Phase II Study of Amrubicin in Patients with Refractory or Resistant Relapsed Small-Cell Lung Cancer: Japan Clinical Oncology Group Study (JCOG0901)

Annals of Oncology 23 (Supplement 9): ix492–ix498, 2012 doi:10.1093/annonc/mds415

small cell lung cancer and other thoracic malignancies 1519PD

PHASE II STUDY OF AMRUBICIN IN PATIENTS WITH REFRACTORY OR RESISTANT RELAPSED SMALL-CELL LUNG CANCER: JAPAN CLINICAL ONCOLOGY GROUP STUDY (JCOG0901)

abstracts

Background: Standard therapy for refractory or resistant relapsed small-cell lung cancer (SCLC) has not yet been established. We conducted an open-label, multicenter, non-randomized phase II study to confirm the efficacy and safety of amrubicin, a topoisomerase inhibitor, in the treatment of refractory or resistant SCLC. Material and methods: Patients with SCLC that is refractory or relapsed within 90 days of completing previous treatment received amrubicin at a dose of 40 mg/m2 for 3 consecutive days, every 21 days.The study treatment was repeated until disease progression or intolerable toxicity. The primary end point was overall response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival (OS), and safety. Planned sample size was 80 patients to achieve power of at least 80% with one-sided alpha of 0.05, and expected and threshold value for primary endpoint as 20% and 10%. All patients were followed-up until one year after the last patient enrollment. Results: Between November 2009 and February 2011, 82 patients were enrolled from 25 institutions. The median number of treatment cycles was four (range, one to 22 cycles).The ORR was 32.9% ( p < 0.0001 by the exact binomial test for null hypothesis that ORR = <10%, 95% CI, 22.9% to 44.2%), with two complete responses and 25 partial responses according to independent assessments.Median PFS and OS were 3.5 months (95% CI, 3.0 to 4.3 months) and 8.9 months (95% CI, 7.6 to 11.3 months), respectively. The most common grade 3 and 4 adverse events were neutropenia (93.9%), leukopenia (85.4%), anemia (25.6%) and thrombocytopenia (20.7%). Twenty-two patients (26.8%) experienced febrile neutropenia. No treatment-related death was observed. Conclusions: Amrubicin demonstrated the favorable tumor response and survival with acceptable toxicity. Single-agent amrubicin could be considered as a standard regimen in the treatment of refractory or resistant relapsed SCLC. Disclosure: All authors have declared no conflicts of interest.

1520PD

COMPARATIVE STUDY BETWEEN BELOTECAN/CISPLATIN AND ETOPOSIDE/CISPLATIN (COMBAT) IN PATIENTS WITH PREVIOUSLY UNTREATED, EXTENSIVE STAGE SMALL CELL LUNG CANCER - INTERIM ANALYSIS

Y. Kim1, K. Kim2, I. Oh2, H. Ban2, K. Na2, S. Ahn2, H. Kang1, W. Kim1, C. Park1, S. Yang3 1 Pulmonology, Chonnam National University Hwasun Hospital Lung Cancer Clinic, Hwasun Gun, KOREA, 2Lung Cancer Clinic, Chonnam National University Hwasun Hospital, Jeonnam, KOREA, 3Pulmonology, Wonkwang University Hospital, Jeonbuk, KOREA Purpose: Belotecan (camtobell™) is a topoisomerase I inhibitor, and effective in small cell lung cancer (SCLC). The objective of this study is to compare the efficacy and safety of belotecan + cisplatin (BP) and etoposide + cisplatin (EP) in first line setting.

1521PD

LUNG MALIGNANCIES AND SECOND NEOPLASIAS IN PATIENTS WITH HODGKI⍰S LYMPHOMA

E. Almagro-Casado1, D. Pérez-Callejo1, A. López-González2, P. Ibeas1, A. Ruiz-Valdepeñas3, M. Palka3, C. Maximiano1, M. Méndez García1, S. Mellor1, M. Provencio Pulla1 1 Clinical Oncology, Hospital Puerta de Hierro Majadahonda, Madrid, SPAIN, 2 Clinical Oncology, Hospital de León, Leon, SPAIN, 3Medical Oncology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, SPAIN Background: Patients with Hodgkińs Lymphoma (HL) have an increased risk of developing second neoplasias (SN). We analyzed and compared the long-term risk of developing thoracic malignancies (TM), (lung cancer or mesothelioma) to other neoplasias. Patients and methods: We retrospectively analized from 1968 to 2011 a total of 514 patients with HL treated and monitored in our hospital. We reviewed as variables: date, age and initial staging at diagnosis, type of treatment (chemo, radiotherapy or combined), presence of bulky mass, date of SN diagnosis, type and staging of tumor (we included non- HL, leukemia, breast, colon, thyroid cancer and sarcoma) and overall survival (OS). The contrasts between proportions were performed using Chi-square test and the survival curves using the Kaplan-Meier method and logrank test. Results: Out of 514 patients, SN occurred in 79 cases (16%). 24 (30,4%) patients developed lung cancer, 2 mesothelioma and 55(69,6%) other type of tumor. No differences were found between the average age at diagnosis of both HL or SN, 35,7 and 33,5 respectively ( p = 0,56), although they were found between the relapsed time before the SN diagnosis (median of 16,4 years in TM and 9,7 in others ( p = 0,03)). In the group of patients with TM, 21 (88%) of 24 patients were men ( p = 0,001) whereas in the other tumors group no gender differences were found. 35 patients (44%) presented advanced stage (III or IV) at diagnosis, 7 (20%) with TM and 28 (80%) with other tumors ( p = 0,074). Radiotherapy when compared with combined treatment was associated with increased risk of TM (RR = 2,5, IC95% 1,03-6,1) than other neoplasias. There were no differences between both groups when bulky mass was found. The OS from diagnosis of SN in TM and other tumors is 58% and 37% in one year and 61% and 42% in 5 ( p = 0,54), with median of monitoring 1 year in TM and 1,5 in others. Conclusions: Lung cancer and mesothelioma in patients with Hodgkin’s lymphoma is much more prevalent in male patients according to our study. The treatment using radiotherapy leads to raised risk of lung cancer, compared to combined treatment. Although we did not find any difference in OS, we found differences between the relapsed time to diagnosis between both groups. Disclosure: All authors have declared no conflicts of interest.

© European Society for Medical Oncology 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]

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H. Daga1, H. Murakami2, N. Yamamoto2, T. Shibata3, M. Endo4, H. Watanabe5, Y. Ichinose6, N. Yamamoto7, Y. Ohe8, T. Tamura7 1 Department of Clinical Oncology, Osaka City General Hospital, Osaka, JAPAN, 2 Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, JAPAN, 3Regulatory Science Section Multi-institutional Clinical Trial Support Center, National Cancer Center Hospital, Tokyo, JAPAN, 4Department of Radiology, Shizuoka Cancer Center, Shizuoka, JAPAN, 5Department of Radiology, National Cancer Center Hospital, Tokyo, JAPAN, 6Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, JAPAN, 7Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, JAPAN, 8Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, JAPAN

Methods (materials): This is a multicenter, randomized, prospective controlled trial to prove non-inferiority of BP compared to standard EP regimen. The primary endpoint is overall response rate (ORR), and secondary endpoints are toxicity, overall survival (OS) and progression-free survival (PFS). BP was administrated by belotecan 0.5 mg/m2 for 4 days combined with cisplatin 60 mg/m2 only for first day. Treatment response was evaluated according to version 1.0 of Response Evaluation Criteria in Solid Tumors. Results: We enrolled 129 (BP: 63, EP: 66) patients, and response evaluation was possible in 111 (BP: 50, EP: 61) patients. In BP group, there were 1 complete response, 32 partial responses (PR), 7 stable diseases (SD), and there were 33 PR and 11 SD in EP group. There were no significant differences in ORR (BP: 66.0%, EP: 54.1%, p = 0.25) and disease control rate (BP: 80.0%, EP: 72.1%, p = 0.38). Median OS (BP: 483, EP: 340 days, p = 0.21) and PFS (BP: 192, EP: 150 days, p = 0.08) were not significantly different. The frequency of grade ≥ 3 anemia (BP: 29.0%, EP: 7.5%, p < 0.01) and thrombocytopenia (BP: 35.5%, EP: 16.4%, p = 0.02) were higher in BP group. Non-hematologic toxicities were not different between two groups. Conclusions: In this interim analysis, BP and EP have similar ORR, OS and PFS in extensive stage SCLC. Toxicity profiles except anemia and thrombocytopenia were similar between two groups. (ClinicalTrials.gov number, NCT00826644) Disclosure: All authors have declared no conflicts of interest.

