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Jin -Ji Yang

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    ES 06 - Communication Skills in the End of Life/ Symptom Management in Lung Cancer (ID 515)

    • Event: WCLC 2017
    • Type: Educational Session
    • Track: Nursing/Palliative Care/Ethics
    • Presentations: 6
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      ES 06.01 - Advanced Directives - Are They Useful? (ID 7605)

      15:45 - 17:30  |  Presenting Author(s): Maiko Fujimori

      • Abstract
      • Presentation
      • Slides

      Abstract:
      It is required to improve patient-physician communication and that patients be offered participation in informed decisions regarding their care ethically in the context of serious and life-limiting illnesses, citing effects of good communication on quality of care and life. Many patients with advanced cancer and caregivers seek empathetic communication from physicians. Inadequate communication about prognosis and treatment choices is common and is associated with unrealistic patient expectations regarding curability, provision of aggressive treatment that is not concordant with patients’ wishes and enrollment in hospice too late to deliver discernable benefit. Conversations related advance directive and advance care planning typically do not happen, or happen in hospital shortly before a patient’s death. In order to complete advance directives and prepare an appropriate advance planning, it is necessary to promote physicians’ empathic communication. Therefore, we developed the 2-day communication skills training (CST) for physicians based on patient preferences and confirmed the effectiveness for both patients’ psychological distress and physicians’ empathetic communication behaviors through a randomized controlled trial. After confirming the effectiveness at RCT, CST was conducted for doctors nationwide as a clinical implementation as a consignment project by the Ministry of Health, Labor and Welfare. Meanwhile, we developed question asking prompt list (QPL) for patients who were newly advanced lung and gastrointestinal cancer use in consultations and confirmed the usefulness through a randomized controlled trial. However, the QPL did not affect the number of actual question from the patient to the physician. It was needed to develop apamphletn intervention with QPL. Furthermore, the evaluation of caregivers is also needed. This presentation aims to determine the effectiveness of an integrated communication support program for promoting empathetic communication between rapidly progressive cancer patients, families and doctors, and to estimate the intervention effects on distress and QOL of patients and caregivers, faith in their physicians. These evidence of an effective intervention to promote communication and decision-making process based patients’ values and preferences between patients, caregivers and physicians with reducing physicians’ burden will be created. Based on the results, we will reflect clinical guideline regarding communication between patients and physicians in cancer care and develop a train-the-trainer workshop program with related academic society. It is also expected that providing supportive therapy at cancer hospitals will be standardized and subsequently the quality of life of cancer patients will be improved.

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      ES 06.02 - Discussing Advance Care Plans - What Do You Say? (ID 7606)

      15:45 - 17:30  |  Presenting Author(s): Florian Strasser

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Patients with advanced, incurable cancer, and also their family members, typically struggle between hopes to have long lives or even get cured and the concious, unconcious or denied reality of limited life time due to cancer. This struggle becomes more pronounced in modern oncology, making predictions of response to anticancer treatments or survival increasingly difficult. Adressing existential issues and uncertainties is an often feared theme for cancer clinicians (doctors, nurses, other professionals) in clinical practice: concerns about destroying hope, hesitation about own professional role (e.g., authentic, paternalistic, servant for patients autonomy), doubts about involvement of family members, incertitude about decisional processes on anticancer treatments, or prudence on patients emotional condition (e.g., stress, trauma, anxiety, depression, anger) may constitute real challenges. Adequate communication skills including empathetic communication and concepts of shared decision making are necessary, but often not suffcient to perform as an accountable, understanding, educating, empowering, self-reflective, and competent clinician guiding patients and families to address the reality of limited live time, death, dying and bereavement. Preparation for illness-deterioration and end-of-life encompasses continuous engagement in a) patients illness understanding (e.g., causes and impact of pain, fatigue, or cachexia); b) decisional processes for or against anticancer treatments (e.g., concrete goals, significance of burdens, characterization of patients values and expressed definition of own quality-of-life); c) worst and best time range scenarios of life expectancy (never say a concrete mean estimate !) These communicative, educational and counselling interventions are part of early integrated palliative care, supported by high quality evidence to improve patients quality-of-life and symptoms. To integrate palliative care early services may adapt the name (supportive) but not the content. Advanced care plans (ACP) shall include most relevant elements to prepare for the end-of-life period, but often they are limited to power of attorney and life-sustaining treatment choices (e.g., POLST, Advanced Directives); evidence suggests that such limited processes may not alleviate existential distress, but still are important. ACP shall encompass a structured process delivered in several encounters of patient and family members with cancer clinicians, built on a trustful relationship invigorated in good decisions, patients values and life concept including spiritual aspects and patients and families’ adequate illness- and prognosis understanding. Evidence supports that ACP do not deteriorate hope and that even in cultures not used to ACP patients welcome them. Key elements of ACP encompass patients’ life values, expressed understanding and preferences of management of typical complications and disease deteriorations, concrete professional support (nurses, specialized palliative care nurses, physicians, other professionals, 24/7), timeschedule of family members offering support, preferred place of death, adressing premortal grief with important people, adressing premortal preparation for postmortal roles, preferences for funeral arrangments, legacy work, finish business including legal & financial issues and words of love, excuse, forgiveness and love, use time left conciously, prepare for prolonged live and lazarus effects. To engage in ACP clinicians may self-reflect about own accountability to have an opinion, offered in a humble, reliable, and attentive way. Also clinicians may embrace concepts of healthy denial and the power of the double way: the reality of death and dying together with promises of modern oncology. In summary it is less the issue of what to say, but how to support the process, offer advice and continuous, accountable support.

