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J. Vansteenkiste



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    MINI 01 - Pathology (ID 93)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI01.11 - Transcriptome Sequencing of Tumor vs. Surrounding Non-Malignant Lung Tissue in Non-Small Cell Lung Cancer (ID 1765)

      11:45 - 11:50  |  Author(s): J. Vansteenkiste

      • Abstract
      • Slides

      Background:
      Both the response and the therapeutic ratio of targeted agents in NSCLC may depend on the expression of the target molecules in the tumor and the surrounding non-malignant lung tissue. We therefore performed transcriptome analysis and investigated correlations with histology, gender, age, CRP level and smoking status as well as evaluated the differential pathway expression in primary resected NSCLC and the surrounding non-malignant lung of the same patient.

      Methods:
      Transcriptome sequencing was performed on the primary tumor and distant lung tissue of the same patient from resection specimens of NSCLC patients. Differential gene expression between different conditions was identified using the statistical algorithms Cufflinks, EdgeR and DeSeq. Differential expression with P-values <0.05 after Benjamini-Hochberg correction was considered significant. Pathway analysis for overall tumor versus distant lung tissue was performed with the PANTHER gene classification platform using the Cufflinks, DeSeq and EdgeR differentially expressed gene sets as input.

      Results:
      Twenty-five patients were studied, 19 males and 6 females, with a median age of 69 years. Ten were current smokers, 14 former smokers (>4 weeks before surgery) and 1 non-smoker. Eleven patients had squamous cell carcinoma, 14 adenocarcinoma. A heat map with the results for the most commonly targeted genes in NSCLC is represented in figure 1. When compared to distant lung tissue, PD-L1 was downregulated in tumor tissue of adenocarcinoma and active smokers, but not in squamous cell carcinoma or ex-smokers. Internal control of tumor tissue of squamous vs. adenocarcinoma and ex-smokers vs. active smokers shows an important trend towards a higher expression of PD-L1 in squamous cell carcinoma and ex-smokers in both Cufflinks and EdgeR algorithms. Additional pathway analysis revealed 188 differentially regulated pathways. The most notable were downregulation of VEGF signaling, angiogenesis and B and T cell activation in tumor tissue when compared to distant lung tissue. Figure 1



      Conclusion:
      Our first results show a higher expression of PD-L1 in squamous tumors than in adenocarcinoma and a higher expression in tumors of ex-smokers than in those of active smokers. This may have consequences for the therapeutic ratio with anti-PD-L1 treatment. Downregulation of VEGFR-genes in tumor tissue was observed across almost all conditions. We will make this data more complete by adding methylation data as well as immunohistochemistry for protein localization.

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    MINI 22 - New Technology (ID 134)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI22.06 - The Challenge of Molecular Testing for Clinical Trials in Advanced Non-Small Cell Lung Cancer Patients: Analysis of a Prospective Database (ID 1240)

      17:15 - 17:20  |  Author(s): J. Vansteenkiste

      • Abstract
      • Presentation
      • Slides

      Background:
      Molecular testing has become important in managing advanced non-small cell lung cancer (NSCLC), both in clinical practice, as well as in clinical trials. For the latter, tissue samples often have to be analysed in a central laboratory. We evaluated the turnaround time and possible delay in start of therapy in this process.

      Methods:
      We reviewed our prospective database on all molecular testing cases for clinical trial suitability in patients with advanced NSCLC between March 1, 2011 (start) and October 31, 2014. The following time points were considered: T1 (request for tissue sections from the pathology lab); T2 (receipt of sections and shipment); T3 (arrival of sections in central lab (CL)); T4 (receipt of biomarker result from CL).

      Results:
      251 patients were considered for biomarker-driven trials. Twenty-three cases did not have further analysis, as the request for central molecular testing was cancelled: insufficient tissue (n=11); exclusion criterion (n=10); patient refusal (n=2). Results for the remaining 228 patients were: failure of central biomarker analysis due to insufficient quantity of tissue (n=18), or quality of tissue (n=3, i.e. decalcification or poor fixation). Valuable results were obtained for 207 patients. In 91 of 228 (39.9%) samples sent, a biomarker of interest was documented. This led to 34 clinical trial inclusions. Other patients were no longer eligible due to loss of performance status (n=20), loss of contact (n=14), no trial slot available at the appropriate time (n=18), or exclusion criteria (n=5). The mean waiting time between signing informed consent (T1) and receiving results of the biomarker analysis (T4) was 25.1 calendar (SD 17.3) days (Table). The preparation of the unstained slides by the pathology lab took about 9.1 (SD 6.8) days, the time of the biomarker testing itself accounted for 12.8 (SD 7.3) days. For 18 of 228 (7.9%) patients, repeated sample shipments were needed because of insufficient tumor cells, their mean waiting time between informed consent and receiving the biomarker result was 62.2 (SD 38.4) days. Table: Waiting times (t) in molecular testing for 228 patients.

      Time interval Mean StDev Median Range
      Pathology lab (T2-T1) 9.1 6.8 7.0 1 - 70
      Shipment (T3-T2) 1.8 1.6 1.0 0 - 17
      Analysis (T4-T3) 12.8 7.3 12.0 2 - 58
      Request to result (T4-T1) 25.1 17.3 22.0 7 - 184


      Conclusion:
      While molecular testing is important in many NSCLC trials, our results show that waiting times for central laboratory analysis can cause an important delay in treatment initiation, and even ineligibility for the trial(s) under consideration. Start of therapy based on properly validated local testing, with a posteriori central biomarker testing to guarantee the integrity of the trial, would be more rewarding for quite some patients.

