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E. Ruffini

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    GR 03 - Extensive Small Cell with Excellent Response to 1st Line Rx (PCI, Chest and/or Oligomet RT) and Second Line and Treatment of Thymic Malignancies (ID 16)

    • Event: WCLC 2015
    • Type: Grand Rounds
    • Track: Small Cell Lung Cancer
    • Presentations: 6
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      GR03.01a - SCLC Therapy (ID 1838)

      14:20 - 14:40  |  Author(s): R.U. Komaki

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The incidence of lung cancer has been declining since the advent of tobacco cessation efforts, and screening has improved 5-year overall survival rates among smokers to some extent. Nevertheless, about 13% of lung cancers are of the small cell subtype (SCLC), and many such cases present as extensive disease. Outcomes for patients with extensive SCLC remain poor, with median times to progression of 4–6 months, median survival times of 7–11 months, and 2-year survival rates of <5%.[1] Chemotherapy has been the cornerstone of treatment, with the current standard being 4–6 cycles of platinum-based chemotherapy. Other approaches involving other chemotherapeutic agents, molecular targeted drugs, or maintenance chemotherapy have not led to improvement. A notable exception, however, is prophylactic cranial irradiation (PCI) for patients who experience a complete response after induction chemotherapy. PCI has been shown to eliminate the progressive increase in the risk of brain metastasis that accompanies extended survival in patients with SCLC, and in that context is important for maximizing the probability for cure for such patients.[2] Indeed, PCI has led to extended survival among patients with limited-stage SCLC and some patients with extensive SCLC. A randomized phase III trial of patients with extensive SCLC reported by Slotman et al.[3] showed that PCI reduced the incidence of symptomatic brain metastases (15% versus 40% in a no-PCI control group) and increased the 1-year overall survival (OS) rate from 13% to 27%. However, a benefit of PCI for patients with extensive SCLC has not been noted consistently. A multicenter trial from Japan (UMIN000001755, reported in abstract form at ASCO 2014)[ 4] was terminated early because the futility boundary was crossed for OS. That study indicated that receipt of PCI after response to chemotherapy for extensive SCLC reduced the risk of developing brain metastases but had a negative effect on OS (median OS time 10.1 months for PCI vs. 15.1 months for observation, HR=1.38, 95% CI 0.95-2.01, stratified log-rank test P=0.091). Differences between that study and the phase III trial reported by Slotman included the use of magnetic resonance imaging to rule out brain involvement at enrollment, use of only platinum-based doublet chemotherapy, and use of a single PCI schedule (25 Gy in 10 fractions). Another multicenter study involving PCI, RTOG 0937, was also closed early for crossing a survival futility boundary. Further, although the Japanese study showed no difference between the PCI vs. observation groups in terms of incidence of grade >2 adverse events, a disproportionate distribution of grade 4 and 5 events in RTOG 0937 between groups (PCI with or without consolidative extracranial irradiation) also contributed to the early closure of that trial. In addition to PCI, thoracic radiation therapy can improve local control and extend survival for patients with limited-stage disease and possibly for some patients with extensive disease. Controlling intrathoracic tumors remains problematic in SCLC, as such disease remains after induction chemotherapy in most patients and progresses in nearly all patients within the first year after diagnosis. Evidence of benefit for patients with extensive disease includes a single-institution trial of patients with a complete response to induction chemotherapy at distant disease sites, and a complete or partial local response, who received additional low-dose chemotherapy with or without thoracic radiotherapy; that study showed significant improvements in local control and survival after thoracic radiotherapy.[5] Other evidence of benefit comes from two retrospective analyses,[6,7] one non-randomised phase II trial,[8] and a recent phase III multicenter trial of thoracic radiotherapy with PCI for patients with extensive SCLC that had responded to chemotherapy.[9] The latter study involved 247 patients who received thoracic radiation and PCI and 248 who received PCI only after responding to chemotherapy. Although OS at 1 year was no different between groups (33% [95% confidence interval {CI} 27–39] thoracic vs. 28% [95% CI 22–34] control), a secondary analysis showed that the 2-year OS rate was better (13% [95% CI 9–19] vs. 3% [95% CI 2–8], P=0.004) and progression was less likely in the group that received thoracic radiotherapy (hazard ratio 0.73, 95% CI 0.61–0.87, P=0.001). These findings, in combination with low rates of severe toxic effects (no grade 5; grade 3-4 in 26 thoracic and 18 control patients), led the authors to recommend that thoracic radiotherapy be considered, in addition to PCI, for all patients with extensive SCLC who respond to chemotherapy. References 1. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the Surveillance, Epidemiology, and End Results database. J Clin Oncol 2006;24:4539–44. 2. Komaki R, Cox JD, Whitson W. Risk of brain metastasis from small cell carcinoma of the lung related to length of survival and prophylactic irradiation. Cancer Treat Rep 1981;65(9-10):811-814. 3. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007;357:664–672. 4. Seto T, Takahashi T, Yamanaka T, et al. Prophylactic cranial irradiation has a detrimental effect on the overall survival of patients with extensive disease small cell lung cancer: results of a Japanese randomized phase III trial (abstract). J Clin Oncol 2014;32:5s (suppl; abstr 7503). 5. Jeremic B, Shibamoto Y, Nikolic N, et al. Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: a randomized study. J Clin Oncol 1999;17:2092–2099. 6. Giuliani ME, Atallah S, Sun A, et al. Clinical outcomes of extensive stage small cell lung carcinoma patients treated with consolidative thoracic radiotherapy. Clin Lung Cancer 2011; 12: 375–379. 7. Zhu H, Zhou Z, Wang Y, et al. Thoracic radiation therapy improves the overall survival of patients with extensive-stage small cell lung cancer with distant metastasis. Cancer 2011; 117: 5423–5431. 8. Yee D, Butts C, Reiman A, et al. Clinical trial of post-chemotherapy consolidation thoracic radiotherapy for extensive-stage small cell lung cancer. Radiother Oncol 2012;102:234–238. 9. Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 2015;385:36–42.

