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Chunxue Bai

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    JCSE01 - Joint IASLC-CSCO-CAALC Session (ID 63)

    • Event: WCLC 2019
    • Type: Joint IASLC-CSCO-CAALC Session
    • Track:
    • Presentations: 24
    • Now Available
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      JCSE01.02 - The Opportunity of Drugs Development on Immunotherapy in China (Now Available) (ID 3416)

      07:00 - 11:15  |  Presenting Author(s): Qing Zhou

      • Abstract
      • Presentation
      • Slides

      Abstract

      Immunotherapy gets the breakthrough after almost 100 years of silence. PD1/PD-L1 inhibitors as the representative have been extensively studied in various human malignant tumors and get promising long term response with relatively fewer adverse events. The first PD1 inhibitor indication was approved for melanoma in Japan on July 2014. Up to now, the US Food and Drug Administration had approved several PD-1 pathway blockade treatments including nivolumab, pembrolizumab and atezolizumab using in first line and second line of NSCLC. In China, nivolumab was approved for second line setting for advanced NSCLC and pembrolizumab combined with chemotherapy were approved for first line setting of advanced NSCLC. Two novel PD-1 inhibitors from Chinese pharmaceutical companies were approved for melanoma and lymphoma by National Medical Products Administration (NMPA) of China. And, a lot of clinical trials about domestic novel PD-1 and PD-L1 inhibitors from Chinese pharmaceutical companies are now ongoing.

      IO arena faces intense in-class competition from both MNC (Multi-National Corporation) and domestic pharmaceutical company in China. Now there are more than 20 IO antibodies from 10 MNCs and 16 pharmaceutical companies in China. Besides PD1/PD-L1 and CTLA4, other hot IO drugs such as IDO or Lag3 et al are also under investigation. Clinical trials about some novel combination, for example, CMET inhibitor plus IO, anti-angiogenesis drugs plus IO, et al, are also ongoing.

      There are special questions which need to be settled in China. Chinese population has relatively high rates of hepatitis B virus infection and much higher proportion of EGFR mutation. The delightful changing recently is some studies emerging to consider the characteristics of the Chinese or Asian populations. Some clinical trials are trying to answer these questions. Besides clinical trials for advanced NSCLC, Clinical trials focus on local advanced NSCLC, early stage NSCLC and SCLC are also ongoing. New adjuvant and adjuvant IO trials have started in China. Most importantly, some novel combinations overcoming previous IO resistance are now on the way, which will give more interesting results in the near future.

      Research about Chinese IO treatment remains in their early stage and further efforts are needed to improve the design of future clinical trials and translational research. Meanwhile, the other hot IO drugs and phase I studies need to speed up in China.

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      JCSE01.03 - Any Difference on Efficacy and Toxicity Between East and West? (Now Available) (ID 3417)

      07:00 - 11:15  |  Presenting Author(s): Jie Hu

      • Abstract
      • Presentation
      • Slides

      Abstract

      Any difference on efficacy and toxicity between east and west?

      Jie Hu

      Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China.

      Abstract

      Lung cancer is now the most commonly diagnosed cancer and the leading cause of cancer related mortality, taking about 1.6 million lives each year. There has been long evidenced that different population display differential sensitivity and safety profiles on different treatment. in addition, many other factors can also influence therapeutic response of patients, such as lifestyle, metabolism, dietary etc. Here we try to explore the impact and underlying mechanism of ethnic difference on response and tolerance of various therapeutic regimens such as cytotoxic chemotherapy, TKIs, antiangiogenic drugs and ICIs.

      Treatment patterns of lung cancer has been transformed over the years, leading to the better outcomes of patients. The 5-year overall survival (OS) rate of advanced NSCLC is less than 5% in the standard chemotherapy era. Although widely used of tyrosine kinase inhibitors (TKIs) prolonged progression-free survival (PFS) and OS in patients harboring driver gene mutations, the long-time survival rate was still low due to acquired drug resistance. Over the last five years, emergence of immune checkpoint inhibitors(ICIs)has greatly improved outcomes of NSCLC with objective response rate (ORR) about 20% and 5-year OS rate nearly 16% in previous treated patients based on multiple clinical trials data. A retrospective review of the SEER database found that Asian population presented with higher percentage of metastatic lung cancer but significantly greater overall survival rate among nine different ethnic groups. Furthermore, among the total Asian population, Chinese has the highest percentage of adenocarcinomas (69.4%). The latest data show mutation rate of epidermal growth factor receptor (EGFR) in Adenocarcinoma is 40.3~64.5% and 75% in certain clinically enriched population such as non-smoking adenocarcinoma. These data can fully explain the better outcomes of TKIs in Asia population.

      There has evidence that different population has different sensitivity and toxicity to different anti-tumor regiments. Studies showed that hematological toxicities of docetaxel were more frequently observed in Japanese compared to US/European patients. In addition, it is reported that docetaxel-induced grade 3/4 neutropenia is higher in Asian clinical trials than non-Asian trials. On the other hand, the discrepancy of dosage regimen between Japanese (60 mg/m2) and western population implies ethnic difference in PK. Similar data of carbo-platin/paclitaxel and irinotecan-based regimens have been reported in many phase 3 or phase 2 trials.

      Meanwhile, there are many studies compared the adverse events of TKIs in different ethnics and data suggested that incidence of ILD caused by gefitinib and erlotinib is higher in Japan (1.2~5.4%) than in the rest of the world.

      Despite promising outcomes of ICIs, the clinical trials for Asia population is still rare now. Checkmate 078 was the first trial to predominantly recruit Chinese NSCLC patients, the ORR of Chinese population was 17%, which is in accordance with Caucasian population. However, according to PMS study of Japan and several published meta-analysis results, Asian patients were more likely to develop pneumonitis with the incidence rate 5.7~9.6% in ICIs mono-therapy and these rate would be increased significantly when combined with other drugs. Many genetic studies have revealed the prevalence of genetic polymorphisms (i.e. mutation of SFTPC, ABCA3; telomere-associated genes like TERT, TERC, RTELI, PARN; SNP of MUC5B etc.) was associated with susceptibility to ILD in Japanese. Understanding characteristics of genomic profile will be of no doubt to facilitate the selection of targeted population of ICIs.

