Receptor Tyrosine Kinase Inhibitor Therapy Research Articles

Is EGF Receptor–Tyrosine Kinase Inhibitor Therapy in Non-Small-Cell Lung Cancer Patients with EGFR Mutations the Best Option?

441 ISSN 1758-1966 10.2217/LMT.13.57 © 2013 Future Medicine Ltd Lung Cancer Manage. (2013) 2(6), 441–443 In non-small-cell lung cancer (NSCLC), the discovery that EGF receptor (EGFR) signaling plays a key role in regulating cell proliferation, differentiation and tumorigenesis has emphasized the importance of targeted therapy. Small molecule tyrosine kinase inhibitors of EGFR (EGFR–TKIs), such as gefitinib and erlotinib, compete with ATP for binding to the tyrosine kinase pocket of the receptor, thereby inhibiting receptor kinase activity and EGFR signaling. Early clinical trials showed that specific NSCLC patient populations experienced a rapid, remarkable and durable response to EGFR–TKI treatment [1]. Clinical characteristics associated with high EGFR–TKI response rates include female gender, Asian ethnicity, never-smoker status and adenocarcinoma [2]. In 2004, several groups demonstrated that remarkable response rates to EGFR–TKIs were seen in NSCLC patients who harbored somatic mutations in EGFR [3–5]. Subsequently, several Phase II trials of EGFR–TKIs in NSCLC patients with EGFR mutations demonstrated a favorable overall response rate. We performed an integration analysis of data from seven clinical trials of gefitinib in NSCLC patients in Japan and showed that overall response rate and progression-free survival (PFS) time in response to gefitinib were 76.4 and 9.7 months, respectively [6]. The substantial clinical benefits of gefitinib led to a Phase III trial to compare the efficacy of first-line gefitinib versus cisplatin plus docetaxel for the treatment of advanced NSCLC patients with EGFR mutations (WJTOG 3405) [7]. The gefitinib group had significantly longer PFS than the cisplatin plus docetaxel group, with a median PFS of 9.2 versus 6.3 months (hazard ratio [HR]: 0.489; p < 0.0001). At approximately the same time as the WJTOG 3405 study, the NEJ002 study confirmed that PFS, the primary end point, was significantly longer in the gefitinib group than in the carboplatin plus paclitaxel group (10.8 vs 5.4 months; HR: 0.30; p < 0.001) [8]. Furthermore, two Phase III trials revealed the PFS benefit of erlotinib compared with standard chemotherapy. In the OPTIMAL study, which was conducted in China, the erlotinib arm had significantly longer PFS than the carboplatin plus gemcitabine arm, with a median PFS of 13.1 versus

Resource Use and Costs Associated With The Treatment Of Hematologic and NON-Hematologic Adverse Events In Chronic Myeloid Leukemia (CML) Brazilian Patients

IntroductionChronic myeloid leukemia (CML) is a clonal malignant disease characterized by excessive proliferation of myeloid lineage, followed by a progressive loss of cell differentiation, with evolution including progression from chronic phase to accelerated or blastic phase. The disease is associated with a specific cytogenetic abnormality, the Philadelphia chromosome, which results from a reciprocal translocation between the long arms of chromosomes 9 and 22 [t(9;22)(q34;q11)], leading to the generation of the new leukemia-specific gene BCR-ABL, resulting in the production of an oncoprotein with tyrosine kinase activity, responsible for the pathophysiology of disease. Effective treatments with tyrosine kinase inhibitors (TKI) are available for CML patients and differences in adverse events (AE) and incidences occurring during therapy are reported in the literature depending on the type of TKI. ObjectiveImprove the standard of resources used and reduce later treatment costs of treatment-related haematological and non-hematological adverse events of CML patients, from the perspective of the Brazilian National Health System. Cost of treatment per event will be presented as a result. MethodA Delphi methodology was applied in Brazil to study the management of adverse events related to CML treatment by collecting data on resource used., considering the resource use and its cost associated. Based on the literature, a questionnaire was developed on the available resources for the treatment of select adverse events. Ten experts completed the questionnaires and the results were compiled and validated. The data collected were related to percentage of patients affected by each AE and percentage of each resource used to manage the AE. A consensus meeting was held after questionnaire completion. The unit cost of resources was based on the Bank Price and Health Management System Procedures Table of SUS (SIGTAP). Cost of treatment of the AEs consisted of the cost of the treatment options and monitoring costs (e.g., outpatient visits, laboratory tests and procedures, hospitalizations) in the Brazilian Public Health System. ResultsAmong non-hematologic adverse events grade 3-4, gastrointestinal bleeding and central nervous system (CNS) hemorrhage presented the highest costs of treatment per event (R$ 1.022,90 and R$ 1.173,34, respectively). Hospitalization is the resource with more impact; mainly in CNS hemorrhage, with an average length of hospitalization reported by the experts of 1 week and also being demanded by 100% of patients affected by this AE. Management of cardiac events is R$973,35 and Pericardial effusion is R$3.896,55. Cytopenias are the most commonly occurring events in patients with CML receiving BCR–ABL inhibitors. Experts suggest the use of growth factors, such as granulocyte colony-stimulating factor, interleukin-11 and erythropoietin in patients with CML receiving TKI therapy. The Panel experts agreed the cost associated with the management the hematologic adverse events are: Anemia: R$14,93, Thrombocytopenia: R$14,47 and neutropenia: R$211,54. ConclusionAll adverse events related to treatment of CML, with differences in the occurrence and intensity should be valued and recorded as contributing to the estimated total cost of treating the disease. Adverse event management in CML patients has important clinical and economic impact.I Banco de Preço em Saúde. Disponível em: http://bps.saude.gov.br/visao/consultapublica/publico_interno_item.cfm - Accessed in 08/04/2013II Sistema de Gerenciamento da Tabela de Procedimentos, Medicamentos e OPM do SUS. DATASUS – SIGTAP. Available in http://sigtap.datasus.gov.br/tabela-unificada/app/sec/inicio.jsp - Accessed in: 08/04/2013 Disclosures:Alves: Novartis: Employment. Lemos: Novartis: Employment. Boquimpani: Novartis: Consultancy.

