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J. Jassem



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    ED10 - Locally Advanced NSCLC: State-of-the-Art Treatment (ID 279)

    • Event: WCLC 2016
    • Type: Education Session
    • Track: Locally Advanced NSCLC
    • Presentations: 1
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      ED10.03 - New Developments in Radiotherapy of Stage III NSCLC (ID 6483)

      16:00 - 17:30  |  Author(s): J. Jassem

      • Abstract
      • Presentation
      • Slides

      Abstract:
      NSCLC accounts for 80-85% of all lung cancers, and stage III disease constitutes about 40% of the total cases. The main treatment modality in these patients is radiotherapy, usually combined with concurrent chemotherapy. Five-year overall survival in stage III disease is merely 10-15%. Radiotherapy of thoracic tumors poses several challenges, such as tissue heterogeneity, tumor and organ motion and changing anatomy over the treatment course. Main approaches addressing these problems include dose intensification, altered fractionation and advanced radiotherapy techniques. Until recently, dose escalation was considered the main means to increase radiotherapy efficacy. Despite encouraging results of phase I–II studies, the results of recent RTOG trial 0617 were disappointing (1). This study compared high-dose radiotherapy (74 Gy/37 fractions) to a standard-dose (60 Gy/30 fractions) concurrently with weekly paclitaxel/carboplatin, with or without cetuximab. Surprisingly, median overall survival in the high-dose arms was significantly shorter (20 months vs. 29 months in the standard-dose arms; p=0.004) (1). It was speculated that the inefficacy of high-dose radiotherapy could be due to long overall treatment time and accelerated tumor repopulation. Shortening treatment time may be accomplished by accelerated radiotherapy. A phase III study investigating continuous hyperfractionated accelerated radiotherapy (CHART; 54 Gy/36 fractions of 1.5 Gy delivered 3 times daily over 12 consecutive days) showed increased efficacy compared to conventional fractionation (2). A CHARTWEL study, using the same fractionation but with weekend breaks, was not superior to conventional fractionation (3). A meta-analysis of 10 trials (2000 patients) demonstrated an absolute 5-year survival benefit of 2.5% with hyperfractionated and/or accelerated radiotherapy over conventional fractionation, at the expense of significantly increased grade 3–4 acute esophagitis (4). Important developments in lung radiotherapy represent new imaging techniques. PET-CT, currently a routine procedure, allows better patient selection for radical radiotherapy and facilitates selective irradiation of involved volumes (5). Image guided radiation therapy (IGRT), such as daily volumetric kilovoltage cone-beam computed tomography (CBCT), provides actual positional information, allowing for online repositioning and more precise tumor localization. Image-guided adaptive radiotherapy (IGART) additionally accounts for changes and deformations occurring during the radiotherapy course, thus allowing treatment re-planning (6). Currently, dose delivery in NSCLC is commonly accomplished by intensity modulated radiotherapy (IMRT). This technique improves the conformality of radiotherapy by modulating the radiation beam intensity profile, and allows decreasing the mean lung dose, particularly in patients with larger tumor volumes (7). The problem of intrafraction motion in thoracic malignancies has been traditionally managed by extension of treatment margins, leading to excessive radiation to normal tissues. Currently, tumor motion may be managed individually by respiratory-correlated 4-dimensional CT (4DCT) based on the acquisition of organ and tumor imaging data at extreme phases of the breathing cycle. An innovative option allowing for safe dose intensification is isotoxic therapy (8). This approach includes dose prescription defined by the maximal doses achievable to normal tissues. More recently, several clinical studies investigated the role of proton beam therapy in NSCLC. A dosimetric advantage of proton- over conventional photon radiotherapy is mediated by its unique properties: low doses upon tissue penetration, maximal dose deposition towards the end of the beam’s path (Bragg peak) and finite range with minimal dose beyond the tumor. Retrospective data and phase II studies suggested promising survival rates, and reduced pulmonary and esophageal toxicity with protons. However, the results of recent phase III trial did not confirm the superiority of this method over IMRT (9). In summary, recent diagnostic and therapeutic advances the use of radiation in stage III NSCLC allow for more accurate treatment planning, more precise dose delivery and managing tumor and organ motion. Some of these developments have been adopted in clinical practice, despite relatively few evidence of their advantages in terms of better local control and survival. The paucity of phase III trials testing new radiotherapy approaches is partly due to relying on better dose distribution and reduced exposure of normal tissues, making comparisons with less advanced techniques an ethical dilemma (10). References 1. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015;16:187-99. 2. Saunders M, Dische S, Barrett A, et al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. Lancet 1997;350:161–5. 3. Baumann M, Herrmann T, Koch R, et al. Final results of the randomized phase III CHARTWEL-trial (ARO 97–1) comparing hyperfractionated-accelerated versus conventionally fractionated radiotherapy in non-small cell lung cancer (NSCLC). Radiother Oncol 2011;100:76–85. 4. Mauguen A, Le Pe´choux C, Saunders MI, et al. Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis. J Clin Oncol 2012;30:2788–97. 5. Chang JY, Dong L, Liu H, et al. Image-guided radiation therapy for non-small cell lung cancer. J Thorac Oncol 2008;3:177–86. 6. Sonke JJ, Belderbos J. Adaptive radiotherapy for lung cancer. Semin Radiat Oncol 2010;20:94-106. 7. Bezjak A, Rumble RB, Rodrigues G, and al. Intensity-modulated radiotherapy in the treatment of lung cancer. Clin Oncol 2012;24:508–20. 8. De Ruysscher D, van Baardwijk A, Steevens J, et al. Individualised isotoxic accelerated radiotherapy and chemotherapy are associated with improved long term survival of patients in stage III NSCLC: a prospective population-based study. Radither Oncol 2012;102:228-233. 9. ZX Liao, J. JJ Lee, R Komaki, et al. Bayesian randomized trial comparing intensity modulated radiation therapy versus passively scattered proton therapy for locally advanced non-small cell lung cancer. J Clin Oncol 2016;34(15S):435s. 10. Dziadziuszko R, Jassem J. Randomized clinical trials using new technologies in radiation oncology: ethical dilemma for medicine and science. J Thor Oncol 2007;7:3-4.

