Virtual Library

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    IS09 - Symposium by Physicians' Education Resource, LLC (PER): Leveraging The Lung Cancer Team In Stage III NSCLC With Immuno-Oncology Strategies (Not IASLC CME Accredited) (ID 373)

    • Event: WCLC 2019
    • Type: Industry Symposia & Workshops
    • Track:
    • Presentations: 0
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    IS14 - Symposium by PeerVoice: Paving The Way To Better Outcomes In EGFR-Mutant NSCLC: Time To Take A Step Further? (Not IASLC CME Accredited) (ID 383)

    • Event: WCLC 2019
    • Type: Industry Symposia & Workshops
    • Track:
    • Presentations: 0
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    IS17 - Symposium by MSD: Prioritizing Lung Cancer: Strengthening Public Policy Responses To Unmet Needs (Not IASLC CME Accredited) (ID 381)

    • Event: WCLC 2019
    • Type: Industry Symposia & Workshops
    • Track:
    • Presentations: 0
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    IS18 - Symposium by MSD: Redefining Survival Expectations In Lung Cancer (Not IASLC CME Accredited) (ID 382)

    • Event: WCLC 2019
    • Type: Industry Symposia & Workshops
    • Track:
    • Presentations: 0
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    OC01 - Opening Ceremony (ID 82)

    • Event: WCLC 2019
    • Type: Opening Ceremony
    • Track:
    • Presentations: 3
    • Now Available
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      OC01.01 - Welcome Addresses (Now Available) (ID 3551)

      19:00 - 20:30  |  Presenting Author(s): Ramon Rami-Porta, Enriqueta Felip, Antoni Rosell, Giorgio Vittorio Scagliotti, Dave Mesko

      • Abstract
      • Presentation

      Abstract not provided

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      OC01.02 - IASLC Distinguished Awards (Now Available) (ID 3553)

      19:00 - 20:30  |  Presenting Author(s): Giorgio Vittorio Scagliotti  |  Author(s): David P Carbone, Tetsuya Mitsudomi, Heather A Wakelee

      • Abstract
      • Presentation

      Abstract not provided

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      OC01.03 - Conference Presidents Announce New Things at WCLC 2019 (Now Available) (ID 3554)

      19:00 - 20:30  |  Presenting Author(s): Ramon Rami-Porta, Enriqueta Felip, Antoni Rosell

      • Abstract
      • Presentation

      Abstract not provided

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    PL01 - New Questions with Imaginative Answers (ID 88)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track: Advanced NSCLC
    • Presentations: 4
    • Now Available
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      PL01.01 - Tumor-Agnostic Biologically Driven Treatments: An Endless Dream? (Now Available) (ID 3580)

      08:15 - 09:45  |  Presenting Author(s): Robert C. Doebele

      • Abstract
      • Presentation
      • Slides

      Abstract

      The identification of several oncogenes in non-small cell lung cancer (NSCLC) along with the development of cognate, targeted tyrosine kinase inhibitors (TKIs) has revolutionized the treatment approach for patients with this disease. Several oncogene targets have been successfully deployed in other malignancies, including melanoma (BRAF), GIST (KIT), CML (BCR-ABL) and other malignancies. However, until recently, the conventional wisdom has said that targeted therapies will not have similar efficacy for the same class of oncogenes across different tumor histologies. This point of view was likely largely grounded in two perceptions: 1) certain oncogenes are heavily associated with certain tumor histologies (e.g., BCR-ABL in CML or EGFR in NSCLC) and 2) based on the differential activity of BRAF/MEK inhibition in melanoma compared to colorectal cancers (CRC) harboring BRAF V600E mutations. Since then, BRAF +/- MEK inhibition has demonstrated remarkable response rates in NSCLC, anaplastic thyroid cancer, and hairy cell leukemia suggesting that CRC may be the exception rather than the rule. In 2012, we identified the first NTRK1 fusion in NSCLC,1 and while prior reports of NTRK gene fusions existed,2 there were no therapies developed for this oncogene. Preclinical in vitro and in vivo models suggested that ATP-competitive inhibitors had activity irrespective of NTRK1/2/3 gene (TRKA/B/C kinases) and also irrespective of tumor histology.3 Clinical trial data with the two lead TRK inhibitors, larotrectinib4 and entrectinib,5 confirmed both of these preclinical findings of activity in NTRK1/2/3 across tumor histologies, validating the concept of tumor (or tissue) agnostic therapeutic strategies in cancer. Similar to NTRK gene fusions, ALK, ROS1 and RET gene fusions have not only been identified in NSCLC, but also in other tumor histologies. Clinical data suggest similar opportunities for these oncogene targets. For examples, entrectinib generated a robust and durable response in a patient with GOPC-ROS1 fusion melanoma6 and similar responses have been noted in ROS1 fusion IMT.7 Basket clinical trials of ROS1 inhibitors are now ongoing. RET gene fusions are targetable alterations in NSCLC as well as other malignancies, and now improved, highly RET-selective inhibitors under development with encouraging activity.8 NRG1 gene fusions represent another opportunity for a tumor agnostic development. Although first described in NSCLC (specifically, invasive mucinous adenocarcinomas),9 these novel fusion genes that signal via HER2/HER3 heterodimers have been described across numerous tumor types, including pancreatic, ovarian, and other cancers, albeit at a low estimated frequency of 0.2%.10 This low frequency is a common reason cited to not pursue such strategies, but given the immense heterogeneity of cancer it is likely that we will further fragment cancer types based on their underlying biology. Additional tumor agnostic targets include ALK gene fusions, HER2 mutations, EGFR mutations (including exon 20 insertions), FGFR1/2/3 fusions, BRAF fusions, MET (exon 14 skipping, gene amplification, and fusions), and others. Indeed, several KRAS mutant selective inhibitors are under development and may open the flood gates for tumor agnostic trials given the frequency of mutations in this oncogene. Success of tumor agnostic strategies will be dictated by appropriate biomarker selection, which may differ for each tumor types, robust testing methods that capture the majority of oncogenic variants (NRG1 is a good example that is not currently covered on many assays), and implementation of panel-based next generation sequencing applications in more routine practice. While it is likely that we already have the testing capability and even the appropriate drugs to to target these tumor agnostic oncogenes, infrastructure changes at institutions may need to be enacted to allow for clinical trial teams that enroll from many disease types, similar to existing phase I teams. The NSCLC community of oncologists, researchers, pathologists, patient advocates, and commercial partners has had immense success in realizing the dream of precision oncology strategies and can lead the way to distribute the knowledge gained over the last decade in precision oncology strategies.tumor agnostic.png

      References

      1. Vaishnavi A, Capelletti M, Le AT, et al: Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med 19:1469-1472, 2013

      2. Vaishnavi A, Le AT, Doebele RC: TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov 5:25-34, 2015

      3. Doebele RC, Davis LE, Vaishnavi A, et al: An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101. Cancer Discov 5:1049-57, 2015

      4. Drilon A, Laetsch TW, Kummar S, et al: Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med 378:731-739, 2018

      5. Drilon A, Siena S, Ou SI, et al: Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1). Cancer Discov 7:400-409, 2017

      6. Couts KL, McCoach CE, Murphy D, et al: Acral Lentiginous Melanoma Harboring a ROS1 Gene Fusion With Clinical Response to Entrectinib. JCO Precision Oncology:1-7, 2017

      7. Lovly CM, Gupta A, Lipson D, et al: Inflammatory myofibroblastic tumors harbor multiple potentially actionable kinase fusions. Cancer Discov 4:889-95, 2014

      8. Subbiah V, Gainor JF, Rahal R, et al: Precision Targeted Therapy with BLU-667 for RET-Driven Cancers. Cancer Discov 8:836-849, 2018

      9. Fernandez-Cuesta L, Plenker D, Osada H, et al: CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov 4:415-22, 2014

      10. Jonna S, Feldman RA, Swensen J, et al: Detection of NRG1 Gene Fusions in Solid Tumors. Clin Cancer Res, 2019

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      PL01.02 - The Evolution of Tissue Testing for Immunotherapy - Where Next? (Now Available) (ID 3581)

      08:15 - 09:45  |  Presenting Author(s): Keith Kerr

      • Abstract
      • Presentation
      • Slides

      Abstract

      Biomarkers have, to date, had an uneasy relationship with immunotherapy in lung cancer, a conflict between the degree of biomarker expression (largely PD-L1) being related to treatment efficacy, and a desire to give these drugs to everyone, either as monotherapy or, increasingly, in combination with other drugs. PD-L1 immunohistochemistry (IHC) is well established as a companion or complementary diagnostic, depending on indication, and tumour mutational burden (TMB) is an item of interest, with a surrogate, MSI-high, approved by the FDA in a tumour-type agnostic setting for second/greater line therapy.

      Where is PD-L1 testing going?

      PD-L1 IHC will remain a useful test. PD-L1 IHC scoring in cytology-type samples has been validated outside clinical trials and will become accepted in daily practice. New IHC clones will challenge the place of existing ones, hopefully validated by comparative study and EQA. Data are emerging on the clinical validity of PD-L1 scoring on small amounts of tumour (the heterogeneity issue), how few cells can be used, and the clinical impact of scoring PD-L1 on insufficient material.

