A pH-responsive polycarbonate nanoplatform enables sequential drug release for enhanced apoptotic cascade synergy in non-small cell lung cancer therapy.

Emerging Advances in the Management of Lung Cancer

Axl Receptor Axis: A New Therapeutic Target in Lung Cancer

Second-Line Chemotherapy for Non-small Cell Lung Cancer

Introduction : For patients with advanced non-small cell lung cancer (NSCLC), chemotherapy alone or in combination with radiation (IR) is considered the standard treatment. However, after the documentation of the over-expression of epidermal growth factor receptor (EGFR) in 50% to 80% of NSCLCs and transforming growth factor-alpha in 81% to 93% of NSCLCs, EGFR has emerged as an important target molecule in NSCLC therapy. The cellular effects of EGFR activation include increased proliferation, promotion of cell motility, adhesion, invasion, angiogenesis and enhanced cell survival. However, activation of EGFR in some tumor cell lines excessively expressing EGFR resulted in cellular apoptosis and growth inhibition. This study attempts to define the role of EGFR kinase activity in sensitizing the responsiveness of EGFR-overexpressed NSCLC cells to IR. Methods: Cell survival, proliferation, cell cycle distribution, reporter activity of EGR-1 and protein expression was studied by colony forming assays, cell counting, flow cytometry, 14Cchloramphenicol acetyl transferase (CAT) reporter assay and Western analysis respectively in A549 and H460 cells. Results: Interestingly, we observed that EGFR activation mediated sensitization of IR effects in A549 cells over-expressing EGFR. Tyrosine kinase inhibitor (TKI), AG1478 blocked EGF effect on sensitization of IR in A549 cells but not in H460 cells. To understand the molecular mechanism underlying the response of A549 cells to IR and EGFR, we investigated the effects of EGFR signaling and IR on expression of early growth response (EGR-1), a transcription factor that sensitizes IR therapy, in both IR-sensitive and insensitive lung cancer cell lines. However, we observed that EGR-1 is not involved in EGFR signaling-mediated IR sensitization since inhibition of Erk (EGFR induces expression of Egr-1 through activation of Erk1/2), did not block EGFR-mediated sensitization of IR effect. Further, we observed that JNK kinase activity mediated EGF-dependent IR effects. Interestingly, acute induction of serum EGF expression level was observed in the patients who responded to IR therapy. Conclusions: Results from this study show that EGFR activation and IR synergistically activate JNK signaling that leads to cellular apoptosis that has important implications for anti-EGFR therapy or IR therapy. Although, preclinical studies have shown that EGFR inhibition can render an additive or synergistic effect with radiotherapy in NSCLCs, clinical benefits are modest. This study suggests that tyrosine kinase activity of EGFR might be required for IR sensitivity. Thus, the inhibition of EGFR by TKIs may lead to reduced responsiveness of NSCLCs to IR thereby compromising the treatment efficacy. Understanding the role of EGFR activity in sensitization of NSCLC cells to IR is therefore extremely important for both radiotherapy and the EGFR TKI-based chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5542.

BackgroundThe efficacy of epidermal growth factor (EGF) receptor (EGFR) inhibitors in patients with non‐small cell lung cancer (NSCLC), pancreatic cancer (PC), or colorectal cancer (CRC) has been demonstrated. However, dermatological reactions to these inhibitors can cause significant physical and psychosocial discomfort. The objective of the present study was to evaluate the efficacy of EGF ointment for EGFR inhibitor‐related skin adverse events (ERSEs).Materials and MethodsThis placebo‐controlled, double‐blind, multicenter, pilot phase III trial enrolled patients with NSCLC, PC, or CRC treated with EGFR inhibitors. Patients with grade ≥2 ERSEs were included. Patients were randomized to three treatment arms: arm 1, placebo; arm 2, 1 ppm of EGF ointment; and arm 3, 20 ppm of EGF ointment. Patients applied ointment to their skin lesions twice daily.ResultsEfficacy evaluation was available for 80 patients (9 for PC, 28 for NSCLC, and 43 for CRC). Responses were 44.4% in arm 1, 61.5% in arm 2, and 77.8% in arm 3. There was a linear correlation between EGF concentrations and responses (p = .012). Quality of life (QoL) was assessed for 74 patients. Maximum changes in composite scores by Skindex‐16 after treatment were significantly different among arms (mean ± SD: −5.2 ± 8.6 for arm 1, −11.7 ± 14.2 for arm 2, and − 18.6 ± 17.7 for arm 3; p = .008). EGF arms showed significant improvement in emotions (p = .005) and functioning (p = .044) scores over the placebo arm.ConclusionEGF ointment is effective for managing ERSEs. It can also improve patients’ QoL compared with placebo. Clinical trial identification number. NCT02284139Implications for PracticePatients with non‐small cell lung cancer, pancreatic cancer, or colorectal cancer who are treated with epidermal growth factor (EGF) receptor (EGFR) inhibitors may experience dermatologic reactions to their treatment. This study investigated the benefit of an EGF ointment in the treatment of these adverse events and observed the ointment to be effective in managing EGFR inhibitor‐related skin adverse events.