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    P3.02c - Poster Session with Presenters Present (ID 472)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02c-042 - IMpower110: Phase III Trial Comparing 1L Atezolizumab with Chemotherapy in PD-L1–Selected Chemotherapy-Naive NSCLC Patients (ID 5094)

      14:30 - 15:45  |  Author(s): J. Jassem

      • Abstract

      Background:
      For patients with advanced NSCLC without genetic driver alterations, cisplatin/carboplatin+pemetrexed is a standard-of-care first-line (1L) treatment for non-squamous histology; and cisplatin/carboplatin+gemcitabine for squamous histology. Although immunotherapies targeting PD-L1/PD-1 are currently available for 2L+ NSCLC, chemotherapy remains the main 1L option despite poor survival and toxicities. Atezolizumab, an anti–PDL1 mAb, prevents PD-L1 from interacting with its receptors PD-1 and B7.1, restoring tumor-specific T-cell immunity. Clinical efficacy was demonstrated with atezolizumab in non-squamous and squamous NSCLC, with Phase I and II studies exhibiting durable responses and survival benefit that increases with higher PD-L1 expression on tumor cells (TC) and/or tumor-infiltrating immune cells (IC). IMpower110, a global Phase III randomized, multicenter, open-label trial, will evaluate efficacy and safety of atezolizumab vs cisplatin/carboplatin+pemetrexed or gemcitabine as 1L therapy for PD-L1–selected chemotherapy-naive patients with advanced non-squamous or squamous NSCLC, respectively.

      Methods:
      Eligibility criteria include stage IV non-squamous or squamous NSCLC, measurable disease (RECIST v1.1), ECOG PS 0-1, no prior chemotherapy for advanced NSCLC and centrally-assessed PD-L1 expression ≥1% on TC or IC (TC1/2/3 or IC1/2/3 with VENTANA SP142 IHC assay; expected prevalence, ≈65%). Exclusion criteria include active or untreated CNS metastases, prior immune checkpoint blockade therapy or autoimmune disease. Patients will be randomized 1:1 to receive atezolizumab or cisplatin/carboplatin+pemetrexed (non-squamous)/gemcitabine (squamous) for 4 or 6 21-day cycles. Patients in comparator arms can receive pemetrexed (non-squamous)/best supportive care (squamous) until RECIST v1.1 disease progression. Patients receiving atezolizumab may continue until loss of clinical benefit. Co-primary endpoints are PFS and OS. Key secondary efficacy endpoints include ORR, DOR, IRF-assessed PFS (RECIST v1.1) and TTD. Safety and PK will also be evaluated. Tumor biopsies at RECIST v1.1 progression will be assessed for immunologic biomarkers associated with responses to atezolizumab and to differentiate non-conventional responses from radiographic progression.

      Planned enrollment, N 570
      Histology Non-squamous Squamous
      Experimental arm Atezolizumab (1200 mg q3w)
      Comparator arm Cisplatin (75 mg/m[2] IV q3w) + pemetrexed (500 mg/m[2] IV q3w) or Carboplatin (AUC 6 mg/mL/min IV q3w) + pemetrexed (500 mg/m[2] IV q3w) Cisplatin (75 mg/m[2] IV q3w) + gemcitabine (1200 mg/m[2] IV days 1, 8) or Carboplatin (AUC 5 mg/mL/min IV q3w) + gemcitabine (1000 mg/m[2] IV days 1, 8)
      Stratification factors Sex ECOG Histology (non-squamous vs squamous) PD-L1 expression by IHC
      ClinicalTrials.gov identifier NCT02409342


      Results:
      Section not applicable

      Conclusion:
      Section not applicable

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    PL03 - Presidential Symposium (ID 428)

    • Event: WCLC 2016
    • Type: Plenary
    • Track:
    • Presentations: 1
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      PL03.06 - Discussant for PL03.05 (ID 7154)

      08:35 - 10:25  |  Author(s): J. Jassem

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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