P11 Tyrosine kinase inhibitor use in pulmonary adenocarcinoma

IntroductionPersonalised treatments are becoming increasingly important in medicine, and the use of tyrosine kinase inhibitors (TKI) in the management of the subset of patients with pulmonary adenocarcinomas which express a...

How to make the choice in the retreatment of EGFR-TKI for advanced NSCLC patients who benefited from prior gefitinib therapy: the original drug or switching to a second EGFR-TKI?

背景与目的既往表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitor, EGFR-TKI）治疗获益的晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）患者，再次给予TKI治疗，已逐渐成为一种新的治疗策略。本研究旨在探讨二次TKI治疗时，原药或换药，哪一种选择更为合理。方法回顾晚期或术后复发的NSCLC患者，既往吉非替尼治疗疗效达到完全缓解（complete response, CR）、部分缓解（partial response, PR）或稳定（stable disease, SD），无进展生存期（progression free survival, PFS）≥3个月，病情进展后，间隔时间至少1个月，分别接受吉非替尼或厄洛替尼治疗。就两组患者的疗效、优势人群等进行分析。结果共有61例患者入组，其中吉非替尼组30例，厄洛替尼组31例，两组患者基线特征基本平衡。吉非替尼组与厄洛替尼组疗效比较，有效率（response rate, RR）（10% vs 22.6%, P=0.300, 6）、疾病控制率（disease contral rate, DCR）（60% vs 74.2%, P=0.237, 8）、中位PFS（3.0个月vs 3.5个月，P=0.494, 5）、中位总生存期（overall survival, OS）（8.3个月vs 8.5个月，P=0.140, 8）均未见统计学差异。多因素分析示：首次吉非替尼PFS≥6个月（HR=0.317, 95%CI: 0.102-0.984, P=0.046, 9），两次TKI间隔时间≥3个月（HR=0.224, 95%CI: 0.071-0.713, P=0.011, 3）的患者疾病进展风险降低。而两次TKI间隔时间≥3个月（HR=0.262, 95%CI: 0.097-0.705, P=0.008, 0）的患者死亡风险降低。结论既往吉非替尼治疗获益的晚期NSCLC患者再次TKI治疗，无论选择吉非替尼还是换用厄洛替尼均可获益，这种获益与首次TKI的PFS、以及两次TKI的间隔时间相关。

Recurrence patterns of advanced non-small cell lung cancer treated with gefitinib

Background Gefitinib is widely used in the treatment of advanced non-small cell lung cancer (NSCLC). However, only a small number of reports have described initial failure sites in patients treated with gefitinib. The aim of this study was to investigate survival, recurrence sites, and treatment after recurrence in these patients. Methods A retrospective review was conducted of all patients with stage III/IV NSCLC treated with gefitinib in Peking Union Medical College Hospital from October 2002 to September 2011. Patient characteristics, initial failure sites, associated clinical factors, and subsequent therapy were included in the analysis of prognostic factors. Results A total of 316 patients were identified The median progress free survival (PFS) and overall survival (OS) times were 238 days and 468 days, respectively. The median survival time after progression was 145 days. The sites of initial failure were lung (62.34%), bone (17.72%), central nerve system (CNS, 16.14%), liver (9.49%), and others (7.19%). Patients with single-site progression or multi-site progression were 81.01% and 18.99%, respectively. Progression-free survival time was associated with lung and bone failure. Additionally, the median survival time after progression was lower in patients with multi-site progression and liver progression. Other initial failure sites displayed no relationship with survival, including CNS failure. Subsequent therapy may affect survival after progression. In patients receiving continuous epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy, chemotherapy, radiotherapy, and re-treatment with EGFR-TKIs, survival time after progression was prolonged compared with the best supportive care. Conclusions Our data suggest that patients receiving gefitinib should be closely monitored regarding lung metastasis during follow-up. Liver metastases and multi-site progression were poor prognostic factors. After failure with gefitinib, patients may benefit from radiotherapy, chemotherapy, continuous EGFR-TKI therapy and re-treatment with EGFR-TKIs.