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    MINI 38 - Biology and Prognosis (ID 167)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      MINI38.06 - FP1039/GSK3052230 with Chemotherapy in Patients with Fibroblast Growth Factor (FGF) Pathway Deregulated Squamous NSCLC or MPM (ID 2879)

      19:00 - 19:05  |  Author(s): J. Vansteenkiste

      • Abstract
      • Presentation
      • Slides

      Background:
      GSK3052230/FP1039 is a soluble fusion protein with the ECD of FGFR1c linked to the hinge and Fc regions of human IgG1 and acts as a ligand trap by sequestering FGFs involved in tumor growth and angiogenesis. In contrast to small molecule FGFR kinase inhibitors, GSK3052230 spares the hormonal FGF ligands, namely FGF19, 21 and 23. GSK3052230 combined with chemotherapy was efficacious in xenograft models of FGFR1-amplified NSCLC and malignant pleural mesothelioma (MPM) with FGF2 mRNA overexpression. A phase I monotherapy study determined 20mg/kg weekly as the maximum feasible dose (MFD) achieving the desired blood concentration, with no maximum tolerated dose (MTD) reached.

      Methods:
      This study (NCT01868022 funded by GSK) will evaluate the safety and efficacy of GSK3052230 weekly infusion in combination with paclitaxel + carboplatin in previously untreated FGFR1 amplified metastatic sqNSCLC (Arm A), in combination with docetaxel in FGFR1 amplified metastatic sqNSCLC that has progressed after at least 1 line of chemotherapy (Arm B), or in combination with pemetrexed + cisplatin in patients with untreated and unresectable MPM (Arm C). Each arm involves a dose escalation phase utilizing the 3+3 design, followed by an expansion phase up to 30 patients (pts). Key endpoints include the MTD/MFD of GSK3052230 with chemotherapy, safety, response rates and duration.

      Results:
      Thirty-four pts have been dosed with GSK3052230 at dose levels ranging from 5mg/kg to 20mg/kg in combination with chemotherapy across three Arms, n=15 (A), n=6 (B) and n=13 (C). Baseline characteristics: males/females 29/5; mean age 68.5 years; ECOG PS 0 (n=20), 1 (n=13), 2 (n=1). Most common AEs were: Arm A: asthenia, neutropenia; Arm B: neutropenia, diarrhea, rash; Arm C: decreased appetite, nausea, infusion reaction. Infusion reactions were seen in 8/34 (24%) pts (n=3 Grade (Gr)1, n=3 Gr2, n=2 Gr3). Serious AEs included: Arm A- neutropenia (n=4), fatigue (n=1), asthenia (n=1), fever (n=1), respiratory infection (n=1); Arm B- neutropenia (n=1), abdominal pain (n=1); Arm C-bowel perforation/ischemia (n=1), infusion reaction (n=1), elevated creatinine (n=1). No DLTs have been observed in sqNSCLC pts (Arms A and B). Three DLTs were reported in mesothelioma pts (Arm C 20mg/kg): Gr5 bowel perforation/ischemia, Gr4 elevated creatinine levels and Gr3 infusion reaction. MFD for Arm A is determined at 20mg/kg. Dose escalation is ongoing for Arms B and C. Preliminary PK results revealed no drug-drug interactions. At time of data-cutoff, 10 PR were observed among 23 patients evaluable for efficacy (ORR = 43%) and a clinical benefit rate of 78% with two ongoing subjects on study >300 days. Preliminary efficacy is as follows: Arm A (6 PR, 2 SD, 1 PD, 6= not-yet-evaluable (NE)), Arm B (4 SD, 1 PD, 1 NE), and Arm C (3 PR, 3 SD, 3 PD, 4 NE).

      Conclusion:
      GSK3052230 is in general well tolerated in combination with chemotherapy. The MFD for GSK3052230 is 20mg/kg in combination with paclitaxel + carboplatin in first line sqNSCLC patients. Toxicities typically associated with small-molecule FGFR inhibitors, namely hyperphosphatemia and retinal, nail, and skin changes, were not observed. The initial activity and safety profile of GSK3052230 ​warrant further study.

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    MS 04 - Harnessing the Full Potential of the Immune System (ID 22)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MS04.03 - Vaccines (ID 1862)