      Except for the toxicity of ICIs, we should pay attention to the drug response of particular groups of population, which were excluded from clinical trials according to the entry criteria of RCT. Among these HBV-infected NSCLC patients seemed to be more emergency as HBV infected population of Asia is accounted for 62% of global HBV burden, therefore, efficacy and toxicity of ICIs on HBV infected NSCLC patients will be discussed based on many clinical trials or real world data.

      In a word, ethnic difference can influence efficacy and toxicity of different treatment options. More genomic mapping and preclinical research should be implemented to explore the relationship between ethnic diversity and varying degrees of response.

      Key word: ethnic, efficacy, toxicity, TKIs, ICIs

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      JCSE01.04 - Neo-Adjuvant Immunotherapy in Lung Cancer (Now Available) (ID 3419)

      07:00 - 11:15  |  Presenting Author(s): Nan Wu

      • Abstract
      • Presentation
      • Slides

      Abstract

      Immune checkpoint inhibitors (ICIs) therapy have been recommended as the standard of care in the first-line treatment strategy of selected advanced non-small cell lung cancer (NSCLC) patients. Effective therapies also needed for NSCLC patients in early-stage, whose failure arises both local relapse and remote metastasis after surgery. Lavin et al revealed that an immunosuppressive microenvironment had developed even in stage I disease, which promoted the investigation of immunotherapeutic regimens in early stage population1. The success of ICIs in the metastatic disease has also generated enthusiasm to initiate clinical trials to evaluate the utility of ICIs as neoadjuvant therapy in the setting of resectable NSCLC2. Theoretically, immunotherapy in patients with early-stage NSCLC may have more favorable antitumor effects due to lack of T cell function depletion and less tumor clonal heterogeneity. However, there are lots of details need to be discussed, and this necessitates a review regarding neoadjuvant immunotherapy topic.

      The fundamental premise on the application of neoadjuvant immunotherapy is the safety and feasibility. In a cohort of 21 patients, Forde et al revealed neoadjuvant nivolumab was associated with well tolerance and few side effects, did not delay surgery and induce a major pathological response (MPR) in 45% of resected tumors2. MPR rate is associated with long term survival outcomes, thus it is considered as a surrogate endpoint for recurrence and survival3.Radiologic assessment of treatment cannot predict pathological response accurately after ICIs therapy. Chest CT might underestimate response rate accurate after neoadjuvant ICIs therapy compared with pathological assessment (10% vs. 45%)2. This phenomenon was postulated to be related with T-cell infiltration and peritumoral inflammation during the early stage of treatment, which was defined as “pseudo-progression” by some experts4. Bott et al analyzed operative details and postoperative outcomes in this cohort. Unexpected perioperative morbidity and mortality was not observed. The rate of conversion was moderately high because of hilar inflammation and fibrosis, which might develop as a result of response to treatment5. The surgical outcomes proved the feasibility and safety of pulmonary resection after neoadjuvant nivolumab monotherapy and encouraged the execution of following neoadjuvant immunotherapy trials relevant to surgical practice.

      In the setting of resectable NSCLC, what is optimal sequence of immunotherapy and surgery? There is no straight evidence available to clear the issue right now. However, differing from perioperative chemotherapy, the administration of ICIs in the preoperative phase while the tumor is in situ might provide greater therapeutic efficacy in terms of elevated and sustained peripheral tumor-specific immune responses compared with adjuvant immunotherapy6. Liu et al proved it through utilizing a murine model of triple-negative breast cancer (TNBC). Therefore, the utilization of ICIs prior to surgery has been presumed to be capable of potentially eliminating micrometastatic disease and thus decrease the risk of recurrence in resectable NSCLC. It was also interesting that mice given neoadjuvant chemotherapy displayed no significant anti-tumor benefit over adjuvant chemotherapy in the same murine model, which was consistent with the results of clinical trials7.

      The optimization of neoadjuvant schemes is underway in resectable NSCLC patients. Since the combination of nivolumab plus ipilimumab showed encouraging clinical activity characterized by a high response rate and durable response in setting of advanced NSCLC8-9, the combination of double ICIs has been incorporated into the neoadjuvant care of resectable NSCLC patients. The NEOSTAR trial randomized patients to receive nivolumab or nivolumab plus ipilimumab before surgery10. The combination therapy was associated with an increased number of tumor-infiltrating lymphocytes compared to monotherapy, suggesting superior therapeutic efficacy in doublet ICIs group. However, higher proportion of patients did not receive scheduled surgery (doublet 23.8% vs monotherapy 8.7%) was a problem need attention.

      ICIs in combination with chemotherapy (ICI-CT) was another direction of neoadjuvant immunotherapeutic schemes. Safety and tolerability of neoadjuvant ICIs combined with platinum-based doublet chemotherapy has been proved in the KEYNOTE-189 trial11and KEYNOTE 407 trial12. NADIM trial is an ongoing phase II, single-arm, open-label multicenter study of resectable stage IIIA N2-NSCLC patients with ICI-CT as a neoadjuvant treatment13. In NADIM trial, pathological response rate was also higher than that assessed by RECIST. Neoadjuvant ICI-CT yields an unprecedented response rate prompting the regimen as the most promising neoadjuvant scenario. All the oncologists are eager to observe the long-term outcomes of NADIM, which would finally revise the standard pathway of curing early stage NSCLC.

