Efficacy In Non-small Cell Lung Cancer Research Articles

Phase II study of danusertib (D) in advanced/metastatic non-small cell lung cancers (NSCLC).

e19138 Background: D is an ATP competitive pan-aurora kinases inhibitor with activity also against FGFRs, VEGFR, Ret, TrkA, Scr, and Abl. Methods: Eligible pts had NSCLC progressing for advanced/metastatic disease after 1 prior chemotherapy line (CT). Primary endpoint was progression-free survival at 4 months (PFS-4) evaluated in a Simon two-stage design. Number of successes required for not rejecting the alternative hypothesis (40% PFS-4) was ≥4/19 evaluable pts while the number of successes required to reject at the end of stage 2 the null hypothesis (20% PFS-4) was ≥11/36 (α 1-sided = 0.1). D was administered at 500 mg/m² as 24 hr IV infusion q2w. The expression of Aurora A/B, TPX-2, MDR, Scr, Survivin by IHC and the amplification of FGFR1 by FISH on tumor biopsies of consenting pts were evaluated. Results: 3 out of 19 evaluable pts were PFS-4 at the end of the 1st stage, thus precluding passage to the 2nd stage. Interestingly, in pts with squamous (SCC) (n=7), median PFS and OS were 6.4 and 10.6 mos respectively (vs. 2.2 and 7.6 mos, in non-SCC pts), suggesting a possible specific effect in this subtype. Additional pts with SCC were therefore treated under a protocol amendment. At the end of this 2nd stage, 5/31 evaluable SCC pts (80% CI: 0.08-0.28) were PFS-4 indicating that the predefined threshold required to conclude for activity would not have been reached. Overall 56 pts, all histology NSCLC, were treated: median age 62 yrs (39-79), 64% male, 70% SCC, 36% with >1 prior CT. Best response was a PR in 1 pt and SD in 20 pts; median PFS and OS were 2.1 and 8.3 mos respectively. The most frequent drug-related AEs (any Grade, ≥20%) were: uncomplicated and short lasting neutropenia (94%), nausea (39%), fatigue (37%), asthenia (30%), anorexia and diarrhea (29%), alopecia (23%). Histological analyses by IHC and FISH is still ongoing: results will be presented. Conclusions: Limited evidence of activity was observed, insufficient to meet the predefined threshold to call efficacy in NSCLC when D was administered as monotherapy at this dose/schedule. D confirmed to have a manageable safety profile. Clinical trial information: 2006-003772-35.

Serum APE1 Autoantibodies: A Novel Potential Tumor Marker and Predictor of Chemotherapeutic Efficacy in Non-Small Cell Lung Cancer

Apurinic/apyrimidinic endonuclease 1 (APE1), which has the dual functions of both DNA repair and redox activity, has been reported to be highly expressed in non-small cell lung cancer (NSCLC), and this appears to be a characteristic related to chemotherapy resistance. In this study, we identified serum APE1 autoantibodies (APE1-AAbs) in NSCLC patients and healthy controls by immunoblotting and investigated the expression of APE1-AAbs by indirect ELISA from the serum of 292 NSCLC patients and 300 healthy controls. In addition, serum APE1-AAbs level alterations of 91 patients were monitored before and after chemotherapy. Our results showed that serum APE1-AAbs can be detected in both NSCLC patients and healthy controls. Serum APE1-AAbs were significantly higher than those of healthy controls and closely related to APE1 antigen levels both in tumor tissues and the peripheral blood. Moreover, the change in levels of serum APE1-AAbs in NSCLC is closely associated with the response to chemotherapy. These results suggest that APE1-AAbs is a potential tumor marker and predictor of therapeutic efficacy in NSCLC.

Afatinib for the treatment of patients with EGFR-positive non-small cell lung cancer

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are valuable treatments for EGFR-mutated non-small cell lung cancer (NSCLC). Anti-EGFR antibodies are widely used in the treatment of head and neck squamous cell carcinomas (HNSCC) and in KRAS wild-type colorectal cancer. The first-generation, reversible EGFR inhibitors erlotinib and gefitinib in the first-line setting provide superior progression-free survival and quality of life compared to conventional chemotherapy in NSCLC harboring activating EGFR mutations. However, these therapies eventually fail and new options are needed. Afatinib is a novel irreversible inhibitor of the ErbB family members EGFR, tyrosine kinase-type cell surface receptors HER2 and HER4. It shows preclinical efficacy in NSCLC with common EGFR-activating mutations and the T790M mutation typically associated with EGFR TKI resistance. Preclinical activity is seen in other tumor types as well, including HNSCC. Clinically, afatinib has been evaluated in the broad-reaching LUX Lung trial program, with significant activity seen in the first and later-line settings. It is also under investigation in multiple other tumor types. This review will stress on afatinib's preclinical pharmacology, pharmacokinetics and clinical activity with a focus on NSCLC.

