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J.F. Vansteenkiste



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    MS09 - Immune Therapies for Lung Cancer (ID 26)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Medical Oncology
    • Presentations: 1
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      MS09.4 - Lung Cancer Vaccines (ID 499)

      15:05 - 15:25  |  Author(s): J.F. Vansteenkiste

      • Abstract
      • Presentation
      • Slides

      Abstract
      Surgical resection is the standard therapy for early stage NSCLC, but about half of the patients still develop a relapse and die of their cancer. In case of unresectable locally advanced disease, the combination of chemo- and radiotherapy may cure some patients, but the majority will relapse. Targeted agents have brought progress for patients with advanced NSCLC selected based on molecular factors such as EGFR or ALK mutation, but other novel approaches are needed. One is therapeutic cancer vaccination (TCV), which may become an important part in our future treatment armamentarium, especially for patients with local or locally advanced NSCLC. Cancer immunotherapy in a broad sense is any interaction with the immune system to treat cancer. A first approach is non-antigen-specific modulation of the immune system. Historical experience (BCG, C. parvum, interferon, interleukins, thymosin, etc.) was disappointing. Promising response rates in heavily pre-treated NSCLC patients were reported in recent phase I trials with agents acting on the interaction between antigen presenting cells, T-lymphocytes and tumor cells. Examples are antibodies against Cytotoxic T-lymphocyte Antigen 4 (CTLA-4) or against Programmed Death 1 receptor or its ligands. Antigen-specific immunotherapy aims at specific priming of immune system to recognize the tumor as foreign, thereby generating specific antibodies and/or cytotoxic T cells. This is “therapeutic cancer vaccination”. Conditions for optimal TCV are: 1/ specificity (well-defined target antigen in the tumor, not in other tissues); 2/ selectivity (use in the population expressing the target); 3/ immunogenicity (interaction with antigen leads to effective humoral and/or cellular response); 4/ tumor sensitive to immune kill in order to obtain improvement in patients’ outcome. Although the historical results of TCV for NSCLC were disappointing, knowledge from the last decades about the molecular pathology of tumors, of the immune system in general, and of tumor immunity in particular, has led to the introduction of several modern and more sophisticated TCVs. These vaccine formulations have shown encouraging data in phase II randomized clinical trials, and are now being studies in large phase III studies. Important examples are the MAGE-A3 vaccine in resected early stage NSCLC, the BLP-25 vaccine in locally advanced NSCLC after chemoradiotherapy, and e.g. belagenpumatucel-L and the TG4010 vaccine in advanced stage NSCLC. The MAGE-A3 protein is totally tumor-specific and present in about 35% of early stage NSCLC. In the hypothesis generating double-blind, randomized, placebo-controlled phase II study, 182 patients with completely resected MAGE-A3-positive stage IB-II NSCLC received recombinant MAGE-A3 protein combined with an immunostimulant (13 doses over 27 months) or placebo [1]. No significant toxicity was observed. There was a 24% - non-significant - improvement in disease-free survival (HR 0.76; 95% CI 0.48 to 1.21). Moreover, a predictive gene