      Tumour Mutational Burden

      Difficulties with the PD-L1 IHC biomarker drove the search for alternatives and TMB, as a several times removed surrogate of tumour immunogenicity, emerged. The place for TMB in the diagnostic algorithm remains uncertain but clinical trials looking at tumour tissue or blood TMB continue to provide promising, if confusing, results. Many of the issues with PD-L1 IHC are also in play with TMB. There is no consensus about what is ‘high TMB’? TMB is another biological continuum, like PD-L1 expression, so the creation of a binary high vs low categorization potentially ignores relative biological significance of different levels. There is huge variability in the methodology used to derive or predict TMB, the amount of the genome screened, different definitions of a ‘mutation’, different next generation sequencing platforms, different contexts (tumour tissue vs blood) and a lack of published data on how these different TMB assessment approaches vary. Anecdotal reports so far indicate substantial variation.

      As a predictive biomarker in this setting, TMB works; it enriches a treatment group for benefit. But we have seen relatively little comparative data to suggest superiority over any other singular biomarker in this treatment area. TMB is a crude predictor of tumour neo-antigenicity and perhaps we should look to more specific measures of this aspect of sensitivity to immunotherapy. It is possible to predict probable neo-antigenicity from deep analysis of sequencing data. Neo-antigens should be clonal, rather than subclonal, to maximize their immune impact. Are their particular genes whose alteration would predict greater (or lesser) tumour ‘visbility’ to the immune system, be they involved in DNA repair, maintaining genome stability or integrity, antigen processing and presentation, or more likely to generate immunogenic proteins? Other factors such as loss of heterozygosity at MHC coding genes may also provide useful information.

      So, it may well be possible to refine our assessment of TMB into a more specific and meaningful metric. This then raises the question of whether it is practical to do so, and whether this provides clinically useful information.

      Tumour inflammation

      For immune checkpoint inhibitors (ICI) to work, a tumour specific immune response must be ‘available’ and somehow inhibited by the checkpoints being therapeutically targeted. Assessments of tumour inflammation, as a presumptive sign of such an available but inhibited immune response, have been successfully used to enrich a treatment group for benefit from ICI therapy. In lung cancer, these assessments of inflammation have been relatively complex assays of immune gene signature expression using mRNA extracted for fresh/frozen tumour tissue. Initially large panels of immune response-related genes have been reduced to single digit-sized panels. Interferon gamma seems to be important as is, unsurprisingly, PD-L1.

      The same questions arise with respect to immune gene signatures. Is this any better than a more simplistic approach such as PD-L1 IHC? Evidence is at best marginal, that it would be superior. Is this practical and affordable in a daily practice setting? Probably not. Are there alternative ways to derive the same information? Probably yes. In other tumour sites, a morphological assessment of tumour inflammation has been more keenly pursued than in lung cancer. This approach has tended to focus on the presence and location of the immune cell infiltrate and to some extent, on the nature of the infiltrating cells. When tumour sample area allows, immune cell activity at the tumour-stromal interface, and the presence of CD8-expressing T cells have been associated with better responses to ICI. There is much more that could be investigated, especially in relation to other immune-active or immune-suppressive cell types and their location within the tumour and its microenvironment (TME). Immunohistochemistry is readily available, but in order to understand the complexity of this process and find new biomarkers, in limited tissue samples, multiplex IHC and digital pathology analysis tools will almost certainly be required. These tools already exist but the challenge will be generating the data in relation to clinical response and then deployment in daily practice.

      Other regulation in the TME

      Other factors in the TME, such as tissue hypoxia and lactate dehydrogenase, are relevant biomarkers, indicating an immune-suppressive environment, and potential resistance to ICI therapy. Other factors like IDO, and other immune checkpoints like LAG3 and TIM3 may also confer resistance to current ICI therapy and provide new therapeutic targets.

      Conclusion

      There is much more to be learned about factors that regulate responsiveness to ICI therapy. The multifactorial complexity of the immune response suggests that combinations of biomarkers are more likely to provide better prediction of therapeutic benefit. Many of these factors are more likely to be continuous variables rather than binary metrics, and oncology will have to learn to deal with this situation, perhaps more akin to a complementary rather than a companion diagnostic, leading to more nuanced therapeutic decisions. It remains to be seen whether oncology, regulatory authorities or industry has an appetite for such an approach.

      References

      Blank CU et al. Science 2016;352,658

      Camidge DR et al. Nat Rev Clin Oncol 2019;16,341

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      PL01.03 - Will the Immunotherapy with Newer Biomarkers, Combination Therapy or New Technology Eventually Cure Lung Cancer? (Now Available) (ID 3582)

      08:15 - 09:45  |  Presenting Author(s): Tetsuya Mitsudomi

      • Abstract
      • Presentation
      • Slides

      Abstract

      The recent introduction of immune checkpoint therapy has greatly changed the clinical practice of non-small cell lung cancer (NSCLC). A battery of clinical trials showed the superiority of either PD-1 antibody monotherapy or PD-1/L1 antibody combined with chemotherapy as a first-line treatment of NSCLC over standard platinum doublet chemotherapy that has long been a standard of care. Hence, most if not all of NSCLC patients receive PD-1/L1 antibodies unless contraindicated due to coexisting immune-related comorbidities.

      The recent update of the Keynote-001 trial showed that 5-year survival of the high expressors of PD-L1 treated with pembrolizumab as a first-line treatment was 23%. Especially, the 5-year survival rate of patients who received the first-line pembrolizumab more than 2 years was 79%. This really indicates that at least some of the NSCLC patients may be cured by monotherapy of PD-1 antibodies.

      Conversely, about three fourth of patients, even with high expression of PD-L1 cannot survive for more than 5 years. This is natural considering the complexity of immunologic mechanisms against cancer. To be eliminated effectively by PD-1/L1 treatment, cancers should express their unique antigens typically generated by somatic mutations in the context of MHC. Therefore, the adequate quantity as well as the adequate quality of somatic mutations and intact antigen presentation, are prerequisite for immune response. When abnormal peptide is recognized by immune cells, adaptive expression of PD-L1 on the tumor cells occurs by secretion of interferon γ by T cells as a negative feedback that dampens antitumor immunity, Upon binding of PD-L1 with PD-1 on T cells downregulates T cell function. This tumor microenvironment (TME) is the best candidate for anti-PD-1/PD-L1 therapy. However, not all cancer has this TME. Besides PD-1/L1 systems, there are many other molecules such as CTLA4, TIGIT, TIM3, LAG3, etc. that negatively regulate the immune response. Regulatory T cells and myeloid-derived suppressor cells (MDSC) are also major players of immunosuppressive TME

      To overcome these immunologic evasions, many strategies are being extensively sought. To enhance immune recognition of mutations and to prime new response, polypeptide or RNA-based vaccines that contain mutation-derived epitopes are being tested. For tumor cells that lost HLA molecules, enhancement of NK cell activities through NKG2A antibody or anti KIR antibody may be effective. To overcome adaptive immune resistance by molecules other that PD-1, use of blocking antibodies against above-mentioned other co-inhibitory molecules or agonistic antibodies against co-stimulatory molecules such as ICOS, GITR, 4-1BB, OX40, etc. is a rational way. Finally, to reverse immune suppressive TME, use of antibodies against CSF-1R and CCR4 to suppress MDSC and regulatory T cells, respectively, may be effective. Antagonists for immunosuppressive molecules such as adenosine A2AR, IDO, TGFb, etc are also expected to enhance tumor immunity.

      Will the Immunotherapy eventually cure lung cancer? Currently, I have to say "Yes, for some but not sure for every patient". In this talk, I would like to discuss ongoing efforts to further improve outcomes of immune-therapy of lung cancer and future perspectives.

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      PL01.04 - Artificial Intelligence, Big Data and Lung Cancer: Ready to Implement? (Now Available) (ID 3583)

      08:15 - 09:45  |  Presenting Author(s): Hugo Aerts

      • Abstract
      • Presentation
      • Slides

      Abstract

      A critical barrier present in cancer research and treatment today is when and how to act based on the information provided from tumor data. One important reason for the slow progress in the fight against cancer, is the fact that cancer is a “moving target”. It is constantly evolving and diversifying, changing its phenotype, its genomic composition, and through metastatic spread, even its location. This is even more true when subjected to the pressure of therapeutic intervention, where cancer evolution rapidly explores and exploits resistance mechanisms, potentially even aided by the mutagenic nature of cancer treatments, leaving the treating oncologist chasing a constantly changing disease.

      Artificial Intelligence (AI) and Deep Learning technologies have recently led to revolutionary advances in areas ranging from computer vision to speech recognition - tasks that up to a few years ago could only be done by humans. AI has the potential to fundamentally alter the way medicine is practiced, as it excels in recognizing complex patterns in medical data and provides a quantitative, rather than qualitative, assessment of clinical conditions. AI-powered radiographic-biomarkers (“radiomics”) may quantify non-invasive information of the cancer phenotype that is clinically actionable, and may further improve diagnosis, characterization, and longitudinal tracking through therapy. AI methods are precise and allow specific quantification of features not otherwise quantifiable by human experts. Radiomic-analysis is performed on the entire tumor as compared to just a small sample for molecular analysis and provides a non-invasive window into internal growth pattern of the tumor (including internal textural heterogeneity, macroscopic necrosis, and viable tumor mass). Radiomics can thus quantify the phenotypic state of a tumor within its evolutionary process, thereby sidestepping issues relating to biopsies.