Anti-angiogenic agents in Non-Small-Cell Lung Cancer (NSCLC): a perspective on the MONET1 (Motesanib NSCLC Efficacy and Tolerability) study.

Since the discovery of the critical role played by angiogenesis in tumor growth and development (1), there has been increased interest in evaluating anti-angiogenic agents in the treatment of various malignancies, including non-small-cell lung cancer (NSCLC). Bevacizumab is a humanized monoclonal antibody to vascular endothelial growth factor (VEGF) and is approved for use in combination with chemotherapy in multiple countries for the treatment of patients with metastatic NSCLC.

Activation of IL-6R/JAK1/STAT3 Signaling Induces De Novo Resistance to Irreversible EGFR Inhibitors in Non–Small Cell Lung Cancer with T790M Resistance Mutation

The secondary T790M mutation in epidermal growth factor receptor (EGFR) is the major mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (TKI) in non-small cell lung cancer (NSCLC). Although irreversible EGFR TKIs, such as afatinib or dacomitinib, have been introduced to overcome the acquired resistance, they showed a limited efficacy in NSCLC with T790M. Herein, we identified the novel de novo resistance mechanism to irreversible EGFR TKIs in H1975 and PC9-GR cells, which are NSCLC cells with EGFR T790M. Afatinib activated interleukin-6 receptor (IL-6R)/JAK1/STAT3 signaling via autocrine IL-6 secretion in both cells. Inhibition of IL-6R/JAK1/STAT3 signaling pathway increased the sensitivity to afatinib. Cancer cells showed stronger STAT3 activation and enhanced resistance to afatinib in the presence of MRC5 lung fibroblasts. Blockade of IL-6R/JAK1 significantly increased the sensitivity to afatinib through inhibition of afatinib-induced STAT3 activation augmented by the interaction with fibroblasts, suggesting a critical role of paracrine IL-6R/JAK1/STAT3 loop between fibroblasts and cancer cells in the development of drug resistance. The enhancement of afatinib sensitivity by inhibition of IL-6R/JAK1/STAT3 signaling was confirmed in in vivo PC9-GR xenograft model. Similar to afatinib, de novo resistance to dacomitinib in H1975 and PC9-GR cells was also mediated by dacomitinib-induced JAK1/STAT3 activation. Taken together, these findings suggest that IL-6R/JAK1/STAT3 signaling can be a potential therapeutic target to enhance the efficacy of irreversible EGFR TKIs in patients with EGFR T790M.

EJ-1 - Epidermal Growth Factor Receptor Pathway in Non-Small-Cell Lung Cancer

ABSTRACT Although chemotherapy remains the standard of care for patients with advanced stage non-small-cell lung cancer (NSCLC) because of the modest improvement in survival and quality of life, its efficacy is at least modest and there is evidence that has already reached a plateau. The development of biological agents represents an opportunity in the treatment of advanced NSCLC either in combination with cytotoxic drugs or as a single-agent therapy, both in first- or second-line setting. Furthermore, on the basis of the established activity of some of these agents in NSCLC coupled with a reasonable toxicity profile, these drugs have recently been considered also for maintenance therapy. The epidermal growth factor receptor (EGFR) could be considered as one of the most relevant targets for cancer treatment: growth of human tumours is frequently related to aberrant cellular signalling by inappropriate activation of receptor tyrosine kinase via mutation, over expression or ectopic ligand production. Strategies to block such pathway include tyrosine kinase inhibitors (TKIs) and monoclonal antibodies. Erlotinib and gefitinib are two EGFR-TKIs active against NSCLC. Activating mutations in EGFR were initially described in 2004, when researchers found a very clear association between the presence of an EGFR-activating mutation and radiographic response to gefitinib. In contrast, patients without EGFR mutations had a very low likelihood of responding to gefitinib or erlotinib. The L858R mutation in exon 21 and a deletion of a conserved sequence in exon 19 represent the most commonly observed EGFR mutations. Experimental data indicate the oncogenic potential of EGFR mutations: for instance, the L858R mutation in exon 21, the G719S mutation in exon 18 and the insertion in exon 20 confer ligand-independent cellular transformation. Prospective and retrospective trials confirmed that the response rate to EGFR tyrosine kinase inhibitors (TKIs) in patients with EGFR mutations is up to 80% consistently associated with a significant improvement in time to progressive disease and patients with EGFR-mutated tumours have significantly longer survival than those with EGFR wild-type tumours. The same evidence does not apply to the monoclonal antibody cetuximab, which efficacy in NSCLC was recently demonstrated in one phase III study. The good tolerability profile of EGFR inhibitors make these agents suitable for maintenance setting, while sequencing of EGFR-TKIs and chemotherapy seems to be preferred.

