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Findings from the phase 3 First-Line ErbituX in lung cancer (FLEX) study showed that the addition of cetuximab to first-line chemotherapy significantly improved overall survival compared with chemotherapy alone (hazard ratio [HR] 0·871, 95% CI 0·762-0·996; p=0·044) in patients with advanced non-small-cell lung cancer (NSCLC). To define patients benefiting most from cetuximab, we studied the association of tumour EGFR expression level with clinical outcome in FLEX study patients.We used prospectively collected tumour EGFR expression data to generate an immunohistochemistry score for FLEX study patients on a continuous scale of 0-300. We used response data to select an outcome-based discriminatory threshold immunohistochemistry score for EGFR expression of 200. Treatment outcome was analysed in patients with low (immunohistochemistry score200) and high (≥200) tumour EGFR expression. The primary endpoint in the FLEX study was overall survival. We analysed patients from the FLEX intention-to-treat (ITT) population. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798.Tumour EGFR immunohistochemistry data were available for 1121 of 1125 (99·6%) patients from the FLEX study ITT population. High EGFR expression was scored for 345 (31%) evaluable patients and low for 776 (69%) patients. For patients in the high EGFR expression group, overall survival was longer in the chemotherapy plus cetuximab group than in the chemotherapy alone group (median 12·0 months [95% CI 10·2-15·2] vs 9·6 months [7·6-10·6]; HR 0·73, 0·58-0·93; p=0·011), with no meaningful increase in side-effects. We recorded no corresponding survival benefit for patients in the low EGFR expression group (median 9·8 months [8·9-12·2] vs 10·3 months [9·2-11·5]; HR 0·99, 0·84-1·16; p=0·88). A treatment interaction test assessing the difference in the HRs for overall survival between the EGFR expression groups suggested a predictive value for EGFR expression (p=0·044).High EGFR expression is a tumour biomarker that can predict survival benefit from the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC. Assessment of EGFR expression could offer a personalised treatment approach in this setting.Merck KGaA.

A prognostic index for second-line chemotherapy of NSCLC was previously developed, based on individual patient data (IPD) of nine randomized trials. In order to validate the prognostic score in an external dataset, we analysed IPD of a non-inferiority phase III trial comparing vinflunine vs. docetaxel in second-line treatment of advanced NSCLC. Primary endpoint of this analysis was overall survival (OS). The following variables were considered for survival analysis and score calculation: gender, performance status, stage of disease, tumour histology, type of first-line treatment, response to first-line treatment. Cox model, stratified by treatment arm, was used for multivariate analysis. Individual prognostic scores were derived, and patients were divided into 3 categories:5 (best), 5-9 (intermediate),9 (worst). All 551 patients enrolled in the trial had complete information for the calculation of prognostic score. Median OS in the whole group was 6.9 months, with similar efficacy in the two treatment arms. Median OS was 12.9, 6.9 and 3.8 months in the best, intermediate and worst category, respectively. Cox model showed a significant effect comparing intermediate vs. best category (Hazard Ratio 1.79, 95%CI 1.31-2.47, p=0.0003) and comparing worst vs. best category (Hazard Ratio 3.25, 95%CI 2.18-4.83, p0.0001). The C-index of the model was high (0.926), indicating a good discrimination according to the proposed three risk categories. Prognostic ability of our score for candidates to second-line treatment in advanced NSCLC was successfully validated, allowing the identification of subgroups of patients with more vs. less favourable outcome. Prognostic score could be useful in daily decision-making in clinical practise, because a better understanding of factors conditioning life expectancy of patients could greatly help a careful evaluation of risks and benefits associated with therapeutic decisions.

Background: Chemotherapy is the principal treatment method for patients with advanced non-small-cell lung cancer (NSCLC). Treatment with platinum-based and novel chemotherapeutic regimens, compared to monotherapy, slightly increases the response rates to 20-40%. The predictive and prognostic values of molecular factors are highly variable; however, data on clinical-demographic factors are still burdened by significant limitations. Objectives: The aim of this study was to assess the prognostic value of synaptophysin and chromogranin A protein expression in patients receiving palliative chemotherapy for advanced NSCLC. Methods: The study population consisted of 23 women and 116 men. The median age was 57.3 years. Expression of synaptophysin and chromogranin was assessed using a two-step model of immunohistochemical staining. Level 0 represented lack of activity, while level 1 represented its expression. Results: Expression of synaptophysin and chromogranin A was observed in 12 (8.6%) and 5 (3.6%) patients, respectively. The risk of death was significantly lower in patients with expression of synaptophysin (p = 0.008) and chromogranin A (p = 0.014). The 12- and 24-month survival rate of patients with synaptophysin expression was 64% (95% CI 0.35-0.93), while for patients without expression it was 46% (95% CI 0.36-0.56) and 16% (95% CI 0.07-0.25), respectively. The 12- and 24-month survival rate of patients with chromogranin expression was 80% (95% CI 0.44-1.00), while for chromogranin A-negative patients it was 47% (95% CI 0.37-0.57) and 19% (95% CI 0.10-0.28), respectively. We did not observe associations between expression of synaptophysin and chromogranin A and the other typical prognostic factors. Conclusions: Expression of synaptophysin and chromogranin A was associated with a longer median overall survival and might have prognostic value. These results should be confirmed in a prospective study.

Background: We evaluated the effectiveness of docetaxel or erlotinib in second-line treatment of non-small cell lung cancer (NSCLC) and focused on the impact of predictive factors on the outcome of therapy. Methods: 204 patients with progressive disease after platinum-based therapy were enrolled: 102 received an infusion of 75 mg/m2 of docetaxel and 102 received 150 mg of erlotinib orally. Results: Response rate (RR) was 6.9 and 8.8% for docetaxel and erlotinib, respectively. Progression-free survival (PFS) was 1.2 months for docetaxel and 1.6 months for erlotinib (hazard ratio, HR = 1.2, p = 0.17). Overall survival was 5.5 versus 7 months for docetaxel and erlotinib, respectively (HR = 1.35, p = 0.06). Using Cox regression, we found clinical factors (performance status and weight loss) with predictive values for RR and PFS in second-line-treated patients. Prior radiotherapy, smoking status and EGFR mutation might help to predict outcome of erlotinib treatment and βIII-tubulin mRNA expression that of docetaxel, but histopathological diagnosis did not have any predictive value. Conclusions: Erlotinib and docetaxel show similar efficacy in the treatment of NSCLC. The application of predictive factors may facilitate qualification for second-line treatment with both drugs.

Polymorphisms in genes encoding CD28, ICOS, and CTLA-4 were demonstrated to be associated with susceptibility to malignancies. To the best of our knowledge, no study on this association has been performed in a Caucasian population for non-small-cell lung cancer (NSCLC). In the present work, we investigated the polymorphisms CTLA-4c.49A>G (rs231775), CTLA-4g.319C>T (rs5742909), CTLA-4g.*642AT(8_33), CTLA-4g.*6230G>A (CT60) (rs3087243), CTLA-4g.*10223G>T (Jo31) (rs11571302), CD28c.17+3T>C (rs3116496), and ICOSc.1554+4GT(8_15) in 208 NSCLC patients and 326 controls. The distributions of the allele and genotype were similar in both groups for CTLA-4, CD28, and ICOS gene polymorphisms. However, we noted a tendency toward overrepresentation of individuals possessing the CTLA-4c.49A>G[A] allele in NSCLC patients compared with controls (0.84 vs 0.79, p = 0.09). The association became significant compared with controls in women for the CTLA-4c.49A>G[A] allele and CTLA-4c.49A>G[AA] genotype (0.67 vs 0.54, p = 0.01, and 0.47 vs 0.30, p = 0.02; respectively). Moreover, the constellation of alleles CTLA-4c.49A>G[A]/CT60[G]/CD28c.17+3T>C[T]/ICOSc.1554+4GT(8_15)[>10] increased the risk of NSCLC about 2-fold (p = 0.002). The same constellation of alleles combined with smoking, CTLA-4g.319C>T[T], and ICOSc.1554+4GT(8_15)[>10] was associated with a decreased overall survival rate. In conclusion, the constellation of specific alleles in CTLA-4, CD28, and ICOS genes contributes to the susceptibility and clinical course of NSCLC.