      This is particularly important for patients with cancer, where different cancer lesions can express different microenvironments that could ultimately lead to heterogeneous response patterns. Despite the remarkable success of novel cancer therapies, the clinical benefit remains limited to a subset. Cancer therapies are often expensive and could bring unnecessary toxicity, there is a direct need to identify beneficial patients, but this remains difficult in the clinic today. Radiomics biomarkers could provide this information on a lesion and patient level using standard-of-care CT scans. Unlike biopsy assays that - by definition - only represent a sample within the tumor, imaging can depict a full picture of the entire tumor burden, providing information of each cancer lesion within a single non-invasive examination.

      Another field that will be impacted by AI and big data is radiation oncology. Radiation oncology as a therapeutic specialty presents itself as an exemplary field that will be impacted by AI automation. Especially as much of the current radiation therapy work flow requires time-consuming, manual labor by both radiation oncologists and a team of medical staff including medical physicists, certified medical dosimetrists, and radiation therapists. The growing complexity of the human-machine and human-software interactions in conjunction with the increasing incidences of cancer have created a workforce shortage throughout the world. In fact, variations in the radiation treatment planning process can lead to significant differences in the quality of care, and negatively impact overall survival even in clinical settings where extra care is given to standardizing segmentation and planning approaches. Furthermore, the knowledge and experience gap between more developed and under-resourced health care environments poses an enormous public health challenge and represents one of the great global inequities in cancer care.

      In this talk, Dr. Aerts will discuss recent developments from his group and collaborators performing research at the intersection of artificial intelligence big data, and oncology. Also, he will discuss recent work of building a computational image analysis system to extract deep learning algorithms and use these to build radiomic signatures. The presentation will conclude with a discussion of future work on building integrative systems incorporating both molecular and phenotypic data to improve cancer therapies.

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    PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track:
    • Presentations: 11
    • Now Available
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      PL02.02 - Lung Cancer Screenee Selection by USPSTF Versus PLCOm2012 Criteria – Interim ILST Findings (Now Available) (ID 2804)

      08:00 - 10:15  |  Presenting Author(s): Stephen Lam  |  Author(s): Renelle Myers, Mamta Ruparel, Sukhinder Kaur Atkar-Khattra, Emily Stone, Renne Manser, Annette Maree McWilliams, Paul Fogarty, David CL Lam, John Yee, John Mayo, Christine Dorothy Berg, Sam Janes, Kwun M Fong, Martin Tammemagi

      • Abstract
      • Presentation
      • Slides

      Background

      The National Lung Screening Trial showed that lung cancer screening of high-risk individuals with low dose computed tomography can reduce lung cancer mortality by 20%. Critically important is enrolling high-risk individuals. Most current guidelines including the United States Preventive Services Task Force (USPSTF) and Center for Medicare and Medicaid Services (CMS) recommend screening using variants of the NLST eligibility criteria: smoking ≥30 pack-years, smoking within 15 years, and age 55-80 and 55-77 years. Many studies indicate that using accurate risk prediction models is superior for selecting individuals for screening, but these findings are based on retrospective analyses. The International Lung Screen Trial (ILST) was implemented to prospectively identify which approach is superior.

      Method

      ILST is a multi-centred trial enrolling 4000 participants. Individuals will be offered screening if they are USPSTF criteria positive or have PLCOm2012 model 6-year risk ≥1.5%. Participants will receive two annual screens and will be followed for six years for lung cancer outcomes. Individuals not qualifying by either criteria will not be offered screening, but samples of them will be followed for lung cancer outcomes. Outcomes in discordant groups, USPSTF+ve/PLCOm2012-ve and PLCOm2012+ve/USPSTF-ve, are informative. Numbers of lung cancers and individuals enrolled, sensitivity, specificity and positive predictive values (PPV) of the two criteria will be compared.

      Result

      As of March 2019, ILST centers in Canada (British Columbia), Australia, Hong Kong, and the United Kingdom had enrolled and scanned 3673 individuals. Study results are summarized in Figure 1.

      presentation5.jpg

      Conclusion

      Interim analysis of ILST data, indicates that classification accuracy of lung cancer screening outcomes support the PLCOm2012 criteria over the USPSTF criteria. The PLCOm2012 criteria detected significantly more lung cancers. Individuals who are USPSTF+ve and PLCOm2012-ve appear to be at such low baseline risk (0.2%) that they may be unlikely to benefit from screening.

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      PL02.03 - Early Detection of Cancer of the Lung Scotland (ECLS): Trial Results (Now Available) (ID 557)

      08:00 - 10:15  |  Presenting Author(s): Frank Sullivan  |  Author(s): Stuart Schembri

      • Abstract
      • Presentation
      • Slides

      Background

      Scotland has one of the highest rates of lung cancer in the world -- 460 men and 340 women in 100 000 are diagnosed with lung cancer every year. In the UK, survival from lung cancer is poor with less than 9% of patients still alive at five years after diagnosis, due primarily to the late stage of presentation. The EarlyCDT®-Lung Test is a novel Autoantibody(AAB) diagnostic test for the early detection of lung cancer allowing stratification of individuals according to their risk of developing lung cancer. The Test measures seven AABs; p53, NYESO-1, CAGE, GBU4-5, HuD, MAGE A4 & SOX2. It identifies 41% of lung cancers with a high specificity of 90%. This compares to CT scanning, which when used
      alone as a prevalence screening test, identifies 67% of lung cancers developing over the following 12 months, but has a low specificity of around 49%. The autoantibodies detected in the test have not been shown to vary with age, gender and ethnicity. The primary research question is: ‘Does using the EarlyCDT®-Lung Test, followed by X-ray and CT scanning, to identify those at high risk of lung cancer reduce the incidence of patients with late-stage lung cancer (III & IV) or unclassified presentation (U) at diagnosis, compared to standard clinical practice?’

      Method

      An RCT in 12,208 participants

      Participants
      Asymptomatic adults aged 50 to 75 who had a high risk of developing lung cancer over the next 24 months were eligible to participate. 5 290/12 209 (43.3%) of the subjects lived in the most deprived quintile with the mean age at recruitment 60.5 years and the mean pack years smoked 38.2 . Participants were allocated to intervention or comparison group during the recruitment visit using a web-based randomization system. Test positive patients were offered a chest X-ray followed by a non-contrast thoracic CT scan. If the initial CT scan revealed no evidence of lung cancer then subsequent CT scans were offered 6 monthly for 24 months. Individuals with abnormalities were followed up over the study period or referred for clinical care as appropriate. All individuals entering the study were followed up via record linkage including the Scottish Cancer Registry.

      Control

      UK standard clinical practice

      OUTCOMES

      Primary

      The difference, at 24 months after randomisation, between the rates of patients with stage III, IV or unclassified lung cancer at diagnosis in the intervention arm & control arm;

      Secondary

      Eight further measures including mortality, economic and psychological.

      Power
      Using an assumption of 600/100,000 for late stage lung cancer in the population studied and acknowledging that recruitment is over a 2 year period the study has a power of 80% to detect a 35% reduction associated with the use of the EarlyCDT-Lung test to identify cases.

      Analysis
      Cox proportional hazards models were used to estimate the hazard ratio of the rate of late stage lung cancer in the intervention arm compared to the control arm. Participants who were lost to follow up were censored. The models adjust for age, gender, smoking history, and practice. Random cluster effects were included rather than fixed effects for practices. Comparisons of proportions were carried out using chi square tests. Fisher’s Exact test was used if the numbers of events are small.

      Result

      127 lung cancers were diagnosed in the study period (56 in the intervention group and 71 in the control arm). 9.8% of the intervention group had a positive EarlyCDT-Lung test and 3.4% (n=18) of these were diagnosed with lung cancer in the study period.

      Fewer participants in the intervention group were diagnosed at a late-stage (III & IV) compared with the control group (33 vs 52). The rate of late-stage (III & IV) lung cancer diagnosis in the intervention group was 58.9% and in the control group was 73.2%. The number of early-stage (I & II) lung cancers diagnosed in the intervention group was higher than in the control group (23 vs 19). The EarlyCDT-Lung test was positive for 12 of
      the 23 early cancers (sensitivity 52.2%, 95% CI 30.6% to 73.2%) and for 6 of the 33 late-stage cancers (sensitivity 18.2%, 95% CI 7.2% to 35.5%).

      The study was not powered to detect a difference in mortality, however there was a non significant trend suggesting fewer deaths in the intervention arm compared to the control (87 vs 108 respectively). Similar results were noted relating to lung cancer-specific mortality (17 vs 24).

      Conclusion

      Our results show that the combination of the EarlyCDT-Lung followed by CT imaging in those with a positive blood test, results in a significant decrease in late stage diagnosis of lung cancer and may decrease all cause and lung cancer specific mortality. We shall continue follow up of all participants’ lung cancer and mortality outcomes at 5 years using Scottish ISD (Information Services Division) data to study these effects further.

      Blood-based biomarker panels, such as the EarlyCDT-Lung test, may have an important role in future lung cancer screening programmes. Further studies including ones to establish the ideal testing frequency are required.

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      PL02.04 - Blood MicroRNA and LDCT Reduce Unnecessary LDCT Repeats in Lung Cancer Screening: Results of Prospective BioMILD Trial (Now Available) (ID 907)

      08:00 - 10:15  |  Presenting Author(s): Ugo Pastorino  |  Author(s): Mattia Boeri, Stefano Sestini, Federica Sabia, Mario Silva, Paola Suatoni, Carla Verri, Anna Cantarutti, Nicola Sverzellati, Giovanni Corrao, Alfonso Marchianò, Gabriella Sozzi

      • Abstract
      • Presentation
      • Slides

      Background

      The National Lung Screening Trial (NLST) showed that lung cancer (LC) screening by three annual rounds of low-dose computed tomography (LDCT) reduced lung cancer mortality, and MILD trial provided additional evidence that extended intervention beyond 5 years, with annual or biennial rounds, enhanced the benefit of screening. The new bioMILD trial tested the additional value of blood microRNA (miRNA) assay at the time of LDCT on a large series of volunteers, with the aim of targeting next LDCT intervals on the basis of individual risk profile.