Design of a phase III clinical trial with prospective biomarker validation: SWOG S0819.

The role of cetuximab in the treatment of advanced non-small cell lung cancer (NSCLC) is currently unclear. The molecular target of cetuximab, epidermal growth factor receptor (EGFR), as measured by FISH, has shown potential as a predictive biomarker for cetuximab efficacy in NSCLC. SWOG S0819 is a phase III trial evaluating both the value of cetuximab in this setting and EGFR FISH as a predictive biomarker. This work describes the decision process for determining the design and interim monitoring plan for S0819. Six possible designs were evaluated in terms of their properties and the hypotheses that can be addressed within the design constraints. A subgroup-focused, multiple-hypothesis design was selected for S0819 that incorporates coprimary endpoints to assess cetuximab in both the overall study population and among EGFR FISH-positive (FISH(+)) patients, with the sample size determined based on evaluation in the EGFR FISH(+) group. The chosen interim monitoring plan specifies interim evaluations of both efficacy and futility in the EGFR FISH(+) group alone. The futility-monitoring plan to determine early stopping in the EGFR FISH-nonpositive group is based on evaluation within the positive group, the entire study population, and the nonpositive group. SWOG S0819 uses a design that addresses both the biomarker-driven and general-efficacy objectives of this study.

Multitargeted Tyrosine Kinase Inhibitors in Unselected Patients With Advanced Non–Small-Cell Lung Cancer (NSCLC): Impressions From MONET (the Motesanib NSCLC Efficacy and Tolerability Study)