Annals of Oncology

1522PD

A MULTI-CENTER PHASE II CLINICAL TRIAL OF THE CHIMERIC ANTI-MESOTHELIN MONOCLONAL ANTIBODY AMATUXIMAB IN COMBINATION WITH CHEMOTHERAPY FOR FRONTLINE THERAPY OF MALIGNANT PLEURAL MESOTHELIOMA: UPDATED CLINICAL OUTCOMES AND CORRELATIVE STUDIES

M. Reck1, R. Hassan2, T. Jahan3, H.L. Kindler4, L. Bazhenova5, P. Fatato6, J. W. Heyburn6, J. Parno6, J.D. Maltzman6, B. Wallin6 1 Thoracic Oncology, Krankenhaus Grosshansdorf, Grosshansdorf, GERMANY, 2 Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, MD, UNITED STATES OF AMERICA, 3Division of Hematology/Oncology, University of California - San Francisco, San Francisco, CA, UNITED STATES OF AMERICA, 4 University of Chicago, Division of Oncology, Chicago, IL, UNITED STATES OF AMERICA, 5Health Sciences, UCSD Moores Cancer Center, La Jolla, UNITED STATES OF AMERICA, 6Oncology, Morphotek, Exton, PA, UNITED STATES OF AMERICA

1523P

THE 8.1 ANCESTRAL HAPLOTYPE IS STRONGLY ASSOCIATED WITH THE RISK OF SMALL CELL LUNG CANCER

J. Kocsis1, L. Graf1, A. Szilagyi2, B. Dome3, L. Tamasi4, G. Galffy4, Z. Orosz5, Z. Prohaszka2, G. Fust2, Z. Bartfai6 1 3rd Dept of Internal Medicine, Oncology, Semmelweis University, Budapest, HUNGARY, 23rd Dept of Internal Medicine, Semmelweis University, Budapest, HUNGARY, 3Tumor Biology, National Koranyi Institute of Pulmonology, Budapest, HUNGARY, 4Pulmonology, Semmelweis University, Budapest, HUNGARY, 5Radiology and Oncotherapy, Semmelweis University, Budapest, HUNGARY, 6Pulmonology, Erzsebet Hospital, Sopron, HUNGARY Background: It is well established that the risk of lung cancer is related to the individual genetic background as it is reflected in the increased incidences among first degree relatives. The discovery of these genetic variations can lead to the identification of those individuals who are at high risk of developing lung cancer. AH8.1 is a haplotype which extends through the whole MHC region in the short arm of chromosome 6. It is the most frequent and a very conservative haplotype in the Caucasian population. Previously we have reported a strong association between AH8.1 and colorectal cancer with an odds ratio higher than any risks reported for SNPs in genome-wide association studies or candidate gene studies. Published data indicate that AH8.1 is a strong risk factor for ovarian cancer and for non-Hodgkin lymphoma as well.

Volume 23 | Supplement 9 | September 2012

1524P

COMBINATION OF THREE CYTOTOXIC AGENTS IN SMALL CELL LUNG CANCER

G. Stathopoulos1, D. Traphalis1, J. Dimitroulis2, C. Kosmas3, J. Stathopoulos1, D. Tsavdaridis4 1 A’ Oncology Clinic Errikos Dunant, Dr. Georgios Stathopoulos, Athens, GREECE, 26th Pneumonic Clinic, Hospital for Thoracic Disease, Athens, GREECE, 3Oncology Clinic, Anticancer Hospital Piraeus, Piraeus, GREECE, 4 Oncology Clinic, Anticancer Hospital, Thessaloniki, GREECE Background: Small-cell lung cancer treatment has been tested by using combinations of several cytotoxic agents. For quite a number of years, the established treatment has been cisplatin and etoposide as the most effective chemotherapy regimen. Paclitaxel has also been used in combination with cisplatin and etoposide; the latter three drug treatment has been effective but unacceptable due to toxicity. Patients and methods: In the present trial we tested the aforementioned three-drug combination and avoided the toxicity in the majority of the patients by administering all 3 drugs on day 1 instead of on the established three days of treatment. Fifty patients were recruited from 5 oncology clinics. All patients had histologically- or cytologicallyconfirmed small-cell-lung cancer with limited and extensive disease in 40% and 60% of the patients respectively. Treatment was as follows: cisplatin 75mg/m2, etoposide 120mg/m2 with no dosage higher than 200mg/m2 and paclitaxel 135mg/m2. The agents were administered on day 1 and repeated every three weeks for 6 cycles in total. Results: The median survival was 14 months (95% CI 10.6-17.4) Forty-five patients (90%) achieved a response: 20(40%) patients a complete response and 25 (50%) a partial response. Adverse reactions was grade 3 and 4 neutropenia in 12% and 2% of the patients, respectively. Other side effects involved very low toxicity. Conclusion: The one-day three-agent (cisplatin, etoposide, paclitaxel) treatment of small-cell lung cancer is beneficial with respect to response rate and survival, and has low and well-tolerated toxicity. Disclosure: All authors have declared no conflicts of interest.

1525P

THIRD-LINE CHEMOTHERAPY IN SMALL CELL LUNG CANCER: AN INTERNATIONAL ANALYSIS

D. Simos1, G. Sajjady2, M. Sergi3, M.S. Liew4, R. Califano5, C. Ho2, N.B. Leighl3, S. White4, Y. Summers5, P. Wheatley-Price1 1 Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, ON, CANADA, 2 Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, CANADA, 3 Medical Oncology, Princess Margaret Hospital, Toronto, ON, CANADA, 4Austin Health, Joint Austin-Ludwig Oncology Unit, Victoria, AUSTRALIA, 5Medical Oncology, The Christie NHS Foundation Trust & University Hospital South Manchester NHS Foundation Trust, Manchester, UNITED KINGDOM Background: Small cell lung cancer (SCLC) is an aggressive disease and chemotherapy (CT) is the mainstay of treatment. Despite good response rates most patients ( pts) will relapse and die of this disease. Standard 1st-line CT in limited (LD) and extensive stage disease is usually etoposide with platinum (P) or CAV (cyclophosphamide, doxorubicin, vincristine). At progression, 2nd-line CT may involve re-challenging with the 1st-line regimen. For pts who progress after 2 lines of CT, there is little evidence to guide treatment decisions, and the benefit of 3rd-line CT is unclear. Objective: To determine the clinical benefit of 3rd-line CT for SCLC. Study design: An international multi-centre retrospective analysis of pts who received 3 lines of CT for SCLC from 2001-2011 was performed. Baseline demographics, known prognostic factors and CT details were recorded. The main end-points were response rate (RR) and overall survival (OS) after 3rd-line CT. Results: A total of 124 eligible pts were identified; 59% male, median age 61, 89% ECOG 0-1, 40% LD. First-line P-based CT was given to 99% of pts, with a RR of 90%. In the 2nd-line, 70 pts (56%) were re-challenged with similar CT, with the

doi:10.1093/annonc/mds415 | ix

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Background: Amatuximab (MORAb-009) is a chimeric monoclonal antibody to mesothelin, a cell surface glycoprotein highly expressed in malignant mesothelioma (MPM). Based on amatuximab results in a phase I clinical trial and pre-clinical studies showing synergy in combination with chemotherapy, a single arm phase II study of amatuximab plus pemetrexed (P) and cisplatin (C) was initiated in MPM patients (Pts). Methods: Eligibility criteria: unresectable epithelial or biphasic MPM, no prior chemotherapy and Karnofsky Performance Status (KPS) >70%. Pts received amatuximab 5 mg/kg on days 1 and 8 with P 500 mg/m2 and C 75 mg/m2 (PC) given on day 1 of each 21-day cycle for 6 cycles. Pts with objective response or stable disease received amatuximab monotherapy until disease progression. Primary endpoint: progression-free survival (PFS) at 6 months (mo). Secondary endpoints: overall survival (OS), objective response rate (ORR), pulmonary function (PFT), and safety of amatuximab with PC. Results: 89 pts with unresectable MPM were enrolled at 26 sites. Pt characteristics: median age 67 yrs (range 46-80); 78% male; 70% with KPS >90%; 89% epithelial MPM, 11% biphasic MPM; 88% had stage III/IV disease. Median PC-amatuximab cycles: 5 (range 1-6). 56 (63%) pts subsequently received single agent amatuximab. In addition to expected toxicities from PC, hypersensitivity reactions (12.4%; Grade 3/4 = 5%) from amatuximab were noted. By independent radiological review, 30 pts (39%) had a partial response and 39 (51%) had stable disease. PFS at 6 mo: 52% (95% CI: 39.5-63.5). Median PFS = 6.1 mo (95% CI: 5.4-6.5). Median OS = 14.8 mo (95% CI: 12.4 – 19.2). 29 pts are alive and 5 pts are still receiving maintenance amatuximab. The mean Forced Vital Capacity (FVC) change from baseline was 132ml. The proportion of pts with an FVC improvement of > 400ml was 23%. Conclusions: Amatuximab in combination with PC was generally well-tolerated in this study in MPM pts with a disease control rate of 90%. The median OS of 14.8 months compares favorably with historical controls. Disclosure: M. Reck: Advisory Board (compensated): Hoffmann-La Roche, Lilly, AstraZeneca, Pfizer, Daiichi-Sankyo, BMS. Honoraria for lectures: Hoffmann-La Roche, Lilly, AstraZeneca, Daiichi-SankyoT. Jahan: research funding from Genentech, Lilly and PfizerH.L. Kindler: research funding for morphotekP. Fatato: Employee of MorphotekJ.W. Heyburn: Employee of MorphotekJ. Parno: Employee of MorphotekJ. D. Maltzman: Employee of MorphotekB. Wallin: Employee of MorphotekAll other authors have declared no conflicts of interest.

