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E. Vokes



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    E06 - Issues in Current Multidisciplinary Practice (ID 6)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Combined Modality
    • Presentations: 1
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      E06.1 - Optimal Chemotherapy in Combined Modality Therapy for NSCLC (ID 398)

      14:05 - 14:25  |  Author(s): E. Vokes

      • Abstract
      • Slides

      Abstract
      Over the last decade, combined modality therapy has been established as standard of care for patients with locoregionally advanced unresectable non-small cell lung cancer (1). Both induction chemotherapy followed by radiation as well as concomitant chemoradiotherapy have been shown to be superior to radiotherapy alone and both approaches extend progression-free and overall survival. In direct comparison, concomitant chemoradiotherapy has been shown to be superior to induction in several randomized phase III trials as well as meta-analyses, likely due to enhanced locoregional control due to the chemotherapy radiation sensitization effect (2, 3). Currently about 20 to 30% of patients can be cured. While there are established clinical prognostic factors, very little information exists to more precisely guide prognosis or therapeutic approach for individual patients. In trying to improve survival outcomes induction chemotherapy was added to concomitant chemoradiotherapy but failed to result in superior outcome compared to concomitant chemoradiotherapy alone.(4). Similarly, consolidation chemotherapy or maintenance therapy with erlotinib in patients unselected for molecular characteristics did not improve survival compared with concomitant chemoradiotherapy alone (5,6). Several chemotherapy regimens have been investigated in the concomitant setting including the mitomycin/vinblastine/cisplatin (MVP) regimen, carboplatin/paclitaxel given weekly (and this regimen has consolidation chemotherapy for two cycles built in) and cisplatin/etoposide. The latter two are frequently used standards in control arms for current randomized trials. There has also been interest in the combination of carboplatin and pemetrexed given the superior single modality activity of the platinum/pemetrexed regimen in non-squamous cell tumors (7). It has been demonstrated that this drug combination can be given at full systemic doses in combination with radiation, thus providing good systemic coverage to eradicate micro-metastases as well as locoregional radiation enhancement. Whether any of these regimens is superior to another is not clear and few direct comparisons have been completed. Japanese investigators compared carboplatin/taxol with carboplatin/irinotecan and the MVP regimen in combination with concomitant radiation and reported equivalent outcomes with these regimens(8). In a small trial comparing carboplatin/taxol with cisplatin/etoposide and radiotherapy, the platinum/etoposide regimen appeared to be superior; however, the number of patients was very limited at approximately 30 per arm (9). Cisplatin/pemetrexed vs. carboplatin/pemetrexed has also been compared in a randomized phase II format supporting a trend for superiority of cisplatin-based therapy as has been shown for other stages of non-small cell lung cancer as well (10). A large randomized phase III trial comparing cisplatin/etoposide with cisplatin/pemetrexed each with concomitant radiotherapy to 66 Gy has been completed. This study was closed after a futility analysis at near completion of planned accrual and a full analysis of this trial is awaited for the future. Targeted therapies have also been of interest. While they have matured to be standard therapy for many patients with stage IV disease their role in earlier stages remains under-investigated. In a number of uncontrolled trial, the addition of erlotinib or gefitinib to radiation therapy with or without additional chemotherapy has been shown to be feasible. In the Alliance Cooperative Group (formerly CALGB), a recent trial looking at induction chemotherapy with carboplatin and albumin-bound paclitaxel followed by erlotinib and concomitant radiotherapy for patients with poor-risk stage III non-small cell lung cancer was completed. Median progression-free and overall survival times of 11 months and 16 months respectively were encouraging. However, no comparative arm of radiotherapy alone was included in the trial design (11). Similarly, cetuximab has been integrated into this treatment approach. RTOG 0324 reported encouraging pilot data from the addition of cetuximab to carboplatin/paclitaxel-based concurrent chemoradiation and consolidation chemotherapy(12). A randomized trial comparing the base regimen vs. the base regimen plus cetuximab in this setting has been completed and mature results are expected in the near future. It should be cautioned however, that the larger clinical experience with the addition of cetuximab to concurrent chemoradiotherapy regimens to date has been disappointing. A randomized phase II study conducted by the CALGB (CALGB#30407) found no obvious clinically significant benefit from the addition of cetuximab to carboplatin/pemetrexed radiotherapy (7). Median survival times were 21.2 and 22.4 months respectively for the two study arms. Similarly, controlled trials investigating the addition of cetuximab in patients with esophageal or head and neck cancer to concomitant chemoradiotherapy have not shown a statistically significant benefit compared to chemoradiotherapy alone. Current research interest is focused on the treatment of patients with molecular abnormalities, in particular EGFR mutations or EML/alk translocation. For these patients, a study investigating induction chemotherapy with either erlotinib or crizotinib, respectively followed by standard concurrent chemoradiation vs concurrent chemoradiation alone is about to be activated. Similarly, immunological approaches are of interest. At present, no data from studies investigating CTLA-4 or PD1 inhibitors are available. However, a randomized trial investigating the BLP25 vaccine, a liposome MUC1-based vaccine, has recently been reported. This vaccine attempts to induce a proliferative T-cell response to the MUC1 antigen which is frequently overexpressed and hyper-glycosylated in non-small cell lung cancer. In this trial, patients completed standard combined modality therapy (either induction or concomitant chemoradiotherapy) and were then randomized to either a placebo or the active vaccine. For the overall study cohort a trend in survival was observed which was more pronounced in a planned subset analysis of patients receiving concomitant chemoradiotherapy (13). This study adds support to further investigations to vaccine-based approaches. While current standard therapy approaches do result in consistent cure rates of 20-30% of patients, further progress will depend on the development of more specific combined modality approaches. Immunological and molecularly driven clinical trials will be of particular interest in this regard.