Epidermal growth factor receptor (EGFR) inhibitors, including the small-molecule tyrosine kinase inhibitors (EGFR TKIs) erlotinib (Tarceva; OSI Pharmaceuticals Inc, Melville, NY) and gefitinib (Iressa; AstraZeneca, Macclesfield, United Kingdom), and the monoclonal antibodies directed at the receptor such as cetuximab (Erbitux; BristolMyers Squibb, Princeton, NJ), have demonstrated promising effects in some patients with non–small-cell lung cancer (NSCLC) and other solid tumors. In patients with NSCLC, both erlotinib and gefitinib produced objective response in a minority of patients (9% to 20%). In subsequent randomized trials comparing these agents versus placebo, erlotinib produced a significant survival benefit (hazard ratio [HR] 0.73), but gefitinib failed to produce a significant survival advantage (HR 0.89) in unselected patients. Data on cetuximab have been more sparse. Table 1 lists published, ongoing, and planned NSCLC studies with cetuximab. As a single-agent treatment in chemotherapy-refractory patients, Hanna et al reported an objective response rate of 4.5% and a disease control rate of 35%, which is similar to but numerically lower than that reported from the phase II studies with EGFR TKIs. In this issue of Journal of Clinical Oncology, Robert et al present results of a phase I/II a study of cetuximab in combination with carboplatin and gemcitabine in patients with advanced NSCLC who were EGFR positive by immunohistochemistry (IHC). The drug combination was well tolerated, with acceptable toxicity. Objective response was reported in 10 of 35 patients (28.6%) and an additional 21 patients had stable disease, yielding a disease control rate of 88.6%. As listed in Table 1, the combination studies so far reported have given consistent objective responses of 26% to 35% and median survivals of 7 to 11 months. The question is whether these results are better than chemotherapy alone in unselected or selected patient populations. With cetuximab, there are as yet no phase III study results reported. In a randomized phase II study, which compared vinorelbine/cisplatin alone with the same combination plus cetuximab, the addition of cetuximab resulted in a slightly superior response and survival, leading to initiation of an ongoing randomized phase III trial. Currently, several other randomized studies are ongoing or completed accrual, and more results are waiting. Combination of cytotoxic chemotherapy with EGFR TKIs failed to improve outcome in advanced NSCLC, but there might be significant differences in the mechanisms of sensitivity between monoclonal antibodies and the EGFR TKIs. For example, a recent study showed that EGFR mutations were associated with gefitinib sensitivity in vitro, but this was not the case for cetuximab. Much has to be learned about the combinations of chemotherapy and targeted therapies, and some of the questions that need to be resolved include the following. Do the EGFR monoclonal antibodies provide synergy in combination with chemotherapy? What is the optimal scheduling of chemotherapy and EGFR inhibitors in combination? (A targeted therapy given concomitantly with chemotherapy might produce antagonism, whereas sequential treatment might give synergy as demonstrated in breast cancer and antihormonal therapy.) What is the importance of selecting subgroups of patients to these treatments? The study by Robert et al was performed in an enriched population based on EGFR protein expression detected by IHC. The role of EGFR protein expression for prediction of outcome after EGFR inhibitors has been a subject of debate. In patients with colorectal cancer, the US Food and Drug Administration (FDA) label indicates that patient selection by a Dako test kit (Dako A/S, Glostrup, Denmark) should be used for this particular indication, but JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 36 DECEMBER 2