Dermatologic adverse events associated with afatinib: an oral ErbB family blocker

Dermatologic adverse events (AEs) are frequently observed in patients receiving EGF receptor (EGFR; also known as ErbB1) tyrosine kinase inhibitor therapy. The impact of these AEs goes beyond cosmesis to the discomfort from itching, pain and secondary infections, all of which may significantly impact on patient well-being, adherence and clinical outcomes. Afatinib is a potent, irreversible, oral, ErbB family blocker, inhibiting EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor kinases. It also inhibits transphosphorylation of ErbB3. Similar to EGFR inhibitors, dermatologic AEs have been frequently observed in patients treated with afatinib. Papulopustular (acneiform) rash, pruritus, xerosis, paronychia and alopecia will require patient education and proactive treatment interventions. This article summarizes current data on the dermatologic AEs associated with afatinib treatment across the clinical trial program, and provides strategies for their effective management.

Diarrhea associated with afatinib: an oral ErbB family blocker

Gastrointestinal (GI) adverse events (AEs) are frequently observed in patients receiving EGF receptor (EGFR; also known as HER1 or ErbB1) tyrosine kinase inhibitor therapy. GI AEs are among the most common and most impactful on a patient’s quality of life. Severe diarrhea can result in fluid and electrolyte losses, leading to dehydration, electrolyte imbalances and renal insufficiency. Afatinib is an irreversible, oral, ErbB family blocker, inhibiting EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor kinases. It also inhibits transphosphorylation of ErbB3. Similar to reversible tyrosine kinase inhibitors of EGFR, GI AEs – in particular, diarrhea – have frequently been observed in afatinib-treated patients. This article summarizes current data on afatinib-associated diarrhea and provides strategies for its management. Patient education, early identification, timely management and ongoing assessment will help to prevent aggravation, afatinib dose reductions or therapy discontinuation, encouraging patient compliance and allowing patients to obtain the maximum therapeutic benefit from this agent.

Safety and efficacy of everolimus in Chinese patients with metastatic renal cell carcinoma resistant to vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy: an open-label phase 1b study

BackgroundIn China, there are currently no approved therapies for the treatment of metastatic renal cell carcinoma (mRCC) following progression with vascular endothelial growth factor (VEGF)-targeted agents. In the phase 3 RECORD-1 trial, the mammalian target of rapamycin (mTOR) inhibitor everolimus afforded clinical benefit with good tolerability in Western patients with mRCC whose disease had progressed despite VEGF receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. This phase 1b study was designed to further evaluate the safety and efficacy of everolimus in VEGFr-TKI-refractory Chinese patients with mRCC.MethodsAn open-label, multicenter phase 1b study enrolled Chinese patients with mRCC who were intolerant to, or progressed on, previous VEGFr-TKI therapy (N = 64). Patients received everolimus 10 mg daily until objective tumor progression (according to RECIST, version 1.0), unacceptable toxicity, death, or study discontinuation for any other reason. The final data analysis cut-off date was November 30, 2011.ResultsA total of 64 patients were included in the study. Median age was 52 years (range, 19–75 years) and 69% of patients were male. Median duration of everolimus therapy was 4.1 months (range, 0.0-16.1 months). Expected known class-effect toxicities related to mTOR inhibitor therapy were observed, including anemia (64%), hypertriglyceridemia (55%), mouth ulceration (53%), hyperglycemia (52%), hypercholesterolemia (50%), and pulmonary events (31%). Common grade 3/4 adverse events were anemia (20%), hyperglycemia (13%), increased gamma-glutamyltransferase (11%), hyponatremia (8%), dyspnea (8%), hypertriglyceridemia (6%), and lymphopenia (6%). Median PFS was 6.9 months (95% CI, 3.7-12.5 months) and the overall tumor response rate was 5% (95% CI, 1-13%). The majority of patients (61%) had stable disease as their best overall tumor response.ConclusionsSafety and efficacy results were comparable to those of the RECORD-1 trial. Everolimus is generally well tolerated and provides clinical benefit to Chinese patients with anti-VEGF-refractory mRCC.Trial registrationclinicaltrials.gov, NCT01152801

Clinic characteristics and prognosis in 102 non-small cell lung cancer patients less than 40 years old

