Clinical Trials In Non-small Cell Lung Cancer Research Articles

The effect of gefitinib in patients with postoperative recurrent non-small cell lung cancer harboring mutations of the epidermal growth factor receptor.

It is unclear whether there is a difference in the effect of gefitinib treatment between patients with postoperative recurrent non-small cell lung cancer (NSCLC) and those with stage IV NSCLC harboring mutations in the epidermal growth factor receptor (EGFR). We retrospectively reviewed the medical records of consecutive patients with postoperative recurrent NSCLC (postoperative group) or stage IV NSCLC (stage IV group) harboring EGFR mutations who were treated with gefitinib at the Shizuoka Cancer Center between September 2002 and March 2012 to compare the effect of gefitinib on survival from treatment initiation. A total of 168 patients were treated with gefitinib (postoperative group, 49 patients; stage IV group, 119 patients). The response rate of gefitinib treatment in the postoperative group was similar to that in the stage IV group (58 vs. 61 %, p = 0.613). In contrast, median progression-free survival (PFS; 15.8 vs. 9.8 months, p < 0.001) and median overall survival (OS; 51.1 vs. 22.2 months, p < 0.001) were significantly longer in the postoperative group. In addition, postoperative recurrent disease, performance status (0-1), and a single metastatic organ were independent favorable prognostic factors in the multivariate analysis of survival. PFS and OS were superior in patients with postoperative recurrent NSCLC harboring EGFR mutations treated by gefitinib than in those with stage IV disease. These results suggest that postoperative recurrent disease may be considered a stratification factor in clinical trials for NSCLC with EGFR mutations.

O3-9-1 - Weekly Paclitaxel in Combination with Bevacizumab in Patients with Non-Sq Nsclc Who Have Failed Previous Treatments

Backgrounds: Bevacizumab (BEV) in combination with paclitaxel (PTX) and carboplatin (Cb) has provided survival benefit for advanced non-small cell lung cancer (NSCLC) as first-line treatment. However, tri-weekly PTX therapy induce severe peripheral neuropathy frequently, and may deteriorate quality of life. Because of this toxicity, platinum plus pemetrexed regimen may be preferred as first-line treatment over Cb/PTX/BEV regimen. Weekly paclitaxel (w-PTX) regimen has proved to be effective and safe in a large number of clinical trials for advanced solid tumors. However, few clinical studies have focused on the comparison between w-PTX and tri-weekly PTX in advanced NSCLC. We previously reported that fractionated administration of paclitaxel may be less toxic and more active against advanced NSCLC in clinical trials. Furthermore, several studies have reported that combination chemotherapy of w-PTX and BEV proved survival benefit in patients with advanced breast cancer. Therefore, we conducted a phase II trial to evaluate the efficacy and toxicity for the combination chemotherapy of w-PTX and BEV in patients with advanced non-squamous (non-Sq) NSCLC who have failed previous treatment.Methods: Eligibility required ECOG performance status 0-2 and prior cytotoxic chemotherapy. The primary end point of the phase II study was the progression free survival (PFS). PTX was infused on days 1, 8 and 15, and BEV (15 mg/kg) was administered on day 1 of a 4-week cycle until PD. Toxicity evaluations were based on CTCAE (version 4).Results: Between September 2011 and January 2014 a total of 30 eligible patients were enrolled onto the study.Conclusions: This combination of w-PTX and BEV is both feasible and active in the treatment of patients with advanced non-Sq NSCLC. We will soon start a phase II study evaluating this combination as first-line treatment.

Abstract 3114: Targeting MET in preclinical models to support the clinical development of Volitinib in NSCLC