Angiogenesis is a complex and tightly regulated process that is defined as the growth of new blood vessels, especially those that supply oxygen and nutrients to cancerous tissue, from existing vasculature. Because of the critical role of angiogenesis in the growth and metastases from solid tumors, including non–small-cell lung cancer (NSCLC), its inhibition represents a rational therapeutic strategy. Vascular endothelial growth factor (VEGF) is a key ligand and regulator of both physiologic and pathologic angiogenesis, including that of tumors, with signaling occurring mainly through the VEGF receptor 2 (VEGFR-2). Bevacizumab, a humanized monoclonal antibody against circulating VEGF, was the first antiangiogenesis drug to enter clinical practice for NSCLC. Because of an increased risk of life-threatening bleeding among patients with squamous cell carcinoma in the phase II trial, subsequent trials were limited to nonsquamous histology. The addition of bevacizumab to chemotherapy was associated with improved response rate (RR) and progression-free survival (PFS) in two large randomized trials, Eastern Cooperative Oncology Group (ECOG) 4599 and Avastin in Lung (AVAiL), although only ECOG 4599 was associated with improved overall survival (OS). Unfortunately, the benefit from bevacizumab in patients with advanced NSCLC is modest and transient, with essentially all responding patients developing secondary resistance. One of the mechanisms that is implicated in the development of resistance is the stimulation of compensatory proangiogenic factors such as fibroblast growth factor and platelet-derived growth factor(PDFGR). Tyrosine kinase inhibitors (TKIs) compete with adenosine triphosphate for the active site of the kinase domain. Because of the well-conserved adenosine triphosphate binding sites of the kinases, many TKIs (unlike bevacizumab, which exclusively targets the VEGF ligand) inhibit multiple receptors. This ability to inhibit multiple angiogenesis pathways offers the potential for increased efficacy and decreased development of secondary resistance through redundant pathways. Nevertheless, the decreased specificity may be associated with increased toxicity. Given that single-agent TKIs directed against similar targets such as sorafenib (VEGF-R2, VEGFR-3, PDGFR, RAF-1, BRAF, c-KIT, FLT-3), sunitinib (VEGFR-2, PDGFR, FLT-3, c-KIT, RET), and axitinib (VEGFR-1, VEGFR-2, VEGFR-3, PDGFR, c-KIT) have been well tolerated in NSCLC, the next step would be to pursue their combination with chemotherapy or other biologic agents. Several randomized clinical trials comparing chemotherapy alone or with the addition of TKIs have been conducted (Table 1). In phase II studies, neither the addition of vandetanib nor cediranib improved the median PFS or OS compared with chemotherapy alone using carboplatin and paclitaxel. Lack of OS improvement was also observed in the two randomized phase III studies in the first-line setting, the Evaluation of Sorafenib, Carboplatin, and Paclitaxel Efficacy (ESCAPE) and NSCLC Research Experience Utilizing Sorafenib (NExUS), as well as in previously treated patients. Motesanib is a small-molecule targeted antagonist of VEGF receptors 1, 2, and 3, PDGFR, and KIT. In the phase IB study, five (17%) of 29 patients who were treated with motesanib (50 mg per day, 125 mg per day, or 75 mg twice per day) in combination with carboplatin and paclitaxel achieved partial response. Because of increased toxicity, the twice-daily cohort was discontinued. The recommended motesanib dose for subsequent studies was 125 mg once per day, which had already been established as the maximum-tolerated dose for singleagent therapy. In the phase II study, there were no significant differences in outcomes between patients treated with carboplatin plus paclitaxel and either bevacizumab or motesanib. In the article that accompanies this editorial, Scagliotti et al present the results of the Motesanib NSCLC Efficacy and Tolerability (MONET1) trial, a multicenter, randomized, double-blind phase III trial comparing carboplatin and paclitaxel alone or in combination with motesanib 125 mg per day as first-line therapy for NSCLC. The primary end point was OS. All tumor types were initially included, but squamous cell carcinoma was excluded after increasing gross hemoptysis and mortality JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 23 AUGUST 1

Abstract 850: Activation of autophagy by erlotinib protects NSCLC cells with wild-type EGFR from erlotinib cytotoxicity

Abstract Erlotinib is an orally available EGFR tyrosine kinase inhibitor which has significant clinical activity in previously treated patients with non-small cell lung cancer (NSCLC), as well as in maintenance therapy after frontline chemotherapy. Although it has shown efficacy in NSCLC with both wild-type and mutant EGFR, it is much more effective in tumors with activating EGFR mutations than in those tumors which have wild-type EGFR. This study identifies autophagy induction as a potential mechanism for the relative resistance of wild-type EGFR NSCLC cells to erlotinib. Autophagy is a tightly regulated lysosomal self-digestion process that may promote cell survival and/or be involved in type II cell death. The potential role of autophagy in erlotinib-induced cytotoxicity has not been well defined. We used four wild-type EGFR NSCLC cell lines, which are either erlotinib-sensitive (H322 and H358) or erlotinib-resistant (H460 and A549), to determine if treatment with erlotinib induces autophagy. We then assessed the effect of disrupting autophagy by chemical and genetic approaches on erlotinib-induced cytotoxicity. Erlotinib at a clinically relevant concentration (2 μM) induced autophagy, as shown by increased MDC staining, increased conversion of LC3-I (the cytosolic form) to LC3-II (the lapidated form associated with autophagosome), and the formation of autophagic vacuoles, in all tested cell lines. Autophagy induction by erlotinib was greater in resistant cells than in sensitive cells, suggesting that autophagy is a cytoprotective mechanism. This was confirmed with the use of autophagy inhibitors chloroquine (CQ), 3-methyladenine, and bafilomycin A1, which synergistically increased erlotinib cytotoxicity. Similar enhancement was seen with knockdown of Atg-5 and Beclin-1 gene expression. Cotreatment with CQ did not alter erlotinib-induced EGFR signaling inhibition or G1-phase arrest, but markedly activated mitochondrial-mediated apoptosis. Furthermore, disrupting autophagy by CQ or other inhibitors enhanced erlotinib-induced upregulation of BIM expression, and knockdown of BIM expression by siRNA attenuated the cytotoxicity induced by the combination. In addition, inhibition of autophagy by CQ enhanced erlotinib-induced ROS generation and activation of p38 but not JNK signaling. Inhibition of ROS generation by N-acetyl-cysteine, or inhibition of p38 by SB202190 attenuated the cytotoxic effect of the combination, suggesting that ROS generation and p38 activation are potential mediators of the synergism observed. The ability to adapt to anti-EGFR therapy by triggering autophagy may be a major determinant of resistance to erlotinib in NSCLC tumors with wild-type EGFR. Inhibition of autophagy by CQ or other inhibitors represents a novel strategy to potentiate erlotinib efficacy in NSCLC tumors with wild-type EGFR. Supported by NIH/NCI grants 113360, 132783, and 154755. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 850. doi:1538-7445.AM2012-850