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      GR03.01b - Systemic Therapy of Extensive Stage Small Cell Lung Cancer (SCLC): Contrasting Therapeutic Principles for SCLC and Non-small Cell Lung Cancer (NSCLC) in 2015 (ID 1839)

      14:40 - 15:00  |  Author(s): N. Murray

      • Abstract
      • Presentation

      Abstract:
      Since the 1960’s, SCLC has been recognized as a distinct lung cancer subtype with unique sensitivity to chemotherapy and radiotherapy. Indeed SCLC and NSCLC are generally discussed as separate topics. After 50 years of investigation, it may be useful to recognize similarities as well as differences in therapeutic principles for systemic therapy. For metastatic disease, palliative first-line systemic therapy for SCLC and NSCLC patients without a drugable driver mutation is a platinum-based two drug chemotherapy combination. For SCLC, platinum and etoposide has generally prevailed as standard although platinum plus irinotecan is widely used in Asia. The platinum doublet used for first-line chemotherapy for NSCLC has had a more complex evolution with many variations, however, the evidence for improved survival with modern platinum doublets can be questioned, even for non-squamous cancers.(1) In both pathologic types, single agents or dose attenuation with first-line therapy result in inferior outcomes. Three and four drug chemotherapy regimens are not better than two drug regimens. Dose-dense and high dose cytotoxic regimens do not generate superior survival results. Non-platinum regimens are not superior to platinum-based two drug combinations. Four to six cycles of first-line therapy is sufficient for most patients. Maintenance chemotherapy is not recommended for SCLC whereas it is an option for NSCLC that confers a survival advantage if patients fail to receive second-line therapy. Second-line treatment for both types of lung cancer is single agent chemotherapy and the survival benefit is worthwhile but modest. Topoisomerase-1 inhibitors have been extensively investigated and used in SCLC. Docetaxel is standard second-line therapy for squamous cancers whereas docetaxel and pemetrexed have equal efficacy in second-line chemotherapy of non-squamous cancers. For both types of lung cancer, second-line chemotherapy is usually unrewarding for cases progressing on first-line chemotherapy or relapsing within less than three months as these tumors have demonstrated chemotherapy resistant biology with response rates of about 10%. Tumors that are sensitive to first-line chemotherapy with a long time to progression are somewhat more tractable with second-line therapy. Third line chemotherapy is not evidenced-based for either SCLC or NSCLC, but may be a reasonable option in selected patients that have responded to second-line treatment. The survival outcome for metastatic SCLC and metastatic NSCLC (without EGFR or ALK mutations) is similar with a median survival of 11-12 months and a two-year survival of 5-10%. Although the initial response rate of SCLC of 60-70% is about double that of NSCLC, the median time for chemotherapy resistant clones to cause a fatal outcome is about the same for both diseases. Without doubt, the natural history of metastatic lung cancer unrestrained by any chemotherapy is worse for SCLC than NSCLC. With respect to trials of SCLC with new chemotherapy agents, it is important to recognize themes of investigation that have been unrewarding. Generally speaking, analogues of active drugs have failed to show evidence of improved survival compared to the parent compounds. This has been shown for alkylating agents, platinum compounds, vinca alkaloids, epipodophylotoxins, and anthracyclines. Moreover, randomized trials have demonstrated statistically significantly inferior survival outcomes for two novel analogues when compared to regimens considered to be standard-of-care. The folate antagonist pemetrexed was studied in a phase III trial of first-line chemotherapy. The GALES (Global Analysis of Pemetrexed in SCLC Extensive Stage) randomized pemetrexed/ cisplatin versus etoposide/ cisplatin.(2) Accrual was terminated early by the data safety and monitoring committee. Survival was inferior in the pemetrexed-platinum arm (median survival 8.1 months) compared to 10.6 months for etoposide-cisplatin (p <0.01). Time to progression (TTP) and response rates (RR) were worse as well. The inferior result was not explained by thymidylate synthase expression or other folate pathway biomarkers.