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Jean-Marie Michot

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    GR02 - Improving Patients Quality of Life During Treatment of Metastatic Disease (ID 30)

    • Event: WCLC 2019
    • Type: Grand Rounds Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      GR02.03 - What Is the Best Management of Immunotherapy Toxicity? (Now Available) (ID 3306)

      15:15 - 16:45  |  Presenting Author(s): Jean-Marie Michot

      • Abstract
      • Presentation
      • Slides



      The consultations and advices of the organ specialists for immune-related adverse events (irAEs) management can be of great help. The oncologist who uses the immune-checkpoint inhibitors (ICIs) should in his clinical practice be surrounded by different organ specialists that will support him in the management of irAEs1–3.

      Although guidelines provide detailed algorithms for the management of irAEs4–6, few studies have assessed the real-life medical need of the oncology community. We propose here to report the activity of the immunoTOX assessment board to point the medical needs of oncologists in real life.

      Patients and methods.

      Organization of the immunoTOX assessment board.

      The ImmunoTOX assessment board is an academic group of physicians based at Gustave Roussy, Villejuif and at Paris-Sud University AP-HP Hospital, bringing together physicians specialized in the management of immunological toxicities1. Are present oncologists, pharmacovigilance pharmacists, internists and various specialists from expert bodies in the management of immunological toxicities (dermatologist, nephrologist, gastroenterologist, cardiologist, rheumatologist, hepatologist, neurologist, ear nose and throat specialist, ophthalmologist, hematologist, lung specialist and endocrinologist)


      Over the period studied, 398 requests were sent to the immunoTOX board, for 356 patients. The median time between the occurrence of irAE and the immunoTOX board discussion was 35 days (IQ 13-72). The main requests to the immunoTOX board were about a diagnostic opinion on the relationship between immunotherapy and the side effect (n = 148, 37% of cases), followed by an opinion on the possibility of reintroduction the ICI in a patient after previous irAE (n = 109, 27% of cases), followed by an opinion about the management of a complex immunological toxicity (n = 100, 25% of cases), and by the possibility of starting an ICI in a patient with comorbidities (n = 41, 10% of cases).

      A certain or probable or possible causal relationship between immunotherapy and side-effect was found in 273/356 (77%) of patients. Among the 273 irAEs investigated, the main organ categories were distributed in the lung (n = 58, 21.2%), the gastrointestinal tract (n = 36, 13.2%), the liver (n = 33, 12.1%). %), musculoskeletal (n = 27, 9.9%) and nervous system (n = 23, 8.4%) (figure 1A).


      The question of retreatment was 27% of the requests addressed to the immunoTOX board. The question of retreatment involved the possibility of resuming immunotherapy after prior irAE, which was grade 1-2 in 49% of cases and grade 3-4 in 51% of cases. The immunoTOX board gave a favorable recommendation for retreatment with caution for use in 65% of cases, a notice for maintaining temporary hold in 15% of patients, and a notice in favor of permanent discontinuation in 20% of cases.

      The requests question of the possibility of initiation of immunotherapy in a patient with comorbidities was one in ten. In patients with comorbidities, the immunoTOX board was in favor of initiating immunotherapy and recommended a precaution for use without formal contraindication in 93% of cases.


      The Immunotox board highlights the prominent real-life medical needs in the field of management of immunological toxicities. Questions rely mainly on toxicities affecting lung, digestive tract, hepatic and neuro-muscular system. When discussing a readministration or initiation of ICI in patients with autoimmune comorbidities, the Immunotox board was generally not opposed to give immunotherapy. A model of multidisciplinary management with oncologists working in close collaboration with organ specialists may guarantee to the patient the access to the ICI. This report will provide a basis of medical needs to define future strategies in prospective clinical trials of immunological toxicities management.

      Acknowledgement: The author thank the patients and their families and all investigators and site personnel. The authors thank Janine Nda, Cécile Geniez and Stéphanie Demirdjian and Sandrine Thorel for their assistance in management of patients.

      Figures legends.

      Figure 1. Distribution of irAEs organ categories (figure 1A) and irAEs types (figure 1B) registered by the immunoTOX board assessment. In the figure 2A are showed irAEs with occurrence ≥ 3.