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      ES 06.03 - Palliative Management of Dyspnea (ID 7607)

      15:45 - 17:30  |  Presenting Author(s): Keiko Tanaka

      • Abstract
      • Presentation
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      Abstract:
      [Introduction] Dyspnea is one of the most frequent, refractory and distressing symptoms in lung cancer patients. It is reported that dyspnea interferes will to live in terminally ill cancer patients. Palliation of respiratory symptoms is important to improve quality of life (QOL) of cancer patients and their families. [Definition of dyspnea] 'Dyspnea' is defined as 'a subjective experience of breathing discomfort', while 'respiratory failure' is defined objectively as 'pulmonary dysfunction with hypoxia and/or hypercapnia'. Dyspnea and respiratory failure are different entities, and it is shown that the severity of those do not always correlate with each other. [Impact of dyspnea] Dyspnea experience is derived from interactions among physiological, psychological, social, and environmental factors, and may include secondary physiological and behavioral responses. Dyspnea often triggers panic, fear, anxiety, depression, hopelessness, sense of loss of control to patients. Dyspnea is closely associated with fatigue, pain, and depression, and interfering with general activities, mood and enjoyment of life. Dyspnea at rest is also known to correlate with survival, identified as a predictor of poor prognosis in cancer patients. [Clinical Assessment of Dyspnea] As for the assessment of dyspnea, multi-disciplinary team approach and paying attention to patients' own words are important. The assessment should focused on the following three dimensions; 1) quantities (intensity), 2) qualities, 3) symptom impact or burden. Several appropriate scales in each dimensions will be shown in this session. [Management of Dyspnea] Objectives of dyspnea management are to reduce its frequency and severity, minimize its physical, psychological and spiritual distress, and maximize patients' function and QOL. To achieve these goals, the first step is to identify all the underlying causes, and when they are reversible and modifiable, to treat them with specific modalities accordingly. It is, therefore, important for oncologists to judge treatability, including adverse effects, and to estimate patients' prognosis accurately. This session will provide the outline of palliative management of dyspnea with focus on pharmacological and non-pharmacological means. [Pharmacological interventions] The Japanese Society for Palliative Medicine (JSPM) published 'Clinical guidelines for respiratory symptoms in cancer patients' in 2016. These guidelines are unique because they are more directly focused on 'dyspnea' management specifically, based on the formal development process for clinical guidelines. Some of the important recommendations will be introduced in this session. *Note: Strength of recommendation: 1 (strong) = recommended, 2 (weak) = suggested. Level of evidence: A (High), B (Moderate), C (Low), D (Very low) 1) Opioids Systemic morphine is recommended to be used (1B). Systemic oxycodone is suggested to be used, as alternative to morphine (2C), while systemic fentanyl is suggested not to be used (2C). Systemic codeine/dihydrocodeine is suggested to be used (2C). 2) Benzodiazepine anti-anxiety Benzodiazepine is suggested to be used in combination with opioid (2C), while it is suggested not to be used alone (2C). 3) Corticosteroid Systemic corticosteroid is suggested to be used in patients with lymphangitis carcinomatosa, superior vena cava syndrome and major airway obstruction (2D). It is, however, suggested not to be used routinely without consideration of dyspnea etiology (2D). [Non-Pharmacological interventions] The effectiveness of non-pharmacological interventions for dyspnea in advanced cancer and non-cancer (mostly chronic obstructive pulmonary disease) has been reported in Cochrane reviews. Interventions supported by good evidence include breathing training, walking aids, and exercise. Those with some evidence include handheld fan, follow-up programs by nurses and acupuncture/ acupressure. [Conclusion] It is difficult to conduct high-quality clinical research on symptom control in advanced cancer patients because of patients' vulnerability as well as the ethical conflict. More clinical researches of good designs need to be conducted in this field, so that standard palliative care may be delivered to all the cancer patients anytime and anywhere, helping them live their own lives with dignity. [References] 1) Chan K, Tse DMW and Sham MMK. Dyspnoea and other respiratory symptoms in palliative care. In: Cherny NI, Fallon MT, Kaasa S, Portenoy RK, Currow DC. Oxford Textbook of Palliative Medicine (5[th] ed). Oxford University Press, 421-434, 2015 2) Yamaguchi T, Goya S, Kohara H. et al. Treatment Recommendations for Respiratory Symptoms in Cancer Patients; Clinical Guideline from the Japanese Society for Palliative Medicine. J Palliat Medicine. 2016, 19(9): 925-935 3) Bausewein C, Booth S, Gysels M, and Higginson I. Non-pharmacological interventions for breathlessness in advanced stages of malignant and non-malignant diseases. Cochrane Database of Syst Rev. CD005623, 2008 4) Non-invasive interventions for improving well-being and quality of life in patients with lung cancer. Cochrane Database of Syst Rev. CD004282, 2011

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      ES 06.04 - The Lung Cancer Patient, the Nurse and the Rehabilitation Opportunities in Denmark (ID 7608)

      15:45 - 17:30  |  Presenting Author(s): Marianne Cumberland

      • Abstract
      • Presentation
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      Abstract:
      Lung cancer is the most deadly cancer disease in Denmark, one out of four cancer deaths, is due to lung cancer. 4656 Danes are living with a lung cancer diagnosis in late 2015. There are 4700 new cases each year. This means that lung cancer is responsible for 7,8 % of all deaths in Denmark and 24 % of all cancer deaths.[1]Getting lung cancer has major personal consequences - and major consequences for society. There are rehabilitation services for Danish lung cancer patients, and it has a great potential for improvement. The purpose of lung cancer rehabilitation is to support and assist lung cancer sufferers and their relatives, dealing with the changes in everyday life – including at work – that the disease causes. A lung cancer patient in Denmark meets a nurse in many contexts. Nurses are a necessity for the lung cancer patient and rehabilitation in Denmark. I will present a small sample of the rehabilitation possibilities a lung cancer patient meets in Denmark. My focus is, nurse involvement and whether they have sufficient education for the task. Copenhagen Centre for Cancer and Health provides rehabilitation programs including physical activities, education, and discussion groups or sessions. The rehabilitation programs are for cancer patients living in the City of Copenhagen. A referral from the patient´s GP or hospital department is required in order to participate. There are similar centers in many other cities in Denmark. These centers provide good opportunities for lung cancer patients and rehabilitation. At the Health Care Centre, the lung cancer patient meets nurses.[2] “Well, you know – you have symptoms of something and you come here and tell the others about it and they say “I know just what you are talking about, that is how I´m feeling” – it´s a nice experience and makes me feel that I am all right” - Statement from a man with lung cancer, Copenhagen Centre for Cancer and Health The Danish Cancer Society is the largest disease-fighting organization in Denmark. The organization has more than 430,000 members. They have 3 main work areas in the fight against cancer: #prevention of cancer #giving advice to and supporting cancer patient and their relatives #cancer research. Via this organization, the lung cancer patient can talk to nurses and gets the opportunity to receive information, counseling, social networking and you can be anonymous – if you want to.[3] A Danish lung cancer patient can become a member of the Patient Association for Lung Cancer. It is a nationwide independent association for people with lung cancer and mesothelioma, and their families. You can stay up-to-date on lung cancer treatment, health policy, networking and you can also be a part of a community. You can also help put lung cancer on the agenda. There are 500 members in Denmark.[4] In order for the lung cancer patient's possibilities / conditions to improve, there are many projects in Denmark. The Vision Project - a multidisciplinary working group with professionals across the country and dealing with all aspects of the disease, from surgery to palliative care. Action areas are formulated and concrete initiatives made. In this context, there will be a particular focus on rehabilitation that can improve the life quality of lung cancer patients during and after treatment.[5] Social inequality in cancer rehabilitation - The University Hospital in Copenhagen and the Health Care Center in Copenhagen are developing a concept for motivational conversations offered to vulnerable patients. The hospital assesses the need for cancer rehabilitation to those expected to be at risk of saying no to a rehabilitations process. It is a nurse who coordinates the project.[6] Proluca (the value of Postoperative Rehabilitation of Operation for cancer) is a research project in which the effect of early training after surgery for lung cancer is evaluated. The project aims to investigate whether training shortly after surgery for lung cancer can lead to an improved performance in the post-operation phase. It is as a nurse who coordinates the project in the health care center in Copenhagen.[7] Good lung cancer care is related to nurse education. In Denmark the Bachelore’s degree programme in Nursing has a duration of 3 and a half years; you can also get an Advanced Cancer Nurse Education – this requires 1 and a half year of training.[8] Taking care of a lung cancer patient can often be complicated and requires nursing care at a high level. On a global scale, Denmark has a lot to offer lung cancer patients, but there is obviously still room for improvement, since this group of patients faces so many different challenges in their everyday life. And it takes well-educated nurses to meet the complex demands of lung cancer patients. [1] www.lungecancer.dk/ [2] www.kraeftcenter-kbh.dk/ [3] www.cancer.dk/international/ [4] www.lungekraeft.com/ [5] lungecancer.dk/documents/F1BFDA1D-EBFD-409A-A26A-15FF5385F00A.pdf [6] www.kraeftcenter-kbh.dk/projekter/social-ulighed [7] www.kraeftcenter-kbh.dk/projekter/proluca [8] www.dsr.dk/