背景与目的青年（年龄≤40岁）非小细胞肺癌（non-small cell lung cancer, NSCLC）发病率呈上升趋势。本研究旨在分析青年NSCLC的临床病理生理特征、治疗及预后情况。方法对102例资料完整的青年NSCLC患者进行回顾性分析。结果女性所占比例为43.1%，男女比例为1.32:1；29.4%有吸烟史；以腺癌为主，占77.5%；以低分化癌为主，占64.1%；晚期肺癌（Ⅲb期及Ⅳ期）占87.8%。6例接受手术治疗患者的中位复发时间为13.5个月。87例接受一线化疗患者的客观有效率（objective response rate, ORR）为46.0%，疾控率（disease controled rate, DCR）为79.3%，中位肿瘤进展时间（time to progress, TTP）为5.0个月。38例接受表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitors, EGFR-TKI）治疗患者ORR为40%，DCR为65.7%，中位TTP为5.5个月；12例二次或多次TKI治疗患者DCR为66.7%，中位TTP为3.0个月。结论青年NSCLC中位确诊时间长，女性所占比例相对较高，与吸烟的相关性较弱，以分化差的晚期腺癌为主，确诊后应给予积极的综合治疗，但总体预后不佳。

Real world impact of epidermal growth factor receptor mutation status on treatment patterns in patients with non-small cell lung cancer

BackgroundEpidermal growth factor receptor (EGFR) mutation status is an important predictor of the efficacy of EGFR tyrosine kinase inhibitor (TKI) therapy in patients with non-small cell lung cancer (NSCLC). We evaluated the real impact of EGFR mutation status on chemotherapy patterns of NSCLC patients. Patients and methodsThis is a retrospective cohort study of consecutive advanced NSCLC patients attended at the Samsung Medical Centre in Seoul, Korea, from January 2007 through July 2010. EGFR mutation was analyzed by direct sequencing testing. ResultsAmong 1164 patients treated during the study period, 166 (14.3%) were EGFR mutation positive, 275 (23.6%) were mutation negative, and 723 (62.1%) had mutation status unknown. Overall, 605 (52%) received TKI therapy as a first-, second-, or third-line therapy. The proportions of patients receiving TKI therapy among those with positive, negative and unknown EGFR mutation status were 88.0, 46.5, and 45.8%, respectively. After adjustment for other factors, patients with a positive EGFR mutation status (odds ratio [OR] 7.88, 95% CI 4.58, 13.57), and those who were female (OR 2.83, 95% CI 2.04, 3.92) or had poor performance status (OR 1.58, 95% CI 1.13, 2.22) were significantly more likely to receive TKI treatment. Furthermore, the temporal relationship between EGFR mutation reporting and initiation of TKI therapy significantly differed by EGFR mutation status. ConclusionEGFR mutation status significantly affected the chemotherapy patterns in advanced NSCLC. More widespread EGFR testing and the use of faster and more sensitive mutation tests will result in more timely and appropriate use of TKI therapy in advanced NSCLC.

Analysis of prognostic factors in patients with stage IV lung adenocarcinoma after failure of second-line EGFR-TKIs therapy

背景与目的表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinases inhibitors, EGFR-TKIs）普遍应用后，其治疗失败后预后情况引起学界的关注。本研究旨在回顾性分析Ⅳ期肺腺癌患者的临床资料，探讨EGFR-TKIs治疗失败后影响预后的相关因素。方法收集2009年1月-2012年2月体能状态评分（performance status, PS）为0分-2分的Ⅳ期肺腺癌患者，随访至死亡。主要观察指标为EGFR-TKIs治疗失败后的生存时间（overall survival, OS）。结果共81例患者入组，中位OS为9.6个月（QL-QU: 5.4-19.2）。单因素分析显示，PS评分、多部位的转移及靶向药物治疗后出现中/大量胸水对预后有影响（P < 0.05），靶向治疗失败后血CEA水平正常及曾有手术史也表明患者更能得到生存时间获益的趋势。多因素分析显示，PS评分、多部位转移及靶向药物治疗后出现中/大量胸水可以作为Ⅳ期肺腺癌患者独立的预后因素（P < 0.05）。结论晚期肺腺癌PS评分为0分-1分、单脏器的转移及靶向药物治疗后出现无或少量胸水可获得较好的生存时间，应采取积极的化学药物治疗。

Relationship of Patient-Reported Symptoms to Daily Functioning in Chronic Myeloid Leukemia