Aim/methods: Here we have determined the carrier state of AH8.1 in 102 patients with small cell lung cancer (SCLC) (62 + 7.8 years), 94 patients with non- SCLC (NSCLC) (59+ 8.6 years) and in 248 age-matched control subjects (66.7 + 6.5 years). Subjects carrying all the four marker alleles of AH8.1 (C allele of AGER 429T > C, G allele of HSP70-2 1267A > G, A allele of TNFalpha -308G > A, as well as G allele of LTA 252A > G polymorphisms) were considered as AH8.1 carriers. Results: 23% (23/102) of SCLC patients, 13.8% (13/94) of NSCLC patients, and 13% (32/248) of healthy controls carried the AH8.1 haplotype. We have found a significant increased risk for SCLC in those people carrying AH8.1 with an odds ratio of 1.94 (1.01-3.73; p = 0.046) (for men: 3.09, 1.07-8.82; p = 0.031). However, there was no significant increase in the risk for NSCLC. Summary: These findings indicate that carriers of the AH8.1 haplotype are at increased risk for SCLC and it can be due to the altered immune response that is characteristic for 8.1 AH. Disclosure: All authors have declared no conflicts of interest.

Annals of Oncology

remaining receiving either CAV or topotecan based CT, with an RR of 50%. In the 3rd-line, 35 pts (28%) were re-challenged with CT similar to a prior regimen. Only 27 pts (22%) received 3 distinct lines of CT. Median progression free survival (PFS) in the 1st, 2nd and 3rd-lines were: 9.0, 4.6 and 2.0 months respectively. The RR in the 3rd-line was 17%, with no complete responses. Median 3rd-line OS was 4.8 months. Factors associated with longer OS were: normal baseline serum LDH ( p = 0.02), response to 2nd-line CT ( p = 0.04) and PFS >3 months after 2nd-line CT ( p = 0.05). Age, sex, initial disease stage, and CT re-challenges did not predict longer survival. After the 3rd-line, 35 pts received further CT. Conclusions: In 5 cancer centres, over 10 years, few SCLC pts received 3 lines of CT. Most who received 3 lines had been re-challenged with a similar regimen at least once. OS and RR in the 3rd-line are modest. Lack of response to, or progression after 2nd-line CT may predict particular lack of benefit in the 3rd-line. Prospective research in this area is needed. Disclosure: All authors have declared no conflicts of interest.

1526P

HYPONATRAEMIA AS A MARKER OF INFERIOR OUTCOMES IN SMALL CELL LUNG CANCER (SCLC)

N.J. Coleman1, J. Clince2, W.M. Grogan2, O.S. Breathnach1 1 Medical Oncology, Beaumont Hospital Cancer Centre, Dublin, IRELAND, 2 Medical Oncology, Beaumont Hospital, Dublin, IRELAND

1527P

SMALL CELL LUNG CANCER (SCLC) TREATED IN FIRST LINE WITH HYBRID SCHEME WITH CARBOPLATIN AND ETOPOSIDE INTRAVENOUS (IV) AND ORAL. COMPARISON BETWEEN PATIENTS UNTIL 65 YEARS OLD AND OLDER

A. Ruiz-Valdepeñas1, M. Palka1, E. Almagro Casado1, D. Pérez Callejo1, P. Ibeas2, B.G. Doger de Speville3, C. Maximiano1, B. Cantos1, G. Diaz4, M. Provencio Pulla5 1 Medical Oncology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, SPAIN, 2Clinical Oncology, Hospital Puerta de Hierro Majadahonda, Madrid, Spain, Majadahonda, SPAIN, 3Medical Oncology, Hospital Universitario Puerta de Hierro, Majadahonda, SPAIN, 4Neumology, Hospital Universitario Puerta de Hierro, Majadahonda, SPAIN, 5Medical Oncology, Hospital Universitario Puerta de Hierro Majadahond, Majadahonda, SPAIN

1528P

M. Fiegl1, A. Pircher1, W. Sterlacci2, H. Jamnig3, T. Schmid4, M. Nevinny5, G. Pall6, W. Oberaigner7, G. Zangerl8, W. Hilbe1 1 Hematology and Oncology, Internal Medicine V, Medical University Innsbruck, Innsbruck, AUSTRIA, 2Department of Pathology, Hospital of Feldkirch, Feldkirch, AUSTRIA, 3Pneumology, Hospital of Natters, Natters, AUSTRIA, 4Thoracic Surgery, Medical University of Innsbruck, Innsbruck, AUSTRIA, 5Radiooncology, Medical University of Innsbruck, Innsbruck, AUSTRIA, 6Internal Medicine I, Medical University of Innsbruck, Innsbruck, AUSTRIA, 7Institute of Epidemiology Tilak, Medical University of Innsbruck, Innsbruck, AUSTRIA, 8Internal Medicine, Hospital of Zams, Zams, AUSTRIA Introduction: Consecutive SCLC cases treated in Innsbruck/Natters Comprehensive Cancer Center were analysed in order to achieve results in the routine setting and to depict cohorts with long term survival. Methods: All patients with SCLC were documented with respect to disease and therapy features aiming at describing this disease and treatments applied in most possible detail. Results: Of 484 patients, 326 (67%) were male. Extensive stage at diagnosis in 269/ 483 informative cases (56%), (former) smokers, 316/323 (98%); unfavorable ECOG PS (≥2), 100/303 (33%). Symptoms at initial diagnosis: hemoptysis 44/293 (15%), cough 165/299 (55%); dyspnoea 153/302 (51%); tumor pain 135/305 (44%); neurologic symptoms (incl. paraneoplasia) 69/314 (22%); hyponatremia (≤130 mmol/l)/SIADH 47/339 (14%); prior/present other malignancy 86/436 (20%). 27 patients (6%) did not receive any treatment. 26 limited disease patients were radically operated, with excellent outcome (median OS, 91 months). In the 406 evaluable patients with palliative therapy, overall response (ORR) was 56% (CR 18%, PR 39%, PD 31%, interruption 5%, death under therapy 8%); however, best response (at any time during treatment) was 78%. ORR was dramatically inferior in patients with advanced stage, unfavorable PS, and elevated LDH ( p < 0.001). Median PFS from start of palliative therapy, evaluable in 415 patients, was 6.9 months. PFS was slightly superior in women ( p = 0.041), and clearly inferior in patients with elevated CRP ( p = 0.011) and LDH levels ( p <0.001), unfavorable performance status ( p = 0.001), and extensive disease ( p <0.001); median OS from start of palliative therapy, evaluable in 415 patients was 11.3 months: more interestingly, there is plateau of long term survivors (5-ys survival 9.3%), mainly attributable to radiochemotherapy in limited disease (n = 118, median OS 20.3 months, 5-ys survival 22%). LDH and CRP, and PS are simple parameters significantly predictive for OS ( p < 0.001). Second line palliative therapy was administered in 206 patients (ORR 23%); third line, 93 patients (ORR 14%); fourth line, 26 patients (ORR 8%) and fifth line, 9 patients (ORR 0%). Conclusion: We are working on the establishment of diagnostic and therapeutic algorithms for an optimized management in this unfavourable disease. Disclosure: All authors have declared no conflicts of interest.