      In this new era of immunotherapy for NSCLC, multiple questions remain regarding the integration of immunotherapy and traditional therapy protocol. For instance, whether concurrent chemoradiotherapy combined with ICIs could be a neoadjuvant regimen for resectable stage IIIA (N2) NSCLC? Accrued evidence indicates that radiation could stimulate the immune system via upregulating tumor-associated antigens, augmenting MHC class I surface expression, increasing T-cell tumor-specific CD 8+ T cells, et al14. PACIFIC trial has delineated ICI significantly prolonged overall survival among patients with stage III, unresectable NSCLC following concurrent chemoradiotherapy15. If irradiation could produce systemic effects under ICI and contribute to the development of a broader range of cancer treatments16, surgery would be asked to perform a better local tumor control. Surgery for advanced NSCLC are increasingly expanding in setting of partial or complete treatment response after immunotherapy17. It will indeed take years before we exactly know how to most effectively incorporate ICI into other traditional therapies, including surgery.

      It is always attractive to predict which individuals will have a long-lasting response. Fortunately, neoadjuvant therapy allows for an assessment of treatment effect, as well as pathological response due to the convenience of specimencollection after surgery. Optimal biomarkers should be capable to improve patient selection for ICI treatment. Therapeutic selection based on actionable genomic alterations can clearly delineate patients who will receive survival benefit from a given therapy. However, the same scenario cannot certainly happen for immune-based biomarkers. Some experts deem deescalating therapy of single agent checkpoint blockade should be approached with caution regarding the lack of transformative immune-based biomarker18. Except PD-L1 express and TMB, dynamics of the immune system need to be standardized to ensure the accuracy of results and uniformity across clinical trials19. To capture a perfect biomarker to predict clinical responses to ICIs is an unrealistic goal in the short-term. Further studies are desiderated to identify biomarkers associated with improved survival.

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      JCSE01.05 - Biomarker in Immunotherapy: Myth or Reality? (Now Available) (ID 3418)

      07:00 - 11:15  |  Presenting Author(s): Alfredo Addeo

      • Abstract
      • Presentation
      • Slides

      Abstract
      Background: NSCLC treatment landscape has rapidly evolved with several immune checkpoint inhibitors (ICIs) approved initially in second line as monotherapy and subsequently in first line as either monotherapy or in combination with chemotherapy. The recent presentation at the ASCO 2019 of the 5 years overall survival (OS) of the Keynote 001 has further strengthened the importance and impact of ICIs on patients with NSCLC, showing unprecedented 5 years overall OS. However up to 50-60% of NSCLC patient does not benefit from such a treatment. The need to validate and find out new effective biomarker (BM) remains crucial.

      Discussion: PD-L1 expression is the only approved BM in NSCLC that proved to be predictive of better OS for anti-PD1 (Pembrolizumab). Despite several advantages such as short turnaround time (TAT), relatively simple IHC assay (gone through an harmonized process in the blueprint2) there are several limitations: PD-L1 non expresser could still be responders and benefit form ICIs or in driven mutated NSCLC the PD-L1 level might be very high, generally mediates by the JAK3 pathway, but not being responsive to ICIs for the rarity of T cell infiltrations.

      A new promising BM is the tumour mutation burden (TMB). The prevalence of somatic mutation varies between 0.01 mut/Mb to 400 mutations/Mb. Some of these mutations led to the translation of novel peptide epitopes or neoantigens that should enhance the immunogenicity of the tumour by eliciting T cell repertoire. The hypothesis then is that in case of high TMB ICIs should work better than chemo. So far this has been partially seen in some studies in term of response rate (RR) an progression free survival (PFS) but no study has been designed yet as having primary endpoint better OS in High TMB patients. Furthermore there are several aspects to consider about TMB: TAT is at least 2 week (it the first studies were conducted by using whole exome sequencing), high cost, no clear cut-off, unclear if it should be performed on cancer tissue or circulating tumour DNA (ctDNA) and the most important one the prospective trial has ever validated TMB as predictive of better OS compared to chemotherapy.

      There are several new BM in embryonic phase: role and importance of TILs, immune gene signature, INFgamma relatedmRNAbased signatures, myeloid-derived suppressor cells(MDSCs) or the neutrophil-to-lymphocyte ratio (NLR) at baseline. None of them is ready for prime time but there are ongoing studies that hopefully will validate useful BM to adopt in clinical practice

      Conclusion: are BMs reality? Yes we already have a reliable predictive BM which remains PD-L1 expression. TMB might represent a possible alternative to identify a different subgroup of NSCLC patients. PD-L1 high and high TMB might partially overlap but they highly likely correspond to 2 different patients populations. There is indeed room for improvement and more BMs are needed: possibly simple to adopt in clinical practice, with short TAT and most important showing OS benefit, to definitively move from the myth to the reality.

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      JCSE01.06 - New Era Beyond PD-1/PD-L1 (Now Available) (ID 3420)

      07:00 - 11:15  |  Presenting Author(s): Luis Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Abstract

      Over the past few years, targeting immune checkpoints such as PD-1/PD-L1 (and in some extend CTLA-4) has changed the landscape of lung cancer therapy and largely impacted patients with notable therapeutic benefits. However, not all lung cancer patients respond to immune checkpoint inhibitors and actually only some 15-20% of those with metastatic disease achieve long term survival, reflecting to the complexity of immune checkpoints and daunting tumor resistance. In order to broaden the possibilities of lung cancer immunotherapy, we need to seek alternative immune checkpoints beyond PD-1/ PD-L1, test novel combination strategies of immune checkpoint inhibitors and more conventional treatments, and increase the predictive potential of biomarkers to optimally guide clinical practice. Meanwhile, there are a number of unsolved questions that may require our attention for future better clinical performance.

      The wide range of immune-related adverse effects (irAEs) that accompany immune checkpoint inhibitors can complicate this efficacious immunotherapy and restrict its use in cancer patients. The precise pathophysiology underlying irAEs is frequently unknown, but may be related to breaking the balance of immunologic homeostasis. Although any organ system is possibly influenced, irAEs most commonly involve the gastrointestinal tract, endocrine glands, and skin. Most of the toxic effects are reversible, but deaths due to severe irAEs such as myocarditis and pneumonitis can occur. The serious problem of irAEs particularly requires to define optimal strategies for multidisciplinary and collaborative management, and ad-hoc education programs. Of note, recent data suggest that prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy.

