T. De Pas

Grading the neuroendocrine tumors of the lung: an evidence-based proposal.

Lung neuroendocrine tumors are catalogued in four categories by the World Health Organization (WHO 2004) classification. Its reproducibility and prognostic efficacy was disputed. The WHO 2010 classification of digestive neuroendocrine neoplasms is based on Ki67 proliferation assessment and proved prognostically effective. This study aims at comparing these two classifications and at defining a prognostic grading system for lung neuroendocrine tumors. The study included 399 patients who underwent surgery and with at least 1 year follow-up between 1989 and 2011. Data on 21 variables were collected, and performance of grading systems and their components was compared by Cox regression and multivariable analyses. All statistical tests were two-sided. At Cox analysis, WHO 2004 stratified patients into three major groups with statistically significant survival difference (typical carcinoid vs atypical carcinoid (AC), P=0.021; AC vs large-cell/small-cell lung neuroendocrine carcinomas, P<0.001). Optimal discrimination in three groups was observed by Ki67% (Ki67% cutoffs: G1 <4, G2 4-<25, G3 ≥25; G1 vs G2, P=0.021; and G2 vs G3, P≤0.001), mitotic count (G1 ≤2, G2 >2-47, G3 >47; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001), and presence of necrosis (G1 absent, G2 <10% of sample, G3 >10% of sample; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001) at uni and multivariable analyses. The combination of these three variables resulted in a simple and effective grading system. A three-tiers grading system based on Ki67 index, mitotic count, and necrosis with cutoffs specifically generated for lung neuroendocrine tumors is prognostically effective and accurate.

A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)

BACKGROUND KRAS mutations are detected in 25% of non-small-cell lung cancer (NSCLC) and no targeted therapies are approved for this subset population. Trametinib, a selective allosteric inhibitor of MEK1/MEK2, demonstrated preclinical and clinical activity in KRAS-mutant NSCLC. We report a phase II trial comparing trametinib with docetaxel in patients with advanced KRAS-mutant NSCLC. PATIENTS AND METHODS Eligible patients with histologically confirmed KRAS-mutant NSCLC previously treated with one prior platinum-based chemotherapy were randomly assigned in a ratio of 2 : 1 to trametinib (2 mg orally once daily) or docetaxel (75 mg/m(2) i.v. every 3 weeks). Crossover to the other arm after disease progression was allowed. Primary end point was progression-free survival (PFS). The study was prematurely terminated after the interim analysis of 92 PFS events, which showed the comparison of trametinib versus docetaxel for PFS crossed the futility boundary. RESULTS One hundred and twenty-nine patients with KRAS-mutant NSCLC were randomized; of which, 86 patients received trametinib and 43 received docetaxel. Median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm (hazard ratio [HR] 1.14; 95% CI 0.75-1.75; P = 0.5197). Median overall survival, while the data are immature, was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; 95% CI 0.52-1.83; P = 0.934). There were 10 (12%) partial responses (PRs) in the trametinib arm and 5 (12%) PRs in the docetaxel arm (P = 1.0000). The most frequent adverse events (AEs) in ≥20% of trametinib patients were rash, diarrhea, nausea, vomiting, and fatigue. The most frequent grade 3 treatment-related AEs in the trametinib arm were hypertension, rash, diarrhea, and asthenia. CONCLUSION Trametinib showed similar PFS and a response rate as docetaxel in patients with previously treated KRAS-mutant-positive NSCLC. CLINICALTRIALSGOV REGISTRATION NUMBER NCT01362296.

Vatalanib for metastatic gastrointestinal stromal tumour (GIST) resistant to imatinib: final results of a phase II study

Background:Vatalanib (PTK787/ZK 222584) inhibits a few tyrosine kinases including KIT, platelet-derived growth factor receptors (PDGFRs) and vascular endothelial growth factor receptors (VEGFRs). We report efficacy and safety results of vatalanib in advanced gastrointestinal stromal tumour (GIST) resistant to imatinib or both imatinib and sunitinib.Patients and methods:Forty-five patients whose metastatic GIST had progressed on imatinib were enrolled. Nineteen (42.2%) patients had received also prior sunitinib. Vatalanib 1250 mg was administered orally daily.Results:Eighteen patients (40.0%; 95% confidence interval (CI), 25.7–54.3%) had clinical benefit including 2 (4.4%) confirmed partial remissions (PR; duration, 9.6 and 39.4 months) and 16 (35.6%) stabilised diseases (SDs; median duration, 12.5 months; range, 6.0–35.6+ months). Twelve (46.2%) out of the 26 patients who had received prior imatinib only achieved either PR or SD compared with 6 (31.6%, all SDs) out of the 19 patients who had received prior imatinib and sunitinib (P=0.324). The median time to progression was 5.8 months (95% CI, 2.9–9.5 months) in the subset without prior sunitinib and 3.2 (95% CI, 2.1–6.0) months among those with prior imatinib and sunitinib (P=0.992). Vatalanib was generally well tolerated.Conclusion:Vatalanib is active despite its narrow kinome interaction spectrum in patients diagnosed with imatinib-resistant GIST or with imatinib and sunitinib-resistant GIST.

