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Clarissa Mathias



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    GR 02 - Management of Immunotherapy-Related Adverse Events (ID 521)

    • Event: WCLC 2017
    • Type: Grand Rounds
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      GR 02.04 - Current Standard in Monitoring of Immunotherapy-related Toxicity (ID 7632)

      11:00 - 12:30  |  Presenting Author(s): Clarissa Mathias

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Checkpoint protein inhibition is associated with on- and off-target, cell and metabolic toxic effects that need to be carefully monitored and managed during and after treatment[1]. Despite important clinical benefits, immunotherapy is associated with a unique spectrum of side effects termed immune-related adverse events (irAEs) or, occasionally, adverse events of special interest. IrAEs include dermatologic, gastrointestinal, hepatic, endocrine, and other less common inflammatory events. Most irAEs remain mild in intensity but approximately 10% of patients treated with immune checkpoint blockade agents will develop severe, sometimes life-threatening, grade 3–4 dysimmune toxicities. Before prescribing immune checkpoint blockade agents to patients, oncologists need to be aware of the toxicity spectrum and must identify potential risk factors that could favor the emergence of irAEs[2]. Patients should be informed that most of these irAEs are mild and reversible if detected early and specifically addressed. Therefore, patients should be educated about signs of organ inflammation that would require prompt referral such as diarrhea, blood or mucus in the stool, severe abdominal pain, fatigue, weight loss, nausea, vomiting, thirst or appetite increase, polyuria, extensive rash, severe pruritus, shortness of breath, coughing, headache, confusion, muscle weakness, numb-ness, arthralgia or swelling joints, myalgia, unexplained fever, hemorrhagic syndrome
and severe loss of vision in one or both eyes. Any new symptom or deterioration of pre-existing symptoms must at least be monitored attentively and if necessary be explored to determine its etiology and rule out any dysimmune cause that could be worsened by immunotherapy continuation. Although early recognition and treatment improves symptoms and severity, a broad differential diagnosis should be entertained. It is recommended that all patients receiving these agents routinely have thyroid function studies, complete blood counts, and liver function and metabolic panels at each treatment and at intervals of 6 to 12 weeks for the first 6 months after finishing treatment. Adrenocorticotropic hormone, cortisol, and in men, testosterone should also be checked in patients who develop fatigue and nonspecific symptoms. Follow-up testing may need to increase in frequency based on individual response and adverse events that occur[3]. It is challenging to differentiate between infection, early pulmonary edema, alveolar hemorrhage, immune-mediated pneumonitis, immune-related tumor inflammation, and tumor progression (figure 1). Infections, thromboembolism, congestive heart failure, and COPD are among the many diagnoses to consider before committing patients to a long course of steroid therapy with additional consideration of prophylaxis for opportunistic (i.e., pneumocystis with or without fungal) infections. Pulmonary specialty consultation and consideration of bronchoscopic evaluation with lavage to assess for infections alongside biopsies of lung tissue can help narrow the diagnosis. IrAEs can develop at any time: at the beginning, under treatment and after immunotherapy termination. As shown with nivolumab, the majority of irAEs occur within the first 4 months[4]. On the basis of this median time to onset, irAEs could be classified as early (median time to onset <2 months) and late toxicities (median time to onset >2 months). Early toxicities include skin (5 weeks), gastrointestinal (7.3 weeks) and hepatic (7.7 weeks), whereas late toxicities include pulmonary (8.9 weeks), endocrine (10.4 weeks) and renal (15.1 weeks). However, clinicians should keep in mind that all toxicities can develop at any time since confidence interval may vary widely among organs: 0.1–57 weeks for skin; 0.1–37.6 weeks for gastrointestinal. Rarely, other irAEs may occur after week 24 with any checkpoint-blocking antibodies. In trials including maintenance ipilimumab, colitis has been seen 47 months from initiation of treatment[5]. Patients with prior autoimmune diseases or a history of viral hepatitis have been excluded from receiving ipilimumab on trials, but recent data suggest that the drug can be given safely to those patients. Nonetheless, extreme caution should be taken in treating patients with recent or ongoing autoimmune conditions, particularly any type of inflammatory bowel disease[6]. Management algorithms have been established for patients treated with immunotherapy, which may be useful in helping to manage irAEs but they are based upon clinical experience, since no prospective trials have been conducted to guide the treatment of irAEs. Resolution of irAEs usually follows a temporal pattern: 2 weeks for gastrointestinal, 4 weeks for hepatic, 6 weeks for skin, and 20 weeks for endocrine irAEs[7]. The key to successful management of checkpoint protein antibody toxicities is early diagnosis, high suspicion, excellent patient-provider communication, and rapid and aggressive use of corticosteroids and other immune suppressants for irAEs. Effective biomarkers to predict toxicity could be valuable in the development of these agents. Figure 1 FIGURE 1: CT scan of a patient with non-small cell lung cancer presenting with cough, dyspnea, and hypoxia on an immunotherapy drug. References: Fecher LA, et al: Ipilimumab and its toxicities: A multidisciplinary approach. Oncologist 18:733-743, 2013 Champiat S. et al., Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper Annals of Oncology Volume 27, No. 4, 559-74, 2016 Weber JS et. al. Toxicities of Immunotherapy for the Practitioner, J of Clin Oncol., volume 33, No 18, 2092-2099, 2015 Weber JS et al. Safety profile of nivolumab (NIVO) in patients (pts) with advanced melanoma (MEL): a pooled analysis. J Clin Oncol 2015; 33 (suppl): abstr 9018 Sarnaik AA et al: Extended dose ipilimumab with a peptide vaccine: Immune corre- lates associated with clinical benefit in patients with resected high-risk stage IIIc/IV melanoma. Clin Cancer Res 17:896-906, 2011 Hodi FS, et al: Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: A randomized clinical trial. JAMA 312:1744-1753, 2014 Weber JS, et al. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691-2697