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    O02 - NSCLC - Combined Modality Therapy I (ID 111)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Combined Modality
    • Presentations: 1
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      O02.04 - DISCUSSANT (ID 3945)

      11:00 - 11:15  |  Author(s): E. Vokes

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    P1.09 - Poster Session 1 - Combined Modality (ID 212)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P1.09-009 - Preliminary Safety and Treatment Delivery Data During Concurrent Phase of Chemoradiation Therapy of the PROCLAIM Trial: A Phase 3 Trial of Pemetrexed, Cisplatin, and Radiotherapy Followed by Consolidation Pemetrexed Versus Etoposide, Cisplatin, and Radiotherapy Followed by Consolidation Cytotoxic Chemotherapy of Choice in Patients With Stage III Nonsquamous Cell Lung Cancer. (ID 1196)

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

      • Abstract

      Background
      Pemetrexed platinum regimens, unlike other regimens, can be given at full systemic doses with thoracic radiation therapy (TRT) in locally advanced stage III nonsquamous non–small cell lung cancer (NSCLC). Study JMIG was initiated to determine if this finding would translate into a survival advantage versus contemporary standard of care.

      Methods
      Study JMIG randomized patients with stage III unresectable nonsquamous NSCLC to experimental Pem+Cis (pemetrexed plus cisplatin and concurrent TRT for three 21-day cycles, followed by consolidation pemetrexed) or to control Etop+Cis (etoposide plus cisplatin and concurrent TRT for two 28-day cycles, followed by consolidation chemotherapy regimen of choice [excluding pemetrexed]). The primary objective was overall survival of Pem+Cis compared with Etop+Cis with safety as a secondary objective using Common Terminology Criteria for Adverse Events (CTCAE). Adverse event incidences were analyzed using Fisher’s exact test (2-sided α=0.05).

