Assunta Sgambato

The role of EGFR tyrosine kinase inhibitors in the first-line treatment of advanced non small cell lung cancer patients harboring EGFR mutation.

Lung cancer continues to be the leading cause of cancer death worldwide. Among lung cancers, 80% are classified as nonsmall- cell lung cancer (NSCLC) and are mostly diagnosed at an advanced stage (either locally advanced or metastatic disease). In the last years, the discovery of the pivotal role in tumorigenesis of the Epidermal Growth Factor Receptor (EGFR) has provided a new class of targeted therapeutic agents: the EGFR tyrosine kinase inhibitors (EGFR-TKIs). Since the first reports of an association between somatic mutations in EGFR exons 19 and 21 and response to EGFR-TKIs, treatment of advanced NSCLC has changed dramatically. Histologic profile, clinical characteristics, and mutational profile of lung carcinoma have all been reported as predictive factors of response to EGFR-TKIs and other targeted therapies. In advanced NSCLC patients harboring EGFR mutations, the use of EGFR TKIs in first-line treatment has provided an unusually large progression-free survival (PFS) benefit with a negligible toxicity when compared with cytotoxic chemotherapy in phase III randomized trials. Considering the findings regarding the excellent benefit and better safety profile of EGFR TKIs in EGFR mutation positive patients, these targeted therapeutic agents can be now considered as first-line treatment in this setting of patients. This review will discuss the new evidences in the role of EGFR-TKIs in the first-line treatment of advanced NSCLC and their implication in the current clinical decision-making.

Overcoming resistance to targeted therapies in NSCLC: current approaches and clinical application

The discovery that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by druggable protein kinases has led to a revolutionary change in nonsmall cell lung cancer (NSCLC) treatment. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are the targets of several tyrosine kinase inhibitors (TKIs), some of them approved for treatment and others currently in clinical development. First-generation agents offer, in target populations, a substantial improvement of outcomes compared with standard chemotherapy in the treatment of advanced NSCLC. Unfortunately, drug resistance develops after initial benefit through a variety of mechanisms. Novel generation EGFR and ALK inhibitors are currently in advanced clinical development and are producing encouraging results in patients with acquired resistance to previous generation agents. The search for new drugs or strategies to overcome the TKI resistance in patients with EGFR mutations or ALK rearrangements is to be considered a priority for the improvement of outcomes in the treatment of advanced NSCLC.

Anti PD-1 and PDL-1 Immunotherapy in the Treatment of Advanced Non- Small Cell Lung Cancer (NSCLC): A Review on Toxicity Profile and its Management

The better understanding of immunology and antitumor immune responses have prompted the development of novel immunotherapy agents like PD-1 checkpoint inhibitors (anti-PD-1 and anti- PDL-1 antibodies) that improve the capacity of the immune system to acknowledge and delete tumors, including lung cancer. Currently, two anti-PD-1 (nivolumab and pembrolizumab) and one anti- PD-L1 (MPDL-3280A) agents are in advanced stages of development in advanced or metastatic non-small cell lung cancer (NSCLC). Among these, nivolumab demonstrated a survival benefit versus docetaxel in refractory squamous NSCLC, reporting 41% reduction in risk of death (median overall survival: 9.2 versus 6.0 months; objective response rate: 20% versus 9%), and better safety profile than standard-of-care chemotherapy (grade 3-4 adverse events: 7% versus 55%). However, the enhancement of immune response to cancer targeting specific immune regulatory checkpoints is associated with a toxicity profile different from that related to traditional chemotherapeutic agents and molecularly targeted therapies. The success of immunotherapy is related to ongoing evaluation/identification and treatment of these immunerelated side effects. Herein, first clinical results of PD-1 agents in lung cancer are reviewed, focusing on toxicity profile and its management.