Abstract 4260 Objective:Patients with chronic-phase, Philadelphia chromosome-positive chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitor (TKI) therapy experience symptoms. We investigated the association between patient-reported symptom severity and longitudinal levels of interference with daily functioning. Materials and Methods:In this descriptive, longitudinal study, 156 patients with CML rated the 20 symptom items (13 core cancer and 7 CML-specific symptom items) and 6 interference items of the M. D. Anderson Symptom Inventory for CML (MDASI-CML), on a 0-to-10 scale (0 = not present or no interference; 10 = as bad as can be imagined or complete interference) every 2 weeks for 1 year. Group-based trajectory analysis was used to describe the longitudinal patient-reported interference of symptoms with daily functioning. We used univariate mixed modeling to describe the relationship between symptom severity at time of study entry and patient-reported functional interference across time. These analyses were adjusted for patient factors (age, sex, race, marital status, employment, and time since diagnosis). Results:Mean participant age was 51.1 years (standard deviation [sd]=13.5) and mean years of education was 14.6 (sd=2.3); 72 participants (46%) were male; 116 (74%) were white non-Hispanic with 13 (8%) black non-Hispanic, 15 (9%) Hispanic, and 12 (8%) other races; 124 (80%) were married or lived with another adult; 92 (59%) were employed full or part time, 15 (10%) were homemakers, 26 (17%) were retired, 17 (11%) were on a medical leave of absence or medically disabled, and 6 (4%) were unemployed. Participants were mostly in the chronic phase of CML (95.5%), were receiving TKI therapy (98%), had been diagnosed for a mean of 6.1 years (sd=4.74), and been on TKI therapy for a mean of 4.1 years (sd=3.13) before study entry. Most participants had little evidence of disease with 123 (79%) having a complete cytogenetic response and 81 (52%) having a complete molecular response by polymerase chain reaction at time of study entry. Fatigue (mean=2.93, sd=2.67) was persistently the most severe symptom, followed by disturbed sleep (mean=2.19, sd=2.59), drowsiness (mean=2.07, sd=2.40), muscle cramping (mean=2.02, sd=2.46), and difficulty remembering (mean=1.81, sd=2.17). The highest interference reported was with work (mean=1.69, sd=2.41), followed by general activity (mean=1.67, sd=2.32) and mood (mean=1.50, sd=2.15). Trajectory analysis showed that 69 (43%) participants were in a higher interference group (mean interference=3.01, sd=1.60) and that the remaining 87 (54%) were in a distinctly lower interference group (mean=0.50, sd=0.44) (Figure 1). None of the demographic characteristics or time since diagnosis predicted patient interference scores. Eleven symptom scores at study entry significantly predicted interference scores (pain, p=0.0009; fatigue, p<0.0001; disturbed sleep, p< 0.0001; distress, p<0.0001; shortness of breath, p=0.0005; drowsiness, p=0.0003; dry mouth, p=0.0021; sadness, p=0.0092; peripheral edema, p=0.0049; muscle cramping, p=0.0099; malaise, p<0.0001). Participants with higher symptom severity at study entry had higher interference scores across time. Conclusions:Patients with CML, regardless of disease status, may still experience symptoms that interfere with daily functioning while on oral TKI therapy. Symptoms and their interference with daily functioning can be easily documented by routine assessment and deserve consideration in long-term treatment planning for these patients, as they may interfere with patient compliance with TKI therapy and affect quality of life for survivors with CML. [Display omitted] Disclosures:Williams:Novartis Pharmaceuticals: Research Funding. Ault:Bristol Myers Squibb: Speakers Bureau. Cortes:Bristol Myers Squibb: Consultancy, Research Funding; Novartis Pharmceuticals: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

The detection of EGFR mutation status in plasma is reproducible and can dynamically predict the efficacy of EGFR-TKI.

The validity of epidermal growth factor receptor (EGFR) mutation in serum and plasma DNA as a surrogate of tumor tissue has been comprehensively explored. However, the concordance between peripheral blood and tumor tissue samples in EGFR mutation detection remains variable. The question as to whether real-time samples for EGFR mutation analysis are required before epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy remains unanswered. This study included two cohorts:(i) 822 non-small cell lung cancer (NSCLC) patients with primary tumor tissue and matched plasma samples at initial diagnosis; and (ii) 207 patients with advanced NSCLC who had plasma samples taken immediately before EGFR-TKI therapy, in which 157 cases had matched tumor tissues. Denaturing High-Performance Liquid Chromatography (DHPLC) determined EGFR mutation status. Among a total of 822 patients with matched samples, the EGFR mutation rates were 36.3% and 32.1% in tissue and plasma samples, respectively. Concordance of EGFR mutation between two kinds of samples was 77.0% (631/822),with 63.5% (188/296) of accuracy of EGFR mutation in plasma DNA. In 207 advanced NSCLC patients who had plasma samples taken immediately before EGFR-TKI therapy, the objective response rate (ORR) after EGFR-TKI therapy was significantly higher in EGFR mutant patients than those in EGFR wild-type patients (51.4% vs. 22.6%, P < 0.001), regardless of the treatment lines of EGFR-TKI. In patients with two or more lines of EGFR-TKI therapy, EGFR mutation status in plasma samples, but not in tissues, was a predictor for progression-free survival (PFS) after EGFR-TKI therapy (mutant vs. wild-type: 10.1 months vs. 3.7 months, P = 0.038). An EGFR mutation test using plasma DNA samples was validated and reproducible. Obtaining real-time samples for EGFR mutation detection is critical in order to predict the outcomes of EGFR-TKI.