      Results
      Of 598 randomized patients, 555 received treatment: 283 Pem+Cis and 272 Etop+Cis. Baseline characteristics were similar (Pem+Cis/Etop+Cis); age (mean±SD) 59.2±9.5/58.7±9.3 years; women, n=114 (40.3%) / n=105 (38.6%); stage IIIB, n=153 (54.1%)/n=138 (50.7%); Eastern Cooperative Oncology Group performance standard of 1, n=138 (48.8%)/n=137 (50.4%); and planned target volume (mean±SD) 628.9 ±463.3/581.2±417.0 ml. Pem+Cis mean weekly dose intensities were 95.9% for both pemetrexed and cisplatin; Etop+Cis dose intensities were 96.4% and 94.1% for etoposide and cisplatin. TRT therapies were similar (Pem+Cis/Etop+Cis); TRT median (range) of 66.0 (2.0–66.3) gray (Gy)/66.0 (2.0–66.0) Gy, mean (SD) number of fractions 31.4 (4.3)/31.1 (5.2), V20 of 27.5% (6.5%)/26.7% (7.3%). Table 1 summarizes AEs during the concurrent phase by treatment. Few patients (n≤4) had grade 3 or 4 CTCAE of mucositis/stomatitis or rash. Pem+Cis had fewer SAEs of febrile neutropenia and pneumonia but increased vomiting compared with Etop+Cis. Nine patients died during the concurrent phase (not included in this safety analysis by treatment to preserve the integrity of final efficacy analysis).

      Table 1. Summary of Common Terminology Criteria for Adverse Events Grade 3 Plus 4 Occurring in ≥2% of Patients Randomized and Treated
      CTCAE (Grades 3 and 4) Pem+Cis N=283 n (%) Etop+Cis N=272 n (%) p-value
      Patients with ≥1 CTCAE* 170 (60.1) 186 (68.4) 0.042
      Neutrophils/granulocytes* 52 (18.4) 78 (28.7) 0.005
      Leukocytes* 44 (15.5) 65 (23.9) 0.014
      Esophagitis 42 (14.8) 47 (17.3) 0.488
      Lymphopenia 48 (17.0) 37 (13.6) 0.290
      Hemoglobin 14 (4.9) 20 (7.4) 0.289
      Febrile neutropenia 9 (3.2) 18 (6.6) 0.075
      Dysphagia 18 (6.4) 16 (5.9) 0.861
      Platelets 15 (5.3) 16 (5.9) 0.854
      Vomiting 12 (4.2) 13 (4.8) 0.839
      Hypokalemia 6 (2.1) 12 (4.4) 0.153
      Infection—lung (pneumonia)*[a] 1 (0.4) 9 (3.3) 0.010
      Dehydration 11 (3.9) 8 (2.9) 0.643
      Nausea 13 (4.6) 8 (2.9) 0.376
      Anorexia 10 (3.5) 7 (2.6) 0.625
      Fatigue 9 (3.2) 6 (2.2) 0.603
      Hyponatremia 5 (1.8) 6 (2.2) 0.768
      Thrombosis/thrombus/embolism 7 (2.5) 5 (1.8) 0.772
      Abbreviations: Cis = cisplatin; CTCAE = Common Terminology Criteria for Adverse Events, Version 3.0; Etop = etoposide; N = number of patients dosed; n = number of patients with at least one CTCAE; Pem = pemetrexed.
      * Statistically significant; p<.05 based on Fisher’s exact test.
      [a] CTCAE was defined as Infection (clinical/microbio)—Gr3/4 neutrophils—Pulmonary/upper respiratory—Lung (pneumonia).

      Conclusion
      During the concurrent treatment phase, patients with stage III locally advanced nonsquamous NSCLC in either treatment arm received comparable systemic therapy; however Pem+Cis had significantly lower incidences of some toxicities. Further toxicity differences may emerge with longer follow-up.

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    P2.14 - Poster Session 2 - Mesothelioma (ID 196)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P2.14-002 - Validation of the CALGB and EORTC Prognostic Models for Mesothelioma Based on Multiple CALGB Trials (Alliance) (ID 922)

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

      • Abstract

      Background
      Prognostic models play an important role in the design and analysis of mesothelioma treatment trials. The European Organisation for Research and Treatment of Cancer (EORTC) and the Cancer and Leukemia Group B (CALGB) prognostic models are two well-known tools to predict survival in patients with malignant mesothelioma. In this retrospective validation study, we aim to assess the performance of these two mesothelioma prognostic models for overall survival (OS) with multiple clinical trials data from CALGB.