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      ES 06.05 - Approach to Malignant Pleural Effusions (ID 7867)

      15:45 - 17:30  |  Presenting Author(s): Peter Goldstraw

      • Abstract
      • Presentation
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      Abstract:
      The onset of an MPE usually indicates a significant reduction in prognosis, with a median life expectancy of 3 to 12 months from onset. MPE associated with breast cancer is usually associated with a better than average prognosis whilst lung cancer has the worst prognosis. Confirmation of malignancy and determination of the cell type may be established by increasingly invasive techniques; pleural aspiration cytology, facilitated by ultrasound guidance if the effusion is small or loculated, pleural biopsy, blind or image guided, thoracoscopy (usually now video-assisted) under local or general anaesthesia. Whilst it is reasonable to start with the least invasive procedure suitable in the circumstances, in patients who are reasonably fit it is important to avoid an escalating cascade of failed procedures, each with the risk of causing pleural adhesions and clot formation, making effective palliation more difficult. There is much to commend early acceptance of an approach which combines the best chance of a tissue diagnosis with the best chance of effective palliation. This decision will be influenced by an assessment of prognosis. Prognosis once an MPE has been confirmed is dependent upon the extent of metastatic disease and associated co-morbidity. In a surgically palliated population in-hospital and 30-day mortality was statistically related to blood albumen levels, being 0% and 0.98% in those with normal albumen levels and 6.8% and 19% in those with hypoalbumenaemia (p=0.001) (1). In a series of 278 patients referred to the Department of Thoracic Surgery at the Royal Brompton Hospital over a 72 month period 195 underwent thoracoscopic talc pleurodesis, 39 had a pleuro-peritoneal shunt inserted, 38 had pleurodesis through an intercostal drain, 29 had pleural biopsy alone and 9 were treated with long-term pleural drainage, a total of 310 surgical procedures. Overall median survival was 211 days post operatively. Survival was not significantly different for tumour type or method of palliation but was related to leucocytosis (p<0.0001), hypoxaemia (p=0.014) and hypoalbumenaemia (p0.0001) (2). The summative effect of these factors is shown in the table below. Table 1

      No of factors n Median survival (days) 95% CI p
      None 39 702 473-931 .00001
      One or two 74 200 111-289
      Three 23 42 23-61
      How might this information be used to personalise treatment options in patients for whom effective systemic therapy does not exist. Those whose prognosis is judged to be less than 2 months (having all 3 adverse prognostic factors) palliation may be achieved by repeated pleural aspiration. If prognosis is judged to be greater than 2 months, and especially if the patient is in a poor general condition, adequate palliation could be achieved by the insertion of an indwelling pleural catheter under local anaesthesia. In fitter patients with an estimated survival greater than 6 months VATS insufflation of talc or the insertion of a pleuro-peritoneal shunt should be considered. The choice of talc or shunt will be dictated by the adequacy of lung expansion during positive pressure ventilation. In many respects these 2 techniques are complementary but having both of these techniques available at thoracoscopy allows affective long-term palliation to be achieved in 95% of patients (3). However pleuro-peritoneal shunts can be complicated by occlusion within 4 months in 15% of cases but spontaneous pleurodesis has usually been achieved by this time (4). Pleurectomy is rarely indicated in the palliation of MPE. Reference List (1) Pilling JE, Dusmet M, Ladas G, Goldstraw P. Predictors of early mortality and morbidity follwoing surgical palliation of malignant pleural effusion. Journal of Thoracic Oncology 2[8], s430. 2007. (2) Pilling JE, Dusmet ME, Ladas G, Goldstraw P. Prognostic Factors for Survival after Surgical Palliation of malignant Pleural Effusion. J Thorac Oncol 5, 1544-1550. 2010. (3) Petrou M, Kaplan D, Goldstraw P. The management of recurrent malignant pleural effusions: The complementary role of talc pleurodesis and pleuroperitoneal shunting. Cancer 75, 801-805. 1995. (4) Genc O, Petrou M, Ladas G, Goldstraw P. The long-term morbidity of pleuroperitoneal shunts in the management of recurrent malignant effusions. European Journal of Cardio-thoracic Surgery 18, 143-146. 2000.