Efficacy of Plasma TGF-β1 Level in Predicting Therapeutic Efficacy and Prognosis in Patients with Advanced Non-Small Cell Lung Cancer

We hypothesized that serial assessment of TGF-β1 during chemotherapy might predict therapeutic response and prognosis in non-small cell lung cancer (NSCLC) patients. Plasma TGF-β1 levels were quantified before first, second, and third cycles of chemotherapy in 42 advanced NSCLC patients and correlated with therapeutic response. Plasma TGF-β1 levels measured before first and second cycles of chemotherapy failed to predict response to therapy. The increased presence of TGF-β1 measured before second and third cycles of chemotherapy was associated with poor survival. Estimation of plasma TGF-β1 during the course of chemotherapy might not be a reliable biomarker for predicting therapeutic efficacy in NSCLC.

Highlights of This Issue

The ability to predict the efficacy of molecularly targeted therapies for non-small cell lung cancer (NSCLC) for an individual patient remains problematic. Nagji and colleagues used the refined coexpression extrapolation (COXEN) algorithm to identify tumor biomarkers that predict drug sensitivity and therapeutic efficacy in NSCLC to Vorinostat (histone deacetylase inhibitor) and Velcade (proteasome inhibitor). Importantly, they provide an in silico method to generate biomarkers that predict tumor sensitivity to novel molecularly targeted therapies. Use of this refined COXEN methodology has significant implications for the a priori examination of targeted therapies to more effectively streamline subsequent clinical trial design and cost.Since αvβ3 integrin plays a key role in angiogenesis and metastasis of human tumors, ligands against this integrin are potentially useful in targeted therapy and cancer imaging. Xiao and colleagues report that a novel RGD peptide ligand, LXW7 with a built-in handle, was identified using OBOC combinatorial chemistry. LXW7 demonstrated high targeting efficacy and specificity for the αvβ3 integrin expressed in tumor cells. Moreover, LXW7 permits easier functionalization for payload conjugation without attenuating the binding affinity of the peptide compared with RGD cyclopentapeptide ligands. LXW7, therefore, has great potential as a highly efficient peptide ligand for targeted imaging and drug delivery.Non-small cell lung cancer (NSCLC) with an activating mutation of the epidermal growth factor receptor (EGFR) ultimately develops resistance to EGFR tyrosine kinase inhibitors (TKI). Okamoto and colleagues show that EGFR mutation–positive NSCLC (HCC827) cells engineered to stably overexpress HGF (HCC827-HGF) exhibit gefitinib resistance. TAK-701, a humanized monoclonal antibody to HGF, in combination with gefitinib suppressed their growth in HCC827-HGF cells both in vitro and in vivo. Our findings suggest that the addition of TAK-701 to gefitinib is a promising strategy to overcome EGFR-TKI resistance induced by HGF in NSCLC with an activating EGFR mutation.Aurora A kinase (AAK), a protein kinase critical for tumor proliferation and survival, is a novel target for cancer treatment. MLN8054, an oral small-molecule AAK inhibitor, produces broad preclinical antitumor activity. In this Phase I study, Macarulla and colleagues evaluated safety, pharmacokinetics, and pharmacodynamics in serial tumor and skin biopsies. Total daily doses of 70 or 80 mg led to marked changes in mitotic cell chromosome alignment and spindle bipolarity in some patients. These results provide evidence for the dominant mechanism to inhibit AAK and support ongoing efforts to target this enzyme in the clinical treatment setting.