      15:00 - 15:20  |  Author(s): J. Vansteenkiste

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Cancer immunotherapy in a broad sense is any interaction with the immune system to treat cancer. One approach is non-antigen-specific modulation of the immune system. Historical examples with e.g. BCG, interferon, interleukins, were disappointing in lung cancer. More recently, specific antibodies against the Programmed Death 1 (PD-1) receptor or its ligands (PD-L1) have delivered exciting results, with major patient benefits in randomised controlled trials (RCTs) in relapsing NSCLC {Brahmer, 2015 19949 /id}. Antigen-specific immunotherapy aims at specific priming of immune system to recognize the tumour as foreign, thereby generating specific antibodies and/or cytotoxic T cells. This is “therapeutic cancer vaccination (TCV)”. Conditions for optimal TCV are: 1/ specificity (well-defined target antigen(s) in the tumour, 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/ tumour sensitive to immune kill in order to obtain improvement in patients’ outcome. Better knowledge of tumour immunity has led to encouraging data in phase II RCTs with several TCVs, which then have entered large phase III trials. Examples are the MAGE-A3 vaccine studied 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 tumour-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 (2). No significant toxicity was observed. There was a 24% – non-significant – improvement in disease-free survival (DFS, HR 0.76; 95% CI 0.48 to 1.21). The ensuing large phase III study MAGRIT (MAGE-A3 as Adjuvant Non-Small Cell LunG cancer ImmunoTherapy) was reported at the ESMO 2014 meeting (3). MAGE-A3 positive patients with completely resected stage IB-II-IIIA NSCLC and adjuvant chemotherapy as clinically indicated, were randomly 2:1 assigned to receive MAGE-A3 vaccine or placebo. Almost 14,000 surgical patients were screened, 4210 patients were MAGE-A3 positive (33%), and 2312 patients were randomised. The median DFS (primary endpoint) was slightly better with MAGE-A3 (60.5 versus 57.9 months), but the difference was unfortunately not significant (Hazard Ratio, HR, 1.02, 95%CI: 0.89, 1.18, P=0.74). No subgroups with potential benefit could be identified. Based on this disappointing result, further development of the MAGE-A3 vaccine in NSCLC has been abandoned. 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 (4). 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). This led to START (Stimulating Targeted Antigenic Responses to NSCLC Trial), a phase III, double blind, RCT comparing maintenance therapy with Tecemotide (n=829) or placebo (n=410) in patients with unresectable stage III NSCLC who did not progress after sequential or concurrent chemo-radiotherapy (5). The primary endpoint – OS – was not significantly different between the vaccine and placebo group (25.6 and 22.3 months). However, pre-planned subgroup analysis showed that the patients treated with concurrent chemoradiotherapy (N=829) had a 10.2-month improvement in OS (30.8 versus 20.6 months, adjusted HR 0.78, P=0.016). The consequential trial was START 2, a similar large RCT in patients who completed concurrent chemoradiotherapy for unresectable stage III NSCLC (NCT02049151). However, this RCT and further development of Tecemotide was abandoned after disappointing results of a smaller trial in Japanese patients with stage III NSCLC and concurrent chemoradiotherapy. Belagenpumatucel-L is a vaccine based on a mixture of allogeneic tumour cells with TGF-β2 antisense blockade as adjuvant. A phase III trial in patients with stage III-IV NSCLC in disease control after first-line therapy was reported at the 2013 ESMO meeting (STOP, NCT00676507) (6). Patients without progression after 1[st] line chemotherapy, were randomly assigned to intradermal belagenpumatucel-L (N=270) versus placebo (N=262)for 24 months. Median OS was 20.3 months with belagenpumatucel-L versus 17.8 months with placebo (HR 0.94, p=0.594). In subgroup analysis of patients randomized <12 weeks after the last chemotherapy, the HR of the median OS was 0.77 (P=0.092). For patients enrolled within 12 weeks and treated with previous radiotherapy, the HR was HR 0.45 (P=0.014). The vaccine was well tolerated with mainly mild local administration side-effects. TG4010 is a vaccine based on a recombinant viral vector (attenuated strain of vaccinia virus) expressing both the tumour-associated antigen MUC1 and interleukin-2. This vaccine is explored in the phase IIB/III RCT TIME trial (NCT01383148). This double-blind, placebo-controlled trial evaluates standard first-line chemotherapy with or without TG4010 in MUC1-positive stage IV NSCLC patients. In the phase IIB part, the predictive value of activated NKs (TrPAL: triple positive activated lymphocytes) was evaluated based on a PFS endpoint, and reported in an interim report at the 2014 ESMO meeting (7). Based on a Bayesian analysis, the predefined endpoint of a HR <1 in the patients with low level of NK cells was met. The PFS was not significantly different between vaccine and placebo (HR 0.78, 95%CI 0.55-1.10]. In subgroup analyses, the effect was more pronounced in patients with non-squamous NSCLC (HR 0.71, 95CI 0.51-0.97) than in squamous histology. Therefore, a decision was made to continue the phase III part of the trial in non-squamous NSCLC only, with OS a the primary endpoint. References 1. Brahmer J, Reckamp KL, Baas P et al. Nivolumab versus docetaxel in advanced squamous cell non-small cell lung cancer. N Engl J Med 2015; on-line May 31. 2. 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. 3. Vansteenkiste JF, Cho BC, Vanakesa T et al. MAGRIT, a double-blind, randomized, placebo-controlled phase III study to assess the efficacy of the recMAGE-A3 + AS15 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small cell lung cancer (NSCLC). Ann Oncol 2014; 25 Suppl 4: abstract 1173O. 4. 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. 5. Butts C, Socinski MA, Mitchell PL et al. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): A randomised, double-blind, phase 3 trial. Lancet Oncol 2014;15:59-68. 6. Giaccone G, Bazhenova L, Nemunaitis J et al. A phase III study of belagenpumatucel-L therapeutic tumor cell vaccine for non-small cell lung cancer (NSCLC). Eur J Cancer 2013; 47 Suppl 2: abstract LBA 7081. 7. Quoix E, Losonczy G, Forget F et al. TIME, a phase 2B/3 study evaluating TG4010 in combination with first-line therapy in advanced non-small lung cancer (NSCLC). Phase 2B results. Ann Oncol 2014; 25 Suppl 4: abstract 1055PD.

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    MS 19 - Global Nursing Issues in Lung Cancer (ID 37)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Nursing and Allied Professionals
    • Presentations: 1
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      MS19.01 - Nursing Challenges in Clinical Trials (ID 1931)

