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Suresh Senan



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    ES06 - Perioperative Therapy for Early Stage NSCLC (ID 221)

    • Event: WCLC 2020
    • Type: Educational Session
    • Track: Early Stage/Localized Disease
    • Presentations: 1
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      ES06.02 - Radiation and IO for Operable Early Stage NSCLC (ID 4047)

      14:15 - 15:15  |  Presenting Author(s): Suresh Senan

      • Abstract

      Abstract

      The goal of surgery in patients presenting with an early-stage NSCLC is cure, but novel treatment strategies are necessary in order to improve current outcomes. In patients presenting with a large primary tumor (T3/4) with limited volume nodal metastases (N1 or single station N2 disease), induction therapies including chemo-radiotherapy have been used to both improve the likelihood of a complete surgical resection, and to treat occult metastatic disease. However, despite trimodality treatments, between 30-50 % of these patients develop distant disease relapse. In fit patients with stage I NSCLC, distant metastases manifest in approximately 30% after primary surgery and a nodal recurrence. New treatment strategies are currently being investigated, notably neoadjuvant immunotherapy either as monotherapy, in combination with chemotherapy, or as a dual combination of immune-agents (IO) such as anti-PD-(L)1 and anti-CTLA-4 (dual-IO). A less commonly explored strategy is the use of combined neoadjuvant radiotherapy plus immunotherapy, either with or without chemotherapy.

      In the presence of a pre-treatment tumor mass, the neoadjuvant administration of immune checkpoint inhibitors can achieve immune priming or boosting as dying tumor cells are engulfed by antigen presenting cells, which in turn can drive tumor-specific memory T-cell responses. Findings of preclinical and early clinical studies suggest that a broader and stronger T-cell response may be induced with this approach (Rudqvist NP, 2018, Formenti S, 2018 ). A relatively unknown aspect of immunoradiotherapy is the optimal dose of radiation required in patients. Murine studies have shown radiation-induced immune responses orchestrated by the cGAS-STING pathway, which is attenuated by the DNA exonuclease TREX1, induced by radiation doses above 12-18 Gy (Vanpouille-Box C, 2017). For optimization of future clinical trial design, clinical information about the immunological effects of dose, fractionation schedule and scheduling with immunotherapy is urgently required. Ionizing radiation induces DNA damage, which can trigger immunogenic tumor cell death leading to a pro-inflammatory immune response (Chen DS, 2013). As the stress responses accompanying surgical trauma disrupt several immunological pathways, leading to immune suppression (Krall JA, 2018 ), the immune activation induced by neoadjuvant treatment can potentially protect against microscopic disease. This can lead to a diminished risk of distant metastases or even local disease recurrence.

      Potential risks of the neoadjuvant approach in general are the possibility of tumor progression with delayed surgery, delays arising from toxicity of induction therapy and uncertainty of the prognostic significance of a major pathological response (MPR) as study end-point. In addition, the optimal radiation doses for use with IO in the neoadjuvant setting are unclear, as is the impact of irradiating tumor draining lymph nodes (TDLN). With the use of highly-precise image guided radiotherapy approaches, not only can organs at risk be spared, but also irradiation of draining lymph nodes, which could lead to improved T-cell mediated immunity (van de Ven R, 2017).

      The relevant issues in trial design will be elaborated upon using ongoing trials exploring the safety and feasibility of radiotherapy and IO in operable early-stage NSCLC, including NCT02904954; EudraCT-Number: 2019–003454-83; EudraCT-Number: 2016‐003819‐36. Translational research will be an essential component of such trials as this may provide signals identifying the most promising immune priming neoadjuvant strategies. For example, the INCREASE trial [2019–003454-83; Dickhoff C, 2020] will investigate (i) the presence and distribution pattern of tumor infiltrating lymphocytes (TIL’s) in the tumor microenvironment (TME) at baseline and after induction therapy; (ii) correlate post induction TIL’s with residual tumor cells/pCR; (iii) changes in immune suppressive subsets/mechanisms in the TME and TDLN between pre and post induction; and (iv) correlation of these changes to residual viable tumor cells.

      Advanced immunological methods like multiplex IHC, multiparameter flow cytometry, immuno-PET imaging (Niemeijer AN, 2018) and molecular techniques (e.g. RNA sequencing , tumor-educated blood platelets [TEPs]) can give insights in immunological responses upon different doses and schemes of ionizing radiation and can provide promising insights for future trial design. Translational endpoints related to the characterization and spatiotemporal visualization of immune cells within the TDLN and TME will reveal whether (chemo-)radiotherapy and IO can induce a more pro-inflammatory immune response (e.g. increase in effector- and memory T cell subsets and activation of antigen presenting myeloid cells) and a decline in immune suppressive subsets (e.g. regulatory T cells and myeloid derived suppressor cells). Furthermore, the role of tertiary lymphoid structures (TLS) (Sautès-Fridman C, 2019) on responses to multimodality therapy, and their correlation with oncological outcomes, is being explored.