Multigene expression-based predictors for sensitivity to Vorinostat and Velcade in non-small cell lung cancer.

The ability to predict the efficacy of molecularly targeted therapies for non-small cell lung cancer (NSCLC) for an individual patient remains problematic. The purpose of this study was to identify, using a refined "coexpression extrapolation (COXEN)" algorithm with a continuous spectrum of drug activity, tumor biomarkers that predict drug sensitivity and therapeutic efficacy in NSCLC to Vorinostat, a histone deacetylase inhibitor, and Velcade, a proteasome inhibitor. Using our refined COXEN algorithm, biomarker prediction models were discovered and trained for Vorinostat and Velcade based on the in vitro drug activity profiles of nine NSCLC cell lines (NCI-9). Independently, a panel of 40 NSCLC cell lines (UVA-40) were treated with Vorinostat or Velcade to obtain 50% growth inhibition values. Genome-wide expression profiles for both the NCI-9 and UVA-40 cell lines were determined using the Affymetrix HG-U133A platform. Modeling generated multigene expression signatures for Vorinostat (45-gene; P = 0.002) and Velcade (15-gene; P = 0.0002), with one overlapping gene (CFLAR). Examination of Vorinostat gene ontogeny revealed a predilection for cellular replication and death, whereas that of Velcade suggested involvement in cellular development and carcinogenesis. Multivariate regression modeling of the refined COXEN scores significantly predicted the activity of combination therapy in NSCLC cells (P = 0.007). Through the refinement of the COXEN algorithm, we provide an in silico method to generate biomarkers that predict tumor sensitivity to molecularly targeted therapies. Use of this refined COXEN method has significant implications for the a priori examination of targeted therapies to more effectively streamline subsequent clinical trial design and cost.

Comparison of gefitinib versus erlotinib in patients with nonsmall cell lung cancer who failed previous chemotherapy

Gefitinib and erlotinib are commonly used for salvage therapy in patients with nonsmall cell lung cancer (NSCLC) who have progressed on prior therapies. Although both agents have similar structure and have demonstrated efficacy in NSCLC, gefitinib and erlotinib have not been directly compared in terms of efficacy and other clinical outcomes in patients with NSCLC who have failed prior chemotherapy. This prompted us to analyze the clinical outcomes between gefitinib-treated and erlotinib-treated patients with metastatic or recurrent NSCLC. A total of 467 patients with metastatic or recurrent NSCLC who had progressed on prior therapies and received gefitinib or erlotinib therapy between January 2006 and December 2008 were retrospectively reviewed. By using a matched-pair case-control study design, 171 pairs of gefitinib-treated and erlotinib-treated patients were matched according to sex, Eastern Cooperative Oncology Group (ECOG) performance status, histologic type, and smoking history. The median age of all patients was 58 years (range, 20-85 years), and the median ECOG performance status was 1 (range, 0-3). Of 342 patients, 294 (86%) received an epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitor as second-line or third-line therapy, whereas the remaining 14% had received >2 prior chemotherapy regimens before starting EGFR TK inhibitor therapy. The confirmed overall response rate was 35.1%, and the disease control rate was 64%. With 13.2 months of follow-up, the median overall survival (OS) for the total 342 patients was 12.4 months (95% confidence interval [95% CI], 10.66-14.14 months), and the median progression-free survival (PFS) was 3.2 months (95% CI, 2.65-3.75 months). The overall response rates and disease control rates in the gefitinib-treated and erlotinib-treated groups were 38% versus 32.2% (P = .273) and 63.2% versus 64.9%, respectively (P = .677). There was no statistically significant difference noted with regard to OS (median, 12.6 vs 12.1 months; P = 0.99) and PFS (median, 4.6 vs 2.7 months; P = .06) between the gefitinib-treated and erlotinib-treated groups. This retrospective analysis shows that gefitinib and erlotinib appear to have similar antitumor activity in terms of response rate and OS in pretreated patients with metastatic or recurrent NSCLC. Further prospective studies are warranted to elucidate any potential differences in toxicity and in dose intensity between gefitinib- and erlotinib-treated patients.