      14:20 - 14:33  |  Author(s): J. Vansteenkiste

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Background: The model of clinical trials in lung cancer has evolved quite dramatically over the past years. Expanded phase I trials in biomarker-driven populations are a new paradigm of accelerated drug approval. Enrolling patients in these clinical trials creates several new challenges. Clinical Research Nurses (CRNs) play an important role in recruitment, actual drug delivery, and monitoring of this whole process. Methods: Identify the different barriers to recruitment that CRNs face with these clinical trials. Barriers to participation can be patient-related, physician-related or tissue-related. Review of literature was the basis for the patient- and physician-related barriers. To identify the tissue barriers, we studied our own database. We also present practical tips to overcome these barriers out of own expertise in the field. Results: Patients’ barriers to participate in clinical trials include individual characteristics, practical issues, and attitudes. The most common barriers are the individual characteristics: cultural background, health literacy, ethnicity, and age. Lack of knowledge, insurance coverage, extra appointments, reimbursement, and patient ineligibility are typical practical barriers. Attitudinal barriers are reluctance to randomisation, fear for side effects, and efficacy concerns (e.g. allocation to placebo) (1-3). To overcome these barriers the trial should be explained clearly. Patient should be supported in what may be a difficult decision and should not be pressured to do so. Dedicated CRNs may help with monitoring the recruitment process, providing additional information, and obtaining informed consent (1). The process of informed consent is the optimal time to define clearly the terms of the clinical trial, and to explain the sometimes difficult to understand medical and legal terms in the informed consent document. Optimally, this should lead to good understanding by the patient of the potential benefits and risks (4). Main physicians’ barriers are lack of time due to competing priorities, insufficient staff and training to meet the ever increasing procedures from competent authorities or institutional review boards and finance departments, worry about the impact on the doctor-patient relation, concern for patients, and lack of reward and recognition. Lack of time is considered a major barrier. Doctors experience time pressure from their usual clinical practice and management duties. Recruitment, the consent process, and the follow up of clinical trials on top of that demand a large piece of extra time (1;4;5). Lack of support staff, for example CRNs, can also account for poor recruitment. A stable clinical research team is likely to be advantageous. CRNs should not only have expert clinical and well developed critical thinking skills, but be well acquainted with the complex scientific, regulatory, and ethical aspects of clinical research (6). Well trained and experienced CRNs truly are “PI-extensions”. By monitoring the clinical activity to find possible candidates for trials, they support the physician with recruitment, and later on with the follow-up of included patients. Over the last years, we saw a major progress in the treatment of advanced non-small cell lung cancer, largely due to new targeted agents, monoclonal antibodies, and immunomodulatory agents. Both in clinical practice, as well as in clinical trials, the availability of tissue for biomarker analysis – in order to make the best choice for the patient – is crucial. Tissue availability is a new important barrier to clinical trials, as we noted from our own experience (7). Moreover, central lab confirmation of an already known biomarker, is often requested before the patient is allowed to start therapy, leading to sometimes important delays. In our respiratory oncology trial unit, we analysed of our molecular database regarding this barrier (7). The mean waiting time between signing informed consent and receiving results of the biomarker analysis from the central laboratory turned out to be 25 calendar days! While delivering a tissue sample for central confirmation of molecular testing is crucial in biomarker-driven NSCLC trials, the mandatory waiting of patients to start therapy is to be discussed. Waiting times for central laboratory analysis not only lead to an important delay in treatment initiation, but even ineligibility for the trial(s) under consideration. Start of therapy based on a properly validated local test, with a posteriori central biomarker testing to guarantee the integrity of the trial, would be more rewarding for quite some patients (8). Conclusion: Recruitment in lung cancer clinical trials is a complex and vulnerable process with different types of barriers. Identifying such barriers can help clinical trial staff to develop strategies to optimize participation and cooperation. Well-trained CRNs have a unique knowledge and set of skills that allows them to make a significant contribution to the clinical research team. CRNs should follow the rapid change in clinical trials closely, so that they can be a guide for patients in their clinical trial journey. Moreover, they have an important role in minimising the patient barriers, give support in physician barriers, and facilitating tissue barriers. References (1) Ross S, Grant A, Counsell C et al. Barriers to participation in randomised controlled trials: A systematic review. J Clin Epidemiol 1999;52:1143-1156. (2) Manne S, Kashy D, Albrecht T et al. Attitudinal barriers to participation in oncology clinical trials: Factor analysis and correlates of barriers. Eur J Cancer Care 2015;24:28-38. (3) Kaplan CP, Napoles AM, Dohan D et al. Clinical trial discussion, referral, and recruitment: Physician, patient, and system factors. Cancer Causes Control 2013;24:979-988. (4) Mills EJ, Seely D, Rachlis B et al. Barriers to participation in clinical trials of cancer: A meta-analysis and systematic review of patient-reported factors. Lancet Oncol 2006;7:141-148. (5) Seruga B, Sadikov A, Cazap EL et al. Barriers and challenges to global clinical cancer research. Oncologist 2014;19:61-67. (6) Hastings CE, Fisher CA, McCabe MA et al. Clinical research nursing: A critical resource in the national research enterprise. Nurs Outlook 2012;60:149-156. (7) Lepers S, Ottevaere A, Oyen C et al. The challenge of molecular testing for clinical trials in advanced non-small cell lung cancer patients: analysis of a prospective database. J.Thorac.Oncol. 2015; 10 Suppl: Mini Oral presentation WCLC 2015. (8) Adam V, Dooms C, Vansteenkiste J. Lung cancer at the intensive care unit: The era of targeted therapy. Lung Cancer 2015;E-pub May 18.

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    ORAL 18 - Non PD1 Immunotherapy and Angiogenesis (ID 114)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL18.03 - Discussant for ORAL18.01, ORAL18.02 (ID 3335)

      11:07 - 11:17  |  Author(s): J. Vansteenkiste

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    ORAL 20 - Chemoradiotherapy (ID 124)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Locoregional Disease – NSCLC
    • Presentations: 1
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      ORAL20.02 - Safety Results of the Consolidation Phase of a Phase III (PROCLAIM): Pemetrexed, Cisplatin or Etoposide, Cisplatin plus Thoracic Radiation Therapy followed by Consolidation Cytotoxic Chemotherapy in Locally Advanced Nonsquamous Non-Small Cell Lung Cancer (ID 645)

      10:56 - 11:07  |  Author(s): J. Vansteenkiste

      • Abstract
      • Presentation
      • Slides

      Background:
      Standard treatment for inoperable stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy. However, many patients die from recurrent disease, indicating that new treatment strategies are needed.