      References

      Rudqvist NP. Radiotherapy and CTLA-4 Blockade Shape the TCR Repertoire of Tumor-Infiltrating T Cells Cancer Immunol Res. 2018 6(2):139-150.

      Formenti S. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat Med. 2018 24(12):1845-1851.

      Vanpouille-Box C. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 2017 8:15618.

      Chen DS. Oncology meets immunology: the cancer-immunity cycle Immunity. 2013 39(1):1-10.

      Krall J.A. The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy. Sci Transl Med . 2018;10(436):eaan3464.

      van de Ven R. High PD-1 expression on regulatory and effector T-cells in lung cancer draining lymph nodes. ERJ Open Res. 2017;3(2):00110-2016.

      Dickhoff C. Ipilimumab plus nivolumab and chemoradiotherapy followed by surgery in patients with resectable and borderline resectable T3-4N0-1 non-small cell lung cancer: the INCREASE trial. BMC Cancer 2020;20(1):764.

      Niemeijer AN. Nat Commun. 2018;9(1):4664. doi: 10.1038/s41467-018-07131-y.

      Sautès-Fridman C. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer. 2019;19(6):307-325.

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    IS02 - Industry Symposium Sponsored by AstraZeneca: Evolving the Role of Immunotherapy in Lung Cancer: ES-SCLC and Unresectable Stage III NSCLC (ID 278)

    • Event: WCLC 2020
    • Type: Industry Symposium
    • Track:
    • Presentations: 1
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      IS02.03 - Future Strategies: The Potential Role of IO Therapy in Unresectable Stage III NSCLC (ID 4311)

      10:30 - 11:30  |  Presenting Author(s): Suresh Senan

      • Abstract

      Abstract not provided

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    P18 - Locoregional and Oligometastatic Disease - Misc. Topics (ID 128)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Locoregional and Oligometastatic Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P18.02 - Factors Influencing Multi-Disciplinary Tumor Board Recommendations in Stage III Non-Small Cell Lung Cancer (ID 3408)

      00:00 - 00:00  |  Author(s): Suresh Senan

      • Abstract
      • Slides

      Introduction

      Treatment patterns in patients with stage III non-small cell lung cancer (NSCLC) vary considerably, with fewer than half of patients in most reports undergoing guideline recommended standard of care (SOC) treatments. The reasons for variations between countries and hospitals are not well understood. We studied factors influencing treatment decision-making at thoracic multidisciplinary tumor boards (MDT) at a regional network comprising 5 hospitals, for patients treated between 2015-2017.

      Methods

      Patients were identified from hospital records from an ethics-approved database and the national cancer registry. Weekly thoracic multidisciplinary tumor boards (MDT) were conducted, and treatment recommendations were based on the ESMO guidelines (2014). For this study, we considered SOC as consisting of concurrent chemoradiotherapy (CCRT) or surgery with systemic therapy, and all other treatments were classified as non-SOC.

      Results

      Of 197 eligible patients identified, 95% (n=187) had been discussed at an MDT. SOC treatments were recommended for 61% (n=115) of patients, but only 48% (n=90) of patients finally underwent SOC treatments (Figure 1). A patient age ≥70 years and a WHO-PS ≥2 were the commonest factors associated with not being recommended a SOC, followed by a diagnosis of diabetes mellitus and having a squamous cell carcinoma.

      Median overall survival in the SOC group was 27.9 months. In the non-SOC group, it was 10.7 months, ranging from 19.1 months for sequential chemoradiation (SCRT) to 3.8 months for palliative care. Disease progression within 2 years (PD≤2yrs) after completing SOC treatment occurred in 61% of patients (surgery 55% and CCRT 63%, respectively). PD≤2yr following SCRT was 54%, and after radical radiotherapy (RT≥50Gy) 29%. Deaths due to comorbidity in the 2 years following SOC, SCRT or RT≥50Gy were observed in 7, 16 and 33% of patients.

      figure1.png

      Figure 1. Overview of MDT recommendations versus actual treatments received by patients. The number of patients finally undergoing MDT recommended therapy is displayed in percentages in the bars.

      Conclusion

      SOC treatments were recommended in only 61% of patients with a newly diagnosed stage III NSCLC following MDT review. The high rates of disease progression and deaths due to comorbidity after non-SOC treatments indicate that more effective and better tolerated systemic treatments are required in stage III NSCLC.

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