e19155 Background: Epidermal growth factor receptor (EGFR) inhibitors are suspected of being a potential cause of interstitial lung disease (ILD). This speculation is based largely on case reports and series in which it is difficult to establish causality. In this meta-analysis we evaluated randomized controlled trials (RCTs) involving EGFR inhibitors to verify if a relationship exists between exposure to EGFR inhibitors and development of ILD and other pulmonary-related events. Methods: EMBASE and Medline were searched for all RCTs evaluating cetuximab, gefitinib or erlotinib in non-small cell lung cancer (NSCLC). Studies were disqualified if the control contained any EGFR inhibitor or drug known to cause ILD. Thirty-one RCTs with 15,736 patients were identified. The primary outcome was ILD incidence. ILD is poorly defined and there is overlap with other pulmonary related outcomes including pneumonia, acute respiratory failure (ARF) and pneumonitis, and these were therefore secondary outcomes of interest. For all outcomes, a fixed-effects meta-analysis was performed. Results: For the primary outcome, there is a 173% increased risk of ILD among patients given EGFR inhibitors (RR 2.73, 95% CI: 1.74-4.23, p<0.001) across 15 RCTs that report on ILD incidence. Among secondary endpoints, there is an 86% increased risk of pneumonia (RR 1.86, 95% CI 1.36-2.53, p<0.001), a 19% increased risk of pneumonitis (RR 1.19, 95% CI: 0.62-2.27, p=0.59) and a 33% increased risk of ARF (RR 1.33, 95% CI: 0.65-2.72, p=0.44) among patients given EGFR inhibitors. There is minimal heterogeneity across trials for all above outcomes. Conclusions: EGFR inhibitors play a direct role in causing or contributing to ILD progression in patients with NSCLC who are susceptible to alveolar damage from prior chemoradiation therapy. Additionally, EGFR inhibitors seem to be associated with an increased risk for other pulmonary related events.This research suggests that caution should be undertaken in administering EGFR inhibitors to patients with poor baseline lung function or pre-existing pulmonary disease.

Commonly observed aberrations in epidermal growth factor receptor (EGFR) signaling have led to the development of EGFR-targeted therapies for various cancers, including non–small cell lung cancer (NSCLC). EGFR mutations and overexpression have further been shown to modulate sensitivity to these EGFR-targeted therapies in NSCLC and several other types of cancers. However, it is clear that mutations and/or genetic variations in EGFR alone cannot explain all of the variability in the responses of patients with NSCLC to EGFR-targeted therapies. For instance, in addition to EGFR genotype, genetic variations in other members of the signaling pathway downstream of EGFR or variations in parallel receptor tyrosine kinase (RTK) pathways are now recognized to have a significant impact on the efficacy of certain EGFR-targeted therapies. In this review, we highlight the mutations and genetic variations in such genes downstream of EGFR and in parallel RTK pathways. Specifically, the directional effects of these pharmacogenetic factors are discussed with a focus on two commonly prescribed EGFR inhibitors: cetuximab and erlotinib. The results of this comprehensive review can be used to optimize the treatment of NSCLC with EGFR inhibitors. Furthermore, they may provide the rationale for the design of subsequent combination therapies that involve the inhibition of EGFR.