Phase I and pharmacological studies of the cryptophycin analogue LY355703 administered on a single intermittent or weekly schedule

LY355703 is a synthetic derivative of the marine cryptophycins, cytotoxic agents which induce mitotic arrest by binding at the microtubule vinca binding domain. Promising preclinical features of LY355703 were the 40-400 greater potency than paclitaxel or vinca alkaloids, the broad spectrum of antitumor activity in xenografts and the antitumour activity in multidrug resistant (MDR)-expressing murine tumours. Aims of this study were to define the maximum tolerated dose (MTD) and the dose recommended for Phase II, the pattern of toxicity, the pharmacokinetic profile and to document hints of antitumour activity of LY355703 given as 2-h infusion on day 1 every 3 weeks (Study 1) or, later on, on days 1, 8 and 15 every 4 weeks (Study 2). The latter weekly regimen was selected because of the acute dose-related toxicity reported in Study 1. The dose was escalated using a modified Continual Reassessment Method. Pharmacokinetic studies were performed on day 1 of cycle 1 in both studies; LY355703 plasma concentrations were assessed by liquid chromatography with tandem mass spectrometry. A total of 35 adult patients with solid tumours entered Study 1; the dose was escalated from 0.1 to 1.92 mg/m(2); at this dose 2 of 5 patients presented grade 3 neuropathy and myalgias; 1.48 mg/m(2) was then recommended for Phase II study. A total of 8 patients were treated in Study 2 at 1 mg/m(2); cumulative long-lasting neuroconstipation and neurosensory toxicity precluded the completion of the cycle in 9 out of 15 cycles; the clinical development of the weekly regimen was then discontinued. Other toxicities included cardiac dysrhythmia and mild alopecia. Pharmacokinetics of LY355703 appeared to be linear over the dose range studied. The administration of LY355703 on a 3-week schedule is associated with an acute dose-dependent peripheral neuropathy and myalgia of high interpatient variability for which possible risk factors and pharmacokinetic correlates could not be identified.

Gemcitabine-induced systemic capillary leak syndrome

Systemic capillary leak syndrome (SCLS) is a rare disorder with a high mortality rate, characterized by rapidly developing edema, weight gain and hypotension, hemoconcentration and hypoproteinemia. This syndrome is caused by sudden, reversible capillary hyperpermeability with a rapid extravasation of plasma from the intravascular to the interstitial space. Even though SCLS has been suggested to be the pathogenic mechanism for the pulmonary toxicity of gemcitabine (GCB), a new deoxycytidine analogue with structural similarities to cytosine arabinoside, a direct correlation between GCB and SCLS has never been reported. We describe a case of repeated SCLS after GCB administration in a 51-year-old male with locally-advanced non-small-cell lung cancer treated with a combination of cisplatin and GCB. The detection of GCB-induced SCLS supports the hypothesis that SCLS could be the pathogenic way of GCB pulmonary toxicity. This finding can help to better understand and treat the potentially deadly GCB-related acute respiratory distress syndrome that is being recognized.

1173OMAGRIT, A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED PHASE III STUDY TO ASSESS THE EFFICACY OF THE RECMAGE-A3 + AS15 CANCER IMMUNOTHERAPEUTIC AS ADJUVANT THERAPY IN PATIENTS WITH RESECTED MAGE-A3-POSITIVE NON-SMALL CELL LUNG CANCER (NSCLC)