(3) Pemetrexed is simply a bad drug for treatment of SCLC. Similarly, the taxane analogue cabizitaxel was tested in the second-line setting against topotecan.(4) Cabizitaxel was signifantly inferior to topotecan for RR, TTP and survival. This result stands as another example of analogue investigation failure and makes one wonder about the use of any taxane in SCLC. The discovery of treatable molecular targets in adenocarcinomas with approved drugs is a conspicuous difference in systemic therapy of NSCLC compared to SCLC. No molecular targets that can be treated with drugs with proven efficacy have as yet been approved for SCLC.(5) This is not due to a lack of trying. A large number of molecular targeted agents have already been studied in SCLC without a signal of sufficient activity to continue development.(6) The roster includes pathways suggested by analysis of the SCLC genome but numerous other molecular targeted drugs of interest in other cancers were also tested. Drugs with better efficacy may be identified by more extensive SCLC genome analysis,(5) but there is no escaping the fact that results reported to date have been disappointing. Data from genome analysis have shown a bewildering array of abnormalities in this tobacco hyper-mutated tumor. Like squamous carcinomas, the SCLC molecular battlefield is bleak and complex with little opportunity for even temporary respite by identification of mutually exclusive oncogenic drivers. An intriguing possibility is that the numerous mutations in SCLC may be an asset for immunotherapy studies. Checkpoint inhibition has already been demonstrated superior to standard of care in second-line therapy of both squamous (8) and non-squamous NSCLC.(9) At ASCO 2015, two phase II studies of immunotherapy in previously treated SCLC were presented and the results are provocative. Nivolumab produced a RR of 18% and nivolumab plus ipilumimab had a RR of 17% in a population unselected for PD-L1 positivity.(10) In patients selected for PD-L1 positivity, pembrolizumab produced responses in 35%.(11) Although data is preliminary, some responses in these immunotherapy studies may be long-lasting. . The therapeutic principles of systemic therapy of SCLC and NSCLC may be converging again with immunotherapy becoming the most exciting advance in both histologic types. References (1) Murray N. Reality check for pemetrexed and maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol 2014 Feb 10;32(5):482-483. (2) Socinski MA, Smit EF, Lorigan P, Konduri K, Reck M, Szczesna A, et al. Phase III Study of Pemetrexed Plus Carboplatin Compared With Etoposide Plus Carboplatin in Chemotherapy-Naive Patients With Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol 2009 October 1;27(28):4787-4792. (3) Smit EF, Socinski MA, Mullaney BP, Myrand SP, Scagliotti GV, Lorigan P, et al. Biomarker analysis in a phase III study of pemetrexed-carboplatin versus etoposide-carboplatin in chemonaive patients with extensive-stage small-cell lung cancer. Ann Oncol 2012 Jul;23(7):1723-1729. (4) Evans TL, Kim J, Shepherd FA, Syrigos KN, Udud K, Chubenko V, et al. Cabazitaxel (Cbz) versus topotecan in patients (pts) with small cell lung cancer (SCLC) that has progressed during or after first-line treatment with platinum-based chemotherapy: A randomized phase II study. ASCO Meeting Abstracts 2013 June 17;31(15_suppl):TPS7609. (5) Rudin CM, Durinck S, Stawiski EW, Poirier JT, Modrusan Z, Shames DS, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 2012 Oct;44(10):1111-1116. (6) Murray N, Noonan K. Can we expect progress of targeted therapy of small cell lung cancer? In: Dingemans A, Reck M, Westeel V, editors. Lung cancer Sheffield: European Respiratory Society; 2015. p. 234. (7) Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015 May 31. (8) Paz-Ares L, Horn L, Borghaei H, Spigel DR, Steins M, Ready N, et al. Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC). ASCO Meeting Abstracts 2015 June 22;33(18_suppl):LBA109. (9) Antonia SJ, Bendell JC, Taylor MH, Calvo E, Jaeger D, De Braud FG, et al. Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032. ASCO Meeting Abstracts 2015 May 18;33(15_suppl):7503. (10) Ott PA, Fernandez MEE, Hiret S, Kim D, Moss RA, Winser T, et al. Pembrolizumab (MK-3475) in patients (pts) with extensive-stage small cell lung cancer (SCLC): Preliminary safety and efficacy results from KEYNOTE-028. ASCO Meeting Abstracts 2015 May 18;33(15_suppl):7502.