BackgroundThe discovery of epidermal growth factor receptor (EGFR) inhibitors for the treatment of lung cancer, most especially non-small cell lung cancer (NSCLC), was one of the major challenges encountered by the medicinal chemist in the world. The treatment of EGFR tyrosine kinase to manage NSCLCs becomes an urgent therapeutic necessity. NSCLC was the foremost cause of cancer mortality worldwide. Therefore, there is a need to develop more EGFR inhibitors due to the development of drug resistance by the mutation. This research is aimed at designing new EGFR inhibitors using a structure-based design approach. Structure-based drug design comprises several steps such as protein structure retrieval and preparation, ligand library preparation, docking, and structural modification on the best hit compound to design new ones.ResultMolecular docking virtual screening on fifty sets of quinazoline derivatives/epidermal growth factor receptor inhibitors against their target protein (EGFR tyrosine kinase receptor PDB entry: 3IKA) and pharmacokinetic profile predictions were performed to identify hit compounds with promising affinities toward their target and good pharmacokinetic profiles. The hit compounds identified were compound 6 with a binding affinity of − 9.3 kcal/mol, compounds 5 and 8, each with a binding affinity of − 9.1 kcal/mol, respectively. The three hit compounds bound to EGFR tyrosine kinase receptor via four different types of interactions which include conventional hydrogen bond, carbon-hydrogen bond, electrostatic, and hydrophobic interactions, respectively. The best hit (compound 6) among the 3 hit compounds was retained as a template and used to design sixteen new EGFR inhibitors. The sixteen newly designed compounds were also docked into the active site of EGFR tyrosine kinase receptor to study their mode of interactions with the receptor. The binding affinities of these newly designed compounds range from − 9.5 kcal/mol to − 10.2 kcal/mol. The pharmacokinetic profile predictions of these newly designed compounds were further examined and found to be orally bioavailable with good absorption, low toxicity level, and permeable properties.ConclusionThe sixteen newly designed EGFR inhibitors were found to have better binding affinities than the template used in the designing process and afatinib the positive control (an FDA approved EGFR inhibitor). None of these designed compounds was found to violate more than the permissible limit set by RO5. More so, the newly designed compounds were found to have good synthetic accessibility which indicates that these newly designed compounds can be easily synthesized in the laboratory.

Targeted therapy has evolved recently as an important treatment modality for cancer, and the most extensively studied pathways for targeted therapy are those related to epidermal growth factor receptor (EGFR). EGFR is widely expressed in different tumor types and strong expression is associated with higher risk of recurrence/metastasis, poorer survival, and resistance to chemotherapy/radiotherapy. Both monoclonal antibody against EGFR and/or tyrosine kinase inhibitors are now in use clinically for treatment of advanced cancer. With the increasing usage of these agents and the availability of more new agents in the future, knowledge on anti-EGFR therapy is highly relevant to the current state of cancer therapy and to new research directions in the field of oncology. The focus of this special issue is on the clinical applications of approved or investigational anti-EGFR therapy in solid tumors with emphasis on efficacy, toxicity, response, assessment, multimodality treatment, prognostic factors and predictive markers. The review by A. Harandi et al. provides a comprehensive and updated overview of the frequently used EGFR inhibitors and summarizes clinical efficacy data of these agents and their associated toxicity and management. This review clearly shows the impact of anti-EGFR therapy on cancer treatment since improved treatment results can be seen with the use of anti-EGFR therapy in many common cancers. One of these cancers is colorectal cancer and the approval of anti-EGFR monoclonal antibodies in the treatment of metastatic colorectal cancer has expanded the armamentarium against this disease. H. Loong et al. in their review summarize the historical progress and recent clinical developments of anti-EGFR therapies in the treatment of metastatic CRC and discuss the novel strategies of targeting the EGFR pathway to improve efficacy as well as ongoing research in identifying specific molecular predictors of response. While the approved use of drugs like the dual kinase inhibitor Lapatinib represents significant advances in the clinical management of breast cancer, confirmatory studies must be considered to foster the use of anti-EGFR therapies including safety, pharmacokinetics, and clinical efficacy in this common cancer. The article by J. Flynn et al. reviews the mechanism of anti-EGFR therapy in breast cancer and summarizes recent advances including the development of improved high-throughput analyses for identifying novel anti-EGFR activity, as well as advances in DNA/RNA-microarray technology for classification purposes, which will contribute to the overall understanding and development of targeted therapy in treatment of breast cancer. Cancers of the esophagus and stomach present a major health burden worldwide. The impact of cytotoxic agents on the disease has been modest. EGFR pathway has also been implicated in pathophysiology of esophageal and stomach cancers. Recently EGFR inhibitors have been explored in patients with esophageal and gastric cancers, and the results are summarized by T. Dragovich and C. Campen in their review. It also appears that tumors of the distal esophagus and gastroesophageal junction are more sensitive to EGFR blockade than distal gastric adenocarcinoma. Similar to cytotoxic agenst, drug resistance remains an important issue and research field in targeted therapy. The article by J. Rolff et al. studied the impact of different resistance markers at protein and mRNA level in patient-derived nonsmall cell lung cancer xenografts in response to erlotinib and other cytotoxic agents. The results suggest that the expression levels of multidrug resistant proteins and mRNA do not play an important role in the drug resistance of nonsmall cell lung cancer. Increased transforming growth factor-β (TGF-β) expression and EGFR amplification accompany the emergence of highly aggressive human carcinomas, and cooperative signaling between these two growth factor/receptor systems promotes cell migration and synthesis of stromal remodeling factors that in turn regulate tumor invasion, neo-angiogenesis and inflammation. R. Samarakoon et al. studied the role of plasminogen activator inhibitor-1 in carcinogensis and explored its potential role as a novel therapeutic target in combination with EGFR inhibition. We hope that this special issue will stimulate interests and new researches in the development of anti-EGFR therapy in cancers, particularly the development of personalized medicine based on predictive biomarkers so that therapy can be tailored and optimized in every patient. Daniel Chua Peter Fasching Brigette Ma Sumitra Thongprasert Lori Wirth