Background: Tyrosine kinase inhibitors of EGFR (TKI-EGFR) induced response in only 10% of Caucasian non-small-cell lung cancer patients in second- or third-line treatment. Independent predictive factors for qualification to TKI-EGFR treatment have not been assessed. In 2008, a prognostic index was reported for patients treated with erlotinib in the BR.21 trial, but its application for real, unselected patients is limited. Objectives: Based on clinical and molecular factors of patients treated with erlotinib, we tried to create a predictive index which could be applied in real treatment practice. Methods: In a Cox regression model, we established 6 factors which affected overall survival for erlotinib treatment: performance status, erlotinib-induced rash, time from diagnosis to treatment, gender, weight loss and LDH level. We analyzed the risk factors of early progression and survival shorter than 6 months. In addition we included: time from first-line chemotherapy to erlotinib treatment, smoking status, mutation status in EGFR and anemia. Results: Our model consisted of 10 factors that were assigned points according to HR or χ2 and p value. The score was used to separate patients into 4 risk categories of unfavorable disease course based on 10th, 50th and 90th percentiles: low risk (I), intermediate low risk (II), intermediate high risk (III) and high risk (IV). Survival probability was significantly higher for group I, intermediate for groups II and III, and significantly lower for group IV (χ2 = 49.5, p < 0.0001). Based on the previously reported index we could not qualify our patients for the low risk group. Conclusions: Our model could be useful for qualification for erlotinib treatment of patients with numerous adverse factors and limited access to genetic examination.

International audience; BACKGROUND: A previously published study of temozolomide concurrent with whole-brain radiation therapy (WBRT) reported significant improvement in response rates and a nonsignificant trend toward improved overall survival compared with WBRT alone in patients with brain metastases primarily from lung cancer. This study sought to confirm the benefit of adding temozolomide to WBRT in patients with non-small-cell lung cancer (NSCLC) with brain metastases. PATIENTS AND METHODS: This planned phase III study (target = 380 events) was converted to a phase II study (target = 70 events) because of poor enrollment. Patients with NSCLC and > or = 1 newly diagnosed brain lesion were randomized to WBRT (30 Gy in 10 fractions) alone or combined with temozolomide (75 mg/m2/day) for 21 or 28 days. Endpoints included overall survival and time to central nervous system (CNS) progression. RESULTS: Median overall survival and median time to CNS progression was 4.4 and 3.1 months in the WBRT + temozolomide arm (n = 47) versus 5.7 and 3.8 months in the WBRT arm (n = 48). However, there were imbalances in the percentages of patients receiving previous chemotherapy and with synchronous brain metastases. Adding temozolomide to WBRT increased the frequency of nausea, vomiting, alopecia, fatigue, anorexia, and constipation. Most adverse events were mild to moderate. CONCLUSION: The benefit of adding temozolomide to WBRT was not confirmed; however, the accrual goal for the planned phase III trial was not reached, and the study regimen differed from regimens used previously. Therefore, the role of temozolomide in treating brain metastases remains unresolved.

Purpose To compare vinflunine (VFL) to docetaxel in patients with stage IIIB/IV non–small-cell lung cancer (NSCLC) who have experienced treatment failure with first-line platinum-based chemotherapy. Patients and Methods Randomized, multicenter, phase III study, 551 patients received either vinflunine 320 mg/m2 or docetaxel 75 mg/m2 every 21 days until disease progression or serious toxicity. The primary end point was progression-free survival (PFS). The noninferiority analysis was based on a 10% difference (types I/II error rates: 5%/20%). Secondary end points included response rate (ORR), response duration, overall survival (OS), clinical benefit, quality of life (QOL), and safety. Results Median PFS was 2.3 months for each arm (HR, 1.004; 95% CI, 0.841 to 1.199). ORR, stable disease, median OS, were 4.4% versus 5.5%, 36.0% versus 39.6%, 6.7 versus 7.2 months (HR, 0.973; 95% CI, 0.805 to 1.176), respectively. No significant difference in patient benefit and QOL (Functional Assessment of Cancer Therapy-Lung). No unexpected adverse events were observed. Grade higher than 0 (vinflunine v docetaxel) anemia (82.1% v 79.8%), neutropenia (49.3 v 39.02%), thrombocytopenia (30.6% v 14.3%), febrile neutropenia (3.3% v 4.7%), constipation (39.2% v 11.7%), fatigue (36.6% v 33.9%), injection site reaction (31.9% v 0.7%), nausea (26.7% v 23.7%), vomiting (23.8% v 14.2%), alopecia (19.8% v 35.4%), stomatis (19.4% v 12.4%), abdominal pain (20.1% v 3.6%), myalgia (14.7% v 6.6%), peripheral neuropathy (10.7% v 15.0%), arthralgia (7.0% v 7.7%), diarrhea (6.2% v 12.4%), edema (1.5% v 5.4%), and nail disorders (1.1% v 5;1%) were observed. Conclusion This noninferiority phase III study showed similar efficacy end points for vinflunine and docetaxel. Despite higher rates of some adverse effects (anemia, abdominal pain, constipation, fatigue) the overall toxicity profile of vinflunine was manageable. Therefore, VFL may be another option in the second-line treatment of patients with advanced NSCLC.

Purpose This phase III, multicenter, randomized, placebo-controlled trial assessed the efficacy and safety of sorafenib, an oral multikinase inhibitor, in combination with carboplatin and paclitaxel in chemotherapy-naïve patients with unresectable stage IIIB or IV non–small-cell lung cancer (NSCLC). Patients and Methods Nine hundred twenty-six patients were randomly assigned to receive up to six 21-day cycles of carboplatin area under the curve 6 and paclitaxel 200 mg/m2 (CP) on day 1, followed by either sorafenib 400 mg twice a day (n = 464, arm A) or placebo (n = 462, arm B) on days 2 to 19. The maintenance phase after CP consisted of sorafenib 400 mg or placebo twice a day. The primary end point was overall survival (OS); secondary end points included progression-free survival and tumor response. Results Overall demographics were balanced between arms; 223 patients (24%) had squamous cell histology. On the basis of a planned interim analysis, median OS was 10.7 months in arm A and 10.6 months in arm B (hazard ratio [HR] = 1.15; 95% CI, 0.94 to 1.41; P = .915). The study was terminated after the interim analysis concluded that the study was highly unlikely to meet its primary end point. A prespecified exploratory analysis revealed that patients with squamous cell histology had greater mortality in arm A than in arm B (HR = 1.85; 95% CI, 1.22 to 2.81). Main grade 3 or 4 sorafenib-related toxicities included rash (8.4%), hand-foot skin reaction (7.8%), and diarrhea (3.5%). Conclusion No clinical benefit was observed from adding sorafenib to CP chemotherapy as first-line treatment for NSCLC.

Anorexia-cachexia syndrome (ACS) often occurs in patients with advanced cancer.To review the effect of megestrol acetate (MA) in patients with ACS.To identify eligible studies, systematic review by Lopez et al. (2004) was used, electronic databases (MEDLINE, EMBASE and CENTRAL) were searched and reference lists of included studies were reviewed. The studies were included in the review if they were randomized, enrolled patients with non-hormone-sensitive cancer and ACS and assessed the effects of MA compared with placebo, other drugs or different doses of MA.The study population is characterized by high mortality and progressive weight loss irrespective of the treatment. Compared to placebo, the effect of MA on survival is similar, but MA increases appetite (number needed to treat [NNT]: 3) and leads to weight gain (NNT: 8) in more patients. The data on other aspects of the quality of life are limited. The comparison of MA and glucocorticosteroids showed no statistical difference in their effect on appetite and weight.Compared to placebo, MA reduces the symptoms of ACS, with no effect on survival. The beneficial effect of MA on the overall quality of life has not been confirmed. In identified studies the effect of MA and glucocorticosteroids on anorexia and cachexia is similar. The estimation of the treatment utility in ACS depends on the weight attributed to discomfort caused by symptoms, adverse effects of the drugs and the treatment cost. Because of the low quality of the included studies a new randomized controlled trial is needed for valid assessment of the effects of MA.

We have recently observed an increased interest in gastro-entero-pancreatic neuroendocrine tumors (GEP NET). They are rare cancer types and therefore collaborative effort of specialists in various disciplines of medicine is necessary to work out the diagnostic and therapeutic guidelines. In this publication we present general guidelines of the Polish Network of Neuroendocrine Tumors for the management of patients with GEP NET, developed at the Round Table Conference which took place in Kliczków near Wrocław in November 2007. In the subsequent parts of this publication, we present the rules of diagnostic and therapeutic management of: - endocrine tumors of the stomach and duodenum (including gastrinoma); - pancreatic endocrine tumors; - neuroendocrine tumors of the small intestine and the appendix; - neuroendocrine tumors of the colon. We hope that the proposed guidelines by Polish and foreign experts representing various disciplines of medicine, including endocrinology, gastroenterology, surgery, oncology, nuclear medicine and pathomorphology, will become a useful tool in the diagnostics and treatment of these patients.