      Method

      BioMILD trial offered a lung cancer screening program combining LDCT and blood microRNA assay, to heavy smokers (current or former ≤10 years) aged 50-75 years (clinicaltrials.gov ID: NCT02247453). At baseline, LDCT and miRNA were tested independently with blind evaluation, choosing a 3-year interval for the next repeat in participants with double negative LDCT and miRNA.

      Result

      From January 2013 to March 2016, bioMILD prospectively enrolled 4,119 volunteers at Istituto Nazionale Tumori of Milan. The median age was 60 years, median pack-years 42, current smokers 79% and females 39%. According to baseline LDCT and miRNA profile, 2384 subjects (58%) with double negative LDCT and miRNA (2neg) were sent to 3-year LDCT repeat, 1526 (37%) with positive miRNA or indeterminate/positive LDCT (1pos) and 209 (5%) with positive miRNA and indeterminate/positive LDCT (2pos) were sent to annual or shorter LDCT repeat, depending on LDCT results. After four screening runs (LDCT 0/1/2/3), a total of 115 LCs were diagnosed (2.8%). Cumulative LC incidence was significantly different in the three groups: 0.6% for 2neg subjects, 3.8% for 1pos and 20.1% for 2pos (p<0.0001); LC mortality was 0.1%, 0.6% and 3.8% respectively (p<0.0001). Interval cancer incidence, proportion of stage I and resected LC were not statistically different among groups.

      Conclusion

      The combination of microRNA assay and LDCT is a valuable and safe tool to assess individual risk profile and reduce unnecessary LDCT repeats in lung cancer screening. Targeting LDCT intervals on individual risk profile did not cause any detrimental effects on LC detection or mortality.

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      PL02.05 - Discussant - PL02.02, PL02.03, PL02.04 (Now Available) (ID 3912)

      08:00 - 10:15  |  Presenting Author(s): Harry J. de Koning

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      PL02.06 - In Hospital Clinical Efficacy, Safety and Oncologic Outcomes from VIOLET: A UK Multi-Centre RCT of VATS Versus Open Lobectomy for Lung Cancer (Now Available) (ID 1257)

      08:00 - 10:15  |  Presenting Author(s): Eric Lim  |  Author(s): Tim Batchelor, Joel Dunning, Michael Shackcloth, Vladimir Anikin, Babu Naidu, Elizabeth Belcher, Mahmoud Loubani, Vipin Zamvar, Tim Brush, Lucy Dabner, Rosie Harris, Dawn Phillips, Chloe Beard, Holly McKeon, Sangeetha Paramasivan, Daisy Elliott, Alba Realpe Rojas, Elizabeth Stokes, Sarah Wordsworth, Jane Blazeby, Chris Rogers, T Violet Trialists

      • Abstract
      • Presentation
      • Slides

      Background

      VATS is currently the most popular form of access for lung cancer resection in the UK. However, there is limited comparative information from high quality randomised controlled trials and no information on early oncologic outcomes for quality assurance for a minimal access approach. VIOLET is the largest randomised trial conducted to date to compare clinical efficacy, safety and oncologic outcomes of VATS versus open surgery for lung cancer.

      Method

      VIOLET is a parallel group randomised trial conducted across 9 UK thoracic surgery centres. Participants with known or suspected primary lung cancer were randomised in a 1:1 ratio to VATS (one to four ports) or open lobectomy. Randomisation was stratified by surgeon. Patients within clinical stage cT1-3, N0-1 and M0 using TNM 8 with disease suitable for VATS or open surgery were eligible to join the trial. We report on early outcomes in the period from randomisation to hospital discharge after surgery.

      Result

      From Jul 2015 to Feb 2019, 2,109 patients were screened to randomise 503 participants to VATS (n=247) or open (n=256) lobectomy. The mean age (SD) was 69 (8.8) years and 249 (49.5%) were male. Baseline clinical T category was cT1 333 (67.3%), cT2 125 (25.2%), cT3 37 (7.5%) with cN0 466 (94%) and cN1 30 (6%). Lobectomy was undertaken in 221 (89.5%) patients randomised to VATS and 232 (90.6%) patients randomised to open surgery. The in-hospital mortality rate was 1.4% (7/502) and the conversion rate from VATS to open was 5.7% (14/246) with the main reasons listed as pleural adhesions (n=4) and bleeding (n=4).

      There were no differences in R0 resection; which was 98.8% (218/223) in the VATS group and 97.4% (228/234) in the open group; P=0.839 or in nodal upstaging from cN0/1 to pN2 disease which was observed in 6.2% (15/244) of the VATS group and 4.8% (12/252) of the open group; P=0.503.

      The median (visual analogue) pain score was 4 (interquartile range, IQR 2 to 5) in both groups on day one with 3 (1 to 5) in the VATS group and 4 (2 to 5) in the open group on day two.

      A significant reduction of overall in-hospital complications was observed in patients receiving VATS at 32.8% (81/247) compared to open 44.3% (113/255) surgery; P=0.008 without any difference in serious adverse events between the two groups, which was 8.1% (20/247) for VATS and 7.8% (20/255) for open surgery; P=0.897.

      Patients randomised to VATS had a shorter median (IQR) length of stay of 4 (3 to 7) versus 5 (3 to 8) days compared to patients randomised to open surgery, P=0.008.

      Conclusion

      In early stage lung cancer, VATS lobectomy is associated with significantly lower in-hospital complications and shorter length of stay compared to open lobectomy. This was achieved without any compromise to early oncologic outcomes (pathologic complete resection and upstaging of mediastinal lymph nodes) nor any difference in serious adverse events in the early post-operative period.

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      PL02.07 - Discussant - PL02.06 (Now Available) (ID 3913)

      08:00 - 10:15  |  Presenting Author(s): Jessica S Donington

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      • Abstract
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      Background

      No targeted therapy is currently approved for patients with RET fusion-positive non-small cell lung cancer (NSCLC). LOXO-292 is a highly selective RET inhibitor with activity against diverse RET fusions, activating RET mutations and brain metastases. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion-positive NSCLC in August 2018.

      Method

      This global phase 1/2 study (87 sites, 16 countries) enrolled patients with advanced RET-altered solid tumors including RET fusion-positive NSCLC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. The phase 1 portion established the MTD/RP2D (160 mg BID). The phase 2 portion enrolled patients to one of six cohorts based on tumor type, RET alteration, and prior therapies. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, CNS ORR, CNS DoR, PFS, OS, safety and PK.

      Result

      As of 17-June 2019, 253 RET fusion-positive NSCLC patients were treated. The primary analysis set (PAS) for LOXO-292 registration, as defined with the US FDA, consists of the first 105 consecutively enrolled RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy; 58 patients (55%) also received prior anti PD-1/PD-L1 agents. The majority of PAS responders have been followed for ≥6 months from first response. Of the remaining 148 patients, 79 had previously been treated with platinum-based chemotherapy, 55 did not receive prior platinum-based chemotherapy and 14 did not have measurable disease at baseline.

      Among PAS patients, the investigator-assessed ORR was 68% (95% CI 58-76%, n=71/105, 2 PRs pending confirmation). Responses did not differ by fusion partner or the type or number of prior therapies, including chemotherapy, anti PD-1/PD-L1 agents and multikinase inhibitors with anti-RET activity. The median DoR was 20.3 months (95% CI 13.8-24.0) with a median follow-up of 8 months; as evidenced by the wide confidence interval, this DoR estimate is not statistically stable due to a low number of events (16 of 69 confirmed responders). The intracranial ORR was 91% (n=10/11: 2 confirmed CRs, 8 confirmed PRs) for patients with measurable brain metastases at baseline.

      The ORR in efficacy evaluable treatment naïve RET fusion-positive NSCLC patients was 85% (95% CI 69-95%, n=29/34, 7 PRs pending confirmation). In the safety data set of all 531 patients, 5 treatment-related AEs occurred in ≥15% of patients: dry mouth, diarrhea, hypertension, increased AST and increased ALT. Most AEs were grade 1-2. Only 9 of 531 (1.7%) patients discontinued LOXO-292 for treatment-related AEs.

      Conclusion

      LOXO-292 had marked antitumor activity in RET fusion-positive NSCLC patients and was well tolerated. These data will form the basis of an FDA NDA submission later this year.

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      PL02.09 - National Lung Matrix Trial (NLMT): First Results from an Umbrella Phase II Trial in Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 2282)

      08:00 - 10:15  |  Presenting Author(s): Gary William Middleton  |  Author(s): Sanjay Popat, Peter Fletcher, Yvonne J. Summers, Alastair Greystoke, David Gilligan, Judith Cave, Noelle O'Rourke, Alison Brewster, Elizabeth W. Toy, James Spicer, Joshua Stephen Savage, Rowena Sharpe, Timothy A. Yap, Charles Swanton, Lucinda Billingham

      • Abstract
      • Slides

      Background

      Oncogene-addicted NSCLC can achieve substantial clinical benefit with single-agent targeted therapy. Seeking to extend this paradigm to other more genetically complex NSCLC, we report first results of NLMT, an umbrella phase II trial whereby a bespoke next-generation sequencing screening panel (Stratified Medicine Programme 2) stratifies NSCLC patients to rationally selected targeted therapies. Uniquely we present results across the entirety of the platform to enable an assessment of the potential to further stratify medicine in advanced NSCLC. Novel methodology is used to ensure that the integrity of this ongoing platform trial is not jeopardised.