      The clinical therapeutic efficacy of immune checkpoint inhibitors remains controversial. Tumor resistance, primary and acquired, is a daunting challenge that limits the responsiveness to immunotherapy, and deserves intensive investigation. Hyperprogressive disease (HPD) following immunotherapy also deserve adequate attention. Evidence suggests that MDM2 family amplification or EGFR, KEAP and LKB1 aberrations may lead to poor clinical outcomes on IO treatment and may account for the risk of HPD.

      Preclinical and clinical testing of alternative immune checkpoints is mandatory, particularly in programs that coupled a biomarker driven strategy. It is noteworthy that tumor infiltrating T cells can simultaneously express PD-1/PD-L1 along with other immune checkpoints. Also, evidence has delineated that upregulation of compensatory inhibitory molecules such as LAG-3, VISTA, and TIM-3 may mediate tumor resistance to immune checkpoint inhibitors. Understanding the precise molecular mechanisms of different immune checkpoints will benefit the design of effective combination therapies and overcome potential resistance.

      More well-designed combination strategies (antiangiogenics, targeted therapies, chemotherapeutics,...) that can yield remarkable and synergistic clinical benefits are critical for immune checkpoint therapy. To optimize the combination therapies, we should carefully explore effective and safe doses of treatments, sequencing of the agents, appropriate timing, and so on. There is a pressing need to study the indepth mechanisms of the interaction between chemo-radiotherapy or targeted therapy and the immune system. In addition, identifying more combinations of immune checkpoint inhibitors and new treatment approaches such as by-specific antibodies, chimeric antigen receptor T cell (CAR-T) immunotherapy, TILs, modulating the microbioma and tumor vaccines is a tantalizing option.

      Finally, due to the complexity of the immune system, developping and validating a multiparametic model of predictive biomarkers is much required. As mentioned earlier, PD-L1 expression can inform treatment decisions, but its clinical value still needs confirmation in different patient cohorts. Meanwhile, certain genomic tumor aberrations, TMB and TME are future directions for routine clinical practice. Different TIL phenotypes, diverse TCRs, immune gene signatures, and genetic features derived from blood monitoring or TME hold high potential, but are ready for clinical use as yet.

      References

      Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate. Clin Cancer Res. 2017; 23: 4242-4250.

      Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158–68.

      Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017;23(15):4242–50.

      Teixeira VH, Pipinikas CP, Pennycuick A, Lee-Six H, Chandrasekharan D, Beane J, et al. Deciphering the genomic, epigenomic, and transcriptomic landscapes of pre-invasive lung cancer lesions. Nat Med. 2019; 25: 517-525.

      Turajlic S, Sottoriva A, Graham T, Swanton C. Resolving genetic heterogeneity in cancer. Nat Rev Genet. 2019; 20:404-416.

      Rosenthal R, Cadieux EL, Salgado R, Bakir MA, Moore DA, Hiley CT, et al. Neoantigen-directed immune escape in lung cancerevolution. Nature. 2019; 567:479-485.

      Wrangle JM, Patterson A, Johnson CB, Neitzke DJ, Mehrotra S, Denlinger CE, et al. IL-2 and Beyond in Cancer Immunotherapy. J Interferon Cytokine Res. 2018; 38:45-68.

      Naing A HJ, Papadopoulos KP et al. Responses and durability of clinical benefit in renal cell carcinoma treated with pegilodecakin in combination with anti-PD-1 inhibitors (oral presentation). Presented at: European Society of Medical Oncology.2018.

      Naing A, Papadopoulos KP, Autio KA, et al. Safety, antitumor activity, and immune activation of pegylated recombinant human interleukin-10 (AM0010) in patients with advanced solid tumors. J Clin Oncol. 2016;34(29):3562–9.

      Paz-Ares L, Kim TM, Vincente D, Felip E, Lee DH, LeeKH,. Et al. Updated results of M7824 (MSB0011359C), a bifunctional fusion protein targeting TGF-B and PD-L1, in second-line (2L) NSCLC. Annals of Oncology 2018; 29 (suppl_8): viii493-viii547.

      Ben-Avi R, Farhi R, Ben-Nun A, Gorodner M, Greenberg E, Markel G, et al. Establishment of adoptive cell therapy with tumor infiltrating lymphocytes for non-small cell lung cancer patients. Cancer Immunol Immunother. 2018; 67:1221-1230.

      Lan Y, Zhang D, Xu C, Hance KW, Marelli B, Qi J, et al. Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. Sci Transl Med. 2018; 17;10(424).

      Strauss J, Heery CR, Schlom J, Madan RA, Cao L, Kang Z, Lamping E, et al. Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, in Advanced Solid Tumors. Clin Cancer Res; 24(6):1287-1295.

      Zitvogel L, Ma Y, Raoult D, Kroemer G, Gajewski TF. The microbiome in cance immunotherapy: Diagnostic tools and therapeutic strategies. Science. 2018; 23; 359: 1366-1370.

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      JCSE01.09 - A Phase II Umbrella Study of Camrelizumab in Different PD-L1 Expression Cohorts in Pre-Treated Advanced/Metastatic Non-Small Cell Lung Cancer (Now Available) (ID 3423)

      07:00 - 11:15  |  Presenting Author(s): Yi-Long Wu  |  Author(s): Cheng Huang, Yun Fan, Jifeng Feng, Hong-ming Pan, Liyan Jiang, Jin-Ji Yang, Xing-Ya Li, Xiao-Qing Liu, Jiang-Ping Xiong, Yan-Qiu Zhao, Ying Cheng, rui Ma, Jie Wang, Yi-Na Wang, Yan-Hui Liu, Dong-Mei Lin, Wei Shi, Xiang Lin

      • Abstract
      • Presentation
      • Slides

      Abstract
      Background
      The role of PD-L1 expression in 2nd line and beyond non-small cell lung cancer (NSCLC) remains controversial. Camrelizumab (SHR-1210) is a potent anti-PD-1 monoclonal antibody and has shown promising activity in NSCLC in Phase I studies. We report results from the SHR-1210-201 study (NCT03085069), a phase II umbrella study of camrelizumab monotherapy in different PD-L1 expression cohorts in Chinese patients with previously treated advanced or metastatic NSCLC.