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      GR03.02 - Treatment of Thymic Malignancies - Surgery (ID 1840)

      15:00 - 15:10  |  Author(s): F. Detterbeck

      • Abstract
      • Presentation

      Abstract not provided

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      GR03.03 - Treatment of Thymic Malignancies - Radiotherapy (ID 1841)

      15:10 - 15:20  |  Author(s): D. Gomez

      • Abstract
      • Presentation

      Abstract:
      Indications and techniques for radiation therapy for thymic malignancies have evolved over the past decade. The primary indication for radiation has historically been mediastinal radiation in the adjuvant setting (postoperative radiation therapy, PORT). The recommendations for PORT vary by stage. As increased evidence suggests high local control rates with surgery alone in Masaoka-Koga stage I-II disease, there is a general consensus that in early stages PORT can be omitted. Several studies have demonstrated that local control rates after surgery alone in stage I disease are excellent, and thus there is no indication for PORT in this setting[1-3]. In contrast, for stage III disease, many studies have shown increased rates of local failure after surgery alone, and with an improvement in outcomes with PORT[3-5]. Indeed, common approaches in stage III disease include neoadjuvant chemotherapy, followed by surgery, and then PORT, based on institutional results that demonstrate high levels of disease control with this approach[6-8], and neoadjuvant chemoradiation followed by surgery[9]. Similar to other thoracic malignancies, the advent of advanced radiation techniques has allowed for increased sparing of mediastinal structures such as the heart, great vessels, and lung. This reduction in dose may ultimately lead to lower side effects, thus enhancing the quality of life for survivors of this malignancy. It is recommended that all patients undergo computed tomography-based simulation and radiation treatment with conformal techniques, to minimize dose to the surrounding structures such as the lungs, heart, and underlying vasculature. If possible, motion management should be performed during treatment planning to encompass the extent of respiratory motion. The radiation treatment field should encompass the preoperative extent of disease, including regions of surgical clips. Radiation oncologists should consult the surgeon in the design of their field to ensure that high-risk operative regions are included. Elective nodal radiation is not indicated, based on studies showing that there are minimal to no recurrences in elective nodes after mediastinal radiation. In addition to PORT to the mediastinal bed, as patterns of failure analyses have demonstrated a propensity for pleural failure, there has been interest in utilizing more extensive radiation fields (e.g. hemithoracic radiation therapy), either as prophylaxis or when pleural recurrence occurs[10]. Given the lack of strong evidence supporting this approach, it is recommended that this treatment primarily be performed in the context of a clinical trial. At this time, there is not an established role for radiation in stage IV disease, and studies assessing this technique using modern radiation modalities are ongoing. References 1. Park HS, Shin DM, Lee JS, et al. Thymoma. A retrospective study of 87 cases. Cancer. 1994;73: 2491-2498. 2. Forquer JA, Rong N, Fakiris AJ, Loehrer PJ, Sr., Johnstone PA. Postoperative radiotherapy after surgical resection of thymoma: differing roles in localized and regional disease. Int J Radiat Oncol Biol Phys. 2010;76: 440-445. 3. Fernandes AT, Shinohara ET, Guo M, et al. The role of radiation therapy in malignant thymoma: a Surveillance, Epidemiology, and End Results database analysis. J Thorac Oncol. 2010;5: 1454-1460. 4. Weksler B, Shende M, Nason KS, Gallagher A, Ferson PF, Pennathur A. The role of adjuvant radiation therapy for resected stage III thymoma: a population-based study. Ann Thorac Surg. 2012;93: 1822-1828; discussion 1828-1829. 5. Gao L, Wang C, Fang W, Zhang J, Lv C, Fu S. Outcome of multimodality treatment for 188 cases of type B3 thymoma. J Thorac Oncol. 2013;8: 1329-1334. 6. Kim ES, Putnam JB, Komaki R, et al. Phase II study of a multidisciplinary approach with induction chemotherapy, followed by surgical resection, radiation therapy, and consolidation chemotherapy for unresectable malignant thymomas: final report. Lung Cancer. 2004;44: 369-379. 7. Huang J, Riely GJ, Rosenzweig KE, Rusch VW. Multimodality therapy for locally advanced thymomas: state of the art or investigational therapy? Ann Thorac Surg. 2008;85: 365-367. 8. Modh A, Rimner A, Allen PK, et al. Treatment Modalities and Outcomes in Patients With Advanced Invasive Thymoma or Thymic Carcinoma: A Retrospective Multicenter Study. Am J Clin Oncol. 2014. 9. Korst RJ, Bezjak A, Blackmon S, et al. Neoadjuvant chemoradiotherapy for locally advanced thymic tumors: a phase II, multi-institutional clinical trial. J Thorac Cardiovasc Surg. 2014;147: 36-44, 46 e31. 10. Sugie C, Shibamoto Y, Ikeya-Hashizume C, et al. Invasive thymoma: postoperative mediastinal irradiation, and low-dose entire hemithorax irradiation in patients with pleural dissemination. J Thorac Oncol. 2008;3: 75-81.

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      GR03.04 - Treatment of Thymic Malignancies - Biology and Standard Treatment (ID 1842)

      15:20 - 15:30  |  Author(s): G. Giaccone

      • Abstract
      • Presentation

      Abstract:
      Thymic epithelial tumors (TETs) are rare malignanices of the thymic epitehlial cells. Recent research has identified recurrent mutations in these tumors, using NextGen sequencing (Petrini et al. Nature Gen 2014; Wang et al Sci. Rep. 2015). GTF2i, a general transcription factor has been found to have a high frequency of a unique muation in over 70% of type A and AB, whereas this mutation decreases in frequency in thymic carcinomas. Mutation in GTF2i may represent an oncogenic event in TETs. Common recurrent mutations in known cancer genes have been found more frequenty in thymic carcinomas, where the number of mutations is higher than in more indolent forms of TETs. In particular genes involved in epigenetic regulation have been found recurrently mutated. Presence of P53 mutations was also found to be related to poorer survival, as well as the number of recurrent mutations. The implications of molecular characterization of TETs on treatment are still relatively small, but they represent a first step toeards more targeted treatments. Chemotherapy remains the standard treatment for first line therapy of patients with un-resectable disease, or as neoadjuvant therapy in large tumors before surgery or radiation. The more commonly employed regimes still are represented by the PAC regimen, PE regimen and more recently carbo-taxol. Targeted therapies have been studied in unselected patients and of all of those tested in properly conducted phase II studies, sunitinib appears to be the most effective in thymic carcinoma (25% response rate; Thomas et al. Lancet Oncol 2015). A phase II of pembrolizumab is actively accruing in patients with thymic carcinomas, where PDL-1 expression is relatively high.

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      GR03.05 - Thymic Epithelial Tumors: New Hope on the Horizon with Novel Therapeutic Strategies (ID 1843)