Abstract MET is a transmembrane tyrosine kinase receptor that is deregulated (gene amplification, mutation and over-expression) across multiple cancer types. Signaling through MET is normally activated through interactions with its specific ligand, hepatocyte growth factor (HGF). Aberrant MET/HGF activation can stimulate tumor growth, promote angiogenesis, induce metastasis and may contribute to resistance mechanisms in several tumor types. Several non-selective MET inhibitors have entered clinical development; results have been mixed based on potency, selectivity, and/or patient selection. Volitinib is a potent (IC50 4 nM) and selective (&amp;gt;650 fold selectivity over 265 kinases), small molecule inhibitor of MET. Recent evaluation of Volitinib across a panel of cancer cell lines demonstrated selectivity for MET-driven disease, with MET amplified cell lines being most sensitive (IC50s of 1nM) and also suggesting limited off target activity. Volitinib resistant cell lines with MET amplification were identified and used to better understand the relationship of concurrent mutations with response. In addition to cancer cell line selectivity, we are analyzing preclinical models of NSCLC (non small cell lung cancer) that are representative of key patient segments, namely MET amplification and over expression. In newly diagnosed NSCLC adenocarcinomas, focal MET amplification events represent ∼3% of the population while over expression of MET (without gene amplification) is observed in the majority of patients. In preclinical models, focal Met amplification in EBC-1 and NCI-H1993 caused significant tumor growth inhibition, confirming sensitivity to Volitinib. Given the prevalence of over expression in NSCLC, however, we sought to build a platform of evidence for the therapeutic use of Volitinib in preclinical models lacking amplification of the MET gene. Using a patient-derived xenograft model (PDX) of EGFR WT, KRAS WT and metastatic NSCLC disease (HLXF-036LN), we demonstrate that Volitinib induces tumor regression as monotherapy and has added therapeutic benefit when used in combination with taxotere. In addition, we show robust efficacy effects for additional preclinical models, LG0567, LG0645 and Calu-3, for either Volitinib alone or in combination with taxotere. In parallel pharmacodynamic studies, we demonstrate that Volitinib inhibits p-MET and downstream signaling in each model. Together, using an integrated platform of molecular characterization and MET FISH and IHC scores, corresponding antitumor responses to Volitinib are being evaluated for several patient segments. We are using these studies to inform the design of patient selection criteria for upcoming clinical trials in NSCLC. Citation Format: Celina D'Cruz, Melanie Frigault, Ammar Adam, Minhui Shen, Garry Beran, Evan Barry, Paul Gavine, Yongxin Ren, Shiming Fan, Feng Zhou, Weiguo Qing, Mike Zinda, Weiguo Su, Edwin Clark. Targeting MET in preclinical models to support the clinical development of Volitinib in NSCLC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3114. doi:10.1158/1538-7445.AM2014-3114

The changing landscape of phase II/III metastatic NSCLC clinical trials and the importance of biomarker selection criteria.

Over the last decade, new cytotoxic treatments and targeted therapies have altered treatment paradigms for patients with metastatic non-small cell lung cancer (NSCLC). We sought to analyze the impact of histology and biomarker selection criteria on outcomes of clinical trials in metastatic NSCLC reported over the last decade at the American Society of Clinical Oncology (ASCO) Annual Meeting. Data were collected from ASCO abstracts of Phase II-IV clinical trials for patients with metastatic NSCLC from 2004-2014. 770 of 2,989 identified metastatic NSCLC category abstracts met selection criteria. Despite a decline in the number of abstracts from 107 to 46 abstracts annually over this period, the proportion of trials with positive progression free survival (PFS) and overall survival (OS) outcomes has increased significantly. Trials with histology selection (6%) or molecular biomarker (15%) criteria were more likely to result in an improvement in PFS than those without selection criteria (21% vs. 8%, p = 0.0001 and 31% vs. 10%, p < 0.0001, respectively). These data demonstrate profound changes in the clinical trial landscape over the last 10 years with significantly increasing proportion of trials with positive outcomes. These changes are likely attributed to the use of histology and biomarker selection criteria in clinical trial design.

Beyond chemotherapy and targeted therapy: adoptive cellular therapy in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is an intractable disease for which effective treatment approaches are urgently needed. The ability to induce antigen-specific immune responses in patients with lung cancer has led to the development of immunotherapy as a novel concept for the treatment of NSCLC. Adoptive cellular therapy (ACT) represents an important advancement in cancer immunotherapy with the utilization of tumor infiltrating lymphocytes, cytokine-induced killer cells, natural killer cells and γδ T cells. In this study, we review recent advances in ACT for NSCLC in clinical trials and provide a perspective on the improvement in ACT and potential therapeutic approaches using engineered T cell therapy for NSCLC.

Relationship between progression-free survival and overall survival in patients with advanced non-small cell lung cancer treated with anticancer agents after first-line treatment failure.