      Methods
      Patients who progressed during or following platinum-based doublet chemotherapy were enrolled and assigned to one of 4 cohorts based on PD-L1 expression. Patients with EGFR or ALK genomic alterations were eligible provided they had disease progression with at least one approved tyrosine kinase inhibitor and with ≥50% PD-L1 expression in tumor. All enrolled patients received camrelizumab at 200 mg IV Q2W until loss of clinical benefit. The primary endpoint was objective response rate (ORR), other endpoints included progression-free survival (PFS) and overall survival (OS).

      Results
      As of Aug 1st 2018, of all the 259 patients who underwent screen, 229 cases could be pathologically evaluated. PD-L1 expression were 47.6% (109/229) in PD-L1 < 1%, 27.1% (62/229) in PD-L1 1-<25%, 8.7% (20/229) in 25-<50% and 16.6% (38/229) in 50%. A total of 63.8% (146/229) patients were enrolled. 89.0% of patients had stage IV NSCLC and 54.8% had non-squamous tumor histology. ORR was 18.5% (95%CI: 12.6%–25.8%) in ITT population. Subgroup analysis showed increased PD-L1 expression was associated with better response rate (Table 1). No response was observed in patients with EGFR mutation. The responders had durable response (median: 15.1 months; 95%CI: 5.5–not reached). Median PFS was 3.2 months (95%CI: 2.0–3.4) and median OS was 19.4 months (95%CI: 11.6–not reached) (Table 1). Treatment-related adverse events (AEs) occurred in 87.7% of patients (all Grade); 20.5% had ≥G3 related AE; and 15.8% had related SAE. 21.2% of AEs led to dose interruption and 7.5% led to treatment discontinuation.

      Table 1 - Efficacy data in subgroups
      Population No of pts ORR, % (95%CI)

      PFS (month),

      median (95%CI)

      1YOS, % (95%CI)

      OS (month),

      median (95%CI)

      PD-L1<1% 74

      12.2% (5.7%, 21.8%)

      2.1 (1.9, 3.2) 47.1% (33.8%, 59.2%) 11.6 (7.8, NR)
      PD-L1 ≥1% and < 25% 31 19.4% (7.5%, 37.5%) 3.1 (1.8, 4.9) 76.7% (57.2%, 88.2%) NR (NR, NR)
      PD-L1 ≥25% and < 50% 11 45.5% (16.7%, 76.6%) 6.0 (1.9, NR) 81.8% (44.7%, 95.1%) NR (2.9, NR)
      PD-L1 ≥50% (without EGFR mutation) 25 28.0% (12.1%, 49.4%) 7.6 (3.3, 11.4) 55.2% (32.3%, 73.2%) NR (8.6, NR)
      PD-L1 ≥50% (with EGFR mutation) 5 0 1.7 (1.2, NR) 40.0% (5.2%, 75.3%) 10.3 (1.2, NR)
      ITT 146 18.5% (12.6%, 25.8%) 3.2 (2.0, 3.4) 56.6% (47.3%, 64.9%) 19.4 (11.6, NR)

      Abbreviation: NR, Not Reached.

      Conclusion
      In Chinese patients with previously treated advanced/metastatic NSCLC, camrelizumab demonstrated improved ORR, PFS, and OS compared with historical data of the 2nd line chemotherapy. The efficacy in patients with PD-L1 <1% is similar as the 2nd line mono-chemotherapy, while patients with higher PD-L1 expression derived greater benefit from camrelizumab, the ORR, PFS and OS in patients with PD-L1 ≥25% was comparable to the 1st line doublet chemotherapy in advanced NSCLC. Camrelizumab was well tolerated. This phase 2 data warrant further clinical studies of camrelizumab in NSCLC.

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      JCSE01.10 - Efficacy and Safety of Neoadjuvant PD-1 Blockade with Sintilimab in Resectable Non-Small Cell Lung Cancer (Now Available) (ID 3424)

      07:00 - 11:15  |  Presenting Author(s): Shuhang Wang  |  Author(s): Ning Li, Jianming Ying, Xiuli Tao, Fan Zhang, Ziran Zhao, Yun Ling, Yushun Gao, Jun Zhao, Qi Xue, Yousheng Mao, Wendong Lei, Ning Wu, Jianchun Duan, Yibo Gao, Zhijie Wang, Nan Sun, Jie Wang, Shugeng Gao, Jie He, Hui Zhou, Shuyan Wang

      • Abstract
      • Presentation
      • Slides

      Abstract
      Background
      NSCLC patients who have potentially resectable disease often subsequently relapse after surgery. New therapy that prevents relapse after surgery is desperately needed. In this study, we tested the efficacy and safety of neoadjuvant sintilimab, an anti-PD-1 antibody, for patients with resectable sqNSCLC in China.

      Methods
      All patients had treatment-naïve resectable sqNSCLC (stage IB-IIIA) that was confirmed by histopathology. Patients received two cycles of sintilimab (200 mg IV) on Day 1 and 22. Surgery was performed between Day 29-43. An enhanced PET/CT was obtained at baseline and seven days prior to surgery. Preliminary analysis of safety profile and efficacy was planned after at least 20 patients had received operation.

      Results
      As of Jan. 28, 2019, 22 patients (20 males and 2 females) with sqNSCLC received two doses of sintilimab followed by radical resection. The median age was 61.5 yr (range, 48 to 70). Six (27.3%) and four (18.2%) patients experienced neoadjuvant treatment emergent adverse events (TEAEs) and neoadjuvant treatment-related AEs (TRAEs), respectively. Most of the TEAEs and TRAEs were grade 1 or 2. Three patients achieved radiological partial response: an ORR of 13.6% based on RECIST 1.1. Ten patients (45.5%) achieved a major pathologic response (MPR, ≤10% viable tumor cells), including four (18.2%) had complete pathologic response (no viable tumor cell). There was a direct correlation between pathological response and decrease in the standardized uptake values (SUV) in the primary tumor. Among nine patients with > 30% decrease of SUV, eight had MPR, compared with no MRP response in the 11 patients with ≤30% decrease of SUV.