      Method

      NLMT uses a Bayesian adaptive design to screen currently 8 targeted drugs for signals of activity in 22 molecularly defined cohorts. For single agents, pre-specified clinically relevant outcomes are either median progression-free survival (mPFS) >3 months or objective response rate (ORR) and/or durable clinical benefit rate at 24 weeks (DCBR) >30%. Target recruitment for each cohort is 30 with futility analyses at 15. Recruitment continues in 19 cohorts. We report posterior probabilities (PP) of a clinically relevant outcome for closed cohorts and Bayesian predictive probability of success (PPoS) given observed data for open cohorts. This novel approach provides insight into the drug-biomarker combinations that have the strongest potential for further research.

      Result

      Over a 4 year period to end of March 2019, NLMT has recruited 286 patients from >4000 screened. Of 6 palbociclib cohorts (all proficient Rb): mPFS in KRAS mutation (n=30) is 5.8 months (PP>0.99); CDKN2A loss/non-squamous (n=27) passed its interim analysis; we predict >75% PPoS, given current data, in CDKN2A loss/squamous (n=16) and CCND1 amplification (n=13). Data for crizotinib show >90% PPoS in ROS1 gene fusions (n=8) and MET exon 14 skipping mutation (n=8), with less clear signal for MET amplification (n=9). Responses to selumetinib/docetaxel in NF1 mutation (n=16) warrant continuation. Recruitment to vistusertib was halted at interim for LKB1 single mutation (ORR=0/15, PP=0.003; DCBR=1/15, PP=0.026), but DCBR in LKB1/KRAS double mutation (n=23) warrant continuation. 4 cohorts receive capivasertib (n=22): data in PIK3CA amplifications (n=9) indicate <15% PPoS.

      Conclusion

      These first results from the largest stratified medicine dataset in NSCLC indicate further molecular stratifications could benefit from targeted therapies. Reporting interim outputs for all cohorts will allow reappraisal of the global stratified medicine strategy in cancer.

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      PL02.10 - Discussant - PL02.08, PL02.09 (Now Available) (ID 3914)

      08:00 - 10:15  |  Presenting Author(s): Robert C. Doebele

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      PL02.11 - Overall Survival with Durvalumab Plus Etoposide-Platinum in First-Line Extensive-Stage SCLC: Results from the CASPIAN Study (Now Available) (ID 2265)

      08:00 - 10:15  |  Presenting Author(s): Luis Paz-Ares  |  Author(s): Yuanbin Chen, Niels Reinmuth, Katsuyuki Hotta, Dmytro Trukhin, Galina Statsenko, Maximilian J. Hochmair, Mustafa Özgüroğlu, Jun Ho Ji, Oleksandr Voitko, Artem Poltoratskiy, Santiago Ponce, Francesco Verderame, Libor Havel, Igor Bondarenko, Andrzej Kazarnowicz, György Losonczy, Nikolay V. Conev, Jon Armstrong, Natalie Byrne, Norah Shire, Haiyi Jiang, Jonathan Goldman

      • Abstract
      • Presentation
      • Slides

      Background

      Extensive-stage (ES)-SCLC is a recalcitrant disease associated with a median OS of ~10 months following etoposide-platinum (EP); new treatments that prolong survival are needed. CASPIAN (NCT03043872) is an open-label, phase 3 study of durvalumab (anti-PD-L1), ± tremelimumab (anti-CTLA-4), combined with EP as first-line treatment for patients with ES-SCLC. Here we report results for durvalumab + EP (D+EP) versus EP from a planned interim analysis.

      Method

      Patients with previously untreated ES-SCLC (ECOG PS 0/1) were randomised (1:1:1) to durvalumab 1500 mg + EP q3w; durvalumab 1500 mg + tremelimumab 75 mg + EP q3w; or EP q3w. Patients in immunotherapy arms received up to 4 cycles of EP followed by maintenance durvalumab until progression. Patients in the EP arm received up to 6 cycles of EP and prophylactic cranial irradiation (PCI), at the investigator’s discretion. Investigator’s choice of cisplatin or carboplatin was allowed across all arms and was a stratification factor at randomisation. The primary endpoint was OS. Data cutoff: 11 March 2019.

      Result

      268 patients were randomised to D+EP and 269 to EP. Baseline characteristics were well balanced between arms. In the EP arm, 56.8% of patients received 6 cycles of EP. At the interim analysis, D+EP significantly improved OS compared to EP with a HR of 0.73 (95% CI, 0.591-0.909; p=0.0047); mOS 13.0 versus 10.3 months, respectively. 33.9% of patients were alive at 18 months with D+EP versus 24.7% with EP. Secondary endpoints of PFS and ORR were also improved with D+EP compared to EP: PFS HR 0.78 (95% CI, 0.645-0.936); mPFS 5.1 versus 5.4 months; 12-month PFS rate 17.5% versus 4.7%; investigator-assessed ORR (RECIST v1.1; unconfirmed) 79.5% versus 70.3% (odds ratio, 1.64 [95% CI, 1.106-2.443]). The incidences of grade 3/4 AEs (61.5% versus 62.4%) and AEs leading to discontinuation (9.4% each) were similar between arms; the incidence of haematological toxicities was numerically higher in the EP arm. The durvalumab + tremelimumab + EP arm continues blinded to final analysis.

      Conclusion

      The addition of durvalumab to EP as first-line treatment for ES-SCLC significantly improved OS (27% reduction in risk of death) versus a robust control arm that permitted up to 6 cycles of EP and PCI. Of note, this chemo-immunotherapy regimen offers flexibility in platinum choice (carboplatin or cisplatin), reflecting current clinical practice for this challenging disease. No new safety signals were identified.

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      PL02.12 - Discussant - PL02.11 (Now Available) (ID 3915)

      08:00 - 10:15  |  Presenting Author(s): Myung-Ju Ahn

      • Abstract
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      Abstract not provided

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    PL03 - Relevant Aspects of Lung Cancer Management (ID 90)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track: Advanced NSCLC
    • Presentations: 4
    • Now Available
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      PL03.01 - Establishing a Nurse Led Follow-Up Service for Patients With Resected Early Stage Lung Cancer (ID 3591)

      09:15 - 10:45  |  Presenting Author(s): Jenny Mitchell  |  Author(s): Elizabeth Belcher

      • Abstract
      • Slides

      Abstract

      Specialist nursing roles within thoracic surgical centres in the UK are unique to each centre and develop to meet the needs of the local service. In Oxford we identified that the follow-up of patients after resection of early stage lung cancer could be improved and would be suitable for management by a specialist nurse.

      Prior to the introduction of the specialist nursing role patients were reviewed by the junior doctors working in the clinic, offering limited continuity of care and often presenting challenges in following-up abnormal results.

      Following the successful development of a nurse led early follow-up clinic1 we instituted a nurse led CT follow-up program for patients on long term surgical follow-up after resection of lung cancer.

      Guidelines recommend that patients are followed up after lung cancer resection2, how this is provided is at the discretion of each individual service and varies in the imaging modality and frequency of interventions3.

      Following review of international guidelines3 and in conjunction with the lung cancer multidisciplinary team we devised a CT follow-up program:

      • CT chest, abdomen and pelvis every 6 months for 2 years after surgery followed by an appointment to be given the results.

      • CT chest, abdomen and pelvis at 3, 4 and 5 years after surgery followed by an appointment to be given the results.

      All patients undergoing lung cancer resection, where adjuvant treatment is either not indicated or declined, are entered into the follow-up program (see diagram). The programme is co-ordinated and CT results triaged by the specialist nurse.

      Following successful introduction of nurse led follow-up in the face to face clinics we found that feedback from patients on our CT follow-up programme indicated they find two trips to the hospital burdensome and they frequently requested results of surveillance imaging over the telephone. In addition, limited capacity in the thoracic surgery clinics led to patients waiting a long time for a face to face appointment to be informed of their imaging results. To address these issues, we developed a model of nurse led telephone follow-up after surveillance imaging. The criteria for telephone appointments are:

      • CT results show no abnormality or minor changes requiring a repeat CT chest in 3 months

      • Patients can communicate adequately over the telephone:

      – Reasonable command of English

      – Able to hear telephone conversations

      – No cognitive impairment

      Patients who do not fit these criteria are given an appointment in a face to face clinic.

      The specialist nurse reviews all the CT follow-up results and allocates patients to the most appropriate clinic, ensuring patients are reviewed in the appropriate setting for their needs and those who need to be see urgently are prioritised. Abnormalities and concerns detected during the follow-up programme are presented at the multidisciplinary meetings by the specialist nurse, who takes responsibility for the actions requested by the team.

      In the period January 2013 to December 2017 there were 546 specialist nurse face to face clinic appointments in 189 clinics for 285 patients with primary lung cancer. The telephone clinic commenced in April 2017 and in the first twelve months there were 254 patient appointments in 51 telephone clinics

      The presence of the specialist nurse within the follow-up clinics has increased clinic capacity and efficiency, reduced waiting time for appointments, promotes junior medical training and ensures continuity of care for the patients. The patients appreciate the continuity of care and improved access to specialist nursing support. The role is appreciated and respected by the multidisciplinary team.