      15:30 - 15:40  |  Author(s): J. Remon-Masip, B. Besse

      • Abstract
      • Presentation

      Abstract:
      Thymic Epithelial Tumors (TET) comprised of thymoma (T) and thymic carcinoma (TC) are rare cancers with an incidence of 1.7 and 1.3 per million per year in Europe[i] and the US[ii], respectively. Five-year overall survival (OS) varies significantly sitting at > 80% for T compared with ~40% for TC[iii],[iv]. Surgery remains the treatment of choice for operable TET, whereas chemotherapy is standard of care for metastatic or inoperable / recurrent disease. The response rate (RR) of TET to current chemotherapy agents differs by histological features: T responds better to first-line platinum based chemotherapy than TC (69% vs. 41%)[v]. No standard treatments are available for advanced TET after failure of first-line platinum-based chemotherapy, although single agents are generally used with modest benefit. For example pemetrexed, has been associated with a 17% partial response (PR) rate in T and 10% of PR in TC, with a median progression free survival (PFS) of 13.8 months and 6.5 months, respectively[vi]. Other drugs have recently been tested in second-line with promising results. In a phase II trial which recruited 14 T and 19 TC patients, amrubicin (a topoisomerase II inhibitor) was administered at 35 mg/m[2] IV days 1-3 on a 21-day cycle, producing an 18% RR (n=6, all PR: 29% in T and 11% in TC) without unexpected toxicity or cardiotoxicity[vii]. Another phase II trial investigated the combination of capecitabine plus gemcitabine in 30 pretreated TET patients (22 T and 8 TC). Overall RR was 40% (3 CR and 8 PR, with 3 PR in TC 3), PFS for T and TC was 11 months and 6 months, respectively and median OS was 16 months[viii]. In octreoscan positive patients with TET, somatostatin analogs with or without prednisone have also been shown to be effective as maintenance or as second-line treatment[ix][,[x]]. Given the poor survival of advanced TET, especially TC, there is a clear need for new treatment options. However, the molecular pathogenesis of TET is poorly understood at present. Profiled somatic genetic variations in 78 advanced-TET[xi] cases showed higher a incidence of somatic non-synonymous mutations in TC compared to T (62% vs. 13%; p<0.0001). TP53 was the most frequently mutated gene (overall in TET was 17% and especially in TC, 26%) and was associated with poorer OS (p<0.0001). Moreover, genes invovlved with histone modification (e.g. BAP1), chromatin remodelling, DNA methylation genes and c-KIT were also frequently mutated in advanced TCs. Although the presence of activating mutations is low in TET, the SPECTA-lung trial (NCT02214134) will allow analysis of more than 360 genes in patients with thoracic tumors, including T and TC. In this EORTC/ETOP umbrella study, eighteen European centres will allocate patients to different treatment arms based on the molecular characteristics of their disease, suggesting that basket trials allow the study of the genetics of less common malignancies[xii]. Despite data demonstrating EGFR and KIT overexpression in TET, EGFR and c-KIT mutations are rare, reported at 2%-10% and 9%, respectively[xiii]. This low percentage could explain the lack of RR observed in phase II studies evaluating Gefitinib, Erlotinib plus bevacizumab, and Glivec. In a recent retrospective analysis of 48 TC and thymic neuroendocrine tumors, the probability to finding c-KIT mutations was higher in CD117-positive thymic squamous cell carcinoma with poorly-differentiation and co-expression of CD5 and p63 in the absence of neuroendocrine markers (6 out of 23, 26%)[xiv], suggesting that a subgroup of TC might respond to c-KIT inhibitors. Recently SRC inhibitors (AZD0530) reported no RR in a phase II trial[xv]. Angiogenesis is another relevant pathway in TET. VEGF-A, -C, -D and VEGFR-1,-2,-3- are all overexpressed in high risk T and TC[xvi]. Sunitinib is an oral tyrosine kinase inhibitor (TKI) of VEGFR, KIT, and PDGFR. In a single arm phase 2 trial of sunitinib (50 mg/day for 4 weeks on, 2 weeks off) after at least one previous line of chemotherapy, a PR was reported in 26% of TC and 6% in T, with a mPFS of 7.2 months and 8.5 months, respectively. Main adverse events (AE) reported were lymphocytopenia, fatigue, and oral mucositis[xvii]. Although response was mainly limited to TC, sunitinib demonstrated an unprecedented activity for a targeted agent so far. Other antiangiogenic compounds that could be of value include Lucitanib, a selective TKI of FGFR1-3, VEGFR1-3, and PDGFR α/β. Efficacy data in 15 patients will be reported for this drug at the WCLC 2015. Insulin-like growth factor-1 receptor (IGF-1R) over-expression has been reported in 86% of TC and 43% of T[xviii], and carries poor prognosis. In a recent phase II trial of 49 patients with recurrent TET (37 T and 12 TC), single agent cixutumumab (a fully human IgG1 monoclonal antibody anti-IGF-1R, 20 mg/kg every 3 weeks), reported clinical activity only in T (14% PR, 28% SD, TTP 9 months and OS 27.5 months). No activity was recorded in the TC cohort (42% SD, TTP 1.7 months and OS 8.4 months). The most common toxicity in both groups was hypoglycemia (10%). Of note, 9 patients with T experienced autoimmune disorders[xix]. A phase II trial, Belinostat (PXD101, a pan-histone deacetylase inhibitor, 1g/m2 on days 1 through 5 in a 3-week schedule) among 41 patients (25 T and 16 TC) has reported only modest activity, with an 8% RR in T and no responses observed in TC. However, based on the duration of response and disease stabilization (median TTP and OS were 5.8 and 19.1 months, respectively), additional testing of belinostat in this disease may be warranted[xx]. Milciclib (PHA-848125AC) is an inhibitor of cyclin-dependent kinase2/cyclin A and SRC family members. Milciclib (150 mg/d 7 days on / 7 days off, 2-week cycles) has been evaluated in a phase II trial with 43 patients (26 TC and 9 B3-T). Out of 30 patients, 14 cases (46.7%) reached the primary end point and were PFS at 3 months, including PR. Five cases of SD lived longer