Everolimus synergizes with gefitinib in non-small-cell lung cancer cell lines resistant to epidermal growth factor receptor tyrosine kinase inhibitors

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy is considered as one of the most important treatments for patients with advanced non-small-cell lung cancer (NSCLC). However, not all patients benefit from this therapy because of primary or acquired resistance, both of which are usually caused by the activation of alternative signaling pathways. Thus, a combination of different signaling pathway inhibitors is a promising strategy. We used the mammalian target of rapamycin (mTOR) inhibitor everolimus in combination with gefitinib in NSCLC cell lines to analyze the efficacy of this combination regimen and the underlying molecular mechanism. Acquired gefitinib-resistant cell lines, together with EGFR wild-type and mutant primary gefitinib-resistant NSCLC cell lines, were treated with everolimus alone, gefitinib alone, or the combination of the two drugs, and the effects were evaluated using cell proliferation assays. The effects of everolimus and gefitinib on the EGFR pathway in NSCLC cell lines were determined by Western blot analysis. Combined treatment resulted in synergistic antitumor effects in gefitinib-resistant cells A549 and H1975. The combination index (CI) of cells increased with increasing dose of everolimus. Everolimus demonstrated no apparent inhibition of phosphorylated Akt (p-Akt) and phosphorylated p44/42 MAPK (p-MAPK) in H1650 cells. Additionally, in gefitinib-resistant cell lines, the combination of gefitinib and everolimus not only showed stronger inhibition of phosphorylated mTOR and phosphorylated p70S6K expression than either drug alone but also reduced the levels of p-Akt and p-MAPK in both cell lines. Our data showed that the combination of everolimus and gefitinib exhibits dose-dependent synergism in primary and acquired gefitinib-resistant NSCLC cells. Thus, a preclinical rationale exists for the use of everolimus to enhance the efficacy of gefitinib in EGFR-TKI-resistant patients with NSCLC.

Cost comparison of second-line treatment options for late stage non-small-cell lung cancer: cost analysis for Italy

Background:Lung cancer is the leading cause of cancer deaths worldwide (1.38 million cancer deaths, 18.2% of the total) and of cancer morbidity (1.61 million new cases, 12.7% of all new cancers). Currently only three second-line non-small-cell lung cancer (NSCLC) pharmacotherapies are licensed in the European Union: the chemotherapies pemetrexed and docetaxel and the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib. These therapy alternatives have shown a comparable efficacy (survival benefit). In the past, cost comparisons showed that erlotinib was less costly compared to docetaxel, which in turn is cheaper than pemetrexed. Nowadays erlotinib (and docetaxel) are still less expensive than pemetrexed; but docetaxel lost patent protection (basic compound patent) at the end of 2010, so docetaxel drug costs have decreased rapidly and the question remains whether erlotinib is still the least costly therapy alternative in second-line NSCLC.Material and methods:Italy was selected for base case analysis to compare the total therapy costs, estimated by combining country-specific drug costs, administration costs, and adverse event costs of erlotinib and generic docetaxel in second-line NSCLC therapy. Sensitivity analyses on central input parameters have been performed.Results:The total costs of treating one patient with erlotinib therapy of €5121 are lower than the docetaxel costs of €6699 for the Italian health care setting. Although the drug costs of erlotinib are higher than generic docetaxel (incremental €3770): the costs of intravenous chemotherapy administration (incremental −€4510), and the costs of adverse event therapy (incremental −€837) lead to higher total therapy costs for docetaxel compared to the epidermal growth factor receptor tyrosine kinase inhibitor therapy erlotinib.Conclusion:The cost comparison findings for Italy show that erlotinib is still the less costly therapy alternative in second-line NSCLC. These results were robust to changes of central input parameters and robust to further potential price decreases for docetaxel.

821P - Everolimus in Patients with Metastatic Renal Cell Carcinoma Who Progress after Initial Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitor (VEGFR-TKI) Therapy: UK Results from the react Trial on Behalf of the UK React Investigators

ABSTRACT Background The phase III RECORD-1 trial demonstrated clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) who had failed initial VEGFr-TKI therapy. REACT (RAD001 Expanded Access Clinical Trial in RCC) was designed to address an unmet medical need by providing everolimus to patients with mRCC prior to regulatory approval. UK results from the REACT trial are reported here. Methods REACT was an open-label, international, expanded-access program. Eligible patients had measurable or nonmeasurable mRCC of any histology, and had progressed on, or were intolerant of, VEGFr-TKI therapy. Patients received a once-daily oral 10 mg dose of everolimus. The primary objective of REACT was to evaluate long-term safety of everolimus. Tumour response was also assessed according to RECIST. Results A total of 120 patients were enrolled in the UK, 9% of worldwide enrolment. Prior sunitinib was received by 76% of patients; only 5.8% of patients received more than one VEGFr-TKI. Everolimus was received for a median duration of 21.8 weeks (range, 2.0–59.0), numerically longer than reported overall for REACT (14.0 weeks; range, 0.1–83.7). Safety findings and tumour responses were consistent with those observed in the global patient population. The most commonly reported grade 3/4 AEs were anaemia (20.8%), hyperglycaemia (10%), and lower respiratory tract infection (7.5%). Stomatitis and pneumonitis occurred in 13.3% and 10% of patients, respectively (all grades); grade 3 events were reported in 6.7% and 3.3% of patients (no grade 4 events). Investigator-assessed best overall responses were stable disease in 67 (55.8%) patients and a partial response in 1 patient (0.8%), comparable with the overall population. No complete responses were documented in this trial. Conclusions The REACT trial provided everolimus in advance of regulatory approval and commercial availability to mRCC patients in the UK who failed initial VEGFr-TKI therapy. Everolimus was well tolerated, and safety findings were consistent with those reported for global REACT. Disclosure S. Chowdhury: Consultant or Advisory: Novartis, Pfizer, GSK, Sanofi-Aventis, Janssen-Cilag, Dendreon. All other authors have declared no conflicts of interest.