signature, initially described in advanced melanoma patients could be confirmed in early stage NSCLC [2].A large phase III study (n=2270) with MAGE-A3 vaccine is recruited and awaiting results (MAGRIT, NCT00480025). Mucins like the MUC1 protein are present in many epithelia, but MUC1 expression is altered (mainly by aberrant glycosylation) in many cancer types, including NSCLC. The tandem repeat MUC1-peptide liposomal vaccine BLP-25 has been studied in patients with stage IIIB-IV NSCLC [3]. Patients in disease control after conventional treatment with chemo(-radio)therapy were randomly assigned to BLP25 (8 weekly s.c. immunizations, followed by administration at 6-week intervals) plus BSC or BSC alone. While overall survival (OS) was not significantly different in the total group, a challenging effect was observed in stage IIIB patients (HR 0.524; 95%CI 0.261-1.052). No significant toxicity was observed. At the 2013 ASCO meeting, the double-blind, randomized, placebo-controlled phase III study was presented (START, NCT00409188) [4]. Patients not progressing after primary chemoradiotherapy for unresectable stage III NSCLC were randomized to BLP25 or placebo. In the primary analysis population (n=1239), OS was better with the vaccine (HR 0.88, 95%CI 0.75-1.03). In the predefined subgroup analysis in patients after concurrent chemoradiotherapy (n=806) there was a median OS difference of 10.2 months (HR 0.78, 95%CI 0.64-0.95). While the most obvious role for TCV is for patients with small residual disease after treatment, several compound are in phase III testing in advanced NSCLC as well. Belagenpumatucel-L is a vaccine based on a mixture of allogeneic tumor cells with TGF-β2 antisense blockade as adjuvant. In a phase II open trial, survival was related to the dose administered [5]. A phase III trial in patients with stage III-IV NSCLC in disease control after first-line therapy is now fully recruited (STOP, NCT00676507). TG4010 is a vaccine based on a recombinant viral vector (attenuated strain of vaccinia virus) expressing both the tumor-associated antigen MUC1 and interleukin-2. In a phase II randomized study, 148 patients with advanced NSCLC expressing MUC1 by immunohistochemistry received either up to 6 cycles of cisplatin-gemcitabine plus TG4010, or the same chemotherapy alone [6]. The primary endpoint, a 6-month progression-free survival more than 40% in the experimental arm was met. A confirmatory phase IIB-III trial is ongoing (TIME, NCT01383148). 1. Vansteenkiste J, Zielinski M, Linder A, et al. Adjuvant MAGE-A3 immunotherapy in resected non-small cell lung cancer: Phase II randomized study results. J Clin Oncol 2013; 31: 2396-2403. 2. Ulloa-Montoya F, Louahed J, Dizier B, et al. Predictive gene signature in MAGEA3 antigen-specific cancer immunotherapy. J Clin Oncol 2013; 31: 2388-2395. 3. Butts C, Murray N, Maksymiuk A, et al. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small cell lung cancer. J Clin Oncol 2005; 23: 6674-6681. 4. Butts CA, Socinski MA, Mitchell P et al. START: A phase III study of L-BLP25 cancer immunotherapy for unresectable stage III non-small cell lung cancer. J Clin Oncol 31 Suppl, abstract 7500. 2013. 5. Nemunaitis J, Dillman RO, Schwarzenberger PO, et al. Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small cell lung cancer. J Clin Oncol 2006; 24: 4721-4730. 6. Quoix E, Ramlau R, Westeel V, et al. Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small cell lung cancer: a controlled phase 2B trial. Lancet Oncol 2011; 12: 1125-1133.