than 1 year. The median PFS was 8.2 months and median OS has not been yet reached. The toxicity profile appeared favourable with nausea, asthenia and neutropenia (8.3%) reported as the most common severe AEs[xxi]. The mTOR inhibitor everolimus (10 mg/d) has been tested in a phase II trial in 50 patients with advanced or recurrent T (n=30) or TC (n=19) previously treated with cisplatin-containing chemotherapy. Preliminary data among the 43 evaluable patients showed a disease control rate (DCR) of 86% (1 CR, 10 PR, 32 SD) that was beyond the pre-specified endpoint of 40% DCR. The median PFS was 11.3 months (T not reached vs. 5.5 months in TC), and median OS was 18.6 months for TC and not reached for T. Few severe AEs were reported (asthenia, dyspnoea, neutropenia and hyperglycemia)[xxii]. Blockade of the immune checkpoint programmed death receptor ligand-1 (PD-L1)/PD-1 pathway has clinical activity in many tumors types. In a cohort of 139 TET, retrospective PDL-1 expression by IHC with the E1L3N antibody has been reported in 70% of TC and 23% of T, respectively. PDL-1 expression was not a significant prognostic factor in multivariable analysis[xxiii], although in other reported cohorts overexpression of PD-L1 was associated with worse prognosis [xxv, xxiv]. These results generally support immunotherapeutic strategies in TET (NCT02364076). At present, antiangiogenics, mTOR and CDK inhibitors, are the most promising drugs in TET treatment. Consensus on meaningful end-points, and knowledge of predictive biomarkers are challenges in this disease. [i] Siesling S, van der Zwan JM, Izarzugaza I et al. Rare thoracic cancers, including peritoneum mesothelioma. Eur J Cancer 2012; 48: 949-60. [ii] Engels EA. Epidemiology of thymoma and associated malignancies. J Thorac Oncol 2010; 5 (10 Suppl 4): S260–S265. [iii] Mariano C, Ionescu DN, Cheung WY et al. Thymoma. A population-based study of the management and outcomes for the province of British Columbia. J Thorac Oncol 2013; 8: 109–117. [iv] de Jong WK, Blaauwgeers JLG, Schaapveld M et al. Thymic epithelial tumours: a population-based study of the incidence, diagnostic procedures and therapy. Eur J Cancer 2008; 44(1): 123–130. [v] Okuma Y, Saito M, Hosomi Y et al. Key components of chemotherapy for thymic malignancies: a systemic review and pooled analysis for anthracyclines-, carboplatin- or cisplatin-based chemotherapy. J Cancer Res Clin Oncol 2015; 141: 323-31 [vi] Liang Y, Padda SK, Riess JW et al. Pemetrexed in patients with thymic malignancies previously treated with chemotherapy. Lung Cancer 2015, 87: 34-8 [vii] Wakelee HA, Padda SK, Burns M et al. Phase II trial of single agent amrubicin in patients with previously treated advanced thymic malignancies. J Clin Oncol 2015; 33 (suppls; abstr 7580) [viii] Palmieri G, Buonerba C, Ottaviano M, et al. Capecitabine plus gemcitabine in thymic epithelial tumors: Final analysisof a phase II trial. Future oncology 2014; 10: 2141-7 [ix] Palmieri G, Ottaviano M, Nappi L et al. Somatostatin analogs as maintenance therapy in heavily pretreated thymic epithelial tumors. J Clin Oncol 2015; 33 (suppl; abstract 7581) [x] Ottaviano M, Damiano V, Nappi L et al. Effectiveness of somatotstain analogs plus prednisone in aggressive histotype and advanced stage of thymic epithelial tumors. J Clin Oncol 2015; 33 (suppl; abstract 7582) [xi] Wang Y, Thomas A, Lau Ch et al. Mutations of epigenetic regulatory genes are common in thymic carcinomas. Scientific Reports 2014; 4: 7336 [xii] Lopez-Chavez A, Thomas A, Rajan A et al. Molecular profiling and targeted therapy for advanced thoracic malignancies: A biomarker-derived, multiarm, multihistology phase II basket trial. J Clin Oncol 2015; 33: 1000-7 [xiii] Yoh K, Nishiwaki Y, Ishii G et al. Mutational status of EGFR and KIT in thymoma and thymic carcinoma. Lung Cancer 2008; 62: 31-20 [xiv] Schirosi L, Nannini N, nociloi D et al. Activating c-KIT mutations in a subset of thymic carcinoma and response to different c-KIT inhibitors. Ann Oncol 2012; 23: 2409-14 [xv] Gubens MA, Burns M, Perkins SM et al. A phase II study of saracatinib (AZD0530), a SRC inhibitor, administered orally daily to patients with advanced thymic malignancies. Lung Cancer 2015; 89: 57-60 [xvi] Lattanzio R, La Sorda R, Facciolo F et al. Thymic epithelial tumors express vascular endothelial growth factors and their receptors as potential targets of antiangiogenic therapy: A tissue micro array-based multicenter study. Lung Cancer 2014; 85: 191-6 [xvii] Thomas A, Rajan A, Berman A et al. Sunitinib in patients with chemotherapy-refrtactory thymoma and thymic carcinoma: an open-label phase 2 trial Lancet Oncol 2015; 16: 177-86 [xviii] Girard N, Teruya-Feldstein J, Payabyab EC et al. Insulin-like growth factor-1 rceptor expression in thymic malignancies. J Thorac Oncol 2010; 5: 1439-46 [xix] Rajan A, Carter CA, Berman A et al. Cixutumumab for patients with recurrent or refractory advanced thymic epithelial tumours: a multicentre, open-label, phase 2 trial. Lancet Oncol 2014; 15:191–200. [xx] Giaccone G, Rajan A, Berman A et al. Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors. J Clin Oncol 2011; 29: 2052-9 [xxi] Besse B, Garassino MA, Rajan A et al. A phase II study of milciclib (PHA-848125AC) in patients with thymic carcinoma. J Clin Oncol 2014; 32 (suppl; abstract 7526) [xxii] Zucali PA, Martino de Pas T, Palmieri G et al. Phase II study of everolimus in patients with thymoma and thymic carcinoma previously treated with cisplatin-based chemotherapy. J Clin Oncol 2014; 32 (suppl; abstract 7527) [xxiii] Katsuya Y, Fujita Y, Horinouchi H et al. Immunohistochemical status of PD-L1 in thymoma and thymic carcinoma. Lung Cancer 2015; 88: 154-9 [xxiv] Programmed cell death 1 (PD-1) and its ligand (PD-L1) expression in thymic epithelial tumors (TETs): Impact on the treatment efficacy and alteration in expression after chemotherapy (C) J Clin Oncol 2015; 33 (suppl; abstr 7515) [xxv] Padda SK, Riess JW, Schwartz EJ et al. Diffuse high intensity PDL-1 staining in thymic epithelial tumors. J Thorac Oncol 2015; 10: 500-8