Pancreatic endocrine tumors (PETs) are rare neoplasms of this organ. The majority of PETs are tumors without hormonal activity. In this publication, we present the diagnostic and therapeutic guidelines for the management of these tumors proposed by the Polish Network of Neuroendocrine Tumors. These guidelines refer to biochemical and location diagnostics, including scintygraphy of somatostatin receptors, endoscopic ultrasonography and other anatomical and functional imaging methods. High importance is attached to correct histopathological diagnosis which determines further management of patients with PETs. Antitumor therapy requires multidirectional procedure, and therefore the rules of surgical treatment, biotherapy, chemotherapy and peptide receptor radionuclide therapy are discussed.

Introduction This phase III trial was conducted in non-small cell lung cancer patients with locally advanced stage II B (only T3N0) III A and III B (only T4 N0). Primary endpoint was 2-year survival; secondary were toxicity, disease-free survival, and overall survival. Methods After three cycles of vinorelbine (N) 25 mg/m 2 on days 1 and 5, ifosfamide/mesna (I) 3 g/m 2 on day 1, cisplatin (P) (NIP), patients were treated by surgery and within 45 days were randomized to two additional cycles of NIP versus observation. Results Median tumor diameter was 5.5 cm (1.2–10.6). Overall, 155 of 156 patients received chemotherapy: 133 (85%) men, median age: 59 years (35–75). Sixty-five percentage of patients were stage III A, 28% II B, and 7% III B. The study has been closed prematurely because of the low inclusion rate. After three cycles of induction in 143 assessable patients, 82 reported an objective response (57.3%) (95% CI: 48.8–65.6), with 3.5% complete response and 53.8% partial response. Relative dose intensity during neoadjuvant NIP (%) was 97, 98, and 98.5 for vinorelbine, ifosfamide/mesna, and cisplatin, respectively. Tolerance: G3 to 4 neutropenia in 3% of patients and G3 to 4 anemia in 4%; nonhematological toxicities included G3 nausea/vomiting in 11%, G3 anorexia and G3 to 4 infection in 6.5%, G3 asthenia in 10% and G3 to 4 alopecia in 25.5%. After a median of 32 days after NIP, 107 patients (69%) underwent operation with complete resection (R0) in 74% (79 of 107 patients). Downstaging (N2 to N0) after surgery was 29%. Operative mortality rate was 2.8%. Twenty-one days (median) after surgery, 79 patients were randomized to adjuvant NIP (47%) or control (53%). Tolerance of adjuvant NIP: 12.5% G3 to 4 nausea/vomiting, 19% G3 alopecia, 6% G3 infection, and G3 asthenia. Overall median survival 32.3 versus 31.8 months in the observation and NIP arms, respectively. Conclusions NIP allows 74% of R0 with no surgery delay. The few number of randomized patients did not allow to conclude on the efficacy of adjuvant chemotherapy.

The management of patients with skeletal metastases includes surgery, palliative radiotherapy and systemic treatment (chemotherapy, hormonotherapy, and the use of bisphosphonates). Hormonotherapy and chemotherapy in the treatment of skeletal metastases are most frequently used in patients with breast and prostate cancer and in patients with myeloma. Bisphosphonates in patients with skeletal metastases from those tumours allow for reduction of skeletal complications and improvement of their life quality.

Bone metastases (secondary bone neoplasms) represent a more significant epidemiological problem than primary bone neoplasms. The differing histogenesis of primary and secondary malignant bone neoplasms (respectively, mesenchymal and epithelial origin) influences the variability of activity and indications for systemic therapy. A common response is the use of systemic therapy within a multidisciplinary therapeutic approach. The principles of chemotherapy used for primary bone neoplasms are essentially similar in spindle-cell and small-cell sarcomas. Initial multi-drug chemotherapy should be administered in all stages. Chemotherapy may also be used following local treatment, although the role of adjuvant chemotherapy is better defined in small-cell sarcomas. Chemotherapy is also applied in the palliative management of disseminated sarcomas. Systemic therapy plays an essential role in the management of patients with bone metastases during the course of breast and prostate carcinoma. The use of hormonal therapy is based on endocrine dependency of both malignancies. Chemotherapy represents a treatment of choice in several clinical situations due to high chemosensitivity of the underlying malignancy (e. g., small-cell lung cancer or lymphoma). Bisphosphonates play an important role in the management of bone metastases. The use of bisphosphonates is most justified in patients with breast cancer, multiple myeloma, and prostate carcinoma.

Cancer-related anemia is a cytokine-mediated disorder resulting from complex interactions between tumor cells and the immune system. Overexpression of certain inflammatory cytokines results in shortened survival of red blood cells, suppression of erythroid progenitor cells, impaired iron utilization, and inadequate erythropoietin production. Numerous other factors may also contribute to the development of anemia in cancer patients. The European Cancer Anaemia Survey (ECAS) has provided the most current, comprehensive, prospectively collected data on the incidence and prevalence of anemia among cancer patients, as well as important perspectives on anemia treatment and relationship of hemoglobin and performance status. ECAS enrolled over 15,000 treated and untreated patients with various malignancies from cancer centers in 24 European countries and followed them for up to 6 months. The initial analysis of the ECAS data revealed that 39% of the total cancer patient population was anemic (hemoglobin

Background The authors previously reported the efficacy of a dose of 4 mg of zoledronic acid in reducing skeletal complications in patients with bone metastases secondary to lung carcinoma and other solid tumors (except carcinomas of the breast and prostate). In the current study, they update these results and report the long-term efficacy and safety of 21 months of treatment with zoledronic acid in a randomized, placebo-controlled trial. Methods A total of 773 patients were randomized to receive zoledronic acid (4 mg or 8 mg) or placebo via a 15-minute infusion every 3 weeks for 21 months. The 8-mg dose later was reduced to 4 mg (8/4-mg group). The primary efficacy endpoint was the percentage of patients at 21 months with >/= 1 skeletal-related event (SRE) (pathologic fracture, spinal cord compression, radiation therapy to bone, or surgery to bone). Secondary analyses (time to first SRE, annual incidence of SREs, and multiple-event analysis) included hypercalcemia of malignancy. Results Fewer patients treated with zoledronic acid developed at least 1 SRE at 21 months compared with patients treated with placebo (39% of those treated at the 4-mg dose [P =0.127] and 36% of those treated at the 8/4-mg dose [P = 0.023], compared with 46% of those treated with placebo). Furthermore, 4 mg of zoledronic acid significantly delayed the median time to first SRE (236 days with 4 mg vs. 155 days with placebo; P = 0.009) and significantly reduced the annual incidence of SREs (1.74 per year with the 4-mg dose vs. 2.71 per year with placebo; P = 0.012). Moreover, the 4-mg dose of zoledronic acid was found to reduce the risk of developing a skeletal event by 31% (hazard ratio of 0.693; P = 0.003). Zoledronic acid was found to be well tolerated with long-term use; the most commonly reported adverse events in all treatment groups included bone pain and the transient, acute-phase reactions of nausea, anemia, and emesis. Conclusions To the authors' knowledge, zoledronic acid is the first bisphosphonate to demonstrate long-term safety and efficacy in this patient population.

The purpose of our study was to evaluate CNS pathology due to chemotherapy neurotoxicity, using MRI and localized proton MRS in patients with lung cancer treated with cisplatine, Vinca alkaloids and etoposide. A reduction in N-acetylaspartate was expected as a result of chemotherapy neurotoxicity.31 patients aged 42 to 73 years underwent the following procedures before and after chemotherapy: clinical examination; MRI of the brain (Elscint Prestige 2T), MRS (PRESS sequence, TR 1500 ms, TE 80 ms) with volumes of interest (VOI) of 8 ml localized in the semi-oval center and a cerebellar hemisphere. The analysis of each patient's NAA/Cr and Cho/Cr ratios was carried out separately for the semi-oval center and cerebellum measurements.None of the patients demonstrated any clinical manifestations of the CNS neuropathy. MRI of the brain did not reveal any abnormalities caused by chemotherapy. Pre-treatment NAA/Cr and Cho/Cr ratios in the semi-oval center did not differ significantly from these measured after chemotherapy. However, the analysis of the cerebellar spectra showed a significant decrease in the NAA/Cr ratio (p0.05) and a time-related decrease in the Cho/Cr ratio (p0.05) after chemotherapy. An analysis of Pearson's correlations showed a very strong linear relationship between NAA/Cr and Cho/Cr ratios (p0.001), both in the semi-oval center and cerebellum.The decreased NAA/Cr ratio can indicate some neuronal loss caused by chemotherapy. The decrease in the Cho/Cr ratio could be associated with some myelin damage. The MRS results suggest the presence of a sub-clinical selective cerebellar neuropathy caused by chemotherapy. The MRS revealed that reaction to chemotherapy was different at the semi-oval center than that in the cerebellum. The results allow theorizing about an alternative or two-stage brain response to the neurotoxic factor found both in the cerebrum (the semi-oval center) and cerebellum. These initial results indicate that proton MR spectroscopy is a potentially useful modality for detecting an early stage of the CNS pathology caused by neurotoxicity of chemotherapy.