Medical treatment of small cell lung cancer: state of the art and new development

Introduction: Small cell lung cancer (SCLC) is a rapidly progressive disease that accounts for approximately 15% of all lung cancers. Chemotherapy remains the cornerstone of treatment of SCLC, but in the last two decades, its progress has reached a plateau. Although a significant sensitivity to chemotherapy and radiotherapy is a feature of SCLC, an early development of drug resistance unavoidable occurs during the course of the disease. Second-line treatment for relapsed patients remains a very challenging setting, with a limited clinical benefit. Areas covered: A thorough analysis of various therapeutic strategies reported in literature for SCLC treatment was performed. This review includes novel therapeutic approaches such as maintenance or consolidation treatments, new chemotherapy agents and targeted therapy. Expert opinion: Against this background, there is a desperate need for the development of novel active drugs. Among these, amrubicin has also shown more favourable antitumor activity, and is the most promising at present. Concerning targeted agents, these have failed to demonstrate effectiveness for SCLC and a better understanding of the molecular mechanisms is clearly needed. In the future, further investigations are required to clarify the role of novel anti-angiogenic or pro-apoptotic agents and hedgehog pathway inhibitors.

Endocrinopathies induced by immune-checkpoint inhibitors in advanced non-small cell lung cancer

ABSTRACT The advent of immunotherapy has recently expanded the therapeutic options in advanced non-small cell lung cancer (NSCLC). In these patients, the recent efficacy demonstration of antibodies against immune checkpoints: the anti-programmed death-1 (PD-1) and anti-programmed death ligand-1 (PD-L1), has led to approval of nivolumab and pembrolizumab (anti-PD-1) in the treatment of advanced NSCLC. The mechanism of action of checkpoint inhibitors explains the development of autoimmune diseases as a side-effect of these medications. Among these, a spectrum of endocrine disorders has been also reported. This manuscript focuses particularly on endocrine disorders induced by immuno-checkpoint inhibitors employed in NSCLC, in order to suggest the strategies for their diagnosis and effective management.

The c-Met inhibitors: a new class of drugs in the battle against advanced nonsmall-cell lung cancer.

Lung cancer, of which non-small-cell lung cancer (NSCLC) is the most common form, remains the leading cause of cancer-related mortality worldwide, with many patients presenting with advanced disease at initial diagnosis. In advanced NSCLC patients whose tumors harbor activating epidermal growth factor receptor (EGFR) mutations, the use of EGFR tyrosine kinase inhibitors (TKIs) as first-line treatment has provided an unusually large progression-free-survival (PFS) benefit, a significantly high response rate (RR) and decreased toxicity when compared with cytotoxic chemotherapy in several phase III randomized trials; however, resistance invariably occurs. There are multiple mechanisms defined by which tumor cells may become independent of EGFR such as the well-characterized example of mesenchymal-epithelial transition factor (MET) amplification. Upon initial diagnosis of NSCLC, MET gene amplification is uncommon; however, acquired MET amplification has been noted in up to 20% of EGFR-mutated tumors that have been pretreated with an EGFR TKI. In tumors containing MET gene amplification, stimulation of the tumor occurs via the co-receptor HER-3 resulting in activation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway, thereby circumventing the effects of an EGFR TKI. Recently, the targeting of the MET pathway has been attempted with small molecules and with monoclonal antibodies. This review will explain the MET signaling pathway and biology in cancer and the recent clinical development and advances of MET/HGF targeting agents in the treatment of advanced NSCLC.

The role of checkpoint inhibitors immunotherapy in advanced non-small cell lung cancer in the elderly

ABSTRACT Introduction: Immune checkpoint inhibition is a novel treatment modality that has brought a new hope to patients with advanced NSCLC. Several molecules targeting cytotoxic T-lymphocyte antigen 4 (CTLA4) or programmed cell death 1 receptor/programmed death ligand-1 (PD1/PD-L1) pathways are under evaluation in NSCLC and three of them are currently approved: nivolumab and atezolizumab for advanced NSCLC after prior chemotherapy and pembrolizumab for advanced NSCLC expressing PD-L1 ≥ 1% after at least one prior chemotherapy regimen and > 50% as a first-line response. Areas covered: To date, the efficacy and toxicity of immune checkpoint inhibitors in the elderly is unclear because available studies involved mainly a low number of elderly patients. In this paper, the authors discuss the frailty of the elderly patient and the challenges of choosing the best therapeutic strategy, focusing on the role of immune checkpoint inhibitors. Expert opinion: There are several outstanding goals that need to be met for the proper and safe use of immunotherapeutic drugs. In terms of the elderly, it is true that age-tailored clinical trials are needed to confirm the real impact of immunotherapy and harmonize the standard of care in this specific demographic.