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    P1.25 - Poster Session 1 - Nurses (ID 248)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Nurses
    • Presentations: 1
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      P1.25-003 - Characteristics and outcome of unplanned admissions in patients with lung cancer: A longitudinal tertiary center study. (ID 1911)

      09:30 - 09:30  |  Author(s): J.F. Vansteenkiste

      • Abstract

      Background
      Unplanned hospital admissions (UHAs) are frequent in lung cancer patients, but literature on this topic is scarce. The aim of this study is to get better insight in the demographics, patterns of referral, presenting symptoms, and outcome of lung cancer patients with UHA.

      Methods
      Data of all consecutive events of UHA between July 1 and December 31, 2012 were reviewed. Details on the factors listed above were examined.

      Results
      There were 247 UHA events during the 6 month study period. Male/female ratio was 185/62, mean age was 66 years (range 40-90), PS on admission was 0-1 in 79 (32%), 2 in 92 (37%), and 3-4 in 76 (31%). Two thirds were stage IV, and 57% did not have ongoing oncological treatment. On 83 occasions (34%), referral was by the general practitioner (GP-REF), for 101 (41%) own initiative (SELF-REF), and for 63 (26%) specialist advice. The most frequent main presenting symptoms were respiratory (21%), infection (15%), general weakness (15%), and pain (13%). The mean hospitalization duration was 9.5 days, shorter and with more same-day-return in SELF-REF patients (Table). Final diagnoses were categorized in nine groups: infection (22%), respiratory problems (17%), lab abnormalities (13%), pain (12%), abdominal problems (11%), cardiovascular problems, neurological events, general weakness and other (6% each). This differed from the problem as recorded in the ER in one third of the events. Final grading (CTC AE v3.0) of the main event was 1-2 in 38%, 3 in 51%, 4 in 8% and 5 in 2%. Causality was decided as therapy-related (THER-REL) in 59, cancer-related (CANC-REL) in 117, unrelated in 48, and unclear in 23. In the THER-REL events, lab abnormalities (36%), infection (34%) and abdominal complaints (22%) were most common, while this was respiratory problems (23%), pain (18%) and infection (16 %) for CANC-REL events. On subgroup analysis (Table), length of stay was higher in CANC-REL events. Nearly all THER-REL events had medical therapy, while for CANC-REL events this was medical 50%, interventional 33% and supportive only 17%. Figure 1

      Conclusion
      UHA in lung cancer are predominantly cancer- rather than therapy-related, with a variety of symptoms. More than half of the events are not seen by the GP first, and the majority results in hospital stay of 9.5 days on average . Our work is a first step in identifying specific groups of events, where better interaction with GPs and education of patients might reduce the incidence of UHAs.

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    P3.09 - Poster Session 3 - Combined Modality (ID 214)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P3.09-004 - Oligometastatic non-small cell lung cancer: a simulation expert multidisciplinary tumor board. (ID 1122)

      09:30 - 09:30  |  Author(s): J.F. Vansteenkiste

      • Abstract

      Background
      Series on aggressive local treatment in selected patients with oligometastatic non-small cell lung cancer (NSCLC) are mostly retrospective, and prospective data are scarce (De Ruysscher et al, JTO 7:1547-1555, 2012). Although a precise definition is lacking, ‘oligometastatic NSCLC’ is considered an intermediate biologic state of restricted metastatic capacity with a limited number of metastases. The turning point between oligometastatic and polymetastatic is merely based on personal opinion and situated somewhere between 1 and 5 distant metastases. In the absence of clear definitions or clinical practice recommendations, a treatment decision is mainly driven by the opinion of each local multidisciplinary tumor board (MDTB).

      Methods
      As the consideration of and the treatment modality for oligometastatic NSCLC is a controversial area in respiratory oncology, in preparation of a recent dedicated workshop, we simulated a MDTB with international experts in the field. Multiple disciplines from 7 different centers participated in the MDTB, including pathology (1), nuclear medicine physician (1), thoracic surgery (3), radiation oncology (3), and respiratory oncology (3). Participants were asked to assess an electronic file describing 10 clinical ‘oligometastatic NSCLC’ cases, with 2 simple questions per case: 1. Do you consider this case ‘oligometastatic’ (Yes/No) and 2. What is your preferred treatment proposal.

      Results
      A full response was returned by all 11 specialists taking part in the simulated MDTB. Only 1 case was considered ‘oligometastatic NSCLC’ by all MDTB members. The presented cases were considered by a median of 78% (range 36-100%) of responders as true oligometastatic disease. Despite the fact that each responder gave only one treatment proposal, a median of 4 different treatment proposals (range 2-6) was made per case. Except for brain metastases, most team members would treat the locoregional thoracic disease before the distant metastases. No preference towards neo-adjuvant or adjuvant chemotherapy could be found. The option for surgery or radiation therapy as part of a combined modality treatment was mainly driven by the physicians’ preference.

      Conclusion
      Our simulated MDTB shows that oligometastatic NSCLC is an entity with many unanswered questions, and thus a major challenge for clinicians. Patients with oligometastatic NSCLC are in the need of 1. discussion at an experienced multidisciplinary tumor board to select patients for a radical combined modality approach; 2. multidisciplinary prospective research protocols to set better definitions of oligometastic NSCLC, evaluate the validity of a radical approach, and to optimize therapeutic modalities.