Purpose: To assess the efficacy and safety of zoledronic acid in patients with bone metastases secondary to solid tumors other than breast or prostate cancer. Patients and Methods: Patients were randomly assigned to receive zoledronic acid (4 or 8 mg) or placebo every 3 weeks for 9 months, with concomitant antineoplastic therapy. The 8-mg dose was reduced to 4 mg (8/4-mg group). The primary efficacy analysis was proportion of patients with at least one skeletal-related event (SRE), defined as pathologic fracture, spinal cord compression, radiation therapy to bone, and surgery to bone. Secondary analyses (time to first SRE, skeletal morbidity rate, and multiple event analysis) counted hypercalcemia as an SRE. Results: Among 773 patients with bone metastases from lung cancer or other solid tumors, the proportion with an SRE was reduced in both zoledronic acid groups compared with the placebo group (38% for 4 mg and 35% for 8/4 mg zoledronic acid v 44% for the placebo group; P = .127 and P = .023 for 4-mg and 8/4-mg groups, respectively). Additionally, 4 mg zoledronic acid significantly increased time to first event (median, 230 v 163 days for placebo; P = .023), an important end point in this poor-prognosis population, and significantly reduced the risk of developing skeletal events by multiple event analysis (hazard ratio = 0.732; P = .017). Zoledronic acid was well tolerated; the most common adverse events in all treatment groups included bone pain, nausea, anemia, and vomiting. Conclusion: Zoledronic acid (4 mg infused over 15 minutes) is the first bisphosphonate to reduce skeletal complications in patients with bone metastases from solid tumors other than breast and prostate cancer.

The aim of the study was to assess the frequency of serum Ab-anti-p53 in 39 patients with advanced NSCLC and to evaluate the predictive value of the test. Antibodies were present in 10 (25.6%) of patients. There was no correlation between Ab-anti-p53 and clinical characteristics including age, gender, and histological type of tumor. In 17 patients response to chemotherapy (CT) was obtained (in one patient--complete, and in 16--partial response). The percentage of patients responding to CT in group with and without serum antibodies did not differ significantly (33% and 48%, respectively; p = 0.48). The results of the study indicate that serum Ab-anti-p53 are relatively often present in advanced NSCLC patients, however the clinical value of this test needs further evaluation.

PURPOSE: Increased expression of metalloproteinases is associated with poor prognosis in small-cell lung cancer (SCLC). This trial was undertaken to determine whether adjuvant treatment with the metalloproteinase inhibitor marimastat could prolong survival in responding patients with SCLC after chemotherapy. PATIENTS AND METHODS: SCLC patients in complete or partial remission were eligible. They were stratified by radiotherapy (early, late, or none), stage (extensive or limited), response (complete or partial), and cooperative group (National Cancer Institute of Canada-Clinical Trials Group or European Organization for Research and Treatment of Cancer). They were randomized to receive marimastat 10 mg or placebo orally bid for up to 2 years. RESULTS: There were 532 eligible patients (266 marimastat and 266 placebo). Stage was limited for 279 patients (52%) and extensive for 253 (48%). Best response to induction therapy was complete remission for 176 patients (33%), partial remission for 341 (64%), and 15 patients (3%) had undergone surgical resection. The median time to progression for marimastat patients was 4.3 months compared with 4.4 months for placebo patients (P = .81). Median survivals for marimastat and placebo patients were 9.3 months and 9.7 months, respectively (P = .90) Toxicity was generally limited to musculoskeletal symptoms (18% grade 3/4 for marimastat). Dose modifications for musculoskeletal toxicity were required in 90 patients (33%) on the marimastat arm, and 87 (32%) permanently stopped marimastat because of toxicity. Patients on marimastat had significantly poorer quality of life at 3 and 6 months. CONCLUSION: Treatment with marimastat after induction therapy for SCLC did not result in improved survival and had a negative impact on quality of life.

Prospective clinical trials on cancer started in Central and Eastern Europe in the early 70s under the auspices of the Council of Mutual Economic Assistance (CMEA). The objective of the CMEA Chemotherapy Group was to conduct prospective phase III studies with particular focus on drugs developed in the member countries. The main organizational problems were insufficient contact with the Trial Center and the excessive formalism of the cooperation. In the mid-80s most of the clinical research was taken over by the new structure: the South and East European Oncology Group (SEEOG), later renamed the Central and East European Oncology Group (CEEOG). CEEOG is a drug-oriented group consisting currently of over 30 institutions from eight countries. Its major interests have included breast cancer, ovarian cancer, lung cancer and head and neck cancer. Most of the studies have been phase II trials carried out in cooperation with various international companies. Most recently another regional cooperative group has been created: the Central European Cooperative Oncology Group (CECOG), whose main objectives are to conduct phase III studies on new chemotherapy combinations.

Aim: Several Phase III studies confirm the efficacy of standard 2nd-line docetaxel (D) in advanced non-small cell lung cancer (NSCLC) patients (pts) previously treated with 1st-line paclitaxel-based therapy irrespective of tumour histology. In LUME-Lung 1, nintedanib (N)—an oral, triple angiokinase inhibitor of VEGF, PDGF and FGF signalling—has demonstrated clinically meaningful efficacy along with 2nd-line chemotherapy (NCT00805194; 1199.13). Here we report the efficacy and safety of N + D in pts previously treated with taxanes as part of a preplanned analysis. Methods: Stage IIIB/IV recurrent NSCLC pts (N = 1314) progressing after 1st-line chemotherapy were randomised 1:1 to receive either N 200 mg bid + D 75 mg/m2 q21d (n = 655) or placebo (Pl) + D (n = 659). Endpoints evaluated included progression-free survival (PFS) by central independent review, overall survival (OS) and safety. Chemotherapy with 1st-line D was an exclusion criterion; subgroup analyses according to the pt's use of 1st-line taxane therapy and NSCLC histology were also performed. Results: Pt characteristics were balanced across all groups. For all pts and those with adenocarcinoma (Ad) in particular, no significant difference in survival benefit was noted regardless of the use of 1st-line taxane therapy (Table). Comparison of N + D and Pl + D showed that the percentage of all pts with grade ≥3 adverse events (AEs) was slightly higher for pts in the N arm (no 1st-line taxane = 71.6% vs 65.5%; prior 1st-line taxane = 70.3% vs 59.4%). Consistent with overall findings in LUME-Lung 1, reversible increases in alanine and aspartate aminotransferases as well as diarrhoea were the AEs that were more common among all pts in the N arm. OS results for LUME-Lung 1 in NSCLC pts who received 1st-line taxane therapy All pts Pts with Ad No taxane 1st-line Taxane 1st-line No taxane 1st-line Taxane 1st-line N, n = 510 Pl, n = 519 N, n = 145 Pl, n = 140 N, n = 245 Pl, n = 271 N, n = 77 Pl, n = 65 Median OS, months 10.0 9.1 11.5 9.0 12.2 10.3 15.1 11.6 HR (95% CI); p-value 0.97 (0.85–1.11); p = 0.67 0.81 (0.62–1.06); p = 0.13 0.86 (0.71–1.05); p = 0.13 0.75 (0.51–1.11); p = 0.15 Interaction between treatment & subgroup variable, p-value p = 0.2562 p = 0.6135 Conclusions: On-study treatment with N + D resulted in a comparably favourable OS improvement regardless of whether pts with tumours of Ad histology were treated 1st line with a taxane- or non-taxane-containing platinum doublet. Disclosure: A. Mellemgaard: Advisory Board: Boehringer Ingelheim; J. von Pawel: Advisory Board/Consultant: AbbVie, Clovis, Daiichi Sankyo, Novartis, Pfizer, Vertex Pharmaceuticals; J. Barrueco: Employee: Boehringer Ingelheim Pharmaceuticals Inc., USA; B. Gaschler-Markefski and R. Kaiser: Employee: Boehringer Ingelheim Pharma GmbH KG, Germany S. Novello: Advisory Board/Honoraria/Invited Speaker: AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Roche; J. Douillard: Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck Serono, Roche; Educational Symposia: Amgen, AstraZeneca, Bayer; Research Grants: Merck Serono; M. Reck: Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Hoffmann-la Roche, Lilly, Novartis, Pfizer. All other authors have declared no conflicts of interest.