      Conclusion
      Neoadjuvant sintilimab for sqNSCLC patients was tolerable and the 45.5% MRP rate is encouraging. A decrease in SUV may be predictive of pathologic response after PD-1 therapy in sqNSCLC.

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      JCSE01.11 - Efficacy and Safety of Sintilimab with Anlotinib as First-Line Therapy for Advanced Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 3425)

      07:00 - 11:15  |  Presenting Author(s): Baohui Han  |  Author(s): Tianqing Chu, Runbo Zhong, Hua Zhong, Bo Zhang, Wei Zhang, Chunlei Shi, jialin Qian, Yuchen Han

      • Abstract
      • Presentation
      • Slides

      Abstract
      Background
      Given the synergy effect of immunotherapy and anti-angiogenic therapy in advanced NSCLC, FDA approved atezolizumab plus bevacizumab and chemotherapy as first-line treatment. However, chemo-free first-line strategy of PD-1/PD-L1 inhibitor combining angiogenesis modulator remains to be explored. This is the first trial evaluating sintilimab (anti-PD-1) plus anlotinib (multi-target TKI against tumor angiogenesis and proliferation) in treatment-naive advanced NSCLC patients and is one arm of Phase I anlotinib-based trial (NCT03628521).

      Methods
      Treatment-naive, stage IIIB/IV NSCLC patients aged 18-75 with ECOG PS 0-1 were eligible. Patients with EGFR, ALK or ROS1 mutations were excluded. Participants were given intravenous sintilimab (200mg q3w) and oral anlotinib (12mg/d 2 weeks on/1 week off) until progression or unacceptable toxicity. The primary endpoints were ORR and safety. The secondary endpoints included DCR, PFS and OS. AEs were graded according to CTCAE v4.0.

      Results
      From September-2018 to February-2019, 22 patients were enrolled. Most were male (95.5%), former/current smokers (63.6%) and squamous cell histology (54.5%). 4 had baseline brain metastases. All patients have received at least once tumor assessment as of Jul-3th-2019. Among all, 16 achieved confirmed PR, 6 achieved SD, ORR was 72.7% (49.8%, 89.3%) and DCR was 100% (84.6%, 100%). 6 month PFS rate is 93.8% (95%CI: 63.23%, 99.10%). Overall, sintilimab and anlotinib was well tolerated. 6 (27.3%) had grade 3 and above treatment related adverse event (TRAE). The most common TRAE included fecal occult blood, hyperuricemia, hyponatremia, foot-hand syndrome, etc. 21 patients had baseline PD-L1-evaluated and 18 patients got TMB status (details in table). Notably, 5 of 6 SD patients developed cavities inside, suggesting a synergetic anti-tumor effect from combination regimen.

      Conclusion

      In this interim analysis, sintilimab plus anlotinib showed high ORR (72.7%) and DCR (100%) with tolerable safety profile, supporting worthy of further development from this convenient chemo-free regimen in first line setting.

      table 1.jpg

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      JCSE01.12 - Discussant Oral Abstracts (Now Available) (ID 3426)

      07:00 - 11:15  |  Presenting Author(s): Bob T Li

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      JCSE01.13 - Discussant Poster Abstracts (Now Available) (ID 3427)

      07:00 - 11:15  |  Presenting Author(s): Shun Lu

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      JCSE01.14 - Higher Prevalence of EGFR Mutations Significantly Correlates with Lower PD-L1 Expression in Chinese Lung Adenocarcinoma (ID 3428)

      07:00 - 11:15  |  Presenting Author(s): Shiyue Zhang  |  Author(s): Shiwang Wen, Yuanzhu Jiang, Jun Guo, Xinglong Fan, Xuedong Pan, Yi Dai, Donglin Chen, Kai Wang, Xiaowei Dong

      • Abstract
      • Slides

      Abstract
      Background
      EGFR mutations are more prevalent in lung adenocarcinoma compared with other non-small cell lung cancer and are more prevalent in East Asians compared with the other populations. At the same time, we observed lower PD-L1 Tumor Proportion Score (TPS) in Chinese lung adenocarcinoma patients (pts) compared with that in Chinese lung squamous cell carcinoma pts and we also observed the proportion of PD-L1 positive (TPS >= 1%) in Chinese lung adenocarcinoma pts was lower than that in other multicenter cohorts. Then we hypothesize that the higher prevalence of EGFR mutations in Chinese lung adenocarcinoma pts correlates with lower PD-L1 expression.

      Methods
      The Origimed-based lung adenocarcinoma cohort was a retrospective cohort consisted of more than one thousand Chinese lung adenocarcinoma pts who underwent both NGS panel sequencing and PD-L1 immunohistochemistry (IHC) in a College of American Pathologists (CAP) certified and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory during the year 2017 and 2018. Antibodies used in the PD-L1 IHC assay included 28-8 (sample size = 883) and 22C3 (sample size = 158). Tumor Proportion Score (TPS) was applied. All the slides were reviewed by the same senior pathologist. All the EGFR mutations were manually reviewed in Integrated Genomics Viewer for confirmation. After confirmation, each pts was assigned to EGFR positive group or EGFR negative group. Fisher' s exact test and Student' s t-test were applied.

      Results
      For antibody 28-8, PD-L1 IHC was positive (TPS >= 1%) in 18% (66/370) EGFR positive pts and was positive in 35% (180/513) EGFR negative pts (fisher exact test p value = 1.6e-5). For antibody 22C3, PD-L1 IHC was positive (TPS >= 1%) in 14% (9/64) EGFR positive pts and was positive in 45% (42/94) EGFR negative pts (fisher exact test p value = 3.8e-3). And we observed a significantly lower PD-L1 TPS in EGFR positive pts for both antibodies (t-test p value = 3.5e-11 for PD-L1 antibody 28-8; t-test p value = 6.0e-5 for PD-L1 antibody 22C3).