      Methods:
      PROCLAIM is a phase III trial comparing overall survival in patients with unresectable stage III nonsquamous NSCLC receiving pemetrexed+cisplatin (PemCis) and concurrent radiotherapy for 3 cycles followed by 4 cycles of pemetrexed consolidation (Arm A) versus etoposide+cisplatin (EtoCis) and concurrent radiotherapy for 2 cycles followed by consolidation with a platinum-based doublet of choice for up to 2 cycles (Arm B). Possible consolidation therapies in Arm B were EtoCis, vinorelbine+cisplatin (VinCis), and paclitaxel+carboplatin (PacCarb). Overall efficacy and safety results for the intent-to-treat population will be presented in a separate disclosure. Safety was a secondary objective. Interim safety results for the concurrent phase were previously presented. Here we present safety results for the consolidation phase. Treatment-emergent adverse events (TEAEs) were assessed according to the Common Terminology Criteria for Adverse Events (v3.0, CTCAE). TEAE incidences were compared using Fisher’s exact test (two-sided α=0.05).

      Results:
      Of 598 randomized patients, 555 were treated in the concurrent phase (Arm A: N=283; Arm B: N=272), most of whom (Arm A: n=229 [80.9%]; Arm B: n=202 [74.3%]) continued on to the consolidation phase (Arm B patients: EtoCis [33.5%], PacCarb [26.8%], VinCis [14.0%]). Baseline characteristics, including age, gender, performance status, smoking status, stage, and origin, were well-balanced across arms. Percentages of patients in Arm A completing ≥2, ≥3, and 4 consolidation cycles were 95.2%, 84.3%, and 73.4%, respectively. Percentages of patients in Arm B completing 2 consolidation cycles (maximum) were EtoCis (89.0%), PacCarb (93.2%), and VinCis (86.8%). Mean dose intensities for pemetrexed, etoposide, vinorelbine, cisplatin, paclitaxel, and carboplatin were 95.4%, 94.0%, 84.2%, 91.2%, 88.7%, and 92.7%, respectively. More patients in Arm B, compared to Arm A, experienced dose reductions, dose omissions, and cycle delays. Patients in Arm B reported more grade 3/4/5 drug-related TEAEs than Arm A (51.0% versus 31.0%, p<0.001; Table). Rates of drug-related serious AEs were similar between groups (Arm A: 14.4%; Arm B: 13.4%).

      Drug-related Grade 3/4/5 TEAEs Occurring in ≥2% of Patients (or of Clinical Relevance) in the Consolidation Phase
      CTCAE Arm A (N=229) n (%) Arm B (N=202) n (%)
      Neutrophils 27 (11.8) 76 (37.6)*
      Leukocytes 19 (8.3) 29 (14.4)
      Hemoglobin 6 (2.6) 9 (4.5)
      Platelets 5 (2.2) 10 (5.0)
      Febrile neutropenia 7 (3.1) 7 (3.5)
      Lymphopenia 8 (3.5) 5 (2.5)
      Pneumonitis/pulmonary infiltrates 5 (2.2) 2 (1.0)
      Fatigue 2 (0.9) 4 (2.0)
      Pneumonia 5 (2.2) 0
      Esophagitis 0 3 (1.5)
      *p<0.001, Fisher’s exact test. Note: Of the TEAEs listed here, only one case (0.4%, Arm A, pneumonia) was grade 5.


      Conclusion:
      During the PROCLAIM consolidation phase, most patients were able to complete the planned number of cycles in either arm, with the highest dose intensity corresponding to pemetrexed. Pemetrexed consolidation had a significantly lower incidence of drug-related grade 3/4/5 TEAEs than the platinum doublets in Arm B. A more detailed analysis of Arm B (by treatment regimen) is underway.

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    ORAL 34 - Quality/Survival/Prognosis in Localized Lung Cancer (ID 153)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 1
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      ORAL34.03 - Prognostic Factors in Early Stage NSCLC: Analysis of the Placebo Group in the MAGRIT Study (ID 24)

      17:07 - 17:18  |  Author(s): J. Vansteenkiste

      • Abstract
      • Presentation
      • Slides

      Background:
      The MAGRIT study was a worldwide, multicenter, phase-3 double-blind, randomized trial evaluating efficacy of the MAGE-A3 Cancer Immunotherapeutic in resected non-small cell lung cancer (NSCLC) (www.clinicaltrials.gov NCT00480025). We examined baseline patient and disease characteristics associated with overall survival (OS) and disease-free survival (DFS) among patients assigned to placebo.

      Methods:
      Study participants were ≥18 years, with histologically proven, MAGE-A3-positive stage IB, II or IIIA NSCLC (AJCC 6.0). Participants had undergone complete anatomical resection of the tumor (lobectomy or pneumectomy) with mediastinal lymph node (LN) dissection or sampling according to standard of care. Up to four cycles of platinum-based adjuvant chemotherapy were allowed. Cox regression models were used to explore characteristics that could predict DFS and OS. Factors statistically significant in univariate analysis (p<0.05) were included in multivariate models using a stepwise approach (p<0.05 to enter/remain in the model).