Aim: CIL is a selective, competitive inhibitor of avb3 and avb5 integrins designed to attack the tumour and its microenvironment. CERTO is a multicentre, controlled, open-label phase II study (NCT00842712) for pts with histologically confirmed newly diagnosed advanced NSCLC. Methods: Pts were initially randomised 1:1:1 to receive cetuximab plus platinum-based chemotherapy alone (CTRL), or combined with CIL 2000 mg 1x/week (CIL1W) or 2x/week (CIL2W). During the study, an amendment triggered by cetuximab data from the FLEX study led to enrolment only of pts with EGFR histoscore ≥200, and closure of CIL2W due to feasibility issues. Primary endpoint was progression-free survival (PFS; independent read); secondary endpoints included overall survival (OS), safety, and biomarker analyses. Results: Overall, 220 pts were randomised: 85 to CIL1W; 51 to CIL2W; and 84 to CTRL. Baseline characteristics were balanced. Median PFS (independent read, ITT) was 6.2 mo in CIL1W vs 5.0 mo in CTRL (HR 0.72 [95% CI, 0.49, 1.05]; p = 0.085). For pts with EGFR ≥200, median PFS was 6.8 mo in CIL1W vs 5.6 mo in CTRL (HR 0.57 [95% CI, 0.32, 0.99], p = 0.045). Investigator-read PFS was not different between CIL1W and CTRL in either population. Median OS was 13.6 vs 9.7 mo in CIL1W vs CTRL, respectively (ITT; HR 0.81 [95% CI, 0.56, 1.17]; p = 0.265); in pts with EGFR ≥200 no difference between CIL1W vs CTR for OS was found. Generally, no relevant differences between adverse events across treatment arms were reported; nausea (56%), neutropaenia (49%), and anaemia (37%) were the most frequent, and there was no increased incidence of thromboembolic events or haemorrhages in CIL-treated pts. Biomarker sample size was small, but avb3 and avb5 expression did not reveal a prognostic correlation to PFS or OS, and was not predictive of treatment outcome. Conclusions: A benefit for addition of CIL1W to cetuximab and chemotherapy was seen for independent-read PFS, and a HR 0.81 for OS, equivalent to a 3.9 mo median survival improvement in favour of the combination, but no consistent efficacy was shown with CIL vs CTRL. The safety profile did not reveal any safety concerns for CIL. Disclosure: J.F. Vansteenkiste: Advisory board: advisory functions for Merck-Serono; F. Barlesi: Corporate-sponsored research: Merck; J. Bennouna: Advisory Board: Roche, Boehringer Ingelheim and Novartis; E. Goekkurt: Advisory board: Merck; H. Lena: Advisory board: Merck; C. Hicking: Ownership: Stock Ownership Merck KGaA Other substantive relationships: Employee of trial sponsor; J. Straub: Other substantive relationships:: Employee of the trial Merck; M. Picard: Other substantive relationships: Employee of the trial sponsor; W. Schuette: Advisory Board: Merck, Amgen, AstraZeneca, Roche Corporate-sponsored research: Roche, Lilly, AstraZeneca, Amgen, Genentech, Daiichi Sankyo; K. O' Byrne: Advisory board: for cetuximab non small lung cancer Corporate-sponsored research: Grant received for clinical trial which was completed 5 years ago Other substantive relationships: Honoraria for speaker bureau lectures. All other authors have declared no conflicts of interest.

Aim: Nintedanib (N) is an oral, triple angiokinase inhibitor of VEGF, PDGF and FGF signalling. Primary analysis of the LUME-Lung 1 trial (NCT00805194; 1199.13) showed a significant improvement in PFS with N + docetaxel (D) in NSCLC patients (pts) regardless of histology; OS was also significantly improved in adenocarcinoma (adeno) pts. Pemetrexed (PEM) is a standard 1st-line and maintenance treatment for nonsquamous NSCLC pts. To determine whether prior PEM would influence outcomes of pts in LUME-Lung 1, we evaluated the efficacy and safety of N + D in pts who received 1st-line and maintenance PEM. Methods: 1314 pts with Stage IIIB/IV recurrent NSCLC were randomised to receive either N 200 mg bid + D 75 mg/m2 q21d (n = 655) or placebo (Pl) + D (n = 659) in LUME-Lung 1. Retrospective subgroup analyses according to prior PEM treatment (1st line or maintenance) were performed to determine OS and safety. Results: The percentage of pts with adeno tumour histology who were treated 1st line with PEM along with platinum was approximately 19% (N arm, n = 61; Pl arm, n = 65). Pt characteristics were balanced across groups. OS results according to receipt of any PEM 1st-line and maintenance therapy for adeno pts are shown in the table. For all pts and those with adeno histology in particular, no significant difference in OS was noted between those who did or did not receive PEM; no significant interaction between treatment groups and any PEM treatment was observed. Further, slightly more pts in the N arms across all subgroups experienced grade ≥3 adverse events; diarrhoea and reversible increases in liver enzymes occurred more frequently in pts in both N arms. OS results in NSCLC pts with adeno histology who received 1st-line and/or maintenance PEM No PEM 1st-line PEM 1st-line No maintenance PEM 1st-line Maintenance PEM 1st-line N n = 261 Pl n = 271 N n = 61 Pl n = 65 N n = 309 Pl n = 322 N n = 13 Pl n = 14 Median OS, months 13.4 10.8 12.0 8.0 12.6 10.0 18.9 12.8 HR (95% CI); p-value 0.83 (0.68–1.00); p = 0.05 0.79 (0.53–1.18); p = 0.25 0.84 (0.70–1.00); p = 0.05 0.78 (0.30–2.07); p = 0.62 Interaction between treatment & subgroup variable, p-value p = 0.9026 p = 0.7162 Conclusions: On-study treatment with N + D resulted in a comparably favourable improvement in OS regardless of whether pts with adeno tumours were treated 1st line with a PEM- or non-PEM-containing platinum doublet. Disclosure: A. Mellemgaard: Advisory Board: Boehringer Ingelheim; J. von Pawel: Advisory Board/Consultant: AbbVie, Clovis, Daiichi Sankyo, Novartis, Pfizer, Vertex Pharmaceuticals; J. Barrueco: Employee: Boehringer Ingelheim Pharmaceuticals Inc., USA; H. Buchner, J. Hocke and R. Kaiser: Employee: Boehringer Ingelheim Pharma GmbH KG, Germany;S. Novello: Advisory Board/Honoraria/Invited Speaker: AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Roche; J. Douillard: Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck Serono, Roche; Educational Symposia: Amgen, AstraZeneca, Bayer; Research Grants: Merck Serono; M. Reck: Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Hoffmann-la Roche, Lilly, Novartis, Pfizer. All other authors have declared no conflicts of interest.

8100 Background: Antiangiogenic treatments, including monoclonal antibodies and TKIs, have shown activity in tumors; however, their use is limited in part by their characteristic side effects (eg, ...

• The current randomised, Phase III study (LUME-Lung 1; NCT00805194) was designed to investigate the efficacy and safety of nintedanib 200 mg twice daily (bid) in combination with docetaxel versus placebo and docetaxel for the treatment of patients with advanced or recurrent NSCLC who had previously failed first-line chemotherapy – during this study, patient-reported quality of life (QoL) was recorded at regular intervals using standard QoL questionnaires and so the effect of treatment on prespecified symptoms of interest in patients with NSCLC is also examined RESULTS

Lung cancer causes about 1.2 million deathsworldwide annually [...]

The efficacy and toxicity profile of gemcitabine was evaluated in this phase II study of chemonaive patients with locally advanced and metastatic non-small cell lung cancer (NSCLC). Eighty patients (62 males, 18 females) were entered into this study. The disease stage was IIIA in ten patients, IIIB in 32, and IV in 38 patients. The median age was 61 (range 41 - 78). Karnofsky performance status was > or = 80 in 88% of patients. All patients were chemonaive, but five patients had received prior radiotherapy and 34 patients had undergone prior surgery. Gemcitabine 1250 mg/m2 was given as a 30-min intravenous infusion on days 1, 8, and 15 of a 28-day cycle. Patients received up to nine cycles (median three cycles). Of 872 doses 815 (93%) were administered without dose delay or modification. Of the 80 patients enrolled, 76 were evaluable for efficacy analysis, and 16 patients had a partial response for an overall response rate of 21.1% (95% CI, 11.9-30.3%). A further 47 patients (61.8%) had stable disease. Partial responses were seen in eight of 41 stage III patients (19.5%) and in eight of 35 stage IV patients (22.9%). The median time to progressive disease was 4.6 months. Median survival for all 80 patients was 7.1 months. Haematological toxicity was mild with grade 3 4 neutropenia in 6.3% of patients, grade 3 thrombocytopenia in 3.8% of patients, and grade 3 anaemia in 2.5% of patients. Grade 3 non-laboratory toxicity was: somnolence (1.3% of patients), infection (1.3%), nausea and vomiting (6.4%) and dyspnoea (5.1%). This study confirms that single-agent gemcitabine is active in advanced NSCLC and its well-tolerated safety profile makes it particularly suited to outpatient use.