Efficient Inhibition of Non-Small-Cell Lung Cancer Xenograft by Systemic Delivery of Plasmid-Encoding Short-Hairpin RNA Targeting VEGF

Vascular endothelial growth factor (VEGF) plays an important role in the growth and metastasis of non-small-cell lung cancer (NSCLC). The aim of this study was to develop an RNA-interference approach that targets VEGF, using a recombinant plasmid, and to explore its antitumor efficacy in NSCLC in vivo. shRNA-targeting VEGF was cloned into pGenesil-2 plasmid vector and then transfected into A549 human lung cancer cells, using cationic liposome. Reverse-transcriptase polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) analysis were used to evaluate the silencing effects of VEGF-shRNA on A549 cells in vitro. Further, the growth-inhibition capacity of VEGF-shRNA on A549 lung carcinoma xenografts was tested in nude mice. Proliferation, apoptosis, and angiogenesis in tumor tissues were measured by PCNA, TUNEL, and CD31 immunohistochemistry, respectively. shRNA-targeting VEGF significantly silenced VEGF expression in A549 lung cancer cells, as confirmed by RT-PCR and ELISA assay (P < 0.01). In vivo, the VEGF-shRNA delayed tumor growth and reduced tumor weight by approximately 61.96%, compared with control groups (P < 0.05), accompanied with angiogenesis inhibition (P < 0.01) and apoptosis induction (P < 0.01). Our data showed that the knockdown of VEGF by shRNA might be a potential therapeutic approach against human NSCLC.

Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors

BackgroundTreatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. RAD001, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in NSCLC. MethodsStage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. ResultsEighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common ≥grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. ConclusionsRAD001 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of RAD001 plus standard therapy for metastatic NSCLC continues.

New Horizons in Chemotherapy: Platforms for Combinations in First-Line Advanced Non-small Cell Lung Cancer

The treatment of advanced non-small cell lung cancer has evolved substantially during the last decade. Chemotherapy with a platinum-based doublet prolongs survival and improves quality of life in patients with good performance status. Recently, the addition of bevacizumab and the use of epidermal growth factor receptor inhibitors in appropriately selected patients have further improved the outcome of patients with advanced non-small cell lung cancer. Newer targeted agents are being developed and tested in the clinical arena at a rapid pace. In addition, the identification by clinical or molecular criteria of patient populations that benefit the most from these agents is under active investigation. In contrast, the development of newer cytotoxic agents, with innovative mechanisms of action, has been comparatively disappointing. Whether standard cytotoxic drugs are required as newer biologic agents are more frequently used or whether a more active and safer chemotherapy can be used as a template for combinations with biologic agents remains an important research topic.

Predictive value of serum MALDI-TOF proteomic profiling from patients treated with erlotinib and bevacizumab for survival in patients with non-small cell lung cancer (NSCLC) treated with erlotinib alone

11014 Background: A multicenter phase I/II study found that inhibition of VEGF and EGFR with the combination of bevacizumab and erlotinib had significant antitumor efficacy in NSCLC (Herbst, et al JCO 2005). We undertook a pilot project to determine if Matrix-Assisted Laser Desorption/Ionization- Time of Flight Mass Spectrometry (MALDI-TOF MS) proteomic analysis of pretreatment patient serum could be used to develop a profile predictive of improved time to progression and overall survival after treatment with the erlotinib and bevacizumab. Methods: Pretreatment serum was available for 35 of 40 patients with advanced NSCLC treated with bevacizumab and erlotinib. MALDI-TOF mass spectra were obtained with a Voyager-DE STR instrument (PerSeptive Biosystems) and the raw spectra were calibrated, baseline-corrected, and normalized prior to analysis. A Compound Covariate based Cox PH model (Tukey, CCT 1993) was fit to the normalized intensities at each m/z value to evaluate correlation with OS and PFS while accou...

Cell transfer regimens in patients with highly advanced surgically unresectable non-small cell lung cancer: Significantly improved overall survival in patients with lower levels of serum immunosuppressive acidic protein

Sixty-one non-small cell lung cancer (NSCLC) patients with stage II and III/IV were enrolled and 49 completed immunotherapy. Patients were grouped based on immunosuppressive acidic protein (IAP). All patients received monthly intravenous infusions containing 1 x 10(10) (mean cell number per patient) ex vivo expanded and IFN-alpha-treated peripheral blood mononuclear cells. No patients had grade 2 or greater adverse events. The patients with < or = 580microg/ml of serum IAP levels (n=33) had significantly longer recurrence-free survival than those with > 580microg/ml of serum IAP levels (n=16). Patients with lower IAP levels are still under immunotherapeutic control after 27 months free of recurrence. The IAP levels may be a prognostic marker for treatment efficacy in NSCLC. This immunotherapeutic regimen was feasible and well tolerated in patients with advanced NSCLC in terms of prolongation of survival.