      Results:
      There were 757 placebo patients in the total treated population; median age 63 years, 76% male, 53% with squamous cell carcinoma (SCC), 34% with adenocarcinoma, 98% with performance status 0-1, 52% had received adjuvant chemotherapy.In univariate analyses, SCC, lower N-category and earlier disease stage were associated with improved DFS. Lower N-category, earlier stage and smaller tumor size were associated with improved OS. In multivariate analysis, N-category (HR 1.34, 95%CI [1.16-1.55]) and histological type (HR for SCC vs non-SCC 0.64, 95%CI [0.51-0.81]) remained significant for DFS. N-category (HR 1.47, 95%CI [1.21-1.79]) and tumor size (HR by unit increase 1.08, 95%CI [1.01-1.15]) did so for OS. No association was found between DFS or OS and age, gender, race, region, baseline performance status, quantitative MAGE-A3 expression, chemotherapy administration or type of chemotherapy, smoking status or type of LN sampling (minimal/systematic). Among patients with SCC, univariate analysis identified increased number of chemotherapy cycles and operative technique (pneumectomy) as associated with improved DFS (p<0.05). Only operative technique remained in the multivariate model. When including N-category (p<0.10 in univariate analysis) in the multivariate model, N-category and number of chemotherapy cycles were also selected. Lower N-category and smaller tumor size were significantly associated with improved OS, in univariate and multivariate analyses. Among patients with non-SCC, univariate analysis identified younger age, being female, lower N-category and earlier disease stage with improved DFS, and lower N-category, earlier disease stage and region (East Asia) with improved OS. N-category and gender, and N-category and region remained significant in the multivariate analysis for DFS and OS, respectively.

      Conclusion:
      This is the first prognostic factor analysis in resected NSCLC performed on data from a large, prospective randomized study. It highlighted that in terms of DFS, SCC patients have a better prognosis than non-SCC patients. N-category plays a major role in determining prognosis. Operative technique (pneumectomy), number of chemotherapy cycles (SCC) and gender (non-SCC) are also associated with outcome. Variables predictive for OS are N-category and tumor size (all) and region (non-SCC). These results confirm retrospective studies done within the context of TNM classification, but add that histopathology subtype is a strong determinant for DFS in resected NSCLC.

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    ORAL 37 - Novel Targets (ID 146)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL37.05 - Prevalence and Clinical Association of MET Gene Amplification in Patients with NSCLC: Results from the ETOP Lungscape Project (ID 444)

      17:28 - 17:39  |  Author(s): J. Vansteenkiste

      • Abstract
      • Slides

      Background:
      The reported prevalence of MET gene amplification in non-small cell lung cancer (NSCLC) varies from 0-21% and clinical correlations are emerging slowly. In a well-defined NSCLC cohort of the ETOP Lungscape program, we explore the epidemiology, the natural history of MET amplification and its association with MET overexpression, overall survival (OS), relapse-free survival (RFS) and time to relapse (TTR).

      Methods:
      Resected stage I-III NSCLC, identified based on the quality of clinical data and FFPE tissue availability, were assessed for MET gene copy number (GCN) and expression analysis using silver in-situ hybridization (SISH) and immunohistochemistry (IHC), respectively, on TMAs (MET and centromere-specific probes; anti total c-MET antibody, clone SP44; Ventana immunostainer). MET amplification was defined as MET/centromere ratio ≥2 with average MET GCN ≥4, high MET GCN at two levels as ≥median CGN and ≥5 (irrespective of amplification) and MET IHC+ as 2+ or 3+ intensity in ≥50% of tumor cells. Sensitivity analysis to define the amplification’s thresholds was also performed. All cases were analysed at participating pathology laboratories using the same protocol, after successful completion of an external quality assurance (EQA) program.

      Results:
      Currently 2709 patients are included in the Lungscape iBiobank (median follow-up 4.8 years, 53.3% still alive). So far, 1547 (57%) have available results for MET GCN with amplification detected in 72 (4.7%; 95%CI: 3.6%, 5.7%) and high MET GCN (≥5) in 65 (4.2%; 95%CI: 3.2%, 5.2%). The median value of average MET GCN per cell is 2.3. IHC MET expression is available for 1515 (98%) of these cases, 350 (23%) of which are MET IHC positive [170 cases (49%) 3+, 180 (51%) 2+]. The median age, for the cohort of 1547 patients, is 66.2 years, with 32.8% women, and 13.5%, 29.7%, 54% never, current, former smokers, respectively. Stage distribution is: IA 23.6%, IB 24.6%, IIA 17%, IIB 12.1%, IIIA 20.9%, IIIB 1.8%, while 52.7%, are of adenocarcinoma and 40.0% of squamous histology. MET amplification and high MET GCN (≥5) are not significantly associated with any histological tumor characteristics or stage (multiplicity adjusted alpha: 0.005). High MET GCN (≥2.3) is less frequent in current smokers (38.3% vs. 55.6% for former or non-smokers, p<0.001). MET amplification and high MET GCN are significantly associated with IHC MET positivity (p<0.001 in all cases). MET amplification is present in 9.7% of IHC MET+ vs 3.1% of IHC MET- patients and high MET GCN (≥5) in 8.6% of IHC MET+ vs 2.8% of IHC MET- patients. MET amplification ranges from 0 to 16% between centers, while high MET GCN (≥5) and (≥2.3) from 0% to 12%, and 11.8% to 98.9%, respectively. MET amplification and both levels of high MET GCN are not associated with OS, RFS or TTR.

      Conclusion:
      The preliminary results for this large, predominantly European, multicenter cohort demonstrate that MET amplification assessed by SISH prevails in 4.7% of NSCLC, is associated with strong MET expression, and has no influence on prognosis. The large inter-laboratory variability in GCN despite EQA efforts may highlight a critical challenge of MET SISH analysis in routine practice.

