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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: 4
    • Now Available
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      GR02.01 - How Can We Incorporate Exercise Practices into Patient's Lives? (Now Available) (ID 3304)

      15:15 - 16:45  |  Presenting Author(s): Clarissa Mathias

      • Abstract
      • Presentation
      • Slides

      Abstract

      Physical activity is any movement using skeletal muscles. There have been over 16 studies examining physical activity and lung cancer risk, 12 cohorts and four case-control studies have examined the association between physical activity and lung cancer. When stratifying by study design, the pooled risk reduction amongst the 12 cohort studies is 23%, and amongst 4 case-control studies, a pooled risk reduction of 38%1. Among In a meta-analysis of 11 studies comparing highest versus and lowest levels of leisure-time physical activity, including odds ratios from studies in which the association between physical activity and cancer prevention was adjusted for smoking intensity: moderate-intensity physical activity was associated with a statistically significant risk reduction in lung cancer incidence, OR=0.87 (95% CI: 0.79–0.95), and vigorous-intensity physical activity was associated with a statistically significant risk reduction in lung cancer incidence, OR=0.70 (95% CI: 0.62–0.79).

      During exercise, particularly moderate-intensity aerobic exercise, T-cell populations transiently, NK cell populations and activity, and neutrophil quantity and activity transiently rise2. Exercise or physical activity haves a profound effect on macrophage physiology, including phagocytosis, chemotaxis, metabolism and anti-tumor activity. In murine models of acute exercise, peritoneal macrophage phagocytosis was increased in vitro, relative as opposed to sedentary conditions3. Although these effects are transient during an acute bout of exercise, the repetitive effects may produce a cumulative (training) effect. Chronic bouts of physical activity have been associated with an inverted ‘J-curve’ such that optimal immune function is achieved with moderate-intensity physical activity and sedentary and vigorous-intensity below optimal immune-system function.

      Physical activity is also a useful adjunct to improve the deleterious sequelae experienced during cancer treatment including fatigue, muscular weakness, deteriorated functional capacity, and many others. There is a growing base of evidence that suggests engaging in exercise, such as brisk walking, yields fewer symptoms and side effects during treatment and retards delays the rate at which physiologic systems are affected4. The mechanistic models hypothesized that includes pathways relating to sex hormones, metabolic hormones, inflammation and adiposity, immune function, oxidative stress, DNA repair, and xenobiotic enzyme systems. During cancer treatment, deconditioning of the cardiovascular and pulmonary system is common and is associated with diminished levels tolerance to of physical activity. However, it appears that the adaptive capacity of the cardiorespiratory system to exercise training remains intact during treatment. Among In a meta-analysis of 17 high-quality studies, aerobic fitness—a marker of cardiorespiratory function—improved significantly in cancer survivors during treatment over the exercise intervention period. Muscle Ffatigue and muscle weakness are also common sequelae of cancer treatment, but may be amenable to exercise training. A meta-analysis of randomized controlled trials concluded that both upper body and lower body strength improve as a result of exercise training during cancer treatment, with d=0.39 (95% CI: 0.12–0.65), and d=0.24 (95% CI: 0.07–0.41), respectively5. Strength improvements in the absence of muscle hypertrophy suggest that the adaptations resulting from strength training may be largely attributable to neural adaptations from better motor unit activation (recruitment, discharge rate), synchronization, and cross education. Neural adaptations occur early on in aduring a strength training program and may explain strength improvements in most short-term training studies. Mmoderate intensity activity may optimize immune activity and promote an anti-inflammatory state. Several biomarkers of immunologic function and inflammation exist including neutrophil and lymphocyte counts, natural killer cell activity, C-reactive protein, IL-6, IL-10, and TNF- alpha. It remains unclear what benefits exercise may have on immune system function after cancer treatment6.

      Despite the large volume of studies examining muscular strength among cancer survivors during treatment, few studies have examined the role of strength training among those with cancer cachexia7. It is interesting, Interestingly, given the success of resistance training among cancer survivors, to increaseincreasing upper and lower body strength that use of this modality among cancer survivors with cachexia is not more commonly studied.