ABSTRACT Aim: Adjuvant chemotherapy (ACT) is the standard of care for Stage II and IIIA NSCLC, and for high risk Stage IB NSCLC. However, the 5-year disease-free survival remains poor (35-50%) and about half of the patients will not receive ACT for various reasons. This Phase III trial investigated whether the recMAGE-A3 + AS15 cancer immunotherapeutic (MAGE-A3 CI) as adjuvant therapy improved disease-free survival (DFS) in patients with resected NSCLC. Methods: MAGRIT was a randomized, double-blind, placebo-controlled trial in patients with completely resected MAGE-A3-positive NSCLC Stages IB, II, and IIIA (TNM version 6) and who did or did not receive ACT. Patients were randomly assigned (2:1) to receive 13 intramuscular injections of MAGE-A3 CI or placebo over a 27-month (m) treatment period. The three co-primary endpoints were DFS in the overall and in the no-ACT population and DFS in patients with a potentially predictive gene signature (GS). Results: Out of 13,849 patients screened, 4,210 patients had a MAGE-A3 positive tumour sample and 2,272 patients were randomised and treated. Overall, 52% of the patients received ACT; 47%, 36% and 17% were Stage IB, II and IIIA, respectively. Median age was 63 years and 24% of patients were females. Mean relative dose intensity was above 98% in both groups throughout the treatment period. Median follow-up at the time of final analysis was 38.8m. Median DFS was 60.5m and 57.9m respectively for MAGE-A3 CI and placebo (HR 1.024, 95% CI 0.891-1.177; p = 0.7379). In patients who did not receive ACT, median DFS was 58.0m and 56.9m for MAGE-A3 CI and placebo groups, respectively (HR 0.970, 95% CI 0.797-1.179; p = 0.7572). The rate of grade ≥ 3 adverse events (16%) did not differ between treatment groups. Conclusions: Treatment of NSCLC patients with MAGE-A3 CI did not increase DFS compared to placebo in either the overall population or in patients who did not receive ACT. Due to the absence of treatment effect, a GS predictive of clinical benefit to MAGE-A3 CI could not be identified. Funding Source: GlaxoSmithKline Biologicals SA. Disclosure: J.F. Vansteenkiste: Pr Vansteenkiste received GSK fees as Primary investigator for the MAGRIT study; B. Cho: Dr Cho received consultancy fees from Novartis and Boehringer-ingelheim; T. De Pas: No conflicts of interest. Fee received from GSK as member of steering committee of the study; J. Jassem: Dr Jassem received grant and personal fees for Consultancy from GSK; M. Yoshimura: Pr Yoshimura received GSK fees as Primary investigator for the MAGRIT and PEARL study; H. Nakayama: Dr Nakayama received GSK fees as Primary investigator for the MAGRIT and PEARL study; T. Mitsudomi: Dr Mitsudomi received personal fees from GSK for an advisory role; B. Spiessens: Bart Spiessens is employee of GSK and do own stock options of GSK; V. Brichard: Dr Birchart is GSK employee and do own Stock options from GSK; C. Debruyne: Dr Debruyne is GSK employee and do own GSK stock options; P. Therasse: GSK employee and Stock options owner; N. Altorki: Dr Altorki received GSK fees for trial conduct of GSK studies. All other authors have declared no conflicts of interest.

High-dose ifosfamide plus adriamycin in the treatment of adult advanced soft tissue sarcomas: Is it feasible?

BACKGROUND Adriamycin (ADM) and ifosfamide (IFO) are the two most active agents in the treatment of soft tissue sarcomas (STS) with a clear dose-response relationship. We evaluated the feasibility and toxicity of a high-dose IFO-plus-ADM combination. PATIENTS AND METHODS Fourteen patients with advanced disease and nine patients in adjuvant setting received IFO 12.5 g/m2 in 120-hour continuous infusion with Mesna uroprotection and ADM 20 mg/m2 on days 1-3 and G-CSF every three weeks. RESULTS Twenty-three patients received 89 chemotherapy cycles (70 cycles at full dose). Seventeen patients received the planned treatment, and nine patients required dose reductions. We observed grade 3-4 neutropenia in 52 cycles (59%)/20 patients; grade 3-4 thrombocytopenia in 16 cycles (18%)/nine patients; grade 3-4 anaemia in 24 cycles (27%)/11 patients. Eight patients experienced febrile neutropenia and six patients required blood transfusions. CONCLUSIONS While feasible, this regimen showed heavy toxicity. Nevertheless, 74% of the patients were able to complete the planned treatment. Adjustment of the schedule of IFO continuous infusion to improve this combination is currently under investigation.