      Conclusion
      The observation demonstrated that lower PD-L1 TPS in Chinese Lung Adenocarcinoma pts was significantly correlated with East-Asian-specific high prevalence of EGFR mutations. The observation reassured that EGFR mutation status should be examined simultaneously with PD-L1 IHC in lung adenocarcinoma pts because it was a confounding factor for predicting immunotherapy outcome using PD-L1 TPS. The observation partly explained the generally higher PD-L1 TPS in Chinese lung squamous carcinoma pts compared with that in Chinese lung adenocarcinoma pts.

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      JCSE01.15 - Liver Metastases Predicts Poorer Prognosis in Advanced NSCLC Patients Who Receiving Nivolumab Monotherapy (ID 3429)

      07:00 - 11:15  |  Presenting Author(s): Guowei Zhang  |  Author(s): Ruirui Cheng, Huijuan Wang, Zhiyong Ma

      • Abstract
      • Slides

      Abstract
      Background
      Nivolumab is a fully human IgG4 monoclonal antibody targeting the programmed death-1 (PD-1). It's a standard second-line treatment for advanced NSCLC. Liver metastases(LM) is one of the worst prognostic NSCLC metastatic sites, but the attention to LM is far lower than brain metastases and bone metastases.

      Methods
      Patients with stage IIIB-IV NSCLC treated with second-line or later nivolumab monotherapy were retrospectively collected from January 2016 to July 2018. The patients were divided into two cohorts based on the presence or absence of LM at the time of first dose. Study endpoints included OS and PFS.

      Results
      65 patients were included, including 10 patients with and 55 patients without LM. Baseline characteristics of the two cohorts were comparable, as shown in the below table.

      The median OS of the patients with and without LM was 7.5 and 20.7 months, respectively(HR =4.81;95%CI, 1.28-18.00;p=0.020). Their median PFS was 1.9 and 5.6 months, respectively(HR =4.47;95%CI, 1.61-12.35;p=0.004). COX multivariate regression analysis suggested LM was an independent prognostic factor. Kaplan-Meier curves of OS and PFS were shown in the below figure.



      Conclusion
      The outcome of advanced NSCLC patients with LM treated with Nivolumab monotherapy is relatively poor compared with those without LM.

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      JCSE01.16 - Metastatic Lymph Nodes as High Immunogenicity Media for Perioperative Immunotherapy in Locally Advanced NSCLC (ID 3430)

      07:00 - 11:15  |  Presenting Author(s): Chao Zhang  |  Author(s): Si-yang Liu, Jian Su, Xuan Gao, Lian-peng Chang, Yan-Fang Guan, Hai-yan Tu, Jin-Ji Yang, Xu-Chao Zhang, Wen-Zhao Zhong

      • Abstract
      • Slides

      Abstract
      Background
      Perioperative chemotherapy showed limited survival benefit and increased toxicities while neoadjuvant immunotherapy achieved great success in early phase trials. Both inter/intra-tumoral heterogeneity (ITH) between primary lesion and metastatic lymph nodes (mLNs), and rationale of superior efficacy for immunotherapy remained poorly explored in locally advanced non-small cell lung cancer (NSCLC).

      Methods
      We retrospectively collected 6 locally advanced lung adenocarcinoma (LUAD) patients. 15 tissue samples were performed multi-region whole exosome sequencing and TCR repertoire analysis as well as 18 matched metastatic lymph nodes (mLNs).

      Results
      290 somatic mutations in average were identified in primary LUAD (PL) and 441.6 for mLNs. Tumor mutation burden as well as tumor neoantigen burden was significant higher in mLNs than in primary LUAD (median value, 6.6mut/Mb vs. 3.4mut/Mb, P=0.0376; 229.5 neo counts vs. 165 neo counts, P=0.0287). Increased transversion ratio was found in mLNs compared to primary lesions. The genomic concordance between primary lesions and mLNs was 58.4%±12.5% and 33.3% for EGFR-mutation. 87 copy number variants were detected in 14 samples with 3q, 8q and X chromosome as frequently mutated cytobands. Small cell lung cancer functional pathway was enriched in mLNs exclusively. Both expression of PD-L1 and CD8 revealed high level (median value 20% and 40%) and consistence (5/6, 83.3%) between primary and metastatsis lesions. TCR clonality was 17.2% and 9.1% for primary and metastasis lesions, respectively with higher T cell diversity and intra-tumoral heterogeneity of TCR found in mLNs.



      Conclusion
      Extensive genomic and TCR ITH was found between primary LUAD and mLNs which may lead to mixed response to perioperative treatment. mLNs may serve as a better immunogenicity media for perioperative immunotherapy suggesting a potential adjuvant modality of immunotherapy performing lymph nodes sampling during surgery. Results of an initiated single cell sequencing program including paired samples were pending to further provide insights of diverse immune-microenvironment.

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      JCSE01.17 - Modelling the Immunosuppressive Difference of SBRT and CRT by Simulating the Dose to Circulating Lymphocytes in Non-Small Cell Lung Cancer (ID 3431)

      07:00 - 11:15  |  Presenting Author(s): Haihua Yang  |  Author(s): Yichao Shen, Yinnan Meng, Xingni Tang, Pinjun Gu, Changhui Yu, Wei Wang, Feng-Ming Spring Kong

      • Abstract
      • Slides

      Abstract
      Background
      Radiation-dose delivered to circulating lymphocyte (CL) has detrimental effect on immune system for cancer patients. Our study established a model to compare the cumulative dose on CL of patients with conventional fractionation radiotherapy (CRT) and stereotactic body radiation therapy (SBRT) in lung cancer with different target volume.