1529P Introduction: The current increase in longevity with a good quality of life in old people, and the prevalence of SCLC in this population, makes necessary an effective and safe treatment to face it. The aims of this study are to evaluate if there are differences in overall survival and toxicity according to the age (comparing older and younger than 65 years old), in patients treated with Carboplatin 300mg/m2 iv on day 1, and Etoposid 100mg/m2 per day (iv on day 1 and oral on days 2 to 5). Material and methods: Medical records of patients diagnosed of SCLC between years 2003 and 2010 and treated in our Hospital by the scheme Carboplatin 300mg/m2 iv on day 1, with Etoposid 100mg/m2 per day (iv on day 1 and oral days two to five), were

ix | Abstracts

THE TYROL STUDY SCLC PROJECT: RETROSPECTIVE ANALYSIS OF CLINICAL FEATURES AND THERAPEUTIC OUTCOME IN 484 SMALL CELL LUNG CANCER PATIENTS DIAGNOSED 1991 – 2011

TREATMENT OF PATIENTS WITH SMALL CELL LUNG CANCER IN ROUTINE CLINICAL PRACTICE: 10 YEAR TREND OF TREATMENT STRATEGIES AND OVERALL SURVIVAL

M. Faehling1, S. Kuom1, M. Leschke1, R. Eckert2 1 Klinik für Kardiologie und Pneumologie, Klinikum Esslingen, Esslingen, GERMANY, 2Oncology Group Practice, Wendlingen, GERMANY Introduction: Treatment of patients with small cell lung cancer (SCLC) is challenging due to the generally poor prognosis of the disease and the lack of new

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Introduction: Small cell lung cancer (SCLC) represents approximately 15% of all lung cancer diagnoses and is reducing in incidence. Hyponatremia is a common and debilitating electrolyte disorder, frequently documented in SCLC. Its occurrence is typically attributed to paraneoplastic syndrome- induced syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH). The influence of hyponatremia on the survival of patients with lung cancer remains poorly understood. Aim: The aim of this retrospective study is to investigate clinical features and the prognostic value of hyponatremia in an unselected Irish patient population with small cell lung cancer (SCLC) with limited disease (LD) and extensive disease (ED). Method: The data of patients diagnosed with SCLC in Beaumont hospital over a 3-year period was analysed retrospectively. Patients were identified from analysis of all lung cancers biopsies via the pathology department databank. Data was collected from clinical notes on identified patients including clinical performance status, serum sodium values, disease stage, chemotherapy regimens and response, radiotherapy, palliative care input and survival. Results: 48 patients (22 male, 26 female) with a median age 64 yrs (range 41-87yrs), 29.17%(n = 14) with limited stage were identified. The standard chemotherapy was carboplatin–etoposide. 7 patients received 2nd line treatment with irinotecan. 16.6% patients did not receive chemotherapy (n = 8) due to poor performance status. Hyponatraemia ( plasma sodium [P-Na] <135 mmol/l) was documented in 47.5% of patients (n = 19) receiving chemotherapy. Profound hyponatraemia (P-Na <128mEq/ L) was noted in 27.5% of these patients (n = 11). The median survival in limited stage SCLC with profound hyponatraemia was 5.6 months, and 5.87 months in extensive stage SCLC. In patients with normal plasma sodium and non-significant hyponatraemia median survival was 9.125 months. Conclusions: Hyponatraemia is a common occurrence in patients with SCLC, and one of the most frequent paraneoplastic syndromes noted. Profound hyponatremia is associated with significantly shorter observed median survival and should be considered in generating treatment in patients with SCLC. Disclosure: All authors have declared no conflicts of interest.

retrospective reviewed. Patient’s characteristics, overall survival and causes of death were obtained and analyzed by group of age (patients until 65 years old and older). Results: 96 patients diagnosed of SCLC between January of 2003 and August of 2010 were treated in our Hospital with the aforementioned scheme of chemotherapy. Seventy of them were Extended Stage, and 26 Limited Stage; 54 were until 65 years old (56.25%) and 42 were older (43.75%). Differences in overall survival were not founded between group of older and younger of 65 years old, in both limited and extended stage. In Extended disease, the elder than 65 years old presented a median overall survival of 10 months (1-22), and the younger than 65 had a median overall survival was 8.23 months, (<1-24). In the group with Limited stage, the median overall survival in older than 65 was 11.5 months (6-81), and for the younger 15 months (4-25). Most of patients died due to tumour progression, but in 6 patients this was caused by thromboembolism, infections, or toxicity due to treatment (in 2 patients, 1 in each group of age), all of them without differences by group of age. Conclusion: In SCLC, hybrid scheme Carboplatin 300mg/m2 iv on day 1, with Etoposid 100mg/m2 per day, iv on day 1 and oral days 2 to 5, provides an acceptable overall survival and toxicity, without significant differences comparing older and younger than 65 years old, both in Limited and Extended Stage. Disclosure: All authors have declared no conflicts of interest.

Annals of Oncology

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EPIDERMAL GROWTH FACTOR RECEPTOR MUTATION IN SMALL CELL LUNG CANCER PATIENTS DETECTED BY MUTANT-ENRICHED LIQUIDCHIP TECHNOLOGY FROM PLASMA

H. Lu1, W. Mao2, Q. Cheng3, J. Cai1, X. Wang1, Y. Zhang4, C. Lou1, J. Qin1, L. Lei1, H. Yang5 1 Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, CHINA, 2 Department of Thoracic Surgery, Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology (Zhejiang Province, China), Zhejiang Cancer Hospital, Hangzhou, CHINA, 3Department of Traditional Medicine, Zhejiang Institute for Food and Drug Control, Hangzhou, CHINA, 4Oncology, Zhejiang Cancer Hospital, Hangzhou, CHINA, 5Department of Research, SurExam Bio-Tech Co. Ltd., Guangzhou, CHINA Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has been widely used in non-small cell lung cancer (NSCLC), and the incidence of EGFR mutation in NSCLC is higher in China than in the United States and European countries. Mutations of EGFR exons 19 and 21 in NSCLC is related to response of tumors to EGFR TKIs, suggesting their usefulness as biomarkers. Some case studies reported a gefitinib-responsive small cell lung cancer (SCLC) with EGFR mutation. However, there are few large studies which reported the mutation status of SCLC patients. It is difficult to obtain tumor tissues to detect EGFR mutations in SCLC patients especially from surgery. The aim of this study was to determine the EGFR mutation status in SCLC patients in China, and evaluate the feasibility of EGFR mutation detection from plasma by mutant-enriched liquidchip (MEL) technology. From September 2011 to March 2012, plasma from 35 cases of SCLC were collected at the Zhejiang Cancer Hospital, Hangzhou, China. There were 7 female, 28 male; age from 46 to 74 years old and median age of 60 years old. The stage (Veterans Administration Lung Study Group, VALSG): limited disease (LD) 8 cases, extensive disease (ED) 27 cases. Smoking history: non-smoker 10 cases, light smoker 0 cases, moderate smoker 3 cases and heavy smoker 22 cases. MEL technology was used to detect EGFR exon 19 and exon 21 mutations from plasma of 35 SCLC patients. One of 35 cases was found with mutation in exon 19 of the EGFR gene. The patient with EGFR exon 19 mutation was a female and non-smoker. EGFR mutation is rare in SCLC patients, and may more easily occur in females and non-smokers. It is feasible to detect EGFR mutation for SCLC from plasma by MEL technology. Disclosure: All authors have declared no conflicts of interest.

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NUCLEAR FACTOR-KAPPA B AS A MOLECULAR TARGET IN MALIGNANT PLEURAL MESOTHELIOMA

K.A. Gately1, E. Jennions2, P. Godwin3, M. Barr3, S. Heavey3, K. Umezawa4, J. Edwards5, S.G. Gray3, K.J. O’Byrne6 1 Clinical Medicine, St James’s Hospital, Dublin, IRELAND, 2Oncology, University of Leicester, Leicester, UNITED KINGDOM, 3Clinical Medicine, Trinity College Dublin, Dublin, IRELAND, 4Oncology, Keio University, Yokohama, JAPAN, 5 Department of Cardiothoracic Surgery, Sheffield Thoracic Institute, Sheffield, UNITED KINGDOM, 6Hope Directorate, St James’s Hospital, Dublin, IRELAND

estimates indicate that the incidence of MPM will peak within the next 10-15 years for the western world. Untreated, MPM has a median survival time of 6 months, and most patients die within 24 months of diagnosis. Nuclear Factor kappa B (NFkB) is a pro-inflammatory transcription factor often described as the master regulator of pro-inflammatory responses within the cellular setting. We and others have shown that NFκB is linked to cisplatin resistance (abstract 2307). Several lines of evidence also link NFkB to the pathogenesis of MPM. Using IHC we examined the expression of NFkB in a cohort of MPM patients (n = 200) and correlated expression with various clinicopathological variables. Cytoplasmic or membranous immunostaining was seen in the majority of tumour samples (96.5%), but nuclear localisation of NFkB was seen in only 11% cases. There was no significant correlation between the level of expression of NFkB and standard clinicopathological prognostic factors. Kaplan-Meier Survival analysis showed that nuclear NFkB expression correlated with reduced survival with ( p = 0.05). NFkB was expressed in all MPM cell lines tested to a varying extent (n = 20), with no associations to histology. Although small-molecule inhibitors of NFkB have been proposed as single-agent therapies for cancers with aberrant NFkB activity, most classic NFkB inhibitors are poorly selective and result in off-target effects. Dehydroxymethyl-epoxyquinomicin (DHMEQ) is a novel NFkB inhibitor of low molecular weight designed from the structure of the antibiotic epoxyquinomicin C. When bound DHMEQ irreversibly inhibits NFkB and prevents its translocation to the nucleus. A series of MPM cell lines including a panel of isogenic parent/cisplatin resistant cell lines were treated with various concentrations of DHMEQ. The effects of DHMEQ on cellular viability were examined using various methodologies (including multi-parametric High Content Screening) and the results will be presented at the meeting. Disclosure: All authors have declared no conflicts of interest.