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      ES 06.06 - Dignity Conserving Therapy (ID 7609)

      15:45 - 17:30  |  Presenting Author(s): Natasha B Leighl

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Dignity has been defined as the “quality or state of being worthy, honored or esteemed”[1]. While dignity-conserving therapy is popularly defined as assisted suicide in the setting of terminal illness, it may also be considered as a larger goal of palliation and achieving a “good death”. Chochinov has defined 8 subthemes in the conservation of dignity at the end of life, including continuity of self, role preservation, maintenance of pride, hopefulness, autonomy/control, generativity/legacy, acceptance and resilience or fighting spirit [1]. Based on how patients and their caregivers define dignity, different interventions may be used to target or support physical and/or psychological distress, a patient’s level of independence, patient perspectives and interactions with others. Dignity Therapy as developed by Chochinov involves a brief therapy session, which may be delivered at the bedside, transcribed and shared with friends and/or family, to support the patient in his or her desire to live in the moment, maintain normalcy as best as possible and to seek spiritual comfort. More commonly, however, dignity conserving therapy refers to physician-assisted death. This has been legalized in at least 8 countries, including the Netherlands, Belgium, Switzerland, Germany, Luxembourg, Columbia, Canada and 6 states in the USA [2]. In Canada, recent legislation decriminalized medically assisted death. Li et al have reported the University Health Network (UHN, Toronto, Canada) experience of establishing a hospital-based physician-assisted program of medical assistance in dying (MAiD) [2]. Three teams were developed including a clinical team, an assessment team and an intervention team. The clinical team is involved in the usual care of the patient, including nurses, allied health professionals, consulting physicians and the physician most responsible for the patient’s care. Upon patient request, the most responsible physician refers the patient to the hospital MAiD program. At this point, full palliative consultation and support is offered if not already in place. An assessment team of two physicians, with expertise in the assessment of prognosis, patient suffering and capacity or ability to provide informed consent, evaluate the patient (MAiD medical specialist, palliative care physician, psychiatrist). To be eligible for MAiD through the UHN program, a person is required to have health care services covered through the Canadian public healthcare system, to be at least 18 years old and capable of making his or her own health care decisions, and to have a grievous and irremediable medical condition. This includes a serious and incurable illness, disease or disability, to be in an advanced state of irreversible decline in capability, such that the illness or state of decline causes enduring physical or psychological suffering that is intolerable to the person and cannot be relieved by means that the person considers acceptable. Natural death must be reasonably foreseeable based on medical circumstances, the request for medical assistance in dying must be voluntary and the person is required to voluntarily provide informed consent after being informed of alternative means to relieve suffering including palliative care. Disagreements between assessors are resolved through discussion involving leaders of the MAiD program. Once deemed eligible for MAiD, the patient completes a request form for the procedures, followed by a mandatory reflection period of at least 10 days unless death or loss of capacity is imminent. The intervention team, comprised of physicians and/or a nurse practitioner, conducts a final evaluation of the person and ensures they retain capacity before obtaining final informed consent and providing the intervention. Psychosocial professionals are available to provide support to family as needed and to conduct debriefing sessions for staff before and after the intervention. A multidisciplinary quality committee provides oversite and reports to the hospital Medical Advisory Committee. Since the program’s inception in March 2016, 111 inquiries have been received, 39% information-seeking only [Dr. Madeline Li, personal communication]. Of these, 71% have a cancer diagnosis, commonly lung cancer. Other diagnoses include neurologic disorders such as ALS (14%), cardio-respiratory chronic disease including CHF, COPD, and interstitial lung disease (9%). Assessments have been conducted for 41 individuals, 7 were found ineligible, 35 have been approved and 24 have completed interventions. Many of these were already receiving specialty palliative care services. The most common reason for not proceeding with the intervention was clinical decline or loss of capacity. Those that received MAiD cited loss of autonomy as the main reason behind their request [2]. Preserving dignity in the face of incurable lung cancer remains a challenge for patients, families and their health care providers. An individualized approach and involving a multidisciplinary support team including palliative care remains key. References: 1. Chochinov HM. Dignity-conserving care – a new model for palliative care. JAMA 2002;282:2253-60. 2. Li M, Watt S, Escaf M, Garedam M, Heesters A, O’Leary G, Rodin G. Medical assistance in dying – implementing a hospital-based program in Canada. New Engl J Med 2017;376:2082-8.

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Author of

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    JCSE 01 - Joint IASLC/CSCO/CAALC Session: Immunotherapy for Management of Lung Cancer: Ongoing Research from East and West (ID 630)

    • Event: WCLC 2017
    • Type: Joint Session IASLC/CSCO/CAALC
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      JCSE 01.26 - Circulating Cell-Free DNA of Cerebrospinal Fluid May Function as Liquid Biopsy for Leptomeningeal Metastases of ALK Rearrangement NSCLC (ID 10922)

      07:30 - 11:30  |  Author(s): Jin -Ji Yang

      • Abstract
      • Slides

      Background:
      Leptomeningeal metastases (LM) are more frequent in non-small cell lung cancer (NSCLC) patients with oncogenic drivers. Resistance mechanisms of LM with ALK rearrangement remained unclear due to limited access to leptomeningeal lesions.

      Method:
      Primary tumor, cerebrospinal fluid (CSF) and plasma in patients with suspected LM of NSCLC were tested by Next-Generation Sequencing.

      Result:
      In patents with ALK rearrangement, driver genes were detected in 66.7%, 50.0% and 28.6% patients of CSF cfDNA, CSF precipitates and plasma, respectively; and all of them had much higher allele fractions in CSF cfDNA than the other two media. The diagnosis criteria of LM were positive in brain MRI or CSF cytology, and driver genes were identified in CSF cfDNA of all patients with positive CSF cytology while in those CSF cytology negative all genes were negative. Resistance mutations including gatekeeper genes ALK G1202R and ALK G1269A were identified in CSF cfDNA but they were absent in their plasma. Moreover, tailor therapy based on CSF cfDNA obtained surprising outcomes, and genetic profiles of CSF cfDNA showed dynamic changes, suggesting the potential role of CSF for follow-up studies. Figure 1



      Conclusion:
      CSF cfDNA could reveal the driver and resistant genes of LM, and it may function as the media of liquid biopsy for LM in NSCLC with ALK rearrangement.

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    OA 09 - EGFR TKI Resistance (ID 663)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA 09.06 - A Phase Ib Trial of Savolitinib plus Gefitinib for Chinese Patients with EGFR-Mutant MET-Amplified Advanced NSCLC (ID 8995)

      11:00 - 12:30  |  Presenting Author(s): Jin -Ji Yang

      • Abstract
      • Presentation
      • Slides

      Background:
      EGFR-tyrosine kinase inhibitor (TKI) treatment failure has been attributed to innate and/or acquired MET-amplification in patients with advanced EGFR-mutant NSCLC. Savolitinib (volitinib, HMPL-504, AZD6094), a highly selective small molecule MET-TKI, demonstrated greater efficacy combined with gefitinib than either compound alone in preclinical EGFR-mutant NSCLC models (D’Cruz et al. AACR, 2015).

