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Umberto Ricardi

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    ES16 - Modern Radiotherapy in Stage III NSCLC (ID 19)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 1
    • Now Available
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      ES16.03 - Optimal Integration of Radiotherapy, TKIs and I/O (Now Available) (ID 3244)

      11:00 - 12:30  |  Presenting Author(s): Umberto Ricardi

      • Abstract
      • Presentation
      • Slides


      Umberto Ricardi, Serena Badellino, Cristina Mantovani, Donatella Caivano, Stefania Martini, Marzia Cerrato, Giuseppe Carlo Iorio

      Department of Oncology, University of Turin, Italy

      Approximately one third of patients affected by non-small cell lung cancer (NSCLC) present with ‘locally advanced’ disease at diagnosis. Most patients are considered inoperable due to disease extension, and chemo-radiotherapy (CT-RT) still represents the standard therapeutic option, with unsatisfactory results in terms of overall survival (OS) despite advances in staging and technological evolution in radiation therapy planning and delivery. Besides radiation dose escalation, a logical step for improving survival in inoperable stage III patients was to evaluate the combination of concurrent/sequential RT-CT with targeted agents (tyrosine kinase inhibitors, TKI; mono-clonal antibody against EGFR; ALK/ROS1 inhibitors) and/or anti- angiogenic therapies, following the positive results obtained in stage IV disease (1, 2). Since the early 2000s, when first-generation TKIs were first approved for clinical use, several studies have been conducted in an attempt to demonstrate the efficacy of targeted therapies combined with radiotherapy (3, 4, Table 1). These studies were testing mainly the feasibility and the tolerability of this combination, with not statistical significant benefit in terms of outcomes (4, Table 1). Mature results of an international trial testing the contribution of TKIs with chemoradiotherapy in patients affected with stage III NSCLC harboring sensitive mutations are still waited.

      Immunotherapy, and in particular immune-checkpoint inhibitors targeting the PD-1/PD-L1 axis, gained wide popularity for NSCLC in light of the positive findings of several trials in metastatic disease (1, 5). Radiation therapy combined with immunotherapy represent a new therapeutic opportunity, given the role of RT in reversing immunosuppressive barriers within the tumor microenvironment (6). The growing enthusiasm for immune-oncology and its possible applications in radiation oncology led to a remarkable expansion of pre-clinical and clinical studies testing various combinations of immunotherapeutic agents and radiation. Stage III unresectable NSCLC is an interesting setting for the combined use of chemo-radiation and immunotherapy, also considering the multiple experimental evidences in favor of a synergistic effect between radiation and immune checkpoint inhibitors, with the potential of enhancing immuno-modulating effects and overcoming resistance. The PACIFIC trial (PD-L1 inhibitor Durvalumab vs placebo, unresectable stage III NSCLC who did not progress following concurrent platinum-based chemo-radiotherapy) showed a major improvement in 2-year PFS and OS, which holds promise for an improved cure rate (7). Even the use of Pembrolizumab (anti-PD-1 agent) is under investigation in a series of trials. A number of studies (e.g. INSPIRE study) investigated the role of Tecemotide (anti-tumor vaccine inducing a specific immune response against MUC-1, glycoprotein overexpressed in NSCLC) (8) in Stage III NSCLC. More evidence is awaited regarding the optimal timing when combining immunotherapy and CT-RT, considering the possibility to improve this synergism even further. Several ongoing trials are testing multiple schedules (5). A predominance of the consolidation/adjuvant/maintenance setting is evident, however many studies also integrated immunotherapy at the beginning of chemo-radiation. The latter schedule should be one of the most efficient ways to fully harness the synergistic effects of chemo-radiation and immunotherapy in terms of boosting the immune-stimulating effects, particularly when using anti-PD-L1 agents, given that enhanced expression of PD-L1 during RT may be one of the main causes of radioresistance. Some attention should also be paid to those trials introducing anti-PD-1 agents before chemo-radiation, as neo-adjuvant: this innovative approach could be promising, by integrating radio-chemotherapy in a tumor micro-environment already modified by immunomodulators, and with a subsequent consolidation phase. When using anti-PD-L1 agents in this setting, PD-L1 expression levels would probably be necessary to stratify patients as highlighted in the PACIFIC trial post-hoc analysis (9).


      Filippi AR, Di Muzio J, Badellino S, Mantovani C, Ricardi U. Locally-advanced non-small cell lung cancer: shall immunotherapy be a new chance? J Thorac Dis 2018;10(Suppl 13):S1461-S1467. doi: 10.21037/jtd.2017.12.53.

      Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre-Finn C, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019 Jan 30. doi: 10.1093/annonc/mdy474.


      Arcangeli S, Jereczek-Fossa BA, Alongi F, Aristei C, Becherini C, Belgioia L, Buglione M, et al. Combination of novel systemic agents and radiotherapy for solid tumors - Part II: An AIRO (Italian association of radiotherapy and clinical oncology) overview focused on treatment toxicity. Crit Rev Oncol Hematol. 2019;134:104-119. doi: 10.1016/j.critrevonc.2018.11.006.

      Kordbacheh T, Honeychurch J, Blackhall F, Faivre-Finn, Illidge. Radiotherapy and anti-PD-1/PD-L1 combinations in lung cancer: building better translational research platforms. Ann Oncol. 2018 Feb 1;29(2):301-310. doi: 10.1093/annonc/mdx790.

      Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol. 2009 Jul;10(7):718-26. doi: 10.1016/S1470-2045(09)70082-8.

      Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med 2018; 379:2342-2350 DOI: 10.1056/NEJMoa1809697.

      Wu YL, Park K, Soo RA, et al. INSPIRE: A phase III study of the BLP25 liposome vaccine (L-BLP25) in Asian patients with unresectable stage III non-small cell lung cancer. BMC Cancer 2011;11:430.

      Kim YH. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2019 Mar 7;380(10):989-990. doi: 10.1056/NEJMc1900407.

      Table 1. Major studies on Radiotherapy and TKIs in LA-NSCLC.

      Author and year

      Study type

      Number of patients

      RT technique/ dose/ fractionation

      Combination (concomitant, other)

      Primary Endopoint

      Treatment outcome

      Martinez et al (2016)

      Phase II Randomised, NSCLC


      3D-CRT 66 Gy/33 fx

      RT alone vs RT+Erlotinib


      Median OS: 11.4 vs 8.9 (p=0.835)

      Lilenbaum et al (2015)

      Phase II, unresectable NSCLC


      3D-CRT 66 Gy/33 fx

      Induction Carbo/Paclitaxel® RT+ Erlotinib


      Median OS: 17 months. 1-yy OS: 57%

      Ramella et al (2013)

      Phase I-II, unresectable NSCLC


      3D-CRT 59.4 Gy/33 fx



      Median OS:23.3months. Median PFS: 4.7 months

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