Cetuximab in advanced non-small cell lung cancer (NSCLC): the showdown?

Nowadays, epidermal growth factor receptor (EGFR) is an important therapeutic target in non-small-cell lung cancer (NSCLC). Monoclonal antibodies (mAbs) targeting the extra-cellular domain of EGFR together with small molecule tyrosine kinase inhibitors (TKIs) have been exploited pharmacologically to block EGFR activation. While the EGFR-TKIs erlotinib and gefitinib are established treatment options for patients with advanced NSCLC, above all in patients with activating EGFR mutations (exon 19 deletion and mutation L858R in exon 21), the role of cetuximab (mAb) was recently clarified. Cetuximab (marketed as Erbitux) is a chimeric human/murine monoclonal immunoglobulin G1 antibody, that inhibits the receptor function, mediates antibody-dependent cell-mediated cytotoxicity and receptor downregulation, leading to a mitigation of EGFR activity. Several phase II trials have evaluated if cetuximab in combination with different first-line chemotherapy regimens could enhance synergic effect. First, the promising efficacy results of the addiction of cetuximab to cisplatin plus vinorelbine as first-line treatment in the phase II Lung Cancer Cetuximab Study [LUCAS; overall response rate (ORR): 35% vs. 28%] (1) led to the FLEX (First-Line Erbitux in Lung Cancer) phase III trial (2,3). In this landmark phase III trial, the combination with cetuximab significantly improved overall survival (OS, primary endpoint) compared with chemotherapy alone (cisplatin plus vinorelbine) in 1,125 chemo-naive patients with advanced EGFR-positive NSCLC (median OS: 11.3 versus 10.1 months, respectively; HR: 0.871, P=0.044). This small but significant survival benefit was seen in all histological subgroups. Progression-free survival (PFS) time was similar, showing a median 4.8 months in both groups (HR: 0.943, P=0.39) (2). As expected with an anti-EGFR antibody, acne-like skin rash, diarrhoea, and infusion-related reactions were more common in patients given cetuximab plus chemotherapy. Interestingly, early-onset acne-like rash of any grade was associated with better outcome: median survival of 15.0 vs. 8.8 months (HR: 0.63, P<0.001) (3). Another phase II trial, SWOG S0342, evaluated concurrent and sequential administration of cetuximab with a standard chemotherapy (carboplatin plus paclitaxel) regimen in untreated patients with advanced NSCLC (4). Both arms meet the predefined efficacy end point of median OS time of ≥10 months; RR and PFS were similar, as well as grade 3 rash, whereas sensory neuropathy was higher in the concurrent arm. The concurrent regimen was chosen in subsequent phase III trial BMS-099 (Bristol-Myers Squibb 099), testing the addition of cetuximab to carboplatin plus paclitaxel in 676 chemo-naive patients with advanced NSCLC, without restrictions based on histology or EGFR expression (5). Although BMS-099 did not meet its primary end point (PFS, 4.4 vs. 4.24 months; HR: 0.902, P=0.24), there were some similarities with the FLEX trial. Both studies reported a statistically significant benefit in ORR with the addition of cetuximab to platinum-based chemotherapy (36% vs. 29% in FLEX; 25.7% vs. 17.2% in BMS), and failed to show any improvement in PFS. However, the difference in OS was similar in both studies (approximately 1.3-month increase in median OS and 11% to 13% reduction in the death risk), although BMS099 lacked power to detect a difference of this magnitude with statistical significance (5). Cetuximab added to a platinum agent (mostly carboplatin) plus gemcitabine in chemo-naive patients with advanced NSCLC, regardless of EGFR expression, resulted in a higher RR (27.7% vs. 18.2%) and longer PFS (median 5.09 vs. 4.21 months) compared to chemotherapy alone, in another phase II trial (6). To better understand the real impact of cetuximab-based treatment in first-line setting, a metanalysis including 2018 patients from four randomized trials, was performed. The survival benefit of chemotherapy plus cetuximab compared to chemotherapy alone [regardless of the chemotherapy protocol used: cisplatin plus vinorelbine (1-3), platin plus paclitaxel (5), and platin plus gemcitabine (6)] was confirmed in chemo-naive patients with advanced NSCLC (7). Despite these positive results—in biomarker unselected population—both the FDA and the EMEA rejected the licensing of cetuximab in combination with chemotherapy for first-line therapy of advanced NSCLC in consideration of the small OS benefit of the addition of cetuximab to chemotherapy, which should be weighed against its side effects, the weekly administration, and costs. The identification of a biomarker predictive of a treatment benefit associated with the addition of cetuximab to first-line chemotherapy for NSCLC would enable a personalised approach to care. To pursue this possibility, retrospective analyses of FLEX and BMS-099 investigated