      The telephone clinic has been very well received by patients. They appreciate the opportunity to receive their results without having to make a second journey to the hospital (traffic and parking in Oxford is notoriously bad). They continue to receive continuity of care as the nurse who calls them is the same nurse who they saw at their first follow-up appointment in the face to face clinic. The introduction of the telephone clinic has increased overall clinic capacity and reduced the waiting time for appointments within the face to face clinics.

      In order to effectively carry out this role the specialist nurse requires advanced practice skills1. Qualifications in history taking and clinical examination, advanced communication skills and non-medical prescribing are all held by the specialist nurse carrying out this role. In order to request CT imaging IRMER training was undertaken and an appropriate requesting protocol approved by the hospital clinical governance committee.

      In conclusion we have demonstrated that nurse-led follow-up after lung cancer resection is an effective way of ensuring high quality care for this group of patients. The specialist nurse is able to provide continuity of care and ensure that all imaging results are followed up appropriately. The role requires the support of the multidisciplinary lung cancer team to work effectively across all elements of the patient pathway.

      1. Mitchell J. Relevance of a specialised nurse in thoracic surgery. J Thorac Dis 2018:S2583-S2587.

      2. National Institute for Health and Clinical Excellence (NICE). CG121 - Lung cancer. London: NICE; 2011 Available at http://publications.nice.org.uk/lung-cancer-cg121. Accessed 2.3.12.

      3. Belcher E, Mitchell J, Benamore R, et al. Does the manner of follow-up after lung cancer surgery improve survival? In: Modi P, ed. Perspectives in Cardiothoracic Surgery. London: Society for Cardiothoracic Surgery in Great Britian and Ireland; 2018;3:247-258.

      abstract image.png

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      PL03.02 - Bringing Immunotherapy into the Curative Setting: Emerging Data on Neoadjuvant Strategies (Now Available) (ID 3592)

      09:15 - 10:45  |  Presenting Author(s): Jamie E. Chaft

      • Abstract
      • Presentation
      • Slides

      Abstract

      Immunotherapy with checkpoint inhibitors targeting PD-1 and PD-L1, as monotherapy or in combination with chemotherapy, have become standard of care in all patients with advanced lung cancer who do not have an actionable oncogene or contraindication.1, 2 Similarly patients with unresectable stage III non-small cell lung cancer who do not progress through concurrent chemoradiotherapy have improved progression free and overall survival with anti-PD-L1 consolidation therapy.3

      In early-stage disease, four randomized phase 3 studies are evaluating the role of adjuvant immunotherapy following standard of care chemotherapy. As is the nature of adjuvant investigation, these studies require years of clinical follow-up and will not mature until sufficient recurrence and/or death events occur.

      Neoadjuvant therapy has many advantages to the patient and for the sake of science. As a therapy, preop treatment is better tolerated and can be monitored for efficacy by imaging and pathologic regression. In terms of research, the early pathologic response endpoint may accelerate trial readouts. Investigation into pathologic response as a surrogate for survival in lung cancer is ongoing.4

      The true excitement about neoadjuvant investigation with immunotherapy and/or chemo-immuno combinations, is the theoretical therapeutic superiority of this approach over an adjuvant approach. This is hypothesized to be due to the tumor with its associated mutation specific neoantigens in situ during exposure to the PD-1 treatment, enabling a more robust tumor specific immune response. In pre-clinical mouse models, PD-1 monotherapy is more effective when administered neoadjuvantly versus adjuvantly.5

      The first experience with neoadjuvant PD-1 therapy in NSCLC was a small pilot study performed for safety and feasibility of this approach. No unexpected safety signals were noted and unanticipated pathologic regression observed.6 Two additional series with neoadjuvant immunotherapy have been presented, the Lung Cancer Mutation Consortiums experience with PD-L1 monotherapy and the MD Anderson study of PD-1 +/- CTLA-4 therapy. Both studies confirmed this approach is both safe and induces pathologic regression (at times pathologic complete response) in some patients.7, 8 Correlative studies to try to identify predictors of response and resistance are ongoing. PD-L1 expression is not as clearly predictive in this patient population as in advanced disease.

      Shortly after PD-1 monotherapy was demonstrated to be safe and have some anti-cancer efficacy, many other monotherapy and combination studies launched. Two combination studies rapidly accrued. The combination of carboplatin, a taxane, and a PD-1/L1 agent have been demonstrated by two groups to induce major pathologic regression in the majority of patients.9, 10 In the Spanish Lung Cancer Group study, complete pathologic response was seen in more than 50% of resected patients.10

      These studies have spurred a tremendous interest in the best neoadjuvant therapy. There are 4 international phase 3 studies enrolling patients to receiving neoadjuvant chemotherapy with or without immunotherapy (NCT03800134, NCT03456063, NCT03425643, NCT02998528). Many of these studies have pre-specified pathologic response co-primary endpoints that will be evaluable well before classic clinical endpoints. These studies will help substantiate the role of immunotherapy in the preoperative setting and pathologic response as a possible surrogate endpoint.

      As the international adjuvant immunotherapy efforts wrap up, the research community should commit to enrolling patients on neoadjuvant studies. This is our best chance to improve cure rates in early stage lung cancer – to identify effective therapy for those cancers of a clinical stage to justify induction therapy and adjuvant therapy for those incidentally upstaged at the time of surgery. Within these therapeutic studies are essential biomarker efforts. These efforts are poised to be successful and position the research community to extend investigation into the earliest stages of non-small cell lung cancer, looking to improve cure rates for all stages of disease.

      1. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:2078-2092.

      2. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med 2018;379:2040-2051.

      3. Antonia SJ, Villegas A, Daniel D, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med 2018;379:2342-2350.

      4. Blumenthal GM, Bunn PA, Jr., Chaft JE, et al. Current Status and Future Perspectives on Neoadjuvant Therapy in Lung Cancer. J Thorac Oncol 2018;13:1818-1831.

      5. Liu J, Blake SJ, Yong MC, et al. Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease. Cancer discovery 2016;6:1382-1399.

      6. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med 2018.

      7. Kwiatkowski DJ. Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): Interim analysis and biomarker data from a multicenter study (LCMC3). J Clin Oncol 2019;37:abstr 8503.

      8. Cascone T. Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC): Clinical and correlative results from the NEOSTAR study. J Clin Oncol 2019;37:abstr 8504.

      9. Shu CA. Neoadjuvant atezolizumab + chemotherapy in resectable non-small cell lung cancer (NSCLC). Journal of Clinical Oncology 2018;36:8532-8532.

      10. Provencio M. NEO-adjuvant chemo-immunotherapy for the treatment of STAGE IIIA resectable non-small-cell lung cancer (NSCLC): A phase II multicenter exploratory study—Final data of patients who underwent surgical assessment. J Clin Oncol 2019;37:abstr 8509.

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      PL03.03 - The Disparity of Lung Cancer Prevention, Diagnosis and Treatment Around the World…What Is the Role of IASLC (Now Available) (ID 3593)

      09:15 - 10:45  |  Presenting Author(s): Suresh S Ramalingam

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer is a global health problem that results in over 1.8 million deaths globally each year. Diagnosis at an advanced stage, lack of effective treatment options and disabling co-morbid conditions, have all contributed to the poor outlook for patients with lung cancer. However, there is now new hope in the global fight against lung cancer. Improved understanding of the biology of the disease, early diagnosis and effective therapies have contributed to growing optimism. The International Association for the Study of Lung Cancer (IASLC) has been at the forefront of research and education by bringing together committed scientists, physicians, care providers, epidemiologists, nursing staff and patient communities to increase awareness, develop improved staging systems, fund research for early career researchers, promote development of novel therapies, and educate healthcare professionals at all levels.

      Tobacco smoking contributes to approximately 85-90% of all cases of lung cancer; while the prevalence of smoking has reduced in many developed countries, it appears to be on the upswing in developing nations. More recently, the introduction of electronic nicotine delivery systems (ENDS) has raised the possibility of creating a new generation of the population addicted to nicotine. Any efforts to reduce the burden of lung cancer has to start with educating the public about the health hazards related to smoking, tobacco cessation programs and reducing the access of teenagers and young adults to tobacco products.

      Early detection by adopting screening programs will be another important strategy to reduce the burden of lung cancer. In recent years, the reduction in mortality related to lung cancer by adopting low dose CT screening in high risk individuals has been proven beyond doubt. Despite this evidence, only a minority of eligible patients are being screened for lung cancer, even in developed nations. To increase adoption of screening, we have to collectively engage in educating the primary care physicians, subjects at risk and the entire health care community. Diagnosis of lung cancer at earlier stages will result in greater likelihood of cure due to the exciting advances that have taken place in the management of patients with stages I, II and III NSCLC.

      Even for patients diagnosed with advanced stage lung cancer, long term survival is possible; precision therapies directed to oncogenic molecular events, immune checkpoint inhibitors and multi-modality treatment approaches have all contributed to the recent progress. For patients with mutations in the epidermal growth factor receptor and aberrations in the anaplastic lymphoma kinase gene, the median survival for stage 4 disease is now measured in years with the use of specific targeted treatment approaches. There are at least five genomic targets in lung adenocarcinoma that can be treated with specific tyrosine kinase inhibitors. It is likely that more genomic mutations will join the list of treatable aberrations, thanks to the rapid pace of drug development. Molecular testing remains critical to the ability to personalize therapies for patients with lung cancer. A recent survey conducted by the IASLC across the world noted several barriers to routine adoption of molecular testing.