      Method:
      This open-label, multi-centre, Phase Ib study (NCT02374645) assessed savolitinib plus gefitinib in patients enrolled in China with EGFR-mutant advanced NSCLC who progressed on prior EGFR-TKI. Primary objective was safety, tolerability, and identification of recommended Phase II dose (RP2D). Secondary objectives included preliminary anti-tumour activity (RECIST 1.1), pharmacokinetics, and ctDNA analysis for EGFR T790M mutation status. Eligible patients (≥18 years) had measurable disease, radiological disease progression on treatment, ECOG performance status 0/1, and adequate organ function. Patients had central evaluation of EGFR mutation (plasma based BEAMing digital PCR) and central screening for MET-amplification (MET/CEP7 ratio ≥2 or MET gene number ≥5, defined by tumour tissue FISH). Patients received gefitinib 250 mg once daily (QD) plus savolitinib 600 mg QD.

      Result:
      As of data-cut off (March 2017), 44 patients received study treatment. Median age was 61 years, 64% of patients were female; 6 patients were EGFR T790M positive and 5 were T790M negative (interim readout). The most common (≥20% patients) all causality adverse events (AEs), were vomiting (n=18, 41%), nausea (n=17, 39%), rash (n=16, 36%), increased ALT (n=14, 32%), increased AST (n=13, 30%), hypoalbuminaemia and gamma‑glutamyl transpeptidase increase (both n=11, 25%), and increased blood alkaline phosphatase (n=9, 21%). Grade ≥3 all causality AEs were reported in 14 (32%) patients; increased AST and increased ALT (both n=3, 7%) were most frequent. Three (7%) patients died due to an AE (respiratory failure [n=1], lung neoplasm [n=2]); none were considered treatment related. Anti-tumour activity was observed; confirmed partial responses were reported in 11/44 (25%) patients and a further 4 patients are awaiting confirmation of response (confirmed and unconfirmed response rate 15/44 [34%]). At the time of the scheduled 12 week study assessment, 20 (46%) patients remained on study treatment. Preliminary steady-state exposures and pharmacokinetic parameters of savolitinib and gefitinib were consistent with historical data.

      Conclusion:
      These encouraging findings warrant further assessment of savolitinib plus gefitinib for patients with EGFR-mutant, MET-amplified NSCLC who progressed on prior EGFR-TKI. The RP2D was confirmed as savolitinib 600 mg QD plus gefitinib 250 mg QD. This study is ongoing; updated safety and efficacy including anti-tumour activity by T790M status will be presented.

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    OA 10 - Liquid Biopsy for Genomic Alterations (ID 678)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA 10.02 - Unique Genetic Profiles from Circulating Cell-Free DNA of Cerebrospinal Fluid in Leptomeningeal Metastases of EGFR Mutant NSCLC (ID 8258)

      11:00 - 12:30  |  Author(s): Jin -Ji Yang

      • Abstract
      • Presentation
      • Slides

      Background:
      Leptomeningeal metastases (LM) are more frequent in non-small cell lung cancer (NSCLC) with EGFR mutations. Resistance mechanisms of LM remained unclear due to limited access to leptomeningeal lesions.

      Method:
      Primary tumor, cerebrospinal fluid (CSF) and plasma in patients with suspected LM of NSCLC were tested by Next-Generation Sequencing with 168 genes panel. Thirty patients diagnosed as LM and harboring EGFR mutation were enrolled in this cohort, and CSF cfDNA and plasma of two patients and CSF precipitates of another two patients were not available

      Result:
      Driver genes were detected in 100% (28/28) , 85.7% (24/28) and 75% (21/28) patients of CSF cfDNA, CSF precipitates and plasma, respectively; and 92.9% (26/28) patients had much higher allele fractions in CSF cfDNA than the other two media. Unique genetic profiles were captured in CSF cfDNA when compared with those in plasma and primary tissue. Multiple copy number variations (CNVs) were privately detected in CSF cfDNA, and CNVs in patients after TKI failure were more complicated when compared to those TKI naïve before LM. MET copy number gain identified in 44.0% (11/25) patients was the most frequent one, other CNVs included ERBB2, KRAS, ALK, MYC and FGFR1. Moreover, loss of heterozygosity (LOH) of TP53 was identified in 67.9% (19/28) CSF cfDNA, which was much higher than that in plasma (2/28, 7.1%; p<0.001), and there was a trend towards higher rate of concomitant resistance mutations in patients with TP53 LOH than those without one (70.6% vs. 25%; p=0.036 ). EGFR T790M was identified in 28% (7/25) patients with progression to TKIs in CSF cfDNA.

      Conclusion:
      CSF cfDNA could reveal the unique genetic profiles of LM, and it should be the most representative medium of liquid biopsy for LM in NSCLC harboring EGFR mutations.

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    P1.01 - Advanced NSCLC (ID 757)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 3
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      P1.01-009 - Clinically Primary and Secondary Resistance to ALK Inhibitors in ALK-Positive Advanced Non-Small-Cell Lung Cancer (ID 8739)

      09:30 - 16:00  |  Author(s): Jin -Ji Yang

      • Abstract
      • Slides

      Background:
      Crizotinib is a standard of care in anaplastic lymphoma kinase(ALK)-positive advanced non-small-cell lung cancers (NSCLC).Undoubtedly,the resistance to crizotinib is a current bottleneck.Hence,it is necessary to explore the resistance mechanisms to ALK inhibitors.

      Method:
      From October 2010 to May 2017,225 ALK-positive NSCLC patients treated with crizotinib were reviewed at the Guangdong General Hospital in China.The status of ALK rearrangement was assessed by Lysis ALK Break Apart fluorescence in situ hybridization,reverse transcription polymerase chain reaction,or Ventana ALK immunohistochemistry.Next generation sequencing(NGS) was used to test the tissue or plasma from patients with resistance to crizotinib.Primary resistance to crizotinib occurred when Progression-free survival was less than 3 months for the patients treated with crizotinib.