      Methods
      The improved model is based on convolution algorithm suggested by Yovino(Cancer Investigation, 2013). The current blood DVHs of each organ were multiplied with treatment field DVH to generate original DVHs. During one second, 0.6% of whole-body blood circulates through each organ and rest body according to blood circulating pattern and then new DVHs of organ were generated. The new DVHs would be used for next second’s calculation with treatment field DVH. Conventional fractionated non-small cell lung cancer plan 60Gy (30 fractions*2.0Gy) and SBRT plan 50Gy (5fractions*10Gy) are constructed for three patients with different target volumes. The primary endpoint is peak cumulative blood dose (PCBC).

      Results
      PCBC of three patients with CRT and SBRT were calculated as Figure 1. PCBC with CRT to circulating lymphocyte (CL) were 2.5Gy, 5.6Gy, 9.5Gy in PTV-volume 17cm3, 33cm3, 120cm3, respectively. And PCBC with SBRT to circulating lymphocyte (CL) were 2.1Gy, 2.9Gy, 6.0Gy in PTV-volume 17cm3, 33cm3, 120cm3, respectively. PCBC gap of SBRT to circulating lymphocyte (CL) was decreased 0.4Gy, 2.7Gy, 3.5Gy in PTV-volume 17cm3, 33cm3, 120cm3, respectively.



      Conclusion
      An improved simulation-model was established, SBRT, compared to CRT, will lead to decreased cumulative dose on CL, which may cause less impact on immune system with the enlargement of PTV-volume.

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      JCSE01.18 - A CT-Based Radiomics Approach to Predict PD1 Inhibitor Response in Non-Small-Cell Lung Cancer (ID 3432)

      07:00 - 11:15  |  Presenting Author(s): Jialei Wang  |  Author(s): Shengping Wang, Hui Yu, Chang Liu, Xinmin Zhao, Si Sun, Jianhua Chang, Jie Qiao, Xianghua Wu

      • Abstract
      • Slides

      Abstract
      Background
      The purpose of this study was to investigate the use of radiomics features as predictive parameters of clinical outcomes of non-small-cell lung cancer (NSCLC) patients treated with PD1 inhibitor.

      Methods
      Forty-three stage IIIB/IV NSCLC patients without EGFR mutation or ALK rearrangement who received nivolumab were enrolled between Apr 2016 and Jan 2019. High-dimensional quantitative feature analysis via Pyradiomics was applied to extract 852 radiomics features of pre-anti-PD1 treatment CT. A radiomic score model was constructed from these features with the use of least absolute shrinkage and selection operator (LASSO) Cox regression. The radiomic score for each patient was computed using an equation in which the coefficients were derived from the LASSO Cox model to subgroup patients by progression-free survival (PFS). The median value of radiomic score was used as the cut-off value to cluster patients into high or low score groups.

      Results
      We developed a radiomic signature for PFS that included seven variables. The median value of radiomic score was 0.23. The objective response rate (ORR) was 16.3% (7/43), the median PFS was 2 months and median overall survival (OS) was 3.2 months of all 43 patients. A low radiomic score was associated with a higher ORR (33.7% vs 0%, p= 0.0036), improved PFS (median: 3 months vs 2 months; HR 0.14, 95% CI   0.053-0.39, P < 0.0001) and longer OS (median: 11.2 months vs 7.0 months; HR 0.12, 95%CI 0.04-0.31, p < 0.0001). Multivariate analysis also showed that a low radiomic score was related to better PFS (HR 0.12, 95% CI   0.041-0.32, P < 0.0001) and OS (HR 0.11, 95%CI 0.03-0.28, p < 0.0001).



      Conclusion
      The radiomic signature as an imaging predictor provided a promising way to predict clinical outcomes for NSCLC patients treated with PD-1 inhibitor.

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      JCSE01.19 - Tumor Mutation Score Is More Powerful Than Tumor Mutation Burden in Predicting Response to Immunotherapy in Non-Small Cell Lung Cancer (ID 3433)

      07:00 - 11:15  |  Presenting Author(s): Yuan Li  |  Author(s): Zuhua Chen, Long Wu, Weiping Tao

      • Abstract

      Abstract
      Background
      Tumor mutation burden (TMB) and PD-L1 expression are the two important biomarkers for immune checkpoint inhibitors (ICIs) in lung cancer. However, growing evidences are showing that not all mutations, such as EGFR mutation, are favorable factors in predicting clinical outcome of ICIs and the power of TMB, which is unselective, might be attenuated. Therefore, we developed tumor mutation score (TMS) as better biomarker for response of ICIs in non-small cell lung cancer (NSCLC).

      Methods
      TMS was defined as the number of genes with nonsynonymous somatic mutations. Mutations were detected by targeted next-generation sequencing (NGS) in 240 NSCLC patients treated with anti-PD-(L)1 monotherapy or in combination with anti-CTLA4. Durable clinical benefit (DCB) was defined as complete response (CR)/partial response (PR)/stable disease (SD) that lasted 6 months. TMS, TMB and PD-L1 expression were compared among DCB and no durable benefit (NDB) NSCLC patients.

      Results
      The total TMS was significantly correlated with TMB (R=0.98, P<0.001) and performed almost equally to TMB in the analysis. 12 genes and 11 genes (5 sharing genes) were significantly associated with longer progression-free survival (PFS) and response (DCB vs NDB), respectively. The number of mutated genes within these 18 genes were defined as TMS18. In the survival analysis of PFS, the HRs of the high group were TMS19 (HR=0.307, P<0.001), TMB (HR=0.455, P<0.001), and PD-L1 expression (HR= 0.403, P=0.02), separately. Moreover, patients with DCB had significantly higher TMS18 (P<0.001), TMB (P=0.006), and PD-L1 expression (P=0.032). High TMS18 group had highest proportion of CR/PR/SD patients, which was 74.1% (CR/PR/SD: 3/17/20), especially in distinguishing CR patients. Taken together, TMS18 was more powerful than TMB and PD-L1 in predicting response of ICIs in NSCLC.

      Conclusion
      Simple transformation from unselective TMB to selective TMS greatly enhanced the power of mutations-based biomarkers. TMS in combination with PD-L1 expression might yield better efficiency in predicting response of ICIs in NSCLC with future validation in larger cohorts.

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      JCSE01.20