The hazard ratio of progression-free survival (PFS-HR) generally does not reflect that of overall survival (OS-HR) in advanced non-small cell lung cancer (NSCLC) patients treated with first-line therapy. Short survival post-progression (SPP) better reflects the PFS-HR and OS-HR in simulations. We aimed to evaluate whether the PFS-HR reflects the OS-HR in NSCLC clinical trials for post-first-line treatments. We reviewed clinical studies of post-first-line anticancer agents for NSCLC. We examined the sample size of the experimental arm (EA), median PFS (mPFS) or median time to progression in the EA, median overall survival (mOS) in the EA, the PFS-HR and the OS-HR. SPP was defined as the difference between mOS and mPFS. The association between mPFS and SPP, mPFS and mOS, and the PFS-HR and OS-HR was tested. We sought for the optimal point of correlation of PFS-HR and OS-HR by every 1 month of SPP. We identified 32 trials (34 arms). mPFS and mOS were weakly correlated (correlation coefficient [r] = 0.376; P = 0.0286). The PFS-HR and OS-HR were also moderately correlated (r = 0.415; P = 0.015). The maximum r value was 0.770 (SPP < 6 months; P < 0.0001) when we tested the associations between the PFS-HR and OS-HR for SPP using 1-month increments. The estimated regression equation at this point was OS-HR = 0.679 × (PFS-HR) + 0.349. The PFS-HR and OS-HR were strongly correlated in advanced NSCLC patients treated with post-first-line anticancer agents, with a SPP of less than 6 months.

Setting the Bar for Therapeutic Trials in Non–Small-Cell Lung Cancer: How Low Can We Go?

Setting the Bar for Therapeutic Trials in Non–Small-Cell Lung Cancer: How Low Can We Go?

Rapamycin downregulates thymidylate synthase and potentiates the activity of pemetrexed in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancer cases, and almost half of newly diagnosed patients have metastatic disease. Pemetrexed is a widely used drug for NSCLC and inhibits several folate-dependent enzymes including thymidylate synthase (TS). Increased expression of TS confers resistance to pemetrexed in vitro and predicts poor response to pemetrexed. Rapamycin is an mTOR inhibitor and suppresses cap-dependent synthesis of specific mRNA species. Here, we show that the combination of rapamycin and pemetrexed synergistically inhibits proliferation of NSCLC cells. Although pemetrexed as a single agent induced TS, pretreatment with rapamycin suppressed pemetrexed-induced TS expression. In vivo, the combination of rapamycin and pemetrexed inhibited growth of NSCLC xenografts, which correlated with decreased mTOR activity and suppression of pemetrexed-induced TS expression. The ability of rapamycin to enhance the efficacy of pemetrexed and prevent TS expression has implications for the design of Phase I and/or Phase II NSCLC clinical trials with mTOR inhibitors in combination with pemetrexed.

C-Met: A Potential Target for Current Non-Small-Cell Lung Cancer Therapeutics

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. In early stages of NSCLC tumor development (stage I/II), surgical resection is often performed; however, when the cancer becomes metastatic, chemotherapy is most commonly implemented. Due to the fact that traditional chemotherapies result in adverse and cytotoxic effects on healthy cells in addition to NSCLC cells, targeted therapeutics have been extensively developed over recent years to combat the disease. These targeted therapies include small molecule inhibitors and monoclonal antibodies (MAbs), some of which are used as first-line treatments for NSCLC patients. Several inhibitors against the mesenchymal-epithelial transition factor (c-Met), and its ligand hepatocyte growth factor (HGF), have shown promising results in NSCLC clinical trials. For example, crizotinib, a multi-kinase inhibitor has been approved by the FDA for the treatment of ALK positive NSCLC. c-Met is known to be overexpressed, mutated and gene amplified, specifically in NSCLC, and has also been implicated in the development of resistance against other small-molecule inhibitors (e.g. EGFR). Thus, this review will discuss the current developments and usages of c-Met inhibitors in NSCLC, and their potential for future therapeutic advancement.