      Despite the favorable profile of physical activity along the cancer continuum, many research gaps still exist. Elucidating the optimal dose of physical activity necessary to maximize the reduction in cancer risk of cancer and the optimal dose of physical activity necessary to improve specific physiologic systems, or treatment-specific side effects is warranted. In July 2010, an expert panel from the American College of Sports Medicine reviewed current studies of exercise training and cancer survivorship and released a roundtable consensus statement, concluding that exercise training is “safe during and after cancer treatments and results in improvements in physical functioning, quality of life, and cancer-related fatigue”8.

      Incorporation of exercise practices should, therefore, be advised and stimulated to prevent lung cancer, decrease treatment related side effects, rehabilitate survivors and possibly help during the cachexia period. Interaction between medical oncologists, thoracic surgeons, pulmonologists, physical therapist and sports medicine experts is mandatory for an optimal design of needed trials that will answer several opened questions related to this topic.

      References

      1. Emaus A et al. Physical activity and lung cancer prevention. Recent Results Cancer Res. 2011; 186:101–133

      2. Shephard RJ et al. Effects of exercise and training on natural killer cell counts and cytolytic activity: a meta-analysis. Sports Med. 1999; 28(3):177–195

      3.Woods JA, et al. Exercise-induced modulation of macrophage function. Immunol Cell Biol 78: 543-553, 2000

      4. Schmitz KH, et al. American college of sports medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc. 2010; 42(7):1409–1426

      5. Speck RM, et al. An update of controlled physical activity trials in cancer survivors: a systematic review and meta-analysis. J Cancer Surviv. 2010; 4(2):87–100

      6. McTiernan A. Mechanisms linking physical activity with cancer. Nat Rev Cancer. 2008; 8(3): 205–211

      7. Bossola M, et al. Cancer cachexia: it’s time for more clinical trials. Ann Surg Oncol. 2007

      8. Schmidt KH, et al. American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc 42: 1409-1426, 2010

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      GR02.02 - What is the Best Management of Targeted Therapy Toxicity? (Now Available) (ID 3305)

      15:15 - 16:45  |  Presenting Author(s): Glenwood D. Goss

      • Abstract
      • Presentation
      • Slides

      Abstract

      GR02.02 - What Is the Best Management of Targeted Therapy Toxicity?

      15:35 - 15:55 | Presenting Author(s): Glenwood D. Goss

      Over the past decade, the discovery of oncogenic driver mutations in NSCLC and the subsequent advent of targeted therapies against these genomic alterations have significantly altered the management of adenocarcinoma of the lung for a significant proportion of patients. While most oncogenic driver mutations are rare, some exist in up to 50% of specific demographic groups, and together, oncogene-driven disease represents the majority of adenocarcinoma cases (1). Targeted therapies permit directed anti-neoplastic efficacy, with less systemic adverse events than chemotherapy. However, these agents are not without their own unique toxicities that must be managed for optimal drug compliance and therapeutic benefit. This talk will focus on the management of toxicities resulting from the targeting of aberrant pathways and common driver mutations in adenocarcinoma of the lung.

      We define targeted agents as pharmaceutical interventions directed specifically at one or more of the actionable genomic alterations that result in oncogenic phenotypes (proteins, signalling, etc.). Given the breadth of agents to be tested in this indication, the primary focus of the talk will be on approved (versus experimental) and commonly used agents, including small molecules and antibodies, but not antibody-drug conjugates. Genomic alterations to be addressed include at minimum the ERBB family of genes, KRAS, ALK, ROS-1, PI3K, VEGF and BRAF.

      For each agent directed against one of these aforementioned alterations, we will approach management of toxicity by contrasting the normal function of the pathway with adverse events associated with inhibition of this pathway. The management of the most frequent and serious adverse events of the pathway blockade will be the focus of the presentation.