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    P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P1.01-085 - A Multicenter Phase 1B Study of Ceritinib plus Nivolumab in Patients with ALK+ NSCLC (ID 1323)

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

      • Abstract

      Background:
      Ceritinib is a novel, highly selective, orally active and potent tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), and has demonstrated clinical efficacy in ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) (ASCEND-1; NCT01283516). Nivolumab is a fully human, immunoglobulin G4 programmed cell death protein-1 (PD-1) immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby promoting antitumor T-cell function, and is approved by the United States Food and Drug Administration for treatment of squamous NSCLC patients with progression following platinum doublet (Checkmate-017; NCT01642004). Nivolumab in combination with chemotherapy, other immune modulators and molecular targeted therapy has shown promising preliminary results in Stage IIIB/IV NSCLC patients (CheckMate-012; NCT01454102). The demonstrated efficacy of ceritinib in ALK+ NSCLC, and nivolumab in Stage IIIB/IV NSCLC, provides a rationale to study ceritinib in combination with nivolumab in patients with ALK+ NSCLC.

      Methods:
      In this prospective, open-label, multicenter phase 1B study (CLDK378A2120C; NCT02393625), the primary objectives are to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) and to evaluate the preliminary efficacy, based on overall response rate of ceritinib in combination with a fixed dose of nivolumab in adult stage IIIB/IV ALK+ NSCLC patients. Secondary objectives include evaluating duration of response, disease control rate, time to response, progression-free survival, overall intracranial response rate for patients with baseline measurable brain metastases, overall survival, and safety profile. In dose escalation phase, patients may have had ≥ 1 prior ALK inhibitors (except ceritinib) or prior chemotherapy regimens. In expansion phase, there will be 2 arms: 1) ALK-inhibitor pre-treated patients with 0 or 1 prior chemotherapies; 2) ALK-inhibitor naïve patients with 0 or 1 prior chemotherapies. Other key inclusion criteria are: presence of ≥ 1 measurable lesion as defined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, and a World Health Organization performance status 0-1. Patients with asymptomatic, untreated brain metastases at baseline are allowed. Dose-escalation phase will consist of successive cohorts of patients (3 to 6) receiving increasing doses of ceritinib (starting dose: 450 mg/d with a low-fat meal; 28-day cycles) plus nivolumab (3 mg/kg Q2W) and will enroll a minimum of 12 patients. In expansion phase, approximately 60 patients will be allocated to arms 1 and 2 (30 in each arm) and treated with ceritinib at MTD/RDE plus nivolumab (3 mg/kg Q2W). Material required for central assessment of ALK rearrangement must be either archival tissue or, preferably, a fresh biopsy. Apart from ALK rearrangement, potential predictive markers of PD-L1 and PD-L2 expression and/or additional immunological biomarkers will also be assessed. Patients may continue treatment until unacceptable toxicity, disease progression, discontinuation at the discretion of the investigator, or consent withdrawal. MTD and/or RDE estimation will be based on the probability of dose-limiting toxicities using an adaptive Bayesian logistic regression model guided by the escalation with overdose control principle and an overall assessment of safety and tolerability data. Tumor responses will be assessed per RECIST v1.1 by investigator assessment.

      Results:
      Not available

      Conclusion:
      Not available

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    P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P3.01-078 - Avelumab (MSB0010718C), an Anti-PD-L1 Antibody, Evaluated in a Phase III Trial versus Docetaxel in Patients with Relapsing NSCLC (ID 1588)

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

      • Abstract
      • Slides

      Background:
      The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against multiple cancers. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody currently being investigated in clinical trials. The phase III study (NCT02395172) is an open-label, multicenter trial of avelumab compared with docetaxel in patients with non-small-cell lung cancer (NSCLC) that has progressed after treatment with a platinum-containing doublet.

      Methods:
      The primary objective of this head-to-head phase III study is to demonstrate superiority defined by overall survival (OS) of avelumab versus docetaxel in patients with locally advanced unresectable, metastatic, or recurrent NSCLC whose tumors express PD-L1 and whose disease has progressed following treatment with a platinum-containing doublet. Approximately 650 eligible patients (ECOG performance status 0-1 at trial entry, tumor archival material or fresh biopsy suitable for PD-L1 expression assessment, histologically confirmed NSCLC, and known-negative ALK mutation status, among other inclusion and exclusion criteria), including 522 patients with PD-L1—positive tumors, will be randomized 1:1 to receive either avelumab at a dose of 10 mg/kg as a 1h intravenous (IV) infusion Q2W or docetaxel at a starting dose of 75 mg/m2 (per label) by IV infusion Q3W. Patients will be stratified according to PD-L1 status. NSCLC histology and EGFR mutation status will be used to define 3 stratified levels for randomization: squamous cell, non-squamous cell/EGFR wildtype, and non-squamous cell/EGFR-activating mutations. Treatment will continue until disease progression, unacceptable toxicity, or any criterion for withdrawal occurs. Responses will be evaluated according to RECIST 1.1 and adjudicated by a blinded independent review committee. In addition to the primary endpoint of OS, secondary endpoints include progression-free survival, best overall response, quality of life assessments, and safety profile. Exploratory endpoints include duration of response, tumor shrinkage in target lesions per timepoint, immunogenicity, PK profile, and evaluation of molecular, cellular, and soluble markers in peripheral blood or tumor tissue that may be relevant to the mechanism of action of, or response/resistance to, avelumab. Safety profiling of trial drugs includes incidence of adverse events (AEs), serious AEs, and other assessments according to NCI-CTCAE v4.03. Patients receiving avelumab who have achieved a complete response (CR) will be treated for a minimum of 6 months and a maximum of 12 months after confirmation. In the case of relapse following a CR, treatment with avelumab may be re-initiated once at the discretion of the investigator and in the absence of treatment-related toxicity. For patients whose disease progresses with avelumab, treatment may continue past the initial determination of disease progression per RECIST 1.1 if the patient’s performance status has remained stable, other criteria are fulfilled, and the investigator’s opinion supports a possible benefit of continued treatment with avelumab. Patients treated with docetaxel may not crossover to the avelumab arm as long as the primary endpoint has not been met in the planned interim or final analyses. Enrollment in this trial began in April 2015. *Proposed INN.