      Finally, access to cutting-edge therapies is a major challenge in several parts of the world. Rising costs of healthcare and medicines have resulted in the inability for patients to receive optimal care.

      Our efforts to improve lung cancer outcomes and reduce the burden of this disease will have to address every one of these issues. The IASLC is launching an ambitious program to double the 5-year survival rate for patients with lung cancer later this year. This will be accomplished by a multi-pronged approach to promote early detection, optimal staging and diagnostic testing and by addressing survivorship issues. A new staging system seeks to integrate molecular knowledge to traditional clinical staging in order to provide precise prognostic information. Investments in improving the sensitivity of CT screening, promoting universal standards for CT imaging and partnering with other societies to increase awareness regarding early detection will all be important components of this strategy.

      The IASLC has made major contributions to diagnosis of lung cancer by developing a new pathology classification system for lung cancer; it has also conducted original research to improve biomarker testing and promote education on molecular diagnosis. In the upcoming years, the IASLC will seek to study the correlation between major pathological response with neo-adjuvant therapy and overall survival. This will allow for earlier utilization of exciting novel agents to be used as part of curative therapies for early stage NSCLC.

      The IASLC will also promote research on issues specific to survivorship; as long-term outcomes for lung cancer patients becomes a reality, it is important to learn about coping with physical and emotional challenges that can be related to their journey. Very little work has been conducted to date on this topic.

      In conclusion, the time is ripe for us to launch a collective campaign to reduce the burden of lung cancer globally. The IASLC will partner with like-minded organizations, and engage its membership to aggressively pursue innovative approaches that will ultimately result in lower number of patients diagnosed with lung cancer, and improved survival and quality of life for patients afflicted with lung cancer.

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      PL03.04 - Lung Cancer and Tuberculosis: Parallel Lives (Now Available) (ID 3594)

      09:15 - 10:45  |  Presenting Author(s): Tamas F Molnar

      • Abstract
      • Presentation
      • Slides

      Abstract

      It is a Battlefield

      Searching for parallelisms, using historical analogies is a well established method in many fields of soft sciences, medical humanities included. A challenge of seemingly repetitive failure patterns and paradigm shift structures are to be answered in the following imaginary experiment. The aim is the creation of a mental model where understanding of developments and mistakes in treatment of tuberculosis might support our fight against lung cancer (1).

      The two diseases are existing parallely – one mainly for the poor and young and the other for the richer and older. History of tuberculosis follows the classic algorhythm: diagnostic (Villemin, Virchow), casuistic (Koch) and therapeutical (Waksman/Streptomycin) stages. The therapeutical phase of lung cancer has been reached without identified cause of the disease. Eradication of the macrosocopic focus by physical interference with the involved tissue mass, in both diseases preceeded medical treatment. Causation is not an absolute sine qua non of an effective treatment, as the tuberculosis-lung cancer analogy also proves. While lung cancer seems to be controlled by an emerging array of new drugs, tuberculosis poses a new challenge.

      Tuberculosis of the lung is a systemic disease, best treated by drugs with additional surgical removal of the focus of the disease as a last option. The disease has a fairly good chance of around 90% of to be cured (2). The prognostic factors include the functional and immunological reserves of the patient.

      Stage I to III lung cancer is a local manifestation of a systemic disease without sufficiently identified aetiology. Therapy response is understood at cohort level, but it is unpredictable where the individual patient’s fate is concerned. For reasons unknown, mechanical eradication offers the best chance for cure in early stages of the tumour.

      Some parallelism between tuberculosis and lung cancer might be of interest..

      In Search of a Character

      If progress takes a standstill categorization, fever takes over. Lymphnodes are the central elements of the Ghon and Ranke complexes.(3) of the tuberculous lung. The TNM system , a topology approach gyrates around the N status as well. (4). The desire to find a strong characteristic prognostic/predictive element resulted in the Gaffky index (5). The number of Koch bacillus in the sputum as a prognostic tool failed to validate the theory. The discussions of stations and size of lymphnodes in lung cancer (6) might share the fate of the Gaffky index. .

      A Burnt out Case?

      There are disturbing similarities in the phenomenon of a late relapse/recurrence in both diseases. The dormant Koch bacillus vs exogenous reinfection debate (7) is paralleled by the dormant cancer cell hypothesis (8).

      Journey without Maps

      Circulating Koch bacillus, and their prognostic value hotly debated in the 1920s, are comparable to the circulating tumor cell question. The bloodstream journey polemic settled down by 1950, the “seed and and soil” theory of cancer cells is subject of intense research.

      The Heart of the Matter

      Till the 1960s all tuberculosis cases seemed to be the same, until atypical tuberculosis was identified and the Mycobacterium xenopi lost its stigmatising power (95). Certain phenotypes of the adenocarcinoma in situ behaves definitely in a more benign way than any other cell type NSCLC. In 2019, we still do not know what is the single causative agent (if it exists at all) of NSCLC (if it exists at all as a single entity). The Copernican revolution in tumour biology is still awaited.

      The Power and the Glory

      Tuberculosis taught us, that the disease affects the body and the soul as well, reflecting to the society around the patient as well. Lung cancer treatment also depend on the immune status of the individual as well as on the protective capabilities of the science and the society. . Affordability and avaibility of anticancer treatments/drugs are key words yet not interchangeable (8). Onco-economy is as a powerful factor as gene sequencing.

      A scalpel for sale

      Our techniques to treat lung cancer are rooted in surgery for tuberculosis (1). VATS techniques take their origin in Jacobeus’ thoracoscopy and Veress needle. Modern thoracic surgical staplers are derivates of the “Russian machines”, Petz staplers adjusted to tuberculotic bronchi. Thoracic surgery practiced in local anesthesia for many decades, is genuine awake/non-intubated thoracic surgery of today. The recent debate over neoadjuvant vs. adjuvant therapy reflects to the bygone dispute on resection before or after antituberculous medical treatment. The different modalities are no mutually exclusive options, but complementary ones.

      The End of the Affair: Conclusion.

      The main message of tuberculosis to present day oncopulmonologists is that no one can forget the interaction between tumour and patient and his/her socioeconomic status around the pathologically identified focus.

      References

      1.)

      Molnar TF.,Tuberculosis: mother of thoracic surgery then and now, past and prospectives: a review J Thorac Dis 2018;10(Suppl 22):S2628-S2642

      2.)

      Silva VD, Mello FC, Figueiredo SC. Estimated rates of recurrence, cure, and treatment abandonment in patients with pulmonary tuberculosis treated with a ¬four-drug fixed-dose combination regimen at a tertiary health care facility in the city of Rio de Janeiro, Brazil. J Bras Pneumol 2017;43:113-20.

      3.)

      Ober WB. Ghon but not forgotten: Anton Ghon and his complex. Pathol Annu 1983;18:79-85.

      4.)

      Rusch Crowley J, Giroux DJ, et al. International Staging Committee The IASLC Lung Cancer Staging Project: Proposals for the revision of the N descriptors in theforthcomingseventheditionoftheTNMclassification for lung cancer. J Thorac Oncol2007;2:603-12.

      5.)

      Gaffky GTA. Scale or Table. JAMA 1913;61:359.

      6.)

      Rami-Porta R, Asamura H, Brierley J, et al. Staging, tumor profile and prognostic groups in lung cancer or the new of Babel. J Thorac Oncol2016;11:1201-3.

      7.)

      Lillebaek Dirksen A, Baess I, et al. Molecular evidence of endogenous reactivation of Mycobacterium tuberculosisafter33yearsoflatentinfection.JInfect2002;185:401-4.

      8.)

      Molnar TF, Szipocs A, Szalai Z Neoadjuvant Crizotinib for ALK Re-arranged NSCLC?

      J Thorac Oncol. 2019;14(4):574-576.

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    PL04 - Food for Thought in the Management of Thoracic Malignancies (ID 91)

    • Event: WCLC 2019
    • Type: Plenary Session
    • Track: Advanced NSCLC
    • Presentations: 4
    • Now Available
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      PL04.01 - Epidemiology and Clinical Characteristics of Lung Cancer in Women (Now Available) (ID 3595)

      16:15 - 17:00  |  Presenting Author(s): Enriqueta Felip

      • Abstract
      • Presentation
      • Slides

      Abstract

      "Non applicable"

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      PL04.02 - What Does Survivorship Mean in the World of Immunotherapy (Physical and Financial)? (Now Available) (ID 3596)

      16:15 - 17:00  |  Presenting Author(s): Michelle Turner

      • Abstract
      • Presentation
      • Slides

      Abstract

      With improvements in diagnostic, therapeutic, and supportive therapies, the number of cancer survivors

      continues growing with over 20 million cancer survivors worldwide and an estimated 2/3 of adults with

      a cancer diagnosis who are anticipated to be alive in 5 years1. Due to this increase in survivors, major

      medical societies such as American Society of Clinical Oncology (ASCO), Institute of Medicine (IOM), and

      the Society for Immunotherapy of Cancer’s (SITC) have highlighted the need for strategies to improve

      the ongoing care of survivors and survivorship plans.2

      The 4 basic tenets of a survivorship plan are surveillance, prevention, intervention and coordination.