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HIGH EXPRESSION OF MACROPHAGE STIMULATING PROTEIN (MSP) CORRELATES WITH SURVIVAL BENEFIT IN MALIGNANT PLEURAL MESOTHELIOMA

D. Easty1, A. Baird1, K.J. O’Byrne2, A. Soltermann3, D. Nonaka4, D. Fennell5, L. Mutti6, H.I. Pass7, I. Opitz8, S.G. Gray9 1 Clinical Medicine, Trinity College Dublin/St. James’s Hospital, Dublin, IRELAND, 2 Hope Directorate, St James’s Hospital, Dublin, IRELAND, 3Institut für Klinische Pathologie, Universitätsspital Zürich, Zurich, SWITZERLAND, 4Pathology, The Christie NHS Foundation Trust, Manchester, UNITED KINGDOM, 5Medicine, University of Leicester, Leicester, UNITED KINGDOM, 6Dept. of Medicine, Vercelli Hospital, Vercelli, ITALY, 7Thoracic Surgery, NYU Langone Medical Center, New York, UNITED STATES OF AMERICA, 8Thoracic Surgery, University Hospital Zurich, Zurich, SWITZERLAND, 9Clinical Medicine, Trinity College Dublin, Dublin, IRELAND Introduction: RON/MST1R is a member of the MET tyrosine kinase family and has a putative role in several cancers. Macrophage stimulating protein (MSP) is the only known ligand for RON/MST1R. The MSP-RON signalling pathway has been implicated in a variety of cellular functions such as macrophage activity and wound healing. We have previously identified MST1R/RON as frequently activated in MPM, and high positivity for RON staining was an independent predictor of favourable prognosis. Methods: A panel of mesothelioma cell lines were screened for the expression of MSP and RON at the mRNA and protein level. The proliferative response of Ju77, H226 and Met5A (non-malignant transformed human pleural mesothelial cells) to MSP treatment was determined. A phospho-kinase array was utilised to detect the downstream signalling pathways activated upon MSP stimulation. The effect of two MST1R/RON inhibitors (a) a pre-clinical monoclonal antibody (RON8, Imclone) and (b) a small molecule inhibitor on proliferation and migration was assessed. In addition, a series of MPM TMAs were stained for MSP and macrophage markers. Results: MSP and MST1R expression varied between the mesothelioma cell line panel at both the mRNA and protein level. Treatment with MSP reduced the proliferative capacity of the Met5A cell, with a modest effect on the Ju77 MPM line. However, MSP stimulation modified the expression of the SRC family of kinases. In terms of targeting MST1R/RON, the small molecule inhibitor resulted in a significant decrease in proliferation and migration. Although treatment with RON8 had no effect on proliferation, it did affect the migration capacity of the MPM cells. High expression of MST1R/RON or MSP correlated with better survival by univariate analysis. In multivariate analysis, MSP was identified as an independent prognosticator for survival in MPM. We observed no correlation with macrophage (CD 68) staining and survival. Conclusion: RON /MST1R comprises of a number of isoforms, the most common of which are flRON (full length) and sf (short form). Our results indicate that although high levels of RON and MSP correlate with increased survival, in vitro observations would indicate that this may be isoform dependant. Experiments are ongoing to further elucidate the RON-MSP axis in MPM, including in vivo studies. Disclosure: All authors have declared no conflicts of interest.

Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer associated with exposure to asbestos. Currently rates of MPM are rising and

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treatment options. There are few data on how delivered treatment has changed during the past decade in routine clinical practice and how this has effected overall survival. Methods: We retrospectively analyzed all patients diagnosed with SCLC at our institution (lung cancer center certified by the German Cancer Society (DKG)) since 2002. Analysis included lines of treatment delivered, progression free survival (PFS) at each therapy line, use of radiotherapy, overall survival (OS), and use of PET-CT. Results: Preliminary analysis included 102 patients, of which 41 % had limited disease (LD) and 59 % had extensive disease (ED). For all patients, platinum doublet with etoposide has remained standard first line therapy. For patients with LD, the use of simultaneous thoracic radiochemotherapy replaced sequential chemotherapy followed by thoracic radiotherapy. In order to achieve a smaller radiation field, simultaneous radiochemotherapy was usually preceded by 2 cycles of chemotherapy. For patients with extensive disease, the use of cisplatinum instead of carboplatin increased in good performance status patients due to improved antiemesis (apprepitant). As second line therapy, oral topotecan has largely replaced EpiCO (epirubicin, cyclophosphamide, vincristin). One patient with early recurrence of brain metastasis after radiotherapy and topotecan was treated successfully with oral temozolomide. Since August 2007, all ED patients responding to first line therapy received prophylactic cranial radiation. OS tended to increase throughout the study period (LD: from 14 to 17 months, ED: from 6.7 to 10.1 months). Conclusions: New treatment options were successfully implemented in routine clinical practice and resulted in improved survival. However, survival remains unsatisfactory emphasizing the need for early detection and development of additional treatment strategies. Disclosure: All authors have declared no conflicts of interest.

Annals of Oncology

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EXPRESSION OF WILM⍰TUMOUR GENE (WT1) IS ASSOCIATED WITH SURVIVAL IN MALIGNANT PLEURAL MESOTHELIOMA: RETROSPECTIVE ANALYSIS IN A SINGLE CENTER SERIES

S. Cedres1, D. Torrejon Castro2, N. Stjepanovic2, P. Martinez2, A. Martinez2, M. Salcedo2, M.A. Montero2, E. Felip2 1 Medical Oncology, Vall d`Hebron University Hospital Institut d’Oncologia, Barcelona, SPAIN, 2Medical Oncology, Vall d´Hebron University Hospital, Barcelona, SPAIN

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M.A. Damiano1, A.K. Patané2, M. Chacon1, R. Chacon1, V. Vilchez1, A. Rosales2, A. Falco1, C. Poleri3, M. Rosenberg2, C. Martin1 1 Clinical Oncology, Instituto Alexander Fleming, Buenos Aires, ARGENTINA, 2 Surgical Oncology, Instituto Alexander Fleming, Buenos Aires, ARGENTINA, 3 Patology, Hospital Ferrer, Buenos Aires, ARGENTINA Introduction: Malignant pleural mesothelioma (MPM) is a rare and aggressive disease arising from the pleural mesothelium, with a reported survival (OS) of less than 12 months. However, patients with early-stage disease and good-performance status are suitable for multimodality ther¬apy (MT) involving surgery, radiotherapy (PORT), and chemotherapy. Objective: Epidemiological description and analysis of effectiveness in patients with MPM who performed MT. Methods Retrospective study of patients treated by multimodality therapy between April 1990 and April 2011 in three institutions from Argentina. Results: Of 110 patients, 24 (22%) went to MT. Median (Md) follow-up of 21 months (2-139). Of 21 patients with complete data, 90.5% were epithelioid. 67% male, Md age 54, 95% PS 0, 43% smokers, mean of 7.6 packs/year, 29% had contact with asbestos. 60% presented with chest pain or pleural effusion, 3 month (R: 0-38) Md time to diagnosis. 60% in the right pleura. Treatment: 90.5% extrapleural pneumonectomy, 9.5% pleurectomy/decortications, by single surgical team 92%. Perioperative mortality 8%, morbidity 63%, 32% bleeding complications (32%). 52% T3N0M0 postoperative staging. 15 performed neoadjuvant, 3 adjuvant chemotherapy and 10 PORT. 67% received pemetrexed associated with platinum. 57% relapse after MT, 80% locoregional, 80% performed chemotherapy. Md disease free survival (DFS) 20.7 months (95% CI 8-46). OS 34.3 months (95% CI 17-43). Conclusions: Epidemiological and efficiency data obtained are similar to reported series. The present work shows that MT achieves higher DFS and OS than those obtained with other treatments that do not include surgery. Disclosure: All authors have declared no conflicts of interest.