Apricoxib upregulates 15-PGDH and PGT in tobacco-related epithelial malignancies

Background:Despite focused research in conventional therapies and considerable advances in the understanding of the molecular carcinogenesis of head and neck squamous cell carcinoma (HNSCC), the 5-year survival rate for patients with advanced disease remains ∼15–20%. The major causes of HNSCC-related deaths are cervical node and distant metastasis. E-cadherin has a key role in epithelial intercellular adhesion and its downregulation is a hallmark of epithelial–mesenchymal transition (EMT), which is associated with invasion, metastasis, and poor prognosis. Epithelial–mesenchymal transition is the major mechanism responsible for mediating invasiveness and metastasis of epithelial cancers. Recently, we reported the role of E-cadherin transcriptional repressors in the inflammation-induced promotion of EMT in HNSCC, which is mediated by COX-2. These findings suggest that therapies targeting the cyclooxygenase pathway may diminish the propensity for tumour metastasis in HNSCC by blocking the PGE2-mediated induction of E-cadherin transcriptional repressors.Methods:Herein, we evaluate the efficacy of the COX-2 inhibitor, apricoxib, in HNSCC cell lines. Apricoxib is effective in preventing tumour cell growth in three-dimensional, and anchorage-independent growth assays, as well as decreasing the capacity for tumour cell migration.Results:Herein, we evaluate the efficacy of the COX-2 inhibitor, apricoxib, in HNSCC cell lines. Apricoxib is effective in preventing tumour cell growth in three-dimensional, and anchorage-independent growth assays, as well as decreasing the capacity for tumour cell migration. Treatment of HNSCC cells with apricoxib also causes greater upregulation of E-cadherin and Muc1 expression and downregulation of vimentin, as compared with celecoxib treatment. This has significant implications for targeted chemoprevention and anti-cancer therapy because E-cadherin expression has been implicated as a marker of sensitivity to epidermal growth factor receptor tyrosine kinase inhibitor and other therapies. We show for the first time the molecular mechanisms underlying the efficacy of apricoxib in HNSCC cells.Conclusion:In addition to reversing EMT via inhibition of COX-2, apricoxib upregulates 15-prostaglandin dehydrogenase and the prostaglandin transporter, thereby reducing the levels of active PGE2 by both suppressing its synthesis and increasing its catabolism. These findings have significant implications for metastasis and tumour progression in HNSCC.

Randomized phase II trial of erlotinib (E) plus high-dose celecoxib (HD-C) or placebo (P) in advanced non-small cell lung cancer.

7518 Background: Cyclooxygenase-2 (COX-2)-dependent signalling represents a potential mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in NSCLC. This is mediated in part through an EGFR-independent activation of MAPK/Erk by the COX-2 metabolite PGE2. In addition, PGE2 promotes downregulation of E-cadherin and epithelial to mesenchymal transition. We hypothesize that EGFR and COX-2 inhibition with E and HD-C will augment EGFR TKI efficacy by increasing tumor E-cadherin expression and blocking PGE2-mediated resistance to EGFR inhibition. Methods: Pts with stage IIIB/IV NSCLC who progressed following at least one line of therapy or refused standard chemotherapy were randomized to E (150mg/day)/HD-C (600mg/2x day) vs E/P in a 28-day cycle. Pts were stratified by smoking status and ECOG PS. The primary endpoint was PFS with 80% power to detect a 50% improvement; assessments were performed every 2 cycles. Secondary endpoints included response rate, OS and evaluation of molecular markers in tissue and serum to assess targeting COX-2-related pathways and evaluate EGFR TKI-resistance. All pts were required to have pre-treatment tissue available. Results: 107 pts were enrolled with comparable baseline characteristics in both arms. Disease control rate (DCR) was similar in both arms, and a trend toward improved PFS was seen in the E/HD-C arm with HR 0.81 (see Table). Analysis of those with EGFR wild type revealed a significantly increased PFS while those with EGFR mutation had similar PFS in both groups. Safety analysis showed similar toxicity in both arms. Additional biomarker correlations will be presented. Conclusions: The combination of E/C in metastatic NSCLC with HD-C is well tolerated and demonstrates significantly improved efficacy in EGFR wt population. This warrants further study into the COX-2-dependent mechanisms of primary resistance to EGFR TKI therapy. Supported by NIH 1P50 CA90388, K12 CA01727 and medical research funds from the Dept of Veterans’ Affairs. [Table: see text]