LBA8011 Background: Nintedanib (N) inhibits VEGFRs, PDGFRs, and FGFRs. LUME Lung 1 is a placebo (P) controlled phase III trial of N + docetaxel (D) in patients (pts) with locally advanced/metastatic NSCLC progressing after first-line therapy. Methods: Stage IIIB/IV or recurrent NSCLC pts (stratified by histology, ECOG PS, prior bevacizumab, and brain metastases) were randomized to N 200 mg bid + D 75 mg/m2 q21d (n=655) or P + D (n=659). 1° endpoint was centrally reviewed PFS after 713 events (2 sided stratified log-rank, α=5%, β=10%). Key 2° endpoint of OS was analyzed hierarchically after 1,121 events (2 sided, adjusted α=4.98%, β=20%), first in adenocarcinoma (adeno) pts line therapy (T

8043 Background: NVBo+P is considered as a standard treatment in M or LA NSCLC. The recent approval of Pem+P as front line chemotherapy (CT) for non SCC demonstrates that today, histology could become a “new guidance” to treat patients (pts). The importance of histological types was highlighted in a phase III trial (Scagliotti. JCO 2008). Moreover, the higher chemosensitivity of non SCC is recognised and reported with other chemotherapies (Ardizzoni. JNCI 2007). In GLOB 3 study, NVBo+P also showed better survival in adenocarcinoma (11.7m) than in SCC (8.9m) (Tan. Ann Oncol. 2009). This trial was set up to assess the efficacy of NVBo+P (Arm A) and Pem+P (Arm B) for pts with Non SCC histological type, evaluated in terms of Disease Control Rate (DCR) (SD+PR+CR). Methods: Pts were randomised to receive q3w NVBo 80 mg/m² D1D8 (60 at Cycle 1) + P 80 mg/m² D1 (Arm A) or Pem 500 mg/m² + P 75 mg/m² D1 (Arm B). After 4 cycles of combination, pts with DCR received single agent NVBo (Arm A) or PEM (Arm B) as maintenance until progression or toxicity. Pts were randomised on a 2/1 basis and stratified according to stage (IIIB - IV - relapse), non SCC confirmed by histology or cytology, gender, smoking status and centre. Results: From 11/09 to 02/11, 153 pts were randomised to Arm A (102 pts) or Arm B (51 pts). DCR after combination and maintenance was 75.0% (95% CI, 65.3 to 83.1) in Arm A and 76.5% (95% CI, 62.5 to 87.2) in Arm B. Median PFS was 4.2 (95% CI, 3.6 to 4.7) and 4.3 months (95% CI, 3.8 to 5.6) in Arm A and Arm B, respectively. Median OS was 10.2 months (95% CI, 7.8 to 11.9) and 10.8 months (95% CI, 7.0 to16.4) in Arm A and Arm B, respectively. During the combination period grade 3/4 neutropenia was 44.0% in Arm A and 18.3% in Arm B but febrile neutropenia was 2% in both arms; grade 3/4 thrombopenia was 0% and 6% in Arm A and Arm B, respectively. Conclusions: Even if the current results should be confirmed in a phase III study, the choice of a platinum-based doublet with oral vinorelbine as front-line chemotherapy could be a useful alternative in non SCC. Clinical trial information: 2009-012001-19.

7500 Background: L-BLP25 is a MUC1 antigen specific cancer immunotherapy. We report results from the phase III START study of L-BLP25 in patients (pts) not progressing after primary chemoradiotherapy (CRT) for stage III NSCLC. Methods: From Jan 2007 to Nov 2011, 1513 pts with unresectable stage III NSCLC that did not progress after CRT (platinum based chemo and ≥50 Gy) were randomized (2:1; double-blind) to L-BLP25 (806 µg lipopeptide) or placebo (PBO) SC weekly x 8 then Q6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m2 x 1 or saline was given 3 days prior to first L-BLP25/PBO dose. Primary endpoint was overall survival (OS). Results: The primary analysis population (n=1239) was defined prospectively to try to account for a clinical hold by excluding pts randomized 6 months (m) before the hold. Arms were balanced for baseline characteristics. Median age was 61 y; 38.2% had stage IIIA and 61.3% IIIB; 65% had concurrent and 35% sequential CRT. Median OS was 25.6 m with L-BLP25 vs. 22.3 m with PBO (adjusted HR 0.88, 95% CI 0.75-1.03, p=0.123). Secondary endpoints time-to-progression and time-to-symptom-progression support consistency of results: HR 0.87 (95% CI 0.75-1.00, p=0.053) and 0.85 (95% CI 0.73-0.98, p=0.023). In predefined subgroup analyses, pts with concurrent CRT (n=806) had median OS of 30.8 m (L-BLP25) vs. 20.6 m (PBO; HR 0.78, 95% CI 0.64-0.95, p=0.016), while median OS with sequential CRT was 19.4 m (L-BLP25) vs. 24.6 m (PBO; HR 1.12, 95% CI 0.87-1.44, p=0.38; interaction p=0.032, Cox PH model). Sensitivity analyses revealed that there was no OS benefit in pts randomized 6 m before the hold (HR 1.09, CI 0.75-1.56, p=0.663). LEBLP25 was well tolerated with no safety concerns identified and no emergent evidence of immune related adverse events. Conclusions: L-BLP25 maintenance therapy in stage III NSCLC was well tolerated, but did not significantly prolong OS. Sensitivity analyses showed a smaller treatment effect due to the clinical hold, suggesting that longer uninterrupted treatment with L-BLP25 is required. Clinically meaningful prolongation of OS was observed in the predefined subgroup of pts with primary concurrent CRT. Clinical trial information: NCT00409188.

LBA8011 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.

Background: Amuvatinib is an oral multi-targeted TKI of c-Kit and PDGFRα and modulates DNA repair by down regulation of Rad51. Rad51 is a key protein in the homologous recombination repair pathway for DNA double strand breaks which can mediate resistance to DNA-damaging agents. Amuvatinib has demonstrated synergistic activity preclinically with DNA damaging chemotherapy agents including etoposide and doxorubicin. Amuvatinib in combination with DNA damaging agents resulted in clinical responses in SCLC patients, induced Rad51 suppression, and increased DNA damage (53BP1 foci) in skin punch biopsies. These results provided the justification for a Phase 2, OL study of amuvatinib in combination with platinum and etoposide (PE) chemotherapy in SCLC patients who have not responded to or relapsed after standard treatment (ESCAPE; TrEatment of Small Cell lung cancer with Amuvatinib in combination with Platinum Etoposide). Methods: Patients ≥ 18 years, ECOG PS 0-2, with confirmed SCLC who met one of the following major eligibility criteria were enrolled based on prior PE response: 1) disease progression during PE, 2) relapse ≤ 90 days, 3) SD as best response after at least 2 cycles. Patients who received second-line therapy were eligible if they met any one of these 3 conditions and all other study eligibility criteria. An optimal Simon 2-stage design was employed (α=10%, β=10%, p0=10%, p1=25%). In Stage 1, 21 patients were to be enrolled and ≥ 3 confirmed responses (CR or PR) were required in order to proceed to Stage 2, where an additional 29 patients were to be enrolled. Amuvatinib was administered PO 300 mg TID. Results: Twenty-three patients, median age of 62 years (range, 44-80); 11 M/12 F; ECOG PS 0 (n=3), 1 (n=12), 2 (n=6), were enrolled in Stage 1 and received a median of two 21-day cycles (range, 1-10). At study entry, 9 (39%), 11 (48%), and 3 (13%) patients presented with disease progression, relapse ≤ 90 days, and SD after at least 2 cycles of PE, respectively. Per PI's assessment, 4 PRs and 7 SDs were observed as best response. Per RECIST 1.1, 2 PRs and 3 SDs were confirmed by follow-up scan ≥ 4 weeks apart for an overall clinical benefit rate (CBR) of 5/23 (22%). No CRs were observed. Grade 3/4 suspected amuvatinib related AEs were neutropenia, thrombocytopenia, atrial fibrillation, diarrhea, esophagitis, and hypercalcemia (1 patient each; 4%); hypokalemia and leukopenia, (2 patients each; 9%). By IHC, baseline expression of RAD51, ERCC1, Chk2, ATM, cKit, and RB will be evaluated and correlated with response. Conclusions: Amuvatinib demonstrated an overall CBR of 22% in refractory SCLC. While clinical activity was observed, the response rate in Stage 1 did not meet pre-specified study primary endpoint. The safety profile of amuvatinib is consistent with previous published reports of manageable toxicity with non-overlapping toxicities with PE chemotherapy. Citation Format: Lauren Byers, Leora Horn, Jitendra Gandhi, Goetz Kloecker, Taofeek K. Owonikoko, Saiama Waqar, Maciej J. Krzakowski, Gavin Choy, Nancy Cecchettini, Pietro Taverna, Amarpal Sahai, Mojtaba Noursalehi, Mohammad Azab, D. Ross Camidge. A phase 2 study of Amuvatinib (MP-470), the first RAD51 inhibitor in combination with platinum-etoposide (PE) in refractory or relapsed small cell lung cancer (ESCAPE). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2095. doi:10.1158/1538-7445.AM2013-2095