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EFFICACY AND TOXICITY OBSERVED IN MALIGNANT PLEURAL MESOTHELIOMA PATIENTS TREATED IN PHASE I TRIALS AT A SINGLE INSTITUTION

J. Raphael1, A. Hollebecque2, G. Le Teuff3, C. Massard2, R. Bahleda2, J. Margery4, B. Besse1, J. Soria1, D. Planchard1 1 Thoracic Group, INSERM U981, Institut Gustave Roussy, Villejuif, FRANCE, 2 Medical Oncology Department, Institut Gustave Roussy, Villejuif, FRANCE, 3 Department of Statistics and Epidemiology, Institut Gustave Roussy, Villejuif, FRANCE, 4Pulmonary Department, Percy Hospital, Paris, FRANCE Background: Malignant Pleural Mesothelioma (MPM) is a locally aggressive disease with a poor prognosis. After failure of first line platinum-based chemotherapy, there is no widely approved salvage regimen. New strategies for treatment are needed and phase I trials appear as a rationale alternative. The results of such an approach have been evaluated. Materials and methods: MPM patients, were enrolled in 20 different phase I trials between March 2005 and January 2012, and their data analysed retrospectively. The primary endpoint was response rate and secondary endpoints were toxicity profile, Overall Survival (OS) and Progression Free Survival (PFS). Median follow-up of patients was estimated through Schemper’s method. The cut-off date for the analysis was April 2012. Adverse events were assessed by NCI-CTC v.3.0 and response rate according to RECIST 1.1 criteria. Results: Forty-six patients with a confirmed histology of MPM were included in the analysis with a median follow up of 20 months. The median age and the sex ratio (M/F) were 61 years old and 2.29 respectively. Radiological disease progression was observed in 50% of pts, clinical progression in 28%, and dose limiting toxicity in 22%. The best tumour response was as follows: 7% of pts had a RECIST partial response, 59% had stable disease for a median duration of 2.8 months and 24% had progressive disease. The median treatment duration in the phase I was 1.9 months. Median OS and PFS were 6 months (95% CI= [4.3-10.7]) and 2.1 months (95% CI= [1.3-2.8]), respectively. The most common grade 3/4 adverse events (41%) were haematological (11%), gastro-intestinal (4%), cutaneous (7%), renal (4%) and hepatic (4%). All adverse events were reversible and no death due to toxicity was reported. Conclusion: Including MPM pts in phase I trials beyond first line of treatment can result in clinical benefits with an acceptable toxicity profile. Several molecular pathways involved in MPM have been identified and further novel biologic therapies might be tested in a phase I setting in a biology-oriented approach rather than a

ix | Abstracts

MULTIMODALITY THERAPY IN MESOTHELIOMA: AN EPIDEMIOLOGICAL AND EFFECTIVENESS ANALYSIS

MULTICENTER INSTITUTIONAL EXPERIENCE OF SURGICALLY RESECTED THYMIC EPITHELIAL TUMORS (TETS): AN OBSERVATIONAL REPORT ON BEHALF OF F.O.N. I.C.A.P. (FORZA OPERATIVA NAZIONALE INTERDISCIPLINARE CONTRO IL CANCRO DEL POLMONE)

G. Genestreti1, M.A. Burgio1, L. Ampollini2, S. Sanna3, M. Monti1, A. Santo4, M. Mezzetti5, G. Gavelli6, A. Verlicchi7, R. Buosi8 1 Medical Oncology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Meldola, Meldola (FC), ITALY, 2Department of Thoracic Surgery, University Hospital, Parma, Italy, Parma, ITALY, 3Department of Thoracic Surgery, Morgagni-Pierantoni Hospital, Forlì, Italy, Forlì, ITALY, 4Department of Medical Oncology, University Hospital, Verona, Italy, Verona, ITALY, 5Department of Thoracic Surgery, San Carlo Clinic, Milan, Italy, Milan, ITALY, 6Department of Radiology, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola (FC), ITALY, 7Dipartimento Di Oncologia/ematologia, Ospedale Civile di Ravenna - S.ta Maria delle Croci, Ravenna, ITALY, 8 Department of Clinical Oncology, Civil Hospital, Novara, Italy, Novara, ITALY Purpose: thymic epithelial tumors (TETs) are a rare neoplasms. Due to their rarity, large-scale prospective trials are lacking. The present retrospective multicenter analysis aimed to evaluate clinical outcome and clinical-pathological features of TETs after complete surgical resection and adjuvant treatments (Adj) such as chemotherapy (CHT) or radiotherapy (RT). Patients and methods: Patients who underwent a complete surgical resections for TETs between 2000 and 2007 were reviewed. WHO histological classification criteria and Masaoka staging system were used. Adj were: anthracycline- and platin-based CHT, RT on irradiation fields covering the primary tumor bed. Overall survival (OS) was calculated from the date of diagnosis until patient death or last follow-up visit. Disease free-survival (DFS) was defined as the interval between surgery and date of first documentation of recurrence. OS, DFS and 95% Confidence Interval (95% CI) were estimated by Kaplan-Meier method. Results: 62 patients were analyzed: 30 patients (48%) male and 32 (52%) female. Median age was 60 years (range: 33 - 86). At the beginning of their cancer history 20 (32%) patients had myasthenia. Clinical staging showed: 31 (50%) stage I disease, 19 (30%) stage II, 5 (8%) stage III, 2 (4%) stage IVa, 5 (8%) stage IVb. Histologies were: 11 (19%) A tumor type, 18 (29%) AB type, 7 (12%) B1 type, 11 (17%) B2 type, 11 (17%) B3 type and 3 (6%) C type. Pathological staging were: 30 (48%) stage I, 22 (35%) stage II, 3 (6%) stage III, 2 (3%) stage IVa, 5 (8%) stage IVb. 3 (5%) patients

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Background: Calretinin and Wilmśtumour gene (WT1) are mesothelial markers used to confirm the diagnosis of malignant pleural mesothelioma (MPM). Recently, calretinin score assessed by immunohistochemistry (IHC) was implicated with poor prognosis in MPM. We investigated the prognostic value of calretinin and WT1 expression in predicting survival in a series of patients ( p) diagnosed of MPM in our institution Methods: Fifty two patients diagnosed of MPM in Vall d´Hebron University Hospital were retrospectively reviewed. Potential prognostic factors analyzed were age, performance status (PS), neutrophil to lymphocyte ratio (NLR), clinical stage, histology, calretinin and WT1 expression. Survival data were calculated by Kaplan-Meier. Results: Patient’s characteristics: median age 68 years (31-88 years), males 75.5%, PS 1: 67.3%, asbestos exposure 53.1%, clinical stage III: 55.1%, epithelial subtype 71.4% and NLR > 5 in 44.9% of all patients. Calretinin and WT1 IHC expression were available in 47 p and 32 p, and were positive in 41 p (83.7%) and 25 p (78.1%) respectively. All patients were considered initially unresectable and 71.4% received CT. We found a significant association of calretinin and WT1 expression with epithelial histology ( p= 0.030 and p = 0.010). The median survival (OS) was 15.2 months. We found a significant increase in OS in patients with epithelial subtype (23.4 vs 5.0 months in epithelial vs no-epithelial, p < 0.001), PS1 (14.7 vs 2.2 m in PS 1 vs PS 2, p = 0.036) and NLR ≤5 (26.5 vs 13.4 m, p = 0.025). In the IHC markers analysis we found a significant increase in OS for p with WT1 positive expression (16.4 vs 2.3 m, p= 0.013), but not differences for calretinin expression (16.6 m vs 5.0 months, p = 0.37). In the multivariate analysis epithelial histology and WT1remained as significant prognostic factors for survival (HR 22.8; 95%CI,2.7-190, p = 0.004 and HR 9.5; 95%CI 1.7-52.3, p = 0.010 respectively). Conclusion: In our series of 52 MPM patients, epithelial histology, PS, NLR and WT1 expression are significant prognostic factors for survival. The prognostic role of WT1 is worth of prospective validation in future studies on MPM. Disclosure: All authors have declared no conflicts of interest.

stochastical one. We are currently offering a tumour molecular profiling in our pts (MOSCATO trial) for a better selection of phase I trial. Disclosure: All authors have declared no conflicts of interest.

Annals of Oncology

received Adj-CHT and 16 (26%) Adj-RT. Median follow-up was 71 months (range 1-145), DFS and OS are the following:

% DFS (95% CI) % OS (95% CI) Events 48 mo 60 o0 72 mo Events 48 mo 60 mo 72 mo 9 89 (80-97) 89 (80-97) 86 (76-96) 7 97 (92-100) 95 (88-100) 92 (85-100) mo, months. Conclusions: TETs are rare and indolent tumors. Surgery offers good results which can be further improved by Adj such as CHT and/or RT. Supported by GIPO. Disclosure: All authors have declared no conflicts of interest.