Evaluation of Contemporary Platinum-Doublet Chemotherapy-Modified dose and Schedules

329 ISSN 1758-1966 10.2217/LMT.13.38 © 2013 Future Medicine Ltd Lung Cancer Manage. (2013) 2(5), 329–332 Often in clinical practice, dose modifications in the form of dose reductions or delays are warranted in response to treatment-related toxicity with systemic therapy administration [1,2]. However, this practice may raise concern about its impact on therapeutic benefit. Current guidelines from the National Comprehensive Cancer Network favor administration of systemic therapy (depending on the line) for patients with advanced-stage nonsmall-cell lung cancer (NSCLC) in good performance status, independent of their age. NSCLC clinical trials have primarily focused on testing new regimens rather than evaluating the impact of maintaining the delivery of dose and schedule of standard chemotherapy regimens. Overall survival (OS) is the primary measure of treatment efficacy, but other end points, such as progression-free survival (PFS) and clinical benefit, should be considered in advanced disease. Even with the recent development of several active molecularly targeted agents for the treatment of NSCLC, systemic cytotoxic chemotherapy still plays a role in disease palliation. In this editorial, we review contemporary clinical trials of platinum-doublet chemotherapy comparing dose and schedules, evaluating their impact on survival and tolerability, and the potential impact these may play in routine clinical practice. We searched PubMed for clinical trials published since 2003 and focused on randomized trials comparing platinum-doublet regimens where the difference between the arms were either dose, schedule or a substitution of carboplatin for cisplatin. For the purposes of this editorial, we have summarized eight representative randomized trials that fit these criteria. Four of these studies evaluated the platinum plus gemcitabine doublet, two studies evaluated the platinum plus paclitaxel doublet and one study evaluated cisplatin and vinorelbine, and cisplatin and docetaxel.

LKB1/AMPK/mTOR Signaling Pathway in Non-small-cell Lung Cancer

Links between cancer and metabolism have been suggested for a long time but compelling evidence for this hypothesis came from the recent molecular characterization of the LKB1/AMPK signaling pathway as a tumor suppressor axis. Besides the discovery of somatic mutations in the LKB1 gene in certain type of cancers, a critical emerging point was that the LKB1/AMPK axis remains generally functional and could be stimulated by pharmacological molecules such as metformin in cancer cells. In addition, AMPK plays a central role in the control of cell growth, proliferation and autophagy through the regulation of mTOR activity, which is consistently deregulated in cancer cells. Targeting of AMPK/mTOR is thus an attractive strategy in the development of therapeutic agents against non-small-cell lung cancer (NSCLC). In this review, the LKB1/AMPK/mTOR signaling pathway is described, highlighting its protective role, and opportunities for therapeutic intervention, and clinical trials in NSCLC.

Non-small cell lung cancer - genetic predictors

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer that is the leading cause of cancer-related mortality worldwide. Several predictive markers have been found in NSCLC patients to date but only a few are currently used for tailored therapy. PubMed and Web of Science online databases were used to search review and original articles on the most important predictive markers in NSCLC. EGFR activating mutations (exons 18 to 21) and EML4-ALK rearrangement are clinically important markers able to select NSCLC patients which benefit from EGFR or ALK tyrosine kinase inhibitors (gefitinib, erlotinib, crizotinib). Other markers, such as KRAS mutation, EGFR T790M mutation and C-MET amplification, are responsible for resistance to these inhibitors. Overcoming of this resistance as well as discovery of new potential markers and inhibitors is the main goal of ongoing research and clinical trials in NSCLC.

Multi-Level Targeting of the Phosphatidylinositol-3-Kinase Pathway in Non-Small Cell Lung Cancer Cells

IntroductionWe assessed expression of p85 and p110α PI3K subunits in non-small cell lung cancer (NSCLC) specimens and the association with mTOR expression, and studied effects of targeting the PI3K/AKT/mTOR pathway in NSCLC cell lines.MethodsUsing Automated Quantitative Analysis we quantified expression of PI3K subunits in two cohorts of 190 and 168 NSCLC specimens and correlated it with mTOR expression. We studied effects of two PI3K inhibitors, LY294002 and NVP-BKM120, alone and in combination with rapamycin in 6 NSCLC cell lines. We assessed activity of a dual PI3K/mTOR inhibitor, NVP-BEZ235 alone and with an EGFR inhibitor.Resultsp85 and p110α tend to be co-expressed (p<0.001); p85 expression was higher in adenocarcinomas than squamous cell carcinomas. High p85 expression was associated with advanced stage and poor survival. p110α expression correlated with mTOR (ρ = 0.276). In six NSCLC cell lines, addition of rapamycin to LY294002 or NVP-BKM120 was synergistic. Even very low rapamycin concentrations (1 nM) resulted in sensitization to PI3K inhibitors. NVP-BEZ235 was highly active in NSCLC cell lines with IC50s in the nanomolar range and resultant down-regulation of pAKT and pP70S6K. Adding Erlotinib to NVP-BEZ235 resulted in synergistic growth inhibition.ConclusionsThe association between PI3K expression, advanced stage and survival in NSCLC suggests that it might be a valuable drug target. Concurrent inhibition of PI3K and mTOR is synergistic in vitro, and a dual PI3K/mTOR inhibitor was highly active. Adding EGFR inhibition resulted in further growth inhibition. Targeting the PI3K/AKT/mTOR pathway at multiple levels should be tested in clinical trials for NSCLC.