The place of targeted therapies in the management of non-small cell bronchial carcinoma: Target therapies in lung cancer management

Epidermal growth factor receptor (EGFR) inhibitors are highly effective in treating non-small cell lung cancers (NSCLC) expressing activated EGFR, particularly those harboring EGFR mutations. However, most patients who benefit from EGFR inhibitors achieve only partial responses or stable disease, facilitating the emergence of resistance. Thus, progression-free survival advantages in responding patients are modest. Combination therapy, preferably using agents with synergistic activity, could both improve responses and reduce acquired resistance rates. We hypothesized that combining MEK inhibitors with EGFR inhibitors could result in such a benefit. The MAPK pathway lies downstream of EGFR and transduces both proliferative and survival signals in a variety of cancer types. Inhibitors of this pathway are currently in clinical trials, but little evidence exists supporting the use of these agents as monotherapy in EGFR-dependent non-small cell lung cancer. In this study, we find EGFR-dependent NSCLC cell lines are moderately sensitive to loss of ERK1/2 activity, either by small molecule inhibition or by siRNA knockdown. The consequence of inhibition is dependent upon the trophic content of the culture media, primarily anti-proliferative in serum-rich conditions and pro-apoptotic in serum-poor conditions. However, when ERK inhibition combined with EGFR inhibitors, cytotoxic synergy was observed for all EGFR-dependent cell lines tested in serum-containing media. Enhanced cytotoxicity is demonstrated in cell lines with and without EGFR mutations, including those harboring the T790M escape mutation. These findings support future clinical studies that combine EGFR- and MEK1/2-targeted agents to investigate whether improved outcomes can be achieved in clinically screened EGFR-dependent NSCLC.

Epidermal growth factor receptor (EGFR) related therapies - mainly tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib, but also monoclonal antibodies targeting EGFR, for example, cetuximab - have been investigated in numerous settings in non-small cell lung cancer (NSCLC) and in different combinations. The overall clinical benefit of EGFR TKI therapy is roughly 10-30%, with higher benefit in nonsmoker Asiatic women with EGFR-mutated adenocarcinoma. Currently, there are several biomarkers that are able to direct and predict the yield of EGFR-related therapies in NSCLC. These include EGFR mutation status, EGFR protein expression, EGFR gene copy number and a serum proteomic marker (Veristrat®, Biodesix; CO). The usage of such biomarkers is important from many aspects. First, it helps clinicians to make the right treatment decisions and second, it leads to a wiser usage of financial resources. This review will focus on EGFR-related biomarkers for their prognostic power and their ability to predict clinical benefit from EGFR-related therapy.

Tyrosine Kinase Inhibitors and Epidermal Growth Factor Receptor (EGFR) Mutations in Non-Small Cell Lung Cancer

Commentary: Another win for immunotherapy