      Surveillance is aimed at monitoring for recurrence, second cancers, and long term toxicities, prevention

      of these sequelae if possible, intervention if they are found, and lastly coordination between hospital

      and community‐based doctors is essential for this plan to be effective.3 These needs are typically

      communicated to the patient’s general practitioner (GP)/primary care physician (PCP) by a “care plan”

      that outlines the patient’s oncology treatment course, potential long‐term toxicity, the

      frequency of follow up visits, scans and links to community resources.

      New cancer therapies such as immunotherapy has resulted in significantly improved overall survivals in

      many advanced cancers, including those that had formerly been considered refractory.6,7,8 However, the

      short‐, intermediate‐, and long‐term complications of these therapeutic agents are still being identified.

      Immune‐mediated events, for example, can occur immediately after therapy initiation or even up to two

      years post treatment as a consequence of overstimulation of the immune system leading to

      autoimmunity with the potential for permanent or long‐term sequelae.4,5

      References:

      1. https://cancercontrol.cancer.gov/ocs/statistics/statistics.html

      2. https://www.canceradvocacy.org/

      3. Denlinger, CS et. Al. Survivorship: Introduction and Definition. J Natl Compr Canc Netw. 2014 Jan; 12(1): 34–45.

      4. Sheela S, Kim ES, Mileham KF. Moving away (finally) from doublet therapy in lung cancer: immunotherapy and KEYNOTE‐189J Thorac Dis. 2018 Sep;10(9):5186‐5189.

      5. Weber JS, Hodi FS, Wolchok JD, et al. Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma. J Clin Oncol 2017; 35:785.

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      PL04.03 - The Relevance of an International Database for the Study of Thymic Neoplasms (Now Available) (ID 3597)

      16:15 - 17:00  |  Presenting Author(s): Vanessa Bolejack

      • Abstract
      • Presentation
      • Slides

      Abstract

      Introduction

      Until the 8thedition of the AJCC/UICC TNM classification of malignant tumours went into effect, no official stage classification was available for thymic malignancies. Some classification systems had been proposed but were generally developed from a limited number of patients and not usually tested in an independent dataset. The system developed by Dr. Akira Masaoka in 1981 did undergo external validation and was widely adopted. However, the adoption of these proposed systems in different institutions and regions was hampered by a lack of uniform nomenclature and varying interpretations of definitions. The current (8thedition) TNM stage classification for thymic malignancies endorsed by AJCC and UICC was informed by a database with 10,808 cases of thymic malignancies from 105 sites worldwide, compiling cases contributed by ITMIG (including patients from North and South America, European, and Korean (KART) and Chinese (ChART) institutions), Japan (JART), and Europe (ESTS) with funding and coordination by IASLC and Cancer Research and Biostatistics (CRAB), with the specific intent of developing a TNM based staging system for these malignancies.

      Methods and materials

      The IASLC Stating and Prognostic Factors Committee - Thymic Domain (SPFC-TD) conducted a web-based cross-sectional survey to assess the implementation of the 8thEdition TNM staging system in the thoracic community. The survey was sent to the major thymic organizations (ITMIG, ESTS, KART, ChART, RYTHMIC, JART) in addition to IASLC membership. A new database to inform the 9thedition TMN staging system is under development to provide updated follow-up from the institutions contributing to the 8thedition database, add additional institutions, and add new cases collected prospectively.

      Results

      According to the survey results, the TNM stage classification of thymic tumors has gained a reasonable acceptance in the scientific community, while the Masaoka stage system remains widely employed. An increased attention to the N descriptor seems to have been incorporated. There is high awareness of the new staging system. The current efforts of the Thymic Domain of the IASLC Staging and Prognostic Factors Committee focus on expanding and updating the database used for the 8thedition to further refine the stage definitions and includes updated follow-up on patients from Turkey, the ESTS, JART, ChART and KART, plus data collected prospectively from ChART.

      Conclusion

      The database created to inform the 9thedition of TNM staging for thymic malignancies will allow for refinement and adjustment of the 8thedition system and attempt to address any perceived deficiencies of the current system. An overview of the current state of the database will be presented at the meeting in Barcelona.

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      PL04.04 - Prognostic Factors in Malignant Pleural Mesothelioma (Now Available) (ID 3598)

      16:15 - 17:00  |  Presenting Author(s): Michaela B Kirschner

      • Abstract
      • Presentation
      • Slides

      Abstract

      Malignant pleural mesothelioma (MPM) is a disease for which we are facing difficulties and challenges at many levels from diagnosis over treatment selection and prediction of treatment response to prediction of the prognosis of individual patients. Besides the necessities to obtain an accurate and early diagnosis and to be able to predict the response to a specific treatment, it is equally important to be able to estimate the overall prognosis of a patient as this will also affect treatment decisions.

      Looking at the research efforts of the last two decades, we see an abundance of studies investigating prognostic markers for MPM, yet to date the most reliable predictors of disease outcome are still the clinical and pathological parameters, which have been used in the past. Probably the most accurate prognostic factor for MPM is the histopathological subtype, with epithelioid MPM being associated with the best prognosis followed by the biphasic subtype and sarcomatoid histology. In addition, it is well recognised that patients presenting with less advanced disease, of younger age and female gender are generally doing better. Some of these factors were combined with additional proposed predictors of outcome into scoring systems suggested by the European Organization for Research and Treatment of Cancer (EORTC, [1]) and the Cancer and Leukemia Group B (CALGB, [2]). Both scores have been subsequently validated and still hold true today, over 20 years later.

      Since then, many studies have attempted to identify additional prognostic biomarkers. One area of extensive research is the investigation of changes in blood cell ratios, which can be linked to the inflammatory and/or nutritional status of the patients [3, 4]. In terms of inflammation-related indicators of poor outcome, elevated C-reactive protein (CRP), a high neutrophil-to-lymphocyte ratio, and a low lymphocyte-to-monocyte ratio (LMR) have been proposed. Some of these inflammatory markers have also been combined with factors reflecting the nutritional status of patients. For example, has the combination of CRP and albumin been suggested to have prognostic value, as shown in the CRP-to-albumin ratio (CAR) and the modified Glasgow Prognostic Score (mGPS). Another proposed combination is that of albumin and lymphocytes into the Prognostic Nutritional Index (PNI). Additionally, radiological factors, such as tumour volume or pleural thickness measured by CT or MRI alone or as part of prognostic scores (e.g. in combination with other factors such as in the multimodality prognostic score [5]), as well as radiomics approaches have shown prognostic potential [6]. While many of these proposed prognostic factors are often routinely collected during standard clinical work-up and blood tests, prospective testing in a clinical setting has yet to be attempted.

      A second area of extensive research in the last decade has been molecular factors, namely the expression of proteins, genes, and microRNAs [3]. Initially, the majority of studies focused on the potential prognostic role of protein expression in tumour tissue. Here, rather frequently, the expression of tyrosine kinases such as epidermal growth factor receptor (EGFR) and c-Met has been investigated, due to the additional potential of targeting those using tyrosine kinase inhibitors. In addition, many cell cycle and apoptosis-related proteins such as p21, p53, survivin or PTEN were evaluated, but in many cases these proteins did not reach significance in multivariate analyses, highlighting that they do not represent independent markers. Other proteins, such as ERCC1 and TS, the target of the antimetabolite drug pemetrexed, did not show consistent results between various studies, hence none of these proteins are used routinely in the clinic. On the level of gene expression, already 15 years ago a 4-gene signature was proposed, which was subsequently independently validated, but never in a prospective fashion. In addition to gene expression, microRNAs have also been proposed to hold prognostic value, but again, independent validation is thus far lacking.

      While many candidate prognostic biomarkers have been proposed, these tend to be dependent on the histological subtype, and the identification of factors predictive of outcome within the individual histological subgroups of MPM patients remains a major challenge. However, with more genetic profiling of larger datasets becoming available also in MPM, investigators have started to address this issue. By aiming to genetically subclassify pathologically purely epithelioid or sarcomatoid tumours, this resulted in the C1/C2 classification [7] and the e-score and s-score classification [8], as well as the 4 cluster iCluster classification generated based on TCGA data [9]. Besides providing potential novel prognostic factors, the molecular characterization of MPM can also provide us with urgently needed deeper insights into the biology of the different subgroups of MPM, which is likely to allow us to identify novel treatment targets together with respective markers predictive of response.

      Nevertheless, these exciting recent findings remain to be independently validated, most importantly in a prospective fashion. A closer look at the literature of the last two decades, however, shows us that rather than aiming at validation of proposed prognostic factors, we are inclined to identify novel candidates. In order to move these promising novel candidates from the bench to the bedside, international collaboration to increase cohort sizes as well as prospective validation will be crucial.

      References:

      1. Curran, D., et al., J Clin Oncol, 1998. 16(1): p. 145-52.

      2. Herndon, J.E., et al., Chest, 1998. 113(3): p. 723-31.

      3. Davidson, B., Hum Pathol, 2015. 46(6): p. 789-804.

      4. Yamagishi, T., et al., Lung Cancer, 2015. 90(1): p. 111-7.

      5. Opitz, I., et al., J Thorac Oncol, 2015. 10(11): p. 1634-41.

      6. Armato, S.G., 3rd, et al., Lung Cancer, 2019. 130: p. 108-114.

      7. de Reynies, A., et al., Clin Cancer Res, 2014. 20(5): p. 1323-34.

      8. Blum, Y., et al., Nat Commun, 2019. 10(1): p. 1333.

      9. Hmeljak, J., et al., Cancer Discov, 2018. 8(12): p. 1548-1565.

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