a panel of candidate pretreatment molecular markers (KRAS mutational status, EGFR mutational status, and EGFR copy number) in tumours, but none of these have a predictive role in clinical benefit (8,9). Interestingly, tumour EGFR expression levels seemed to be associated with clinical outcome in FLEX study patients (10). In a further prospective analysis of this study, Pirker et al. collected tumour EGFR expression data to generate an immunohistochemistry score (H score), to provide a more detailed assessment of EGFR protein expression, and to evaluate its role as predictive biomarker of survival benefit. The H score takes into account the percentage of cells (0-100%) in each intensity category (0-3+) and computes a final score, on a continuous scale between 0 and 300. High EGFR expression according to a tumour IHC score of 200 or more seems to be the only effective pre-treatment biomarker so far identified for the prediction of clinical benefit from chemotherapy plus cetuximab in the first-line treatment of advanced NSCLC (10). Although the predictive role of EGFR expression levels seems to emerge from this analysis, FDA and EMA rejected the approval of cetuximab in high score EGFR expression NSCLC due the fact that the data come from a subgroup analysis. They required a confirmatory prospective trial that the pharmaceutical company has decided not to run. Most patients receiving front-line cytotoxic therapy for advanced NSCLC experience progressive disease. Several single agents are approved for use in advanced, second-line NSCLC, including pemetrexed, docetaxel, and erlotinib. However, in patients who become refractory to front-line chemotherapy, no new treatment has shown significant survival benefit in unselected patient populations for the past decade outside of single-agent therapy. Based on promising safety and efficacy results of combined regimen (cetuximab plus docetaxel) in a phase II trial (11), the SELECT study evaluated if the addition of cetuximab to standard chemotherapy might improve outcome in patients with pretreated advanced NSCLC (12). In this open-label phase III trial, Kim and colleagues randomized 938 patients with metastatic, unresectable, or locally advanced NSCLC to four arms of treatment: 605 patients received pemetrexed (301 patients with cetuximab and 304 alone) and 333 received docetaxel (167 in combination with cetuximab and 166 alone). The initial primary analysis was a comparison of the ORR between chemotherapy alone or combined with weekly cetuximab. However during the trial, the primary endpoint was changed to compare PFS with cetuximab plus pemetrexed versus pemetrexed alone, on an intention-to-treat basis, after data publication of phase III trial, in which pemetrexed showed a clinically equivalent efficacy outcomes to docetaxel, with fewer side-effects (13). The addition of cetuximab to pemetrexed did not improve PFS (2.9 vs. 2.8 months, respectively; HR: 1.03, P=0.76), nor there were improvements in any of the other assessed efficacy or quality-of-life measures, including OS (6.9 vs. 7.8 months, respectively; HR 1.01, P=0.86). Data from pre-specified efficacy subgroup analyses by EGFR status and histology (squamous vs. non-squamous) confirmed any improvement in outcome. There were no significant differences between the two treatment groups in median PFS or in OS, when assessed by EGFR staining intensity (positive: EGFR 1+, 2+, 3+/negative: EGFR undetectable) and H-score (low H-score: <200/high H-score: ≥200). More and worse adverse events (AEs) were recorded with cetuximab plus pemetrexed, mainly due to skin-related toxic effects (grade 3-4 acneiform rash: 11% vs. 0%), gastrointestinal symptoms (grade 1-2 diarrhoea: 27% vs. 13%; grade 1-2 mucositis oral: 18% vs. 7%), and hypomagnesaemia (grade 1-2: 19% vs. 6%). These disappointing results confirmed the ineffectiveness of the combination of cetuximab and pemetrexed, already reported in a single arm phase II study (14), suggesting that the addition of cetuximab in an unselected patient population in this setting is unlikely to result in significantly superior outcomes to single-agent therapy alone. Nowadays, cetuximab failed to demonstrate a great and clinically significantly survival benefit when combined with chemotherapy regimens (mono- or poly-chemotherapy), regardless line setting (first- or second line). Furthermore, the data reported by Kim and colleagues (12) highlighted that the use of cetuximab in unselected patients not only did not improve outcomes, but also worsened toxic effects. So the identification of NSCLC patients that might potentially benefit from treatment with this monoclonal antibody is needful, but not yet clarified. The use of EGFR staining intensity and H-score, for selection of patients need to be confirmed in prospective trials but pharmaceutical company decided to stop the cetuximab clinical development in NSCLC.