      Results:
      not applicable

      Conclusion:
      not applicable

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    P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 2
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      P3.04-009 - Evaluation of RT-PCR Methodology for ALK Assessment in Patients with NSCLC in Europe: Results from the ETOP Lungscape Project (ID 1506)

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

      • Abstract
      • Slides

      Background:
      ALK rearrangement is documented in 2%-7% of NSCLC, depending on the population studied and detection method used. Although the reverse transcriptase-polymerase chain reaction (RT-PCR) was the first used and published method, fluorescence in situ hybridization (FISH) has become the primary standard diagnostic method. Recently, immunohistochemistry (IHC) has also proven to be a reproducible, faster and sensitive technique. This is one of the first studies concurrently comparing all three techniques in resected lung adenocarcinomas from the large ETOP Lungscape cohort.

      Methods:
      95 cases from the ETOP Lungscape iBiobank, selected based on any degree of IHC staining (clone 5A4 antibody, Novocastra, UK), were examined by ALK FISH (Abbott Molecular, Inc.; Blackhall, JCO 2014) and central RT-PCR. For the latter, formalin-fixed, paraffin-embedded (FFPE) unstained slides were collected from participating centers. Slides were de-paraffinized, Toluidine Blue stained, and tumors macro-dissected. Tissue digestion and RNA extraction were performed (Qiagen RNeasy FFPE Kit). Using primers described in the literature covering most of ALK known translocations, RT-PCR (Superscript One-Step RT-PCR with Platinum Taq – 40 loops) was performed, followed by capillary electrophoresis in two separate mixes. Co-amplification of B-actin was done to validate the procedure and RNA quality. All tests were duplicated.

      Results:
      76 of 95 RT-PCR had adequate RNA quality (B-actin co-amplification present). Among these, 18 were FISH positive, 16 were RT-PCR positive, including EML4-ALK V3a/b in 7, V1 in 5, V2 in one, and undetermined variants in 3 cases. 53 of 54 FISH negative cases were also RT-PCR negative (98%). 15 of 18 FISH positives harbored a translocation by RT-PCR (83%). Among the 4 discrepant cases, 2 FISH+/RT-PCR- cases had IHC H-scores of 180 and 260, and 98.3% and 95% of rearranged cells by FISH, probably corresponding to variants not covered by the RT-PCR. One had an IHC H-score of 5, and 16% cells rearranged on FISH, most probably corresponding to a FISH false positive case. The last had an IHC H-score of 200, 13% rearranged cells by FISH, and, thus is defined as a false negative FISH result. Provided IHC is defined as positive by an H-score above 120, all but one case (H-Score 20, FISH and RT-PCR positive) gave concordant results by a combination of FISH and RT-PCR. Overall, using as true negative or true positive the concordant result of two of the methods, the third method is characterized by high specificity and sensitivity with corresponding values of 100/98/100% and 94/94/89% for IHC/FISH/RT-PCR, respectively.

      Conclusion:
      RT-PCR is a very good tool for sorting discordant IHC/FISH cases, however, we do not recommend using this technique as single method due to the lower sensitivity of RT-PCR, as not all variants are covered, and also due to the limitations with RNA preservation.

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      P3.04-053 - SPECTAlung: Screening Patients with Thoracic Tumors for Efficient Clinical Trial Access (ID 1386)

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

      • Abstract

      Background:
      The identification of molecular alteration and its targeting has completely changed the treatment and prognosis of lung cancer. However, designing and implementing clinical trials in small subsets of patients with a particular molecular alteration is challenging because of lack of uniform screening program. Across Europe, screening for molecular alterations is center or country dependent and, generally limited to a small subset of genes. SPECTAlung is the first European standardized, quality-assured molecular screening program of the European Organization for the Research and Treatment of Cancer (EORTC) in collaboration with the European Thoracic Oncology Platform (ETOP) to facilitate clinical trial access for patients with thoracic tumors. It is expected to test 500 to 1000 patients each year with the overall goal of offering patients clinical trials with targeted agents.

      Methods:
      Patients sign the informed consent for their tumor tissue to be collected, centralized and processed according to defined international quality control standards at Gustave Roussy Biobank (Villejuif, France). Next Generation Sequencing (NGS) is performed at Sanger Institute (Cambridge, UK) where a panel of about 360 genes is analyzed for mutation, rearrangements and gene copy number. Eligible patients will be those having a pathological diagnosis of any thoracic tumor (lung cancer, malignant pleural mesothelioma and thymic malignancies) at any stage of disease, availability of tumor tissue, age at least 18 years, PS 0-2, life expectancy > 3 months, no active malignancy in the 5 years before study entry and absence of any exclusion criteria that may prevent inclusion into clinical trials. A molecular report will be released to the investigator highlighting identified molecular alterations and also the trials for which the patients might be eligible. The study has been submitted to ethical committees of 15 selected highly specialized and qualified thoracic centres in 12 countries in Europe. EORTC and ETOP will promote the implementation of clinical trials in molecularly selected groups of patients at the SPECTAlung centers. SPECTAlung offers innovative and attractive models of collaboration with commercial and research organizations, by improving patient access to novel therapeutic clinical trial and support the development of personalized medicine. Clinical trial registry number NCT02214134.

      Results:
      Not applicable

      Conclusion:
      Not applicable