However, due to their poor performance status, many patients with brain metastases are not eligible for surgery or radiosurgery. Furthermore, the role of systemic chemotherapy for the treatment of brain metastases is controversial due to the impenetrable nature of the blood brain barrier (BBB), with reported response rates to chemotherapy ranging from 15-30% (overall survival [OS] 6-8 months). Response rates of brain metastases to EGFR tyrosine kinase inhibitor (TKI) treatment (e.g. gefitinib, erlotinib, afatinib) in patients with NSCLC harboring EGFR mutations reach 60-80%, with a complete response rate as high as 40%. Median OS is 15-20 months, and progression-free survival in the brain reaches 6.6-11.7 months, demonstrating an improved clinical outcome. Metastatic involvement of the CNS appears to be a relatively common complication in patients with ALK-positive NSCLC and the CNS represents a dominant site of progression in ALK-positive patients treated with the ALK TKI crizotinib. In addition, CNS progression on crizotinib contributes substantially to the high levels of morbidity and mortality observed among patients with ALK-rearrangements, a finding that is consistent with low CNS penetration of the drug. Second-generation ALK inhibitors (ceritinib, alectinib) are well-tolerated and demonstrate excellent intracranial activity. The various reports of dramatic and prolonged responses in brain metastases patients treated with EGFR and ALK TKIs suggest that these agents may be a valid treatment option for patients with asymptomatic brain metastases from NSCLC, especially for those with EGFR-activating mutations or harboring ALK rearrangement. However, larger phase III studies are required to fully define the activity of these agents and their place in the therapeutic armamentarium of brain metastases.