New Molecular Targets in the Treatment of NSCLC

Lung cancer is the leading cause of mortality world-wide. Non Small Cell Lung Cancer (NSCLC) is a particularly aggressive cancer, the optimum management of which is still being determined. In the next years modest survival improvement can be expected by chemotherapy. Advances in understanding of the molecular pathogenesis of lung cancer have led to the identification of several specific targets for therapeutic agents. Targeting the epidermal growth factor receptor (EGFR) has played a central role in advancing NSCLC research, treatment, and patient outcome over the last several years. In lung cancer, 10-15% of NSCLC contain activating mutations in the EGFR kinase conferring hypersensitivity to the oral TKIs gefitinib and erlotinib, have been demonstrated to be important predictive factors when selecting patients to be treated with these two agents. More recently, another molecular abnormality, the translocation of the anaplastic lymphoma kinase (ALK) gene that drives NSCLC in a different group of patients has been found in 4 to 5% of NSCLC. The rearrangement results in an EML4 - AKL fusion gene, which increases ALK activity. Inhibitors of ALK kinase have been developed and investigated. Crizotinib, an orally ALK and met proto-oncogene (MET) inhibitor, was very well tolerated and produced dramatic antitumor activity in early-stage trials which facilitated a faster than normal move into late-stage trials for EML4-ALK -positive NSCLC patients treatment. In a phase III randomized that showed progression free survival benefit as compared to chemotherapy in second-line setting. Several novel selective inhibitors of ALK kinase are currently in preclinical or early clinical testing. Since the discovery that Met pathway is one of the most frequently dysregulated pathways in human cancer, Met inhibitors, with varying kinase selectivity profiles ranging from highly selective to multi-targeted have been studied in the clinic and good progress has been achieved. A number of studies suggest that the PI3K/Akt signaling pathway is central to NSCLC growth and survival. Given the importance of activated PI3K signaling in cancer, several PI3K inhibitors are currently one of the most recent drug targets in oncology, with several small molecules in early stages of clinical development. This review will focus on the role of EGFR, ALK, MET, and PI3K inhibitors in the treatment of NSCLC.

Resistance to Crizotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) with ALK Rearrangement: Mechanisms, Treatment Strategies and New Targeted Therapies.

Non-small cell lung cancers (NSCLCs) harboring anaplastic lymphoma kinase (ALK) rearrangement are generally responsive to treatment with ALK tyrosine kinase inhibitors (TKIs). Crizotinib is the first-in-class TKI approved as front-line or salvage therapy in advanced ALK-rearranged NSCLC. Unfortunately, drug resistance develops after initial benefit, through a variety of mechanisms preserving or not the dominance of ALK signaling in the crizotinib-resistant state. The distinction between patients who preserve ALK dominance (secondary mutations alone or in combination with the number of copy ALK gain) compared to those that have decreased ALK dominance (separate or second oncogenic drivers, with or without concurrent persistence of the original ALK signal) is important in order to overcome resistance. Novel second-generation ALK inhibitors are currently in clinical development with promising results in ALK-rearranged NSCLC, as well as in crizotinib-resistant patients. Among these, ceritinib in the United States was granted by Food and Drug Administration accelerated approval for treatment of patients with ALK-rearranged, metastatic NSCLC with progression disease on or intolerance to crizotinib. Fully understanding of the different mechanisms of resistance to crizotinib will help us to continue to exploit personalized medicine approaches overcoming crizotinib resistance in these patients in the future. This review aims to discuss on strategy overcoming crizotinib-resistance starting from molecular mechanisms of resistance until novel ALK kinase inhibitors in ALK-rearranged NSCLC patients.