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    MA 17 - Locally Advanced NSCLC (ID 671)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Locally Advanced NSCLC
    • Presentations: 1
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      MA 17.09 - Discussant - MA 17.06, MA 17.07, MA 17.08 (ID 10794)

      15:45 - 17:30  |  Presenting Author(s): Clarissa Mathias

      • Abstract
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      Abstract not provided

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    P1.01 - Advanced NSCLC (ID 757)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P1.01-043 - Molecular Testing for Non-Small Cell Lung Cancer in Latin American (ID 10391)

      09:30 - 16:00  |  Author(s): Clarissa Mathias

      • Abstract
      • Slides

      Background:
      According to IALSC/CAP guidelines EGFR and ALK testing is recommended for all non-squamous advanced lung cancers. However, the real access to molecular test and treatment, especially in LATAN is unknown.

      Method:
      We conducted an online survey with medical oncologists from LATAN during May 2017. The survey has 20 questions about molecular test and target treatment, but also clinical practice in the management of advanced non-squamous NSCLC.

      Result:
      144 oncologists from 10 countries answer the survey, mostly of them (75%) from Brazil. Although 95% of the oncologists have access to EGFR mutation test and most of them can also test the ALK-fusion protein, only half of them test all patients. Usually these tests are supplied by the pharmaceutical industries (75% of EGFR and 78% of ALK). The mutation status are available in 2 weeks for the EGFR and in 3 weeks for the ALK. The main reason for not testing is lack of sufficient tissue (30% of oncologists), but also some difficulty in access and the long turn-around time where also an issue, 20% and 13% of the oncologist, respectively. Poor performance status and patient clinical characteristics were rarely considered a reason for not testing. Target therapy is available for mostly of the patients with private insurance, but only 50% in the public heath system have access to an anti-EGFR TKI and solely 20% can receive an anti-ALK TKI. New biopsies should be done in the progressive disease, but only 22% of the oncologists perform the procedure in more than 75% of their patient. Immunotherapy is a new treatment modality, especially in the develop countries, but it should be restricted as first line treatment to patients with high expression of PD-L1. In LATAN, immune checkpoints blockage is almost limited to the patients with private insurance (85%), being rare in the public heath system (15%). 83% of the oncologist considered to test the PD-L1 expression only after the results of EGFR /ALK are available.

      Conclusion:
      There are difficulties in the implementation of IALSC guidelines in LATAN. Mostly of the patients have access to EGFR mutation test, however the treatment is not available to everyone. It is clear the importance of the pharmaceutical industries in providing the molecular test by their voucher programs. The most important difficulty point out by the oncologists is the lack of tissue, but simple barriers as long time to get the results and access to the test should also be managed.

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