      Result:
      Among enrolled patients,72.4%(163/225) gained secondary resistance,and 8.9%(20/225) had primary resistance.Molecular mechanisms of clinically primary resistance were shown in Figure a.The variants of ALK fusion were different between primary and secondary resistance patients.There were more variants of ALK fusion appeared in the group with primary resistance except E6-A20 and E13-A20.Among secondary resistant patients,non-EML4 partners fusion,such as DMD-ALK fusion,YWHAQ&TAF1B-ALK fusion,GALNT14-ALK fusion and SLC19A3-CCL20-ALK fusion were found,which responsed to crizotinib treatment.Acquired ALK L1196M/G1269A mutations were found in both primary and secondary resistant patients,and while ALK I1171T mutation was only found in secondary resistantpatients.Wnt signaling pathway was activated significantly after the treatment of crizotinib according to Kyoto Encyclopedia of Genes and Genomes(KEGG) and GeneOntology(GO) analyses.Moreover, AMER1 aberrance was inclined to appear in the primary resistance patients, which was significant different between the two groups in KEGG and GO analyses.Figure 1



      Conclusion:
      ALK mutations could exist in both primary and secondary resistance to crizotinib in ALK-rearranged NSCLC. Response to crizotinib was also observed in ALK-rearranged NSCLC patients with non-EML4 partners. NGS may facilitate precision treatment for both primary and secondary resistant patients though they have a few differences in molecular mechanisms of resistance.

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      P1.01-010 - Circulating Cell-Free DNA of Cerebrospinal Fluid May Function as Liquid Biopsy for Leptomeningeal Metastases of ALK Rearrangement NSCLC (ID 8754)

      09:30 - 16:00  |  Author(s): Jin -Ji Yang

      • Abstract
      • Slides

      Background:
      Leptomeningeal metastases (LM) are more frequent in non-small cell lung cancer (NSCLC) patients with oncogenic drivers. Resistance mechanisms of LM with ALK rearrangement remained unclear due to limited access to leptomeningeal lesions.

      Method:
      Primary tumor, cerebrospinal fluid (CSF) and plasma in patients with suspected LM of NSCLC were tested by Next-Generation Sequencing.

      Result:
      In patents with ALK rearrangement, driver genes were detected in 66.7%, 50.0% and 28.6% patients of CSF cfDNA, CSF precipitates and plasma, respectively; and all of them had much higher allele fractions in CSF cfDNA than the other two media. The diagnosis criteria of LM were positive in brain MRI or CSF cytology, and driver genes were identified in CSF cfDNA of all patients with positive CSF cytology while in those CSF cytology negative all genes were negative. Resistance mutations including gatekeeper genes ALK G1202R and ALK G1269A were identified in CSF cfDNA but they were absent in their plasma. Moreover, tailor therapy based on CSF cfDNA obtained surprising outcomes, and genetic profiles of CSF cfDNA showed dynamic changes, suggesting the potential role of CSF for follow-up studies. Figure 1



      Conclusion:
      CSF cfDNA could reveal the driver and resistant genes of LM, and it may function as the media of liquid biopsy for LM in NSCLC with ALK rearrangement.

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      P1.01-018 - Acquired Resistance to Crizotinib in Advanced NSCLC with De Novo MET Overexpression (ID 10014)

      09:30 - 16:00  |  Author(s): Jin -Ji Yang

      • Abstract
      • Slides

      Background:
      MET exon14 skipping mutation has been regarded the driver mutation for MET activation, but with relatively low frequency of occurrence. MET overexpression can be a promising biomarker to predict the response to crizotinib. However, little is known about acquired resistance to treatments in tumors with de novo MET overexpression.

      Method:
      This prospective observational study included 33 NSCLC patients with MET IHC overexpression received crizotinib treatment From January 2013 to June 2017, 23 eligible patients evaluable for response . MET expression level were detected by immunohistochemistry (IHC) with antibody SP44, and ≥50% tumor cells with moderate to high intensity staining were defined as positive. Gene copy numbers were detected by FISH (Met probes from KREATECHTM.), and referring to Cappuzzo scoring system or MET/CEP7 ratio, ≥5 copies were positive or MET/CEP7 ratio ≥1.8 (low ≥1.8-≤2.2, Intermediate >2.2-<5 and High ≥5) was defined as MET amplification;. The status of EGFR, ALK, KRAS and ROS1 were also tested at baseline. Biopsy specimens obtained both at baseline and at the time of progression using targeted next-generation sequencing to assess for mechanisms of resistance.

      Result:
      Response were evaluable for 23 NSCLC patients with MET overexpression (4 female, 19 male). Fifteen of them achieved partial response (PR, 65.2%), 2 were stable disease (SD) and 6 were progressive disease (PD). All responders had high MET expression , and 12(52.2%) with FISH positive. The PFS and OS in the ITT population were 3.2 and 13.2 month respectively. Median PFS was 7.4m(95% CI,4.5-10.4) for MET IHC (100%+++) patients vs. MET IHC (50%++~100%+++) 1.9m (95% CI 0.9-2.9,P=0.053), For FISH positive patients, mPFS was 8.2 m(95% CI,5.2-11.1) m v.s. FISH negative 1.3m(95% CI,0.2-1.7,p=0.002). Two acquired resistance mechanisms were found after resistance, a 64 male patient with MET IHC 100%×3,FISH (+),crizotinib first line and the best response PR, rebiopsy after resistance showed the MET D1228N mutation by NGS, and the second patient was 50 years old male with MET IHC 100%×3,FISH (+),crizotinib first line and the best response was PR, EGFR amplification were found upon progression when rebiopsy after resistance. The patient acheived PR with subsequent treatment of cetuximab plus Taxel.

      Conclusion:
      Multiple mechanisms of acquired resistance to crizotinib were found in de novo MET overexpressed patients. A secondary mutation in the MET gene and EGFR amplification may be the two main mechanisms. MET overexpression could be as a biomarker for de novo MET positive NSCLC. FISH seems better in predicting efficacy for MET inhibitor.

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    P1.07 - Immunology and Immunotherapy (ID 693)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      P1.07-042 - PD-L1 and CD8 Expression in EGFR-Mutant or ALK-Rearranged Patients with Lung Cancer (ID 10407)

      09:30 - 16:00  |  Author(s): Jin -Ji Yang

      • Abstract
      • Slides

      Background:
      Several studies indicate no response to check-point inhibitors on non-small-cell lung cancer with either EGFR-mutant or ALK-rearranged patients,of whom majority of international clinical trials involving PD-1/L1 inhibitors excluded. No solid evidences to interpret the underlying mechanism of poor clinical benefit to patients through PD-1/L1 inhibitors with driver genes mutation.

      Method:
      From 2010 to 2016, 482 patients and 263 patients with clinically operable lung cancer and advanced lung cancer respectively were collected at Guangdong Lung Cancer Institute (GLCI). All patients have detected for EGFR as well as ALK status. CD8 and PD-L1 expression was scored by immunohistochemistry with SP142 antibody. Five years survival rate was also analyzed.