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    MTE 11 - Mediastinal Tumors Including Thymic Tumors, Lymphoma, Germ-Cell Tumors: Biology, Diagnosis and Treatment (Ticketed Session) (ID 63)

    • Event: WCLC 2015
    • Type: Meet the Expert (Ticketed Session)
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/07/2015, 07:00 - 08:00, 201+203
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      MTE11.03 - Mediastinal Tumors Including Thymic Tumors, Lymphoma, Germ-Cell Tumors: Biology, Diagnosis and Treatment (ID 1996)

      07:40 - 08:00  |  Author(s): E. Ruffini

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The mediastinum is customarily divided into an anterior, middle (visceral) and posterior (bilateral paravertebral) compartment. Studies encompassing large series of patients indicate that more than half of the mediastinal masses arise in the anterior compartment (54-59%), up to 20% in the middle compartment, and 25% in the paravertebral (posterior) compartment. The general approach to a patient with a mediastinal mass include a thorough history and clinical examination. The type of a mediastinal tumor largely depends on the age of the patient and the presence of associated symptoms and/or paraneoplastic conditions. The most common symptoms are nonspecific and include cough, dyspnea, chest pain, arrhythmias, dysphagia, pleural effusion or, in more aggressive forms, superior vena cava (SVC) syndrome. Some tumor markers may be helpful in some forms (germ cell tumors). Chest radiography and CT scan can image the mass and can allocate it to one of the mediastinal compartments. The CT characteristics may somehow guide the clinician to a differential diagnosis and to the nature (benign or malignant) of the mass. In selected cases MRI may be useful to assess the relationship with the vascular structures and the heart. PET or integrated PET-CT have a role to define the activity of the tumor and the correct stage. Biopsy of the mass, either through a fine-needle aspiration (FNA) or core biopsy is indicated in case the imaging is not diagnostic. Very often, a surgical biopsy through an anterior mediastinotomy (Chamberlain procedure), mediastinoscopy or VATS is needed to provide sufficient tissue to the pathologist for a correct diagnosis. A brief description of the histologic types and the diagnostic workup for the most common mediastinal tumors in the three compartments will be presented. In conclusion, diagnostic workup of mediastinal masses include a careful medical history (age, duration and type of symptoms); imaging definition with CT scan is essential to precisely determine the mediastinal compartment, and cyto-histological confirmation is required in case of undetermined lesions. Differential diagnosis is crucial to provide optimal treatment. Anterior mediastinal tumors. They represent more than half of the mediastinal masses at any age. The most common types are thymic tumors (35%), lymphomas (25%), intrathoracic thyroid tumors (15%), germ cell tumors (20%, malignant 10% - teratomas 10%), other tumors (5%). According to age groups, in adults (> 40 years) thymic tumors are the most common type in men and women. Thyroid tumors are the second most common type in elderly patients. In adolescent/young adults (<40 years) lymphomas are the most common type (either Hodgkin or non-Hodgkin), while thymic tumors are the second most common in young adults, and germ cell (teratoma) in adolescents. Finally, in children (<10 years) a similar prevalence of thymic tumors, teratomas, and lymphomas is observed. The diagnosis of an anterior mediastinal mass is based on the duration and type of symptoms. Thymomas, thyroid goitres and teratomas are usually asymptomatic or indolent, Hodgkin lymphoma and seminomas are associated with an intermediate duration of symptoms, while non-seminomatous germ cell tumors (NSGCT) and lymphoblastic lymphomas have a rapid onset of severe symptoms (SVC syndrome is frequent in these patients). High alpha-feto protein (AFP) or beta-HCG levels are diagnostic of NSGCT, and high lactate dehydrogenase (LDH) suggest a diagnosis of lymphoma; the association of Myasthenia Gravis secures the diagnosis of thymoma. Cyto-histological diagnosis is indicated in undetermined forms, usually to differentiate lymphoma from thymic tumors for optimal subsequent treatment. The average sensitivity of needle biopsy (either FNA or core biopsy) in the diagnosis of lymphoma is around 50%, and in most cases a surgical biopsy is needed in suspected cases. Mediastinotomy is preferred to mediastinoscopy (which reaches the middle-visceral mediastinal compartment). Video-assisted thoracic surgery (VATS) is also a reliable technique, particularly in case of associated pleural effusion. Middle mediastinal tumors. The vast majority of middle (visceral) mediastinal masses are benign. Half of these are cysts (bronchogenic, esophageal duplication cysts). The remaining masses are most often from lymphnodes and can be either malignant (lymphadenopathy from lung cancer, lymphomas), or inflammatory/granulomatous (tuberculosis, sarcoidosis). A small percentage of these lesion (<10%) are miscellaneous (Castleman disease, paraganglioma, intrathoracic thyroid mass). Diagnosis is usually easily accomplished with CT scan, which reveals the liquid component of the cyst. MRI is required in undetermined solid lesions. Cyto-histologic diagnosis (FNA/core biopsy or mediastinoscopy/VATS) is sometimes required for undetermined adenopathy for the differential diagnosis between lymphoma and solid tumors. Almost all the benign lesions are asymptomatic or associated with mild nonspecific symptoms (cough, arrhythmias). In the malignant lesions most symptoms result from the underlying disease (lymphoma, lung cancer). Paravertebral mediastinal tumors. Almost all the tumors in the paravertebral compartment arise from the nervous structures (nerves and ganglia). The prevalence of the different types is different in adults and children/adolescents. In adults almost 90% of the masses are benign, including schwannoma (50%), ganglioneuroma (20%) and neurofibroma (15-20%). The little percentage of malignant neurofibrosarcomas are part of a familial neurofibromatosis. In these patients the clinical presentation includes severe symptoms (pleural effusion, chest pain, dyspnea) and a large tumor (> 10 cm.). Benign paravertebral masses without symptoms can be observed over time if there is no spinal extension. Diagnosis is quite easy using CT scan. Intraspinal extension can be documented with MRI. Resection is indicated in symptomatic forms or in case of intraspinal extension. Patients with familial neurofibromatosis and paravertebral mediastinal mass should receive surgery due to the demonstrated high rate of malignant shift. In children less than 4 years of age paravertebral masses are in high percentages malignant neuroblastomas or ganglioneuroblastomas (virtually 100%l in children < 1 year). The percentage of malignant forms decreases with increasing age. In neuroblastomas, serum levels of vanillylmandelic acid (VMA) and metanephrine are almost always elevated and therefore diagnostic.