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PROGNOSTIC FACTOR FOR SURVIVAL IN PATIENTS WITH ADVANCED THYMIC CARCINOMA

Y. Okuma1, Y. Hosomi1, Y. Nakahara1, M. Yomoda1, Y. Takagi2, M. Iguchi1, M. Shibuya1, T. Okamura1 1 Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases, Tokyo, JAPAN, 2Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, JAPAN

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ACUTE EXACERBATION OF PRE-EXISTING INTERSTITIAL LUNG DISEASE (ILD) IN PATIENTS (PTS) WITH LUNG CANCER UNDER VARIOUS TREATMENTS

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K. Das, S. Imtiaz, S. Kumar, I.A. Muazzam, N. Siddiqui, S.A. Kazmi, N. MuzzafarMedical Oncology, Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, PAKISTAN Introduction: Primary mediastinal germ cell tumor (PMGCT) constitutes a rare malignancy and is a diagnostic challenge because of the difficult approach and often small size of the biopsy specimen. These tumours have a worse prognosis than their gonadal counterparts. This study was performed to review clinical characteristics, therapeutic strategies and outcome of patients with PMGCT at Shaukat Khanum Memorial Cancer Hospital and Research Center Lahore Pakistan. Patient and method: Medical records of patients treated in our hospital during 1996 to 2012 were retrospectively studied. Results: Of 25 patients, 23 were males with a median age of 23 years (range 16–48). Forty percent were seminoma and 60% were nonseminoma. More than 80% of nonseminoma had raised baseline alpha feto protein. The clinical presentation in order of frequency included; dyspnea (72%), cough (68%), chest pain (56%), pleural/ pericardial effusion (44%), weight loss (32%), fever (28%), superior vena-caval obstruction (24%), cervical node metastasis (20%) and pulmonary metastasis (12%). All were treated with initial standard platinum based chemotherapy. Eighty percent of our patients achieved biochemical complete response and 80% achieved radiological response (67% Partial response, 13% complete response). Median survival of patients with seminoma was 37 months with three year survival rate of 60%. Median survival of patients with nonseminoma was 13 months with three year survival rate of 31%. During study period eleven patients died (seven had disease progression, 02 had bleomycin lung toxicity and two had neutropenic sepsis). Conclusion: Nonseminoma constitutes the majority of primary mediastinal germ cell tumors, with prominent male preponderance. Seminomas had a better outcome than nonseminomas. Cisplatin based chemotherapy continues to be an effective treatment for these tumours. Disclosure: All authors have declared no conflicts of interest. 1540

H. Asahina1, S. Oizumi1, Y. Fujita2, K. Takamura3, T. Kojima4, T. Harada5, Y. Kawai6, H. Dosaka-Akita7, H. Isobe4, M. Nishimura1 1 First Department of Medicine, Hokkaido University School of Medicine, Sapporo, JAPAN, 2Department of Respiratory Medicine, National Hospital Organization Asahikawa Medical Center, Asahikawa, JAPAN, 3First Department of Medicine, Hokkaido P.W.F.A.C Obihiro-Kosei General Hospital, Obihiro, JAPAN, 4Department of Medical Oncology and Respiratory Medicine, KKR Sapporo Medical Center, Sapporo, JAPAN, 5Center for Respiratory Disease, Hokkaido Social Insurance Hospital, Sapporo, JAPAN, 6 Department of Respiratory Medicine, Oji General Hospital, Tomakomai, JAPAN, 7 Department of Medical Oncology, Hokkaido University School of Medicine, Sapporo, JAPAN Background: Acute deterioration of ILD for unknown causes, sometimes called as acute exacerbation (AE), can occur at any point in the course of ILD. However, little is known about its incidence and prognostic significance in lung cancer pts with pre-existing ILD, who receive various treatments; chemotherapy, surgery, palliative radiotherapy, and best supportive care (BSC). Methods: A total of 242 subjects (6.9% of all) were retrospectively identified to have pre-existing ILD by computed tomography (CT) from a sum of 3524 pts who had been hospitalized for lung cancer treatment at 8 institutions during 2004 to 2009. CT images of all the eligible pts were centrally reviewed. Univariate and multivariate analyses were performed using a Cox proportional hazard model to examine the potential role of any prognostic factors for overall survival (OS) from the initial lung cancer diagnosis.

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PRIMARY MEDIASTINAL GERM CELL TUMOUR IN PAKISTANI POPULATION; A SINGLE CENTER EXPERIENCE

COMPARISON OF SECOND LINE TREATMENT OUTCOMES BETWEEN SENSITIVE AND REFRACTORY SMALL CELL LUNG CANCER PATIENTS: A RETROSPECTIVE ANALYSIS

T. Korkmaz1, S. Seber2, E. Sari2, M. Canhoroz3, B. Oven Ustaalioglu1, U. Kefeli1, O. Balvan1, M. Gumus4, N. Yasar1, S.N. Turhal5 1 Medical Oncology Department, Dr Lutfi Kirdar Kartal Research and Educational Hospital, Istanbul, TURKEY, 2Medical Oncology Department, Marmara University Hospital, Istanbul, TURKEY, 3Medical Oncology Department, Uludag University Hospital, Bursa, TURKEY, 4Dept. Medical Oncology, Kartal Research and Training Hospital Division of Medical Oncology, Istanbul, TURKEY, 5Medical Oncology, Marmara University Hospital, Istanbul, TURKEY Introduction: Small cell lung cancer (SCLC) has a high relaps rate despite being very chemosensitive. The prognosis of these patients is generally poor. The efficasy of second line treatment is dismal when compared to other chemosensitive tumors such as germ cell tumor or lymphoma. Our aim was to evaluate the outcome of second line treatment and to delineate the prognostic factors that would effect the survival times and response rates. Methods: Results we retrospectively assesed 120 SCLC patients who who failed firstline platinum-etoposide chemotherapy and went on to receive second line chemotherapy at 3 medical oncology centers. Results: Median age of the study group was 58 (33-78) and %80 percent of our patients were below 65 years old. %84 patient were male, %82 had an ECOG PS of 0-1. %61 were at extensive stage at the time of diagnosis. Patients who progressed

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Background: Thymic carcinoma is a rare cancer that represents an incidence of 0.15 per 100,000 persons per year. Thus, clinical characteristics and prognostic factors have not been investigated in detail. In this study, we tried to elucidate the disease profiles, outcomes, and prognostic factors for survival among patients with advanced thymic carcinoma treated with palliative-intent chemotherapy. Patients and methods: This study was a retrospective review of medical records of 38 patients treated with palliative-intent chemotherapy for advanced thymic carcinoma between 1991 and 2011. Clinical demographics, histology, overall survival, and factors expected to predict survival were analyzed. Differences in survival were assessed using Kaplan-Meier analysis and uni- and multivariate Cox proportional hazards regression analyses. Results: The study included 20 males (52.6%) and 18 females (47.4%). The median age at diagnosis was 59.5 years. The most common metastatic sites at diagnosis were lung (44.7%), liver (15.8%), lymph nodes (15.8%), bone (13.2%), and brain (5.7%). The most common histological subtypes were squamous cell carcinoma (73.7%), followed by neuroendocrine carcinoma (15.8%), and mucoepidermoid carcinoma (7.9%). The median survival time was 25.4 months. Overall survival rates at 1- and 2-years were 73.6% and 52.6%, respectively. In univariate and multivariate analyses, the only favorable prognostic factor for overall survival was response to first-line chemotherapy ( p = 0.009). Conclusion: Response to first-line chemotherapy may be a prognostic factor for overall survival in patients with advanced thymic carcinoma. Disclosure: All authors have declared no conflicts of interest.

Results: Pts’ characteristics were: male/female = 217/25; median age (range) = 73 (42-98) yrs.; smoking status: ever/never = 223/19; Performance Status: 0/1/2/3/4 = 74/ 121/23/19/5; Stage I/II/III/IV = 48/10/98/86; Histology: adeno/squamous/large/NOS/ small = 90/75/6/19/52; CT pattern: usual interstitial pneumonia (UIP)/non-UIP = 118/124; extent of normal lung on baseline CT: 10-50%/60-90% = 154/88; pre-existing emphysema: yes/no = 178/64. AE occurred in 71 of 242 pts (29%) overall; 56 of 147 pts (38%) with chemotherapy, 6 of 38 pts (16%) with surgery, 2 of 17 pts (12%) with palliative radiotherapy, and 5 of 36 pts (14%) with BSC alone, and chemotherapy was an independent risk factor for the occurrence of AE (P < 0.001). When separated by histology, in NSCLC, multivariate analysis revealed that age (≥70 yrs., hazard ratio [HR]: 1.84, 95%CI: 1.25-2.71, p = 0.002), PS (≥2, HR: 2.90, 95%CI: 1.80-4.68, p < 0.001), stage (≥3, HR: 4.03, 95%CI: 2.42-6.71, p < 0.001), and AE (HR: 1.84, 95%CI: 1.26-2.69, p = 0.002) were significantly associated with OS, while in SCLC, AE was the only significant prognostic factor (HR: 2.26, 95%CI: 1.08-4.73, p = 0.032). Conclusions: The occurrence of AE is not rare in the lung cancer treatment, particularly during chemotherapy, and it is a factor for poor prognosis in pts with pre-existing ILD. Disclosure: All authors have declared no conflicts of interest.