      Result:
      Patients were assigned to EGFR/ALK positive group (344 cases) or negative group (401 cases). EGFR/ALK positive group contains 5.52% PD-L1+/CD8+; 11.92% PD-L1-/CD8+; 18.90% PD-L1+/CD8- and 63.66% PD-L1-/CD8-. EGFR&ALK negative group contains 13.97% PD-L1+/CD8+; 6.98% PD-L1-/CD8+; 30.42% PD-L1+/CD8- and 48.63% PD-L1-/CD8-. In EGFR/ALK positive group, PD-L1+/CD8+ is lower but PD-L1-/CD8- is higher than that of EGFR&ALK negative group (P<0.001). Significant statistical differences of 5 years survival rate were observed between four subgroups in EGFR/ALK positive group (PD-L1+/CD8+:41.9%, PD-L1-/CD8+: 91.0%, PD-L1+/CD8-: 75.4%, PD-L1-/CD8-: 69.7%; P=0.003). And there were no survival differences in EGFR&ALK negative group((PD-L1+/CD8+: 66.5%, PD-L1-/CD8+: 76.9%, PD-L1+/CD8-: 62.3%, PD-L1-/CD8-: 70.6%; P=0.341).

      Conclusion:
      Immunotherapy with PD-1/L1 inhibitors may not be suitable for EGFR-mutant or ALK-rearranged lung cancer patients with little co-expression of PD-L1 and CD8. However, these patients with such diver genes mutation reveal the best survival in PD-L1-/CD8+ subgroup and the worst survival in PD-L1+/CD8+ subgroup. Figure 1



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    P1.13 - Radiology/Staging/Screening (ID 699)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Radiology/Staging/Screening
    • Presentations: 1
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      P1.13-001 - T1 Tumor(≪3cm) with Visceral Pleural Invasion Should Be Classified as T2a in the 8th TNM Classification for Lung Cancer (ID 9004)

      09:30 - 16:00  |  Author(s): Jin -Ji Yang

      • Abstract
      • Slides

      Background:
      The eighth edition TNM classification for lung cancer subclassified T2 into T2a (>3 to ≤4cm) and T2b (>4 to ≤5cm). T1 tumor(<3cm) with visceral pleural invasion(VPI) should be classified as T2a or T2b remain unclear. To elucidate this, we analyzed the survival of non–small-cell lung cancer(NSCLC) patients from Surveillance, Epidemiology and End Results (SEER) registry and our institute.

      Method:
      Within the SEER database, we selected 24245 resected pN0 NSCLC patients from 2010 to 2013 with a special interest in the prognostic impact of VPI. The VPI was defined as including PL1 and PL2 according to the TNM system. The classification of T1 tumor with VPI was investigated via discriminative power of survival curves. The further validation set was selected from Guangdong Lung Cancer Institute (GLCI).

      Result:
      The overall survival (OS) and lung cancer specific survival (LCSS) of T1-VPI and each stage (size only) were compared. The survival differences were statistically significant between T1-VPI and T1c, as well as T1-VPI and T2b. There were no significant survival differences between T1-VPI and T2a (OS: p=0.706; LCSS: p=0.792). And we retrospectively collected pN0 NSCLC patients between 2011-2013 from GLCI. The progression-free survival(PFS) and OS differences were also observed between T1-VPI and other groups except T2a (PFS: p=0.852; OS: p=0.970).

      Conclusion:
      In the 8th TNM classification for lung cancer, in which T1 tumors with VPI are upgraded to T2a, rather than T2b. Figure 1



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    P2.03 - Chemotherapy/Targeted Therapy (ID 704)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      P2.03-054 - EGFR Mutation with Acquired C-MET Positive Reveals Potential Immunotherapeutic Vulnerabilities (ID 10436)

      09:30 - 16:00  |  Author(s): Jin -Ji Yang

      • Abstract
      • Slides

      Background:
      There are few effective strategies for C-MET positive advance non-small-cell lung cancer(NSCLC) patients with epidermal growth factor receptor(EGFR) inhibitor resistance.The efficacy of PD-1 blockade immunotherapy and even the status of PD-L1 expression in such population is unclear.

      Method:
      Patients diagnosed as advanced NSCLC synchronously tested for EGFR status, expression of PD-L1 and C-MET at the Guangdong Lung Cancer Institute (GLCI) from 2015 to 2017 were collected.PD-L1 expression on tumor cells and immune cell was evaluated using a three-tiered grading system. C-MET positive was define as immunohistochemistry staining (2+/3+) in ≥ 50% of tumor cells. A chi-squared test was used to assess the relationships between C-MET positive and PD-L1 expression.

      Result:
      A total of 487 eligible cases were selected including 166 EGFR mutant and 321 wild type patients.In the general population(n=487),the difference of PD-L1 expression were observed between C-MET positive group and C-MET negative group (65.3% vs 31.7%, P=0.001),which was in accordance with the result from the Cancer Genome Atlas (TCGA) dataset (n=512,P<0.001).Furthermore,among the EGFR mutant patients (n=166), PD-L1 expression was showed in 58.1% of C-MET positive group and 28.5% of C-MET negative group,P value <0.001. Subsequently,T790M negative was identified in 55%(47/86) of EGFR TKI resistant patients (n=86).In this subgroup,a significant increase of PD-L1 expression was demonstrated in C-MET positive group compared to C-MET negative group(66.7% vs 34.6%,P=0.027).Finally, clinical efficacy of immunotherapy was further confirmed in 2 C-MET positive advanced lung adenocarcinoma patients with remarkable response to PD-1 blockade immunotherapy who had disease progression after C-MET inhibitors.Figure 1



      Conclusion:
      C-MET positive maybe associated with high PD-L1 expression in advanced NSCLC providing therapeutic insight into targeting the PD-1/PD-L1 pathway in EGFR inhibitor-resistant NSCLC with C-MET positive and T790M negative.

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    P3.01 - Advanced NSCLC (ID 621)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 3
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      P3.01-051 - Dramatic Response to Afatinib in EGFR-Mutant Lung Adenocarcinomas After Resistance to First-Generation EGFR Inhibitors: A Brief Report (ID 9706)

      09:30 - 16:00  |  Author(s): Jin -Ji Yang

      • Abstract
      • Slides

      Background:
      T790M inhibitor, a third-generation epithelial growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), was significantly superior to chemotherapy for EGFR-mutant patients with advanced non-small-cell lung cancer (NSCLC) harboring T790M mutation after resistance to the first-generation EGFR-TKIs. However, for those without acquired T790M mutations or MET amplification, few data showed whether the second-generation EGFR-TKI could overcome resistance to the first-generation EGFR-TKIs.