Background Individualized treatments in NSCLC are now based on molecular and/or histological data. This randomized trial (2/1) was set up to assess the efficacy of NC compared to PC for pts with nSCC. The primary end-point was disease control rate (DCR) including overall response rate (ORR) and stable disease (SD). Methods Pts received N60-80 mg/m2 D1, D8 + C80 mg/m2 D1 or P500 mg/m2 + C75 mg/m2 D1 for 4 cycles q3w; pts with DCR received single agent continuation maintenance (CM) until progression or toxicity. Results From 10/09 to 02/11, 151 pts were treated with NC or PC. ITT = 151 NC n = 100 PC n = 51 Male/Stage IV (%) 62.0/87.0 64.7/88.2 Median age (y, range) 61.0 (38.4-75.1) 63.8 (40.3-75.5) Combination: (%) ITT(95% CI) DCR 75.0 (65.3-83.1) 74.5 (60.4-85.7) ORR 21.0 (13.5-30.3) 23.5 (12.8-37.5) Combination + CM:(%) ITT (95% CI) n= 53 n = 33 DCR 75 (65.3-83.1) 76.5 (62.5-87.2) ORR 24 (16.0-33.6) 31.4 (19.1-45.9) Median PFS ITT (m,range) 4.2 (3.6-4.7) 4.2 (3.2-5.6) PFS ITT at 6/12/18m (%) 33.0/10.3/5.5 27.5/7.4/2.5 Median OS ITT (m,range) 10.6 (7.8-12.1) 10.8 (7.0-14.5) Related toxicities G3/4 (%pts) NC/PC during Combination: anemia 9.0(G3)/8.2, leucopenia 26.0/10.2, neutropenia 44.0/18.3, febrile neutro 2.0/2.0, thrombocytopenia 0/6.1, fatigue(G3) 7.0/3.9, hyperglycemia 4.0/7.8, nausea(G3) 5.0/0, vomiting(G3) 7.0/2.0, stomatitis(G3) 0/2.0, pneumonia(G3) 0/2.0, deep vein thrombosis(G3) 0/2.0, pulmonary embolism(G4) 0/2.0. During Maintenance: anemia 5.0/4.1, leucopenia 2.0/10.2, neutropenia 11.0/20.4, febrile neutro 3.8/0, fatigue (G3) 3.8/0, stomatitis(G3) 1.9/ 3.0, pain 3.8/6.0, Respiratory disorders 0/4.0, deep vein thrombosis (G3)0/2.0. Deaths potentially related to CT 2/1. Conclusions NC and PC had similar efficacy. In the present economic context, the acquisition cost of the two platinum based doublets should be considered in the treatment decision making of pts with advanced nSCC NSCLC. Disclosure S. Malasse: Statistician of the study Employment for the sponsor. F. Biville-Hedouin: Medical Project Manager of the study Employment for the sponsor. All other authors have declared no conflicts of interest.

Introduction Apart from the limited number of therapies registered for the treatment of metastatic colorectal cancer, there are no clear standards for first line chemotherapy. From an intuitive point of view - even in the case of palliative treatment, an unexpectedly high degree of response to treatment can lead to the patient being directed to an attempt of radical treatment. The question of whether using the most intensive triple-drug regimens may lead to an increased number of curative metastasis resections was yet to be answered. The aim of this meta-analysis was to address this particular problem. Methods A literature search was conducted using PubMed. We searched for phase II or phase III prospective randomized controlled trials of palliative treatments of metastatic colorectal cancer, which were testing three versus two active agents used in the first line chemotherapy. Only combinations of drugs registered for use in colorectal cancer were considered. The major question was whether a treatment regimen with more active agents could increase the R0 resection rates of liver metastases. The calculations were done with Review Manager 5.0. Results Six palliative trials, encompassing 3586 patients, met the inclusion criteria for this study. A total of 179 R0-resections occurred in the combined group (114 and 65 in three and two drug first line settings, respectively). The meta-analysis showed an improvement in absolute R0 resection of 3% (95% CI: 1-4%; p Conclusion Three-drug chemotherapy in first line of treatment is related to a higher degree of complete resections of liver metastasis in an unstratified group of palliative patients. Although a low absolute effect was seen, a more pronounced difference should be expected in borderline resectable, patients with a good performance status, with their disease limited to the liver. Therefore, we suggest that triplet regimens should be treated as a standard of care for patients whose disease is limited to the liver, for whom radical resections can be considered if a high degree of response is seen. Surprisingly, a minor correlation is seen between increased response rates and the relative chance for radical resection. This data does not allow us to state that an increased response rate can be a surrogate end point for increased radical resection rates in a palliative setting. Therefore, additional clinical studies are needed to select the optimal treatment for neo-adjuvant therapy of marginally resectable liver metastasis of colorectal cancer origin.

7536 Background: Tigatuzumab (T), a humanized monoclonal antibody that acts as a DR5 agonist induces apoptosis in human cancer cell lines and has shown activity in a phase 1 trial; phase 2 trials are ongoing in several tumor types. In NSCLC cells, single-agent T shows anti-cancer activity. Methods: Patients (pts) with histologically/cytologically confirmed (TNM ed6) NSCLC stage IIIB/IV, measurable disease by RECIST (v1.0), and ECOG-PS 0-1 were enrolled at 15 European sites. Pts received T or placebo (PL) IV + carboplatin/paclitaxel (C/P) every 3 weeks (wks) (1 cycle) for up to 6 cycles. In the case of complete response (CR)/partial response (PR) or stable disease, T or PL was given as maintenance therapy. The dosage regimen was T 10 mg/kg or PL at wk 1/cycle 1 and 8 mg/kg or PL every 3 wks thereafter; P: 175 mg/m2 every 3 wks; C: AUC 6 every 3 wks. Primary endpoint: progression-free survival (PFS); secondary endpoints: overall survival (OS) and objective response rate (ORR) (CR + PR), safety. Efficacy was assessed in both the full population and a prospectively-defined FCGR genotype subset. Results: 97/100 pts (9.3% stage IIIB wet; 90.7% stage IV; 70.1% non-squamous; 29.9% squamous) were eligible for efficacy analyses (49 to T; 48 to PL). Median PFS (95% CI) was 5.4 months (3.3, 6.6) for T vs 4.3 months (4.1, 5.8) for PL; HR = 0.96; 95% CI: 0.6, 1.6. Median OS (95% CI) was 8.4 months (6.9, 16.3) for T vs 9.0 months (7.6, 14.5) for PL (HR = 0.95; 95% CI: 0.6, 1.6). 12 pts (24.5%) in the T arm and 11 pts (22.9%) in the PL arm had PR; no pt had CR. In a subset of pts (n = 25) with FCGR2A-H131R or FCGR3A-V158F genotypes, there was a non-significant trend towards increased PFS with T vs PL (HR = 0.47; 95% CI: 0.16, 1.35) but no difference in OS. T was well tolerated; the only increased grade 3/4 toxicity was grade 3 neutropenia (16% with T vs 4% with PL). The number of treatment cycles was similar in both treatment arms. Conclusions: T does not improve the efficacy of C/P as treatment for systemic therapy-naïve, unselected advanced NSCLC pts. T was well tolerated and is being investigated in other settings.