Safety and efficacy of everolimus in Asian patients with metastatic renal cell carcinoma (mRCC) who failed previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy: A subanalysis of REACT.

e15064 Background: Some targeted agents have shown variable safety profiles in Asian vs non-Asian patients with mRCC. A retrospective analysis of sunitinib in Korean patients with mRCC found increased incidence and severity of certain adverse events (AEs) compared with previous global trials (Hong et al. Cancer Res Treat. 2009;41:67-72). The open-label, expanded-access program REACT (RAD001 Expanded Access Clinical Trial in RCC; NCT00655252) provided everolimus, a mammalian target of rapamycin (mTOR) inhibitor, before its regulatory approval to 1367 patients with VEGFr-TKI refractory mRCC from 34 countries. Final results of REACT were recently published (Grünwald et al. Eur J Cancer. 2012;48:324-332). This analysis compared study end points in Asian patients with those in the total REACT population. Methods: The primary objective of REACT was to assess the safety of everolimus 10 mg/day, as determined by the overall occurrence of grade 3/4 AEs. Best overall tumor response was evaluated based on RECIST 1.0. Results: Baseline characteristics of Asian patients (n = 109; from South Korea, Taiwan, Thailand, and Singapore) were similar to those of the total study population. Median duration of everolimus exposure was longer in Asian patients than in the total population: 24.1 (range, 2.0-72.7) vs 14.0 (0.1-83.7) weeks. Overall incidence of grade 3/4 AEs was slightly higher in Asian patients than in the total population (70.6% vs 61.6%); common grade 3/4 AEs in Asian patients and the total population, respectively, included anemia (26.6% vs 13.4%), hyperglycemia (11.9% vs 5.5%), pneumonia (10.1% vs 4.2%), stomatitis (6.4% vs 5.4%), thrombocytopenia (3.7% vs 1.0%), and pneumonitis (3.7% vs 2.7%). More patients in the Asian population than in the total population had achieved disease control: partial response, 3.7% vs 1.7%; stable disease, 67.0% vs 51.6%. Conclusions: In this subanalysis of REACT, Asian patients treated with everolimus experienced a greater clinical benefit with a slightly higher incidence of AEs. These results are supportive of the use of everolimus in the Asian population.

International, expanded access program of everolimus in patients with metastatic renal cell carcinoma (mRCC) who progressed after previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy (VEGFr-TKI): Subanalysis from emerging growth market (EGM) countries.

e15047 Background: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor shown to benefit patients with mRCC after failure of initial VEGFr-TKI therapy. In the phase 3 RECORD-1 trial, median progression-free survival was 4.9 months with everolimus and 1.9 months with placebo (hazard ratio, 0.33; P &lt; .001). REACT (RAD001 Expanded Access Clinical Trial in RCC; NCT00655252) was an open-label, expanded access program that provided everolimus before commercial availability to 1367 patients with VEGFr-TKI refractory mRCC in 34 countries. Final results of REACT were recently published (Eur J Cancer. 2012;48:324-332). Methods: The primary objective of REACT was to evaluate the long-term safety of everolimus 10 mg/day as determined by the overall incidence of grades 3 and 4 adverse events (AEs). Best overall tumor response was assessed according to RECIST 1.0. This subanalysis was conducted to assess primary and secondary end points in a subgroup of patients from 11 EGM countries: Turkey, Australia, Russia, Israel, Lebanon, Jordan, Saudi Arabia, South Korea, Singapore, Taiwan, and Thailand. Results: Baseline characteristics of the EGM population (n = 243) were similar to the overall REACT population: median age, 60.0 years; clear cell histology, 95.1%; and progression on/intolerance to previous VEGFr-TKI therapy, 89.7%/16.9%. Median duration (range) of everolimus exposure was 20.4 (0.3-83.7) weeks. Clinical benefit was observed in 60.1%/53.3% of EGM patients/all patients (stable disease, 55.6%/51.6%; partial response, 4.5%/1.7%). Common grade ≥3 AEs in EGM patients/all patients included anemia (19.8%/13.4%), pneumonia (7.4%/4.2%), hyperglycemia (7.0%/5.5%), stomatitis (5.8%/5.4%), and pneumonitis (2.9%/2.7%); 13.2%/16.6% of EGM patients/all patients discontinued because of AEs. Conclusions: In patients from EGM countries, safety findings and tumor responses were consistent with the overall REACT population and with RECORD-1. Everolimus was well tolerated, with no new safety issues identified.