Annals of Oncology

more than 3 months after first line therapy were labelled as platin sensitive (%64). The patients who received platin based combination based treatment was % 27. Median PFS and OS starting from the initiation of second line treatment were 4 and 7 months respectively. Multivariate analysis identified PS (P= 0.006), extent od disease at inital stage(0.014) and platin sensitivity (0.001) as the independent prognostic factors for survival. Subgroup analyses of the platin sensitive patients indicated platin re challenge yields higher PFS, OS and RR . There was no difference was found between irinotecan and topotecan in the refractory patient group in terms of treatment outcomes. Conclusion: Patients with good PS, who are platin sensitive or initially staged as limited disease derive the most benefit from second line chemotherapy in the setting of relapsed SCLC. Platin combination therapy should be the treatment of choice in the platin sensitive patients. Disclosure: All authors have declared no conflicts of interest.

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EXPRESSION OF C-KIT (CD 117) IN EPITHELIAL THYMIC MALIGNANCIES

M. Wollner1, E. Flechter1, O. Vaisman2, O. Ben Itzhak2 1 Department of Oncology, Rambam Health Care Center, Haifa, ISRAEL, 2 Department of Pathology, Rambam Health Care Center, Haifa, ISRAEL

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VINORELBINE IN MESOTHELIOMA (VIM): A RANDOMISED PHASE II TRIAL OF ORAL VINORELBINE AS SECOND-LINE THERAPY FOR PATIENTS WITH MALIGNANT PLEURAL MESOTHELIOMA (MPM) EXPRESSING BRCA1 – A STUDY IN PROGRESS

D.A. Fennell1, A. Casbard2, L. Nixon2, J. Lester3, G. Griffiths2 1 Department of Thoracic Medical Oncology, University of Leicester & Leicester University Hospitals, Leicester, UNITED KINGDOM, 2Wales Cancer Clinical Trials Unit, School of Medicine, Cardiff University, Cardiff, UNITED KINGDOM, 3Cancer Centre, Velindre Hospital, Cardiff, UNITED KINGDOM Background: Mesothelioma is increasing worldwide. However there is no approved therapy in the second-line setting. Vinorelbine exhibits promising activity, however there has been no randomised evaluation or validation of biomarkers to support patient stratification. We have recently reported that BRCA-1 is an essential regulator of mesothelioma sensitivity to vinorelbine, and its expression is lost in approximately 38%1. The Cancer Research UK VIM trial is to be sponsored by the University of Leicester in collaboration with the Wales Cancer Clinical Trials Unit. Aims: To evaluate the efficacy of second-line vinorelbine plus active symptom control (ASC), versus ASC. Secondary endpoints: tolerability, response rate, change in tumour volume and overall survival. BRCA1 expression IHC will be evaluated as a stratification factor.

ix | Abstracts

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PHASE I/II STUDY TO ASSESS THE SAFETY, PHARMACOKINETICS (PK) AND EFFICACY OF LORVOTUZUMAB MERTANSINE (LM, IMGN901) IN COMBINATION WITH CARBOPLATIN/ETOPOSIDE IN PATIENTS WITH SOLID TUMORS INCLUDING SMALL-CELL LUNG CANCER (SCLC)

D.R. Spigel1, J. Bendell1, A.C. Mita2, A. Argiris2, C. Kurkjian3, C.L. Hann4, Z. Segota5, R. Guild6, R. Mastico6, M.E. Guiterrez5 1 Gi Oncology Research/drug Development Unit, Sarah Cannon Research Institute, Nashville, TN, UNITED STATES OF AMERICA, 2Oncology, University of Texas Health Sciences Center, San Antonio, TX, UNITED STATES OF AMERICA, 3 Cancer Center, The Univesity of Oklahoma Cancer Inst., Oklahoma City, OK, UNITED STATES OF AMERICA, 4Cancer Center, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, UNITED STATES OF AMERICA, 5 Cancer Center, Holy Cross Hospital, Fort Lauderdale, FL, UNITED STATES OF AMERICA, 6Pharmacokinetics Lab, ImmunoGen, Inc., Waltham, MA, UNITED STATES OF AMERICA Purpose: SCLC expresses CD56 almost universally. LM is a CD56-targeting antibody-drug conjugate. This study was initiated to evaluate LM for the treatment of SCLC when used in combination with carboplatin (C) and etoposide (E). Its phase 1 portion was designed to establish the recommended phase 2 dose (RP2D) of LM with C and E. PK data with the combination also was obtained. Methods: Patients ( pts) with advanced solid tumors were accrued to a standard 3 + 3 dose-escalation study design. Successive cohorts received escalating doses of LM IV on days 1 and 8 in combination with C IV on day 1 and E IV on days 1-3 every 21 days. LM PK was measured by an ELISA-based method. C and E levels were measured using optimized LC-MS/MS assays. PK parameters were determined by noncompartmental analysis. Results: 33 patients (13M, median age = 57.3) were treated in 5 cohorts (2 using C AUC6; 3 using C AUC5) at LM doses ranging from 60-112 mg/m2. The RP2D was defined as LM 112 mg/m2 with C AUC5 and E 100 mg/m2. PK samples were analyzed for Cycle 1, first dose. At the RP2D, LM exposure and maximum concentration were similar to those observed in single-agent trials, with the t1/2 of LM approaching 1 day (24.2 hours). PK findings for C/E were similar to published reports (Oguri, 1988; D’Incalci, 1982) with the observed AUC of C = 5.1 ± 0.7 min*mg/mL and E = 6921 ± 1231 min*µg/mL. The most common treatment-related adverse events (AEs) were anemia, thrombocytopenia, nausea, peripheral neuropathy, decreased lymphocytes and neutrophils, and fatigue. The majority of related grade 3/ 4 AEs were cytopenias which, while known to occur with C/E regimens, typically have not been associated with LM monotherapy. Among 13 pts with SCLC accrued to phase 1, 6 (46%; 4 previously treated) achieved PR after at least one response assessment. Conclusion: The combination is well tolerated with no apparent drug-drug interactions. Preliminary signs of activity have been observed in this predominantly pre-treated population. The randomized phase 2 portion of the study in chemo-naïve patients with SCLC has opened to accrual. Updated data will be presented. Disclosure: R. Guild: Employee of ImmunoGen, Inc.R. Mastico: Employee of ImmunoGen, Inc.All other authors have declared no conflicts of interest.

Volume 23 | Supplement 9 | September 2012

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Study objectives: The expression of c-kit (CD117) was investigated to evaluate its usefulness as a marker supporting differential diagnosis and choice of therapy. In thymic epithelial tumors the expression of c-kit may explain a new model of tumor biology, and support the use of determinate target therapy as a new optional approach. Methods: We examined the immunohistochemical expression of c-kit in 28 cases of thymic epithelial tumors diagnosed in our department between 2003-2010, that had been classified on the basis of the World Health Organization histologic classification system: 24 thymoma and 4 thymic carcinoma (1 type A, 4 type AB, 1 type B1, 12 type B2, 6 type B3 and 4 type C). Results: c-kit expression showed immunoreactivity positive in 18% of the all cases (5 patients). In this subgroup, 1 type B2, 1 type B3 and 3 type C. In contrast no immunoreactivity was found in the thymoma cases (types A, AB and B1). No differences were found in the c-kit expressing group between the genders (12 females, 16 males). All c-kit expressing cases were older than 61 years old. Conclusion: Expression of c-kit is an immunohistochemical marker for the diagnosis of thymic carcinoma, and represent a new model of tumor biology with potential development of new targeted therapies as an option for the treatment of thymic carcinoma on the basis of the kit pathways. Clinical trials are necessary to demonstrate the efficacy of these new theoretical strategies. Disclosure: All authors have declared no conflicts of interest.

Methods: An open label, randomised trial of weekly vinorelbine 80mg/m2 plus ASC versus ASC alone. The control arm of ASC will be defined by local practice. Both study arms will be continued until documented evidence of radiological progression or unacceptable toxicity. The sample size has been calculated using the parameters; α = 0.2, β = 0.1 (90% power), hazard ratio 0.65, 1-sided logrank test and 2:1 randomisation favouring vinorelbine. This requires recruitment of 114 patients. However, as we hypothesis that BRCA-1 expression is required for vinorelbine activity and have estimated its absence in one third of patients, the sample size may be inflated to 171 patients depending on the results of an interim analysis. We aim to open the study in Q1 2013 and recruit over 18 months. The results of this study will be used to inform the design of a future phase III study, with stratification of patients to optimise efficacy. BRCA1 is an essential mediator of vinorelbine-induced apoptosis in mesothelioma. Busacca S et al J Pathol. 2012 Jun; 227(2):200-8 Disclosure: All authors have declared no conflicts of interest.