Phase I and pharmacologic study of weekly gemcitabine and paclitaxel in chemo-naïve patients with advanced non-small-cell lung cancer

BACKGROUND Gemcitabine (GEM) and paclitaxel (TAX) are active, non-cross-resistant drugs in non-small-cell lung cancer (NSCLC). We performed a phase I study to determine the maximum-tolerated dose (MTD), antitumor activity and pharmacokinetics of GEM and TAX given weekly in chemo-naïve patients with advanced NSCLC. PATIENTS AND METHODS Escalating doses of GEM (800-2000 mg/m2) and TAX (60-100 mg/m2) were administered on days 1, 8, 15 every 4 weeks to 35 patients with advanced NSCLC. Plasma pharmacokinetics of TAX and GEM was assessed at the three higher dose-levels. RESULTS Dose-escalation was discontinued in absence of MTD because of increased cumulative toxicity leading to dose modification or treatment delay at levels 6 and 7 (TAX 100 mg/m2 plus GEM 1750 and, respectively, 2000 mg/m2). Hematological toxicity included grade 4 neutropenia in 3% of cycles, grade 3 thrombocytopenia in one cycle and febrile neutropenia in three cycles. Maximal non-hematological toxicity was grade 3 elevation in serum transaminases and grade 2 neuro-sensory toxicity in 8% and 5% of cycles, respectively. At the two higher dose-levels a non-linear pharmacokinetics of GEM was observed with a remarkable variability of Cmax and AUC. No pharmacokinetic interactions were reported. Objectives responses were seen at all dose levels, with an overall response rate of 43% (95% confidence interval (95% CI): 25.5%-62.6%) in 30 evaluable patients. CONCLUSIONS The weekly administration of GEM and TAX is very well tolerated, and has shown promising antitumor activity in NSCLC. In view of the cumulative toxicity and of the pharmacokinetic profile of GEM, doses of 1500 mg/m2 of GEM and 100 mg/m2 of TAX are recommended for phase II studies.

1293PEVALUATION OF CERITINIB-TREATED PATIENTS (PTS) WITH ANAPLASTIC LYMPHOMA KINASE REARRANGED (ALK+) NON-SMALL CELL LUNG CANCER (NSCLC) AND BRAIN METASTASES IN THE ASCEND-1 STUDY

A.T. Shaw1, R. Mehra2, D.S.W. Tan3, E. Felip4, L.Q. Chow5, D.R. Camidge6, J. F. Vansteenkiste7, S. Sharma8, T. De Pas9, G.J. Riely10, B. Solomon11, J. Wolf12, M. Thomas13, M. Schuler14, G. Liu15, A. Santoro16, M. Geraldes17, A.L. Boral18, A. Yovine19, D. Kim20 Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA Department of Medical Oncology, National Cancer Center, SINGAPORE Head Thoracic Oncology Unit, Oncology Department, Vall D’Hebron University Hospital, Barcelona, SPAIN Department of Medicine, University of Washington, Seattle, WA, USA Medicine, University of Colorado, Denver, CO, USA Respiratory Oncology Unit (pulmonology), University Hospital KU Leuven, Leuven, BELGIUM Medical Oncology, Huntsman Cancer Institute, Salt Lake City, UT, USA Thoracic Medical Oncology, European Institute of Oncology, Milan, ITALY Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, AUSTRALIA Department I of Internal Medicine, Center for Integrated Oncology, University of Cologne, Cologne, GERMANY Department of Thoracic Onkology, Thoraxklinik, University of Heidelberg, Heidelberg, GERMANY German Cancer Consortium, Heidelberg, University Hospital Essen, University Duisburg-Essen, Essen, GERMANY Medical Biophysics, Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, CANADA Medical Oncology and Hematology, Humanitas Cancer Center, Rozzano-Milan, ITALY Novartis Pharmaceuticals Corporation, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA Oncology Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge, MA, USA Oncology Clincal Development, Novartis Pharma AG, Basel, SWITZERLAND Department of Internal Medicine, Seoul National University Hospital, Seoul, KOREA

Expression of gemcitabine-and cisplatin-related genes in non-small-cell lung cancer

The aim of this study was to investigate the influence of histology and site of analysis (primary tumor versus lymph node) on the expression of genes involved in gemcitabine and cisplatin activity in non-small-cell lung cancer (NSCLC). Excision repair cross-complementing-1 (ERCC1), human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (dCK), 5′-nucleotidase (5′-NT), cytidine deaminase (CDA) and ribonucleotide-reductase regulatory subunits (RRM1 and RRM2) were analyzed by quantitative-reverse transcription-PCR in 88 microdissected samples from 69 chemonaive patients. The results showed different patterns of expression for all studied genes, suggesting a possible stratification of the patients. No difference was observed between primary tumor and lymph node metastasis, as well as in adenocarcinoma and squamous-cell carcinoma specimens, while we found a correlation between the CDA-A79C polymorphism and gene expression levels. These data suggest a similar genetic susceptibility to gemcitabine–cisplatin regimens for squamous cell and adenocarcinoma and support the use of both lymph node and primary tumor for the expression profiling of NSCLC.