Erlotinib and vinorelbine in advanced malignant solid tumors: a phase I study

Erlotinib is an oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI). Vinorelbine, a vinca alkaloid, interferes with microtubule assembly inhibiting mitosis during metaphase. Both drugs are commonly used as single agents in the treatment of advanced non small cell lung cancer (NSCLC). Given their efficacy in NSCLC and their non-overlapping toxicity profile, we conducted a phase I study of erlotinib and vinorelbine to establish the feasibility and safety of the combination and to determine the maximum tolerated dose (MTD). Patients with advanced solid tumors were treated with vinorelbine intravenously on day 1 and 8 and erlotinib orally daily on a 21 day schedule. The dose levels of vinorelbine/erlotinib were 25 mg/m(2)/100 mg, 25/150 and 30/150. Sixteen patients were enrolled. Five patients were chemo-naïve; 11 had one prior therapy. The majority of patients had NSCLC (n = 7). Dose limiting toxicities included febrile neutropenia (4 patients) and grade 5 infection (1 patient). Non-hematologic grade 3/4 toxicities included diarrhea, hypokalemia, infection, dyspnea and mucositis. Of 12 patients assessable for radiologic response, there were no objective responses; eight had stable disease. (1) The MTD was vinorelbine 25 mg/m2 day 1 and 8 with erlotinib 100 mg/day every 21 days. (2) The combination was associated with high rate of febrile neutropenia (25%). (3) Due to subsequent data demonstrating a lack of efficacy of erlotinib in combination with platinum doublets in advanced NSCLC, this combination has not been explored further.

EGFR mutations (muts), IHC and FISH status, and chromosome 7 gene copy number combined with pAkt expression as potential predictors of survival in non-small cell lung cancer (NSCLC) patients (pts) treated with gefitinib (GEF)

7182 Background: EGFR and pAkt expression by immunohistochemistry (IHC), muts, and FISH status have been identified as possible molecular predictors for GEF efficacy in NSCLC (Cappuzzo, et. al, JNCI, 2005). The goal of this study was to independently evaluate these findings regarding survival (surv), and to assess the predictive value of mean chromosome 7 copy number/cell (C7). Methods: 150 consecutive Expanded Access Trial pts with &gt;1 week GEF therapy were included for analysis. IHC (present vs not detected) was performed for 87 pts, and 58 pts were analyzed for muts by SSCP, mut-specific PCR, and sequencing. Tissue from 81 pts was evaluated for EGFR and C7 gene copy numbers by fluorescence in situ hybridization (FISH). Results: 150 pts (77 female, 73 male; median (md) age 67; 85 adenocarcinoma) received GEF; md follow-up was 5.8 months (mo). Overall response was 8% (2 CR, 10 PR); 56 pts had stable disease. Md Kaplan-Meier surv was 5.9 mo. IHC revealed that 47/87 pts (54%) had EGFR+, and 36/75 pts (48%) had pAkt + tumors. pAkt+ pts had significantly (sig) longer surv than pAkt− pts (11.4 vs 5.8 mo, p &lt; .05). High polysomy was seen in 36/81 pts (44%) who were designated FISH+; 45 pts were FISH−. EGFR IHC and FISH positivity were not sig associated with surv. C7 was defined as low (&lt;3.6, 63 pts) or high (≥3.6, 18 pts); md surv was 6.6 and 17.1 mo, respectively, p &lt; .01. Muts were found in 17/58 tumors (29%). Md surv for pts with and without muts was 23.8 and 7.9 mo, respectively, p &lt; .07. EGFR IHC− pAkt− pts (18 pts) had sig shorter surv than 57 pts with any pos value (4.7 vs 8.8 mo, p &lt; .02). Double-positive pts had sig longer surv than pts with any neg value. Conclusions: These findings resemble but do not duplicate those reported by Cappuzzo, et al. Additionally, high C7, alone or combined with pAKT, may be an important predictor for GEF efficacy in NSCLC. Further studies of C7, a technically simple and reproducible FISH assay, are warranted. [Table: see text] [Table: see text]