2010 Consensus on Lung Cancer, new clinical recommendations and current status of biomarker assessment — First-line therapy

Lung cancer is the most common cancer in the world, and by 2008, there were an estimated 1.6 million new cases, representing 12.7% of all new cancers. It was also the most common cause of death from cancer, with 1.3 million deaths (18.2% of the total) [1]. Every year, in Europe, more than 200,000 new cancer cases are diagnosed, accounting for around 20% of all cancer deaths [2]. Non-small cell lung cancer (NSCLC), including squamous carcinoma, adenocarcinoma and large cell carcinoma, accounts for about 85% of all lung cancer types. The majority of patients diagnosed with NSCLC are unsuitable for surgery since most of them have advanced disease at diagnosis. Unfortunately, in this setting, the prognosis is very poor with a five-year survival <1% and palliative chemotherapy and/or radiotherapy being the standard of care, with the main endpoints represented by the improvement of survival and the relief of disease symptoms. However, chemotherapeutic agents at this stage of the disease seem to have reached a plateau with no doublet combination having a clinically superior result compared with the others [3–5]. These plateaux of effectiveness have led to an increase in the research into understanding cancer biology, with major progress made in recent years towards the mechanisms of oncogenesis, which has allowed the development of novel therapeutic agents that specifically target growth factor pathways dysregulated in tumour cells. Targeting the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways has played a central role in advancing NSCLC research, treatment, and patients’ outcome over the last few years. Several targeted agents have been introduced in clinical trials in NSCLC and a series of phase 3 studies have already produced definitive results with some new biological agents already being used in clinical practice. Retrospective analyses and subsequent prospective studies have taught us how to identify patients who can most benefit from this therapy. All these developments have led to a better definition of the first-line approach, addressing the treatment on the basis of clinical (smoker status, sex, age, performance status [PS] and ethnicity), histological (squamous and non-squamous) and biological (EGFR mutation status) characteristics of patients. Here we will discuss the new evidence in the first-line treatment of advanced NSCLC, focussing in particular on the role of patients and tumour characteristics in the current clinical decision-making.

Insulin-like growth factor receptor-1 (IGF1R) and epidermal growth factor receptor (EGFR) amplification and expression in surgically resected NSCLC.

10519 Background: IGF1R represents a novel molecular target in non-small cell lung cancer (NSCLC). IGF1R and EGFR activation is essential to mediate tumor cell survival, proliferation and invasion. This study investigates the prognostic role of IGF1R and EGFR copy number gain (CNG) by fluorescence in situ hybridization (FISH) and protein overexpression by immunohistochemistry (IHC) in surgically resected NSCLC. Methods: 114 NSCLC patients were evaluated; median age was 66y (range 40–84), Male/Female:96/18; squamous (SCC)/adeno/BAC/other:59/34/9/12; smoker/never smoker:105/9, and stage I/II/III:71/18/25. IGF1R and EGFR FISH were tested by customized and commercial probes, respectively; positive specimens showed gene amplification or polysomy (≥4 copies in ≥10% of tumor cells). IGF1R and EGFR protein expression were evaluated using mouse antibodies (clones 24-31 and 3147, respectively); overexpression was defined by ≥10% positive cells. Kaplan-Meier estimates of survival and time to recurrence were calculated for clinical and biologic variables using Cox model for multivariate analysis. Results: 46 tumors (40%) were IGF1R FISH+ and 76 (77%) were EGFR FISH+. IGF1R FISH+ was associated with EGFR FISH+ (p=0.03) and co-amplification was observed in 34 cases (30%). IGF1R and EGFR FISH+ were associated with SCC (p=0.01 and p=0.05, respectively). IGF1R and EGFR overexpression was detected in 36% and 55% of NSCLC patients and co-expression was detected in 25%. Co-amplification and co-expression of both receptors were significantly associated (p=0.045). IGF1R and EGFR co-amplification and co-expression associated with shorter disease free survival (DFS; p=0.05, p=0.05 respectively), also at multivariate analysis adjusting for stage (p=0.0002). Conclusions: IGF1R and EGFR are frequently co-amplified in NSCLC and CNG correlates with protein overexpression. Both co-amplification and co-expression of IGF1R and EGFR predicts shorter DFS. These results provide a strong rational for targeting simultaneously EGFR and IGF1R in clinical trials for NSCLC. We thank the Italian Association for Cancer Research (AIRC) for supporting the study (AF Fellowship).