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    ORAL 05 - Surgery (ID 97)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Locoregional Disease – NSCLC
    • Presentations: 1
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      ORAL05.08 - Discussant for ORAL05.05, ORAL05.06, ORAL05.07 (ID 3295)

      12:21 - 12:31  |  Author(s): E. Ruffini

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P1.04-104 - Lung Cancer Patients Derived Xenografts: Prospective Molecular Profiling and Potential Evaluation of Drug Resistance (ID 1278)

      09:30 - 09:30  |  Author(s): E. Ruffini

      • Abstract
      • Slides

      Background:
      The discovery of “driver mutations” such as the Epidermal Growth Factor Receptor (EGFR) and the Anaplastic Lymphoma Kinase (ALK) has led to a remarkable improvement in the outcomes of lung adenocarcinoma, which accounts 50% of the non-small cell lung cancer (NSCLC) diagnoses. Up today, no druggable molecular targets have been identified for squamous carcinoma or small cell lung cancer, which are still treated with the “one-fits-all” therapeutic approach, as it is for a relevant percentage of adenocarcinomas too. The precise definition of molecular profile and, possibly, the description of predictive factors are research priority in the thoracic oncology field. The vast majority of preclinical data are based on in vitro studies, but cell lines models do not entirely reflect tumour characteristics and are hampered by genetic divergence from primary tumours. Patient derived tumour xenografts (PDTX) are a valuable alternative to closely reproduce tumour biology and to prospectively characterize in vivo mechanisms of cancer growth and therapeutic response. Through the generation of a cohort of lung cancer xenopatients, the project aims to confirm the reliability of such models in this disease and to prospectively characterize its biomolecular features.

      Methods:
      Metastatic and early stages lung cancer cases are considered for the enrolment. Written informed consent is requested from each patient. Fresh tumour tissue from lung biopsies or lung resections is collected and kept in serum free medium (4° C), embedded in 20% matrigel and subcutaneously engrafted into NSG and NOD SCID mice, within 24 hours from sample collection. The exponentially growing tumours are passaged subcutaneously to other mice for a second passage after which they are archived for subsequent analyses (formalin fixed, snap frozen and RNA later). Each sample from surgical resection is also stored to create a DNA lung cancer bank.

      Results:
      Fourteen samples from TC-guided lung biopsies and sixty-six from radically resected NSCLC were engrafted in NSG and NOD SCID mice lineage in a 1:1 ratio. Due to the low engraftment rate and high morbidity observed in NGS mice in the first 73 samples, subsequent engraftments and expansions were performed in NOD SCID mice only. The overall engraftment rate in biopsy samples was 0 % in NGS and 7.14 % in NOD SCID mice as opposed to 0 % in NGS and 27,27 % in NOD SCID for surgical samples (50% adenocarcinomas, 44,45% squamous carcinomas and 5,55% sarcomatoid carcinomas). Nineteen samples underwent the second passage: of those, 10 samples have been archived after the second successful passage and will be used for further analyses.

      Conclusion:
      The trial is still ongoing and a longer follow-up is needed. In biopsy-derived samples, engraftment is deeply limited by the paucity of tissue. The results of this study will possibly confirm the reliability of PDTX in lung cancer and provide prospective biomolecular characterization for different histological types.

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