      Method:
      EGFR mutation was detected by amplification refractory mutation system (ARMS) technology. Overexpression of MET was determined by immunohistochemistry (IHC), and MET amplification was detected by FISH. Next generation sequencing (NGS) was used to test tumor tissues before and after resistance to TKIs.

      Result:
      Patient 1 was a 53-year-old Asian male, who underwent surgery followed by adjuvant chemoradiotherapy with an 11 months of disease-free survival. A biopsy was performed and revealed an activating deletion mutation in exon 19 of the EGFR. He started gefitinib 250mg once daily and achieved an initially good partial response (PR) followed by continuously stable disease for a progression-free-survival (PFS) about 29 months. A rebiopsy showed that exon 19 deletion mutation still existed without an acquired T790M mutation or MET amplification. He refused to receive chemotherapy so we prescribed afatinib 40mg daily. He then achieved a dramatic PR 23 days later which was confirmed 1.5 months after that. We sent tumor tissue of the patient before and after TKI therapy for NGS, the result showed a decreasing abundance of EGFR exon 19 deletion without T790M mutation, MET amplification and Her2 mutation/amplification. Patient 2 was a 63-year-old Asian female harboring EGFR exon 20 insertion (A763-Y764 ins), who received first and second lines of chemotherapy with short PFSs. He was enrolled in the trial of allitinib (AST-1306) as the third line therapy with the best response of stable disease(SD) and the PFS of 7 months. A later rebiopsy showed the strong overexpression of MET, but the forth-line therapy crizotinib failed. He then received chemotherapy as the-fifth line therapy, 4 cycles later he progressed. So he started afatinib 40mg daily. His symptoms were relieved significantly 5 days later, and PR was confirmed 1.5 months later.

      Conclusion:
      Afatinib might overcome resistance to the first-generation EGFR-TKIs for EGFR-mutant patients with advanced NSCLC without acquired T790M mutation or MET amplification. Further investigations are warranted.

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      P3.01-052 - The Prevalence and Genotype Distribution of Dual in Cis EGFR Mutations in Chinese Advanced Non-Small Cell Lung Cancer Patients (ID 9721)

      09:30 - 16:00  |  Author(s): Jin -Ji Yang

      • Abstract
      • Slides

      Background:
      The prevalence of EGFR mutation has been well elucidated in different ethnicities. Recently, increasing attention has been given to dual EGFR mutations. However, less attention has been invested in dual in cis EGFR mutations. Until now, none of retrospective or prospective research has focused on dual in cis EGFR mutations except case reports.

      Method:
      In this real world study, we performed capture-based ultra-deep targeted sequencing on circulating tumor DNA to identify and investigate the prevalence and genotype distribution of dual in cis EGFR mutations in 3,000 Chinese advanced NSCLC patients. This cohort consisted of both treatment-naïve and previously treated patients. Ten milliliter of peripheral blood was collected from every patient and a minimum of 50ng of ctDNA was needed for library construction. The panel covered critical exons and introns of 168 genes (160kb of human genomic regions).

      Result:
      1,266 patients harbored EGFR mutant in this cohort; among them, 501 patients harbored 19 deletions, 489 harbored L858R, and the remaining harbored other EGFR mutations. We identified 1.5% patients (19/1,266) harboring dual in cis EGFR mutations. Among them 37% (7/19)carried two rare EGFR mutations and the remaining 63% (12/19) carried EGFR L858R in combination with a rare mutation. No patient carried EGFR 19 del in combination with other rare mutations was identified in this cohort, suggesting EGFR 19del is a stronger oncogenic driver than EGFR L858R (p=0.000197, Fisher’s exact test). For patients carried two rare mutations, both mutations were either located on exon 18 or exon 21. The allelic fractions (AF) of both mutations were similar. The AF of either EGFR mutations was the maximum AF in all patients, demonstrating the clones harboring EGFR mutations were major clones. Interestingly, 1 patient carried additional KRAS mutation and 2 patients had EGFR amplification.

      Conclusion:
      In cis dual EGFR mutation was rare (1.5%) in EGFR mutant Chinese advanced NSCLC patients. EGFR L858R was significantly more likely to couple with a rare in cis dual mutation than 19 del. EGFR 19del might be a stronger oncogenic driver than EGFR L858R.

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      P3.01-063 - Concomitant EGFR Mutation and ALK Rearrangement in Non-Small-Cell Lung Cancer (ID 10058)

      09:30 - 16:00  |  Author(s): Jin -Ji Yang

      • Abstract
      • Slides

      Background:
      The concomitance of epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). We investigated the factors associated with the efficacy of targeted therapy and resistance mechanisms in EGFR/ALK co-altered NSCLCs.

      Method:
      EGFR mutation was identified with direct sequencing or Scorpion amplification refractory mutation system (ARMS). Relatively low EGFR-mutant abundance is considered as sequencing (-)/ARMS (+), while high abundance as sequencing (+). ALK-positive is assessed with any of the 3 methods: fluorescence in situ hybridization (FISH), rapid amplification of cDNA ends -coupled polymerase chain reaction and sequencing or Ventana immunohistochemistry (IHC). Next-generation sequencing was employed to analyze genetic profiles in patients with specimens before and after targeted therapy.

      Result:
      From December 2011 to December 2016, sixteen patients were identified with concomitant EGFR/ALK co-alterations, accounting for 0.6% (16/2632) in NSCLC patients, 1.8% (16/867) in EGFR-mutant and 8.6% (16/185) in ALK-positive patients. Five ALK-IHC (-)/FISH (+)/EGFR (+) patients with EGFR-TKIs experienced 3 PR, 1 SD and 1 waitiing for response evaluation, with median PFS of 11 months. Three with relatively low EGFR-mutant abundance achieved PR with crizotinib, while three with relatively high EGFR-mutant abundance obtained 2 PR and 1 SD with EGFR-TKIs. Spatial and inter-tumoral heterogeneity was observed in one EGFR/ALK co-altered patient. (Figure 1B) Two patients with T790M, one with Met pathway activation and two with loss of EGFR mutation were found after resistance to EGFR-TKIs. One with KRAS mutation was found pre- and post-EGFR-TKIs. ALK_F1174C mutation was observed in one patient after progression to crizotinib and ALK_G1202R mutation after resistance to ceritinib.Figure 1



      Conclusion:
      ALK protein expression, EGFR mutation abundance and tumor heterogeneity were associated with efficacy of targeted treatment for EGFR/ALK co-altered patients. Most mechanisms resistance to EGFR-TKIs and crizotinib were similar to those in typical EGFR mutation and ALK rearrangement respectively.

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