Optimal Management of Patients with Non-Small Cell Lung Cancer and Epidermal Growth Factor Receptor Mutations

In recent years, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, which have promising activity and a favourable toxicity profile, have been used in the management of advanced non-small cell lung cancer (NSCLC). The knowledge that EGFR-activating mutations confer sensitivity to EGFR TKIs has led to the design and analysis of phase II and III studies of gefitinib or erlotinib treatment in various clinical scenarios. We review the important NSCLC clinical trials of the efficacy of EGFR TKIs in the context of EGFR-activating mutations. In all phase II single-arm studies or phase III randomized comparative studies, EGFR TKIs as monotherapy were superior to combination chemotherapy in terms of response rate and progression-free survival in patients with activating EGFR mutations. EGFR TKIs have contributed to the superior overall survival time in NSCLC patients with EGFR mutations compared with those patients without EGFR mutations. The results of these studies have led to a paradigm shift in the treatment of patients with advanced NSCLC. NSCLC with EGFR mutations constitutes a new entity requiring different personalized treatment strategies.

Review of Ongoing Clinical Trials in Non-small Cell Lung Cancer: A Status Report for 2009 from the ClinicalTrials.gov Website

Several new agents are being tested in clinical trials for patients with non-small cell lung cancer (NSCLC). A survey of ongoing clinical trials in NSCLC in the ClinicalTrials.gov website would help identify areas that require further attention in the future. We conducted a survey of ongoing clinical trials on NSCLC registered in the ClinicalTrials.gov website. The advanced search option was applied using the terms "non small cell lung cancer," "open studies," "interventional," and "adults 18 years or older." Of the 493 eligible trials, 77 (15.6%) were phase III, 92 (18.7%) were phase I, and 240 (48.7%) were phase II trials. Universities were listed as the primary sponsor for 224 (45.4%) trials and pharmaceutical industry for 166 (33.7%) trials. Majority of the trials were multicenter studies (56.8%) and were being conducted exclusively within the United States (51.3%). A large proportion of phase II and III clinical trials (77.2%) were focused on patients with advanced-stage disease. The most frequently used end points were progression-free survival (27.1%) followed by tumor response rate (22.9%) and overall survival (16.6%). Although biomarker analysis was included in 185 (37.5%) trials, only 39 (7.9%) trials used biomarkers for patient selection. Progression-free survival is the end point most commonly used to assess the effectiveness of experimental regimens, and biomarker-based patient selection is rarely used in ongoing clinical trials for NSCLC.

Current status of vandetanib (ZD6474) in the treatment of non-small cell lung cancer.

Vandetanib (ZD6474) is an oral small molecule inhibitor of multiple intracellular receptor kinases, including the vascular endothelial growth factor receptor (VEGFR) -2 and epidermal growth factor receptor (EGFR). Both VEGFR and EGFR pathways have emerged as instrumental in the growth and metastasis of multiple malignancies, including non-small cell lung cancer (NSCLC). Indeed, inhibitors of each pathway have been approved by the US Food and Drug Administration for use in advanced NSCLC. As there is considerable cross talk between these pathways, dual inhibition with such agents has become an attractive strategy, with encouraging Phase II clinical trial data to date. The convenience of one oral agent targeting both pathways is clear, and clinical trials have established the maximum tolerated daily dose of vandetanib, with data from randomized Phase III trials emerging. This report will review completed and ongoing NSCLC clinical trials evaluating vandetanib, and speculate on the future of this agent in NSCLC.