      Methods
      Using 204 patients with malignant pleural mesothelioma, the EORTC model (Curran et al 1998) was developed using a Cox regression with white blood cell (WBC) count, ECOG performance status (PS), diagnosis, histological type, and gender as prognostic variables. Using 337 patients with malignant mesothelioma, the CALGB model (Herndon et al 1998) was developed using a cross-validated exponential regression tree with PS, age, haemoglobin (Hgb) level, WBC count, chest pain indicator, and weight loss indicator as prognostic variables. In this validation study, 602 mesothelioma patients from fifteen completed CALGB treatment trials accrued between June 1984 and August 2009 were included. As the CALGB model was developed using the seven earlier studies, 266 patients from eight recent studies were included in the validation. For the EORTC model, we analysed all studies as well as just those eight recent studies. The concordance of predicted survival times and risk scores was estimated by c-index (Harrell et al 1996). Secondary endpoint of interest includes progression-free survival (PFS). Sensitivity analysis and multiple imputations were used to handle missing data. We also compared our results with PS alone.

      Results
      (1) For OS, the EORTC model produced c-indices equal to 0.592 and 0.610 for the fifteen and eight studies respectively. For the eight recent studies, the CALGB model produced c-indices equal to 0.618 and 0.593 without and with imputation respectively. PS alone produced c-indices equal to 0.591 and 0.564 for the fifteen and eight studies respectively. (2) For PFS, the EORTC model produced c-indices equal to 0.569 and 0.598 for the fifteen and eight studies respectively. For the eight recent studies, the CALGB model produced c-indices equal to 0.585 and 0.560 without and with imputation respectively. PS alone produced c-indices equal to 0.568 and 0.553 for the fifteen and eight studies respectively. See Table 1. Figure 1

      Conclusion
      The EORTC and CALGB models perform similarly, with little improvement in prognostic ability from either compared to using PS alone. Further improvement on these existing prognostic models is warranted.

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    P3.14 - Poster Session 3 - Mesothelioma (ID 197)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P3.14-011 - Genomic profiling of Epithelial Malignant Pleural Mesothelioma (MPM) using Massively Parallel Sequencing. (ID 2855)

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

      • Abstract

      Background
      Development of targeted therapies in malignant pleural mesothelioma has been limited due to the incomplete understanding of genetic aberrations occurring in this disease. We determined mutational and copy number (CN) events in a comprehensive fashion in 12 patients with epithelial malignant pleural mesothelioma in order to identify characteristic genetic aberrations and new potential treatment targets.

      Methods
      Fresh frozen tumor (≥70% tumor content) and matched normal tissue from 12 patients with treatment-naïve epithelial malignant pleural mesothelioma were evaluated using targeted, massively parallel sequencing (Illumina HiSeq) for 580 cancer-relevant genes using hybrid capture target enrichment and an established bioinformatics analysis pipeline. CN analysis was performed using sequencing data (CONTRA) and validated on the NanoString nCounter. Mutations were modeled bioinformatically using the CHASM oncogenic driver prediction algorithm and reviewed for prior occurrence in COSMIC and evidence supporting usefulness as a treatment target.

      Results
      Loss of CDKN2A was the most common genetic event occurring in 80% of samples. INPP4B and TRAF6 were lost in 20-30% of tumors. No loss of PTEN was observed in any sample. Two BAP1 small frameshift deletions were observed. Copy number aberrations, in particular amplifications, were rare. The only gene with modest increase in copy number was MET (median CN=2.8). We identified multiple somatic missense mutations including: two APC mutations (K1245E, G2502D; both predicted to be damaging), one TSC1 (K587A) and one TSC2 (P952A, predicted driver) mutation, one KIT mutation (L799F; predicted driver), one JAK2 (P953A; predicted driver), as well as single mutations in NF1 (G849R), EPHA1 (P697S), EPHA4 (T532I), and mTOR (L2208P), all of which had driver character. Specific mutations have not been reported in COSMIC. No canonical PI3K or MAPK pathway aberrations were identified.

      Conclusion
      We identified several novel and known mutations and copy number events in epithelial malignant pleural mesothelioma: deletions in CDKN2A and INPP4B were the most common copy number events. Frameshift deletions in BAP1 were identified. Overall few copy number events were observed. Potentially targetable aberrations include missense mutations in NF1, JAK2, EPHA1, TSC2, mTOR and KIT, which are predicted to have driver character and additional experimental validation is indicated. Additional tumor and cell line samples are being processed and will be available at the time of presentation.