      In conclusion, targeted therapies have had a profound impact on progression-free survival in a significant proportion of patients with metastatic adenocarcinoma of the lung, however they can be associated with a unique set of significant toxicities. The appropriate management of these toxicities may often determine whether a patient derives benefit or not from a targeted therapy, as toxicities can impact dose, frequency of delivery and compliance. Moving forward, increasing the specificity of targeted genomic alteration blockade is required to limit unwanted effects on wild-type proteins. The future of targeted therapy mandates that we devise newer agents with minimal toxicity.

      1. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014 Jul 31;511(7511):543–50.

      2. Kowanetz M. Vascular Endothelial Growth Factor Signaling Pathways: Therapeutic Perspective. Clin Cancer Res. 2006 Sep 1;12(17):5018–22.

      f1_sml.pngf2_sml.jpg

      Image 1: known (red) and putative (blue) driver mutations in adenocarcinoma of the lung, TGCA sample (1)

      Image 2: VEGF signaling in cancer and targets of inhibition.(2)

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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

      Abstract

      Introduction.

      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)

      Results.

      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).

      diapositive1.jpg

      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.

      Conclusion.

      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

      References.

      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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      GR02.04 - Immunotherapy: Hyperprogression and Treatment Beyond Progression (Now Available) (ID 3307)

      15:15 - 16:45  |  Presenting Author(s): David R Gandara

      • Abstract
      • Presentation
      • Slides

      Abstract

      Hyperprogression/Fast Progression and Treatment Beyond Progression: Unresolved Issues with Checkpoint Immunotherapy

      David R Gandara, MD

      University of California, Davis Comprehensive Cancer Center

      Sacramento, CA

      The tidal wave of checkpoint immunotherapy (CPI) over the last few years has both opened up a myriad of new treatment options for patients with lung cancer. There are many unique aspects of these PD-1- and PD-L1-directed therapies, turning oncologists into both immunologists and endocrinologists, to better manage a large variety of immune related adverse events. This presentation with address two other aspects of CPI which currently remain both poorly understood and controversial: Hyperprogression/Fast Progression and Treatment Beyond Progression.

      Hyperprogression/Fast Progression (HPD/FP): A phenomenon of accelerated tumor growth, termed hyperprogressive disease (HPD), has been reported in patients receiving checkpoint inhibitor therapy. HPD has been defined as a ≥ 2-fold increase in tumor growth rate (TGR) from baseline to first evaluation, by comparison with pre-treatment Alternate criteria describing rapid progression on CPI therapy have also been described. Whether HPD is unique to CPI remains unclear, as do associated predictive factors. We developed an alternative approach termed fast progression (FP), in order to study this phenomenon retrospectively in prior Phase III trials of CPI. In addition to CT-confirmed rapid early tumor growth, FP includes early death due to PD from cancer. Using these FP criteria, we analyzed data from the Phase III OAK study, demonstrating equivalent rates of FP with atezolizumab versus docetaxel. However more patients met criteria for FP by TGR increase with atezolizumab. Further, FP was not associated with previously reported predictive factors. This presentation will update those results as well as other new data regarding the HPD/FP phenomenon.

      Treatment Beyond Progression (TBP): Cancer immunotherapy may alter tumor biology such that treatment effects can extend beyond radiographic progression. This effect explains the discordance between relatively modest response rate/progression free survival and more impressive overall survival in multiple CPI trials in advanced NSCLC. Presumptive benefit of TBP with CPI therapy has been observed in multiple tumor types including melanoma, renal cancer and NSCLC, leading the FDA to call for randomized trials designed to study this phenomenon. We studied TBP in the Phase III OAK trial of atezolizumab versus docetaxel, and reported that post-PD efficacy was consistent with a positive benefit-risk profile of atezolizumab TBP in patients performing well clinically at the time of PD. INSIGNA, a recently activated joint ECOG-SWOG Phase III study, is the first prospective trial to include an arm evaluating TBP. This presentation will discuss the biologic rationale for TBP with CPIs and detail other recently published data.

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