Abstract 3483: Combining the multi-targeted tyrosine kinase inhibitor, vandetanib, with fulvestrant results in enhanced anti-tumorigenic effects for lung cancer

Abstract Current average survival after a lung cancer diagnosis is only 8-12 months, with a 5-year survival rate of 15% with best available first-line chemotherapy regimens. Thus, innovative approaches to treat lung cancer utilizing molecular targets are necessary. We have previously shown that epidermal growth factor receptor (EGFR) and estrogen receptor β (ERβ) are present in non-small cell lung cancer (NSCLC) and show a functional interaction. This interaction provided the foundation for combinatorial targeting strategies incorporating anti-estrogens into NSCLC treatment in combination with growth factor signaling pathway inhibitors. Vandetanib is a multi-targeted receptor tyrosine kinase inhibitor that potently inhibits vascular endothelial growth factor receptor-2 (VEGFR-2) and shows additional inhibitory activity against Flt-4 (VEGFR-3) and EGFR tyrosine kinases. This inhibitor may be beneficial in tumors that are dependent upon VEGF-mediated angiogenesis or EGF mediated tumor growth and has shown promising anti-tumor activity in NSCLC in clinical trials. We demonstrated that NSCLC cells significantly secrete VEGF protein over time in culture (p&amp;lt;0.001) and that production of VEGF mRNA and protein can be stimulated 2- to 3-fold with 10nM estrogen (p&amp;lt;0.001), suggesting an interaction between the estrogen and VEGF signaling pathways. To confirm this interaction, we showed that vandetanib completely abolished estrogen-induced P-MAPK signaling. Furthermore, long-term treatment of NSCLC cells in culture with 2.5µM vandetanib resulted in a 7.2-fold up-regulation of ERβ expression. These data provide rationale to combine an ER inhibitor with vandetanib to interfere with cross-talk between multiple interdependent growth-stimulatory pathways. The combination of vandetanib (1.25µM) with fulvestrant (5µM) was found to maximally inhibit cell growth of NSCLC cells compared to single agents in vitro (p&amp;lt;0.0001). In an in vivo lung tumor xenograft model, the vandetanib (12.5mg/kg, once-daily p.o)/fulvestrant (30mg/kg, twice-weekly, s.c.) combination decreased tumor volume in athymic nude mice by 64% compared to 51% and 23% for vandetanib and fulvestrant treatment alone, respectively. Antitumor effects of the combination therapy were accompanied by statistically significant increases (up to 2.5-fold) in apoptotic cells in the tumors from the combination treatment group compared to single agent treatment groups. Vandetanib can inhibit EGFR and VEGFR-3, which are expressed on lung tumor cells themselves, while effects inhibiting VEGFR-2 occur on tumor blood vessels that can respond to VEGF by the tumor. The combination of vandetanib and fulvestrant should have clinical efficacy for NSCLC patients. A phase I clinical trial of this combination in lung cancer is planned. This work was supported by P50 CA090440 SPORE in Lung Cancer, to JMS. 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 3483.

Epidermal Growth Factor Receptor Signaling in Nonsmall Cell Lung Cancer

ABSTRACTEpidermal growth factor is a 170-kd protein that binds to a specific tyrosine kinase receptor, epidermal growth factor receptor (EGFR), on the cell surface. EGFR function is dysregulated in various malignancies including nonsmall cell lung cancer (NSCLC) leading to activation of several signal transduction pathways including K-RAS, PIK3, and STAT3 and STAT5, that promote cell cycle progression, proliferation, invasion, angiogenesis, and inhibit apoptosis. EGFR overexpression is seen in a majority of cases of NSCLC, but its prognostic role is controversial. EGFR inhibitors currently undergoing clinical trials in NSCLC include monoclonal antibodies or small molecule tyrosine kinase inhibitors. The only EGFR inhibitor currently approved for the treatment of NSCLC is erlotinib, a small molecule tyrosine kinase inhibitor. Although women, nonsmokers, patients with adenocarcinoma and patients with Asian ethnicity seem to have better outcomes with erlotinib, the factors predictive for response to these agents are currently the focus of investigation.