7090 Background: huKS-IL2 immunocytokine is a humanized antibody specific for EpCAM, fused at its Fc end to two molecules of IL2. Results of a phase 1b study of huKS-IL2 plus low-dose CTX, and preclinical data, provided a rationale to evaluate this combination in SCLC, which is often EpCAM-positive. Methods: Patients (pts) with ED-SCLC responding (PR/CR) to 4 cycles of first-line Pt-based chemotherapy were randomized 1,5:1 to receive huKS-IL2/CTX or best supportive care (BSC). Pts in the huKS-IL2/CTX arm received six 21-day cycles of CTX 300 mg/m2 on day (d) 1, and 1.5 mg/m2/d huKS-IL2 on d2–4, followed by 21-d cycles of CTX on d1 and huKS-IL2 on d2 until progression. Pts were stratified for prophylactic cranial irradiation (PCI) and response to chemotherapy. Primary endpoint was PFS rate at 6 months (mo). Secondary endpoints included OS rates at 12 and 18 mo from start of Pt-based chemotherapy, median PFS and OS, safety, and immunogenicity. Results: 108 pts (64 huKS-IL2/CTX arm, 44 BSC arm) were randomized and treated. Baseline characteristics were balanced between arms; however, higher % of males (75 vs 61.4%) and of ECOG PS 0 (45.3 vs 38.6%) were observed in the active arm. Median age was 61.7 (32; 81) and 59.2 (45; 74) years in the active and BSC arm, respectively. Most pts were in PR at randomization (2 pts – 1 in each arm – had CR). PCI was used in 15 (23.4%) and 11 (25%) pts in the active and BSC arm, respectively. No significant differences in PFS or OS were observed in the active vs BSC arm: PFS rate was 6.4 vs 12.2%; median PFS was 1.5 vs 1.4 mo; OS rates at 12 and 18 mo were 52 vs 61% and 24 vs 29%, respectively; median OS was 12.3 vs 14.1 mo. One PR (45% reduction vs randomization baseline) was observed in the active arm. In a subset of pts who received PCI, median PFS was 1.7 vs 1.5 mo, median OS 21.5 vs 14.3 mo in the active vs BSC arm, respectively. AEs observed more frequently in the active arm were flu-like symptoms, rash, hypotension, lymphopenia, LFT and creatinine elevations; all Grade 3/4 AEs related to huKS-IL2 were reversible/manageable. Conclusions: HuKS-IL2/CTX was well tolerated, but showed no benefit in pts with ED-SCLC in PR/CR after chemotherapy. A trend for improved PFS and OS was observed in pts who received prior PCI.

7575 Background: NVBo+P is considered as a standard treatment (trt) in M or LA NSCLC. The recent approval of Pem+P as front line chemotherapy (CT) for non-SCC demonstrates that today, histology could become a “new guidance” to treat patients (pts). Phase III trial (Scagliotti. JCO 2008) showed efficacy of Pem+P in patients with non-SCC pts. Moreover, the higher chemosensitivity of non-SCC is recognised and reported with other chemotherapies (Ardizzoni.JNCI 2007). In GLOB 3 study, NVBo+P also showed better survival in adenocarcinoma (11.7m) than in SCC (8.9m) (Tan.Ann of Oncol 2009). This trial was set up to assess the efficacy of NVBo+P compared to Pem+P for pts with non-SCC histological type. The primary end-point was disease control rate (DCR) including overall response rate (ORR) and stable disease (SD). Methods: Pts were randomised to receive NVBo 80 mg/m² D1D8 (60 at Cycle 1) + P 80 mg/m² D1 q3w or Pem 500 mg/m² + P 75 mg/m² D1 q3w. After 4 cycles of trt, for pts showing a disease control, single agent as continuation maintenance (CM) was proposed until progression or toxicity. Given that Pem+P is now considered as a reference trt in non-SCC, pts were randomised on a 2/1 basis and stratified according to stage (IIIB - IV - relapse), non-SCC confirmed by histology or cytology, gender, smoking status and centre. Results: From 10/09 to 02/11, 153 pts were randomised to receive NVBo+P (102 pts) or Pem+P (51 pts). The efficacy between the 2 arms is similar: The ORR/DCR (Recist 1.1) after 4 cycles of trt are 26%/75% in the NVBo arm (100 eval pts in ITT population) and 24%/78% in the Pem arm (50 eval pts in ITT population). At the end of December 2011, 7 patients are still treated in CM: 5 pts in the NVBo arm and 2 pts in the Pem arm. Conclusions: The 2 CT regimen, NVBo+P or Pem+P have a similar efficacy in terms of ORR/DCR for pts with advanced non-SCC NSCLC. These results appear to be in line with the published data. As the analysis is currently in progress, final results including safety data, PFS and OS will be presented during the meeting.

e12011 Background: New diagnostic and therapeutic strategies increase survival in cancer patients. Etiology and management of primary lung cancer (LC) are well established, but little is known about incidence of LC as a secondary neoplasm. The study analyzes the clinical characteristic, pathology and management of LC as a secondary neoplasm. Methods: We reviewed medical records of patients (pts) treated in our institution from Feb.1998 to Aug.2011 with diagnosis of LC as a second malignancy. The analysis included median age at the time of diagnosis of primary cancer, histology, type of treatment and time until diagnosis of LC. Results: 84 pts were analyzed – median age at the time of diagnosis of primary cancer was 62 years (range 35-79) (65 years in men and 58 years in women p

7045 Background: In vitro, vinorelbine (NVB) has shown to be a powerful radiosensitizer. Based on the bioavailability of NVBo, a dose-determination study was implemented in patients (pts) with untreated locally advanced or inoperable stage III NSCLC assessing continuous exposure to NVBo through 3 times a week (w) FDI during the RT period, either alone (1st part of the trial) or in combination with CDDP (2nd part). Methods: 3 pts with stage IIIAN2/IIIB NSCLC were expected at each dose-level (L) with 3 additional pts in case of a dose-limiting toxicity (DLT): age 18-70 years, adequate bone marrow, hepatic and renal function, KPS ≥80%. NVBo was given concomitantly with 60 Gy RT (2 Gy/day; 5 days/w) from 60 mg up to 180 mg total-dose/w splited on days (D) 1, 3 and 5 during 6 w. Based on the maximal tolerated dose (MTD) defined as 2 DLT in a L and the recommended dose (RD) of NVBo alone, the trial assessed its RD in combination with CDDP 80 mg/m2 D1 every 3 w (q3w) in a 2nd cohort. Results: In the 1st cohort, ...

7604 Background: MetMAb (M) is a monovalent monoclonal antibody that blocks HGF-induced Met signaling. A Phase II double-blinded, randomized trial of MetMAb+erlotinib (M+E) or placebo+erlotinib (P+E) in 2nd- and /3rd- line NSCLC was recently completed. The M+E arm demonstrated both PFS and OS advantages in the c-Met IHC expression positive 2+ /3+ (Met Dx+) patients only. Methods: Adverse events (AEs) were assessed for MetMAb related toxicities. In addition to AEs, tumor growth rate and onset of new lesions were evaluated to understand their potential contribution to the clinical outcomes. Results: In the M+E arm, median cycles of M were higher in Met Dx+ vs. Met Dx- pts (4 vs. 2) as were median E doses (61 vs. 42 respectively). Overall pattern of AEs were similar in the two treatment arms, with the exception of peripheral edema which was higher on M+E; regardless of c-Met expression levels. Time to onset of any Grade ≥3 AE in M+E treated patients was also similar across groups. In the Met Dx- group, Grade...

10088 Background: Pulmonary metastasectomy (PM) is a well-accepted approach to treat resectable lung metastases from soft tissue sarcomas (STS). The aim of the study was to evaluate results of surg...

7505 Background: Met is associated with a poor outcome in many cancers, including NSCLC. Met activation is a mechanism of resistance to EGFR inhibition, supporting dual inhibition of Met/EGFR. MetMAb is a monovalent monoclonal antibody that specifically binds the Met receptor. Methods: OAM4558g is a global randomized, double-blind phase II study comparing MetMAb plus erlotinib (ME) to placebo plus erlotinib (PE) in 2nd/3rd line NSCLC. Tissue collection was mandatory to assess c-Met IHC expression levels (Met Dx). Co-primary endpoints were PFS in the Met Dx+ and ITT populations. Safety and OS were additional endpoints. Following the initial unblinding, Met Dx- patients (pts) were removed from ME. Results: 128 NSCLC pts were equally randomized to receive ME or PE. 95% of tissue was evaluable for c-Met IHC, 88% for EGFR and KRAS mutations (mut), and 75% for MET FISH. Baseline characteristics were well balanced. 54% of pts had Met Dx+ NSCLC, which was associated with a worse outcome (OS HR 2.52, PE cohort). A...

9115 Background: Bone metastases (mets) are a common complication of advanced cancer. In a study of patients (pts) with metastatic bone disease, denosumab was non-inferior to zoledronic acid (ZA) f...

7556 Background: Prognostic index for second-line chemotherapy of NSCLC was previously developed, based on individual patient data (IPD) of 9 randomized trials (Table) (Di Maio et al, Eur J Cancer ...