      Figure 2. Characteristics of immune-related adverse events registered by the immunoTOX board assessment (among the 273 irAEs registered by the immunoTOX assessment board).

      CLS: Capillary leak syndrome

      CRS: Cytokine Release syndrome

      HPD: Hyperprogressive disease

      Hem-irAEs: Haematological immune-related adverse events

      irAEs: Immune-related adverse events


      1 Champiat S, Lambotte O, Barreau E, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol Off J Eur Soc Med Oncol ESMO 2016; 27: 559–74.

      2 Naidoo J, Zhang J, Lipson EJ, et al. A Multidisciplinary Toxicity Team for Cancer Immunotherapy–Related Adverse Events. J Natl Compr Canc Netw 2019; 17: 712–20.

      3 Cappelli LC, Shah AA, Bingham CO. Immune-Related Adverse Effects of Cancer Immunotherapy— Implications for Rheumatology. Rheum Dis Clin N Am 2017; 43: 65–78.

      4 Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol Off J Am Soc Clin Oncol 2018; : JCO2017776385.

      5 Haanen JB a. G, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Off J Eur Soc Med Oncol 2017; 28: iv119–42.

      6 Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 2017; 5: 95.

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    MA05 - Update on Clinical Trials and Treatments (ID 123)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      MA05.11 - Safety and Efficacy of Nintedanib in Combination with Pembrolizumab in Patients with Refractory/Relapsing Malignant Pleural Mesothelioma (Now Available) (ID 2170)

      13:30 - 15:00  |  Author(s): Jean-Marie Michot

      • Abstract
      • Presentation
      • Slides


      Malignant pleural mesothelioma (MPM) is an aggressive disease with no standard of care after progression to first line pemetrexed and platinum-based chemotherapy. Combinations between anti-angiogenic agents and immunotherapy are being developed as angiogenesis and immunosuppression influence each other leading to a more powerful anti-tumor response. Both Nintedanib and Pembrolizumab have been investigated as single agents or in different treatment combinations in MPM patients with interesting activity.


      The PEMBIB trial is a multi-centric open-label non-randomized basket phase 1 trial evaluating the combination of nintedanib with pembrolizumab in multiple tumor types. The safety and activity of the dose escalation part of the study were reported at AACR & ASCO meetings in 2018 with an established DLT defined as grade 3 alanine and/or aspartate aminotransferase elevation (ALT/AST). The recommended phase 2 dose is set at 150 mg BID of nintedanib with 200 mg flat dose of pembrolizumab. We would like to report the safety and activity of one of the expansion cohorts of patients with relapsing/refractory MPM which has now been completed. Eligible MPM patients were 18 years or older with an ECOG performance status of 0 or 1, histologically proven MPM that relapsed after at least one line of pemetrexed and platinum-based combination, specific anti-angiogenic eligibility criteria such as no radiographic evidence of cavitary/necrotic or tumors with local invasion of major blood vessels.

      Updated results on the safety profile and efficacy of this anti-angiogenic and anti-PD-1 combination therapy including overall response rate as per RECIST, irRC and mRECIST criteria, disease control rate will be presented at the meeting.


      The first patient from the MPM cohort was enrolled in July 2017 and the last one in April 2019. Thirty-one eligible MPM patients have been evaluable at the data cut off onJuly 2019, one of them had been enrolled since the dose-escalation part at dose level of 200mg. The age at inclusion was 68 (ranging from 38 to 85), 68% of the patients having an ECOG of 1 and 58% of the histological type was epithelioid. The most frequent adverse events (grades 1, 2 and 3) related to any of the combination drugs were liver enzymes increase, fatigue, decreased appetite, nausea, diarrhea and hypothyroidism. There were two cases of myocarditis, one of grade 3 (pembrolizumab related) and one of grade 5(pembrolizumab and nintedanib related). At the time of the data analysis the efficacy data shows six partial responses (overall response rate of 21%) and seventeen stable disease (disease control rate at 61%.).


      The combination of Nintedanib with Pembrolizumab shows promising activity in relapsed MPM patients .The toxicity profile appear consistent with previous reports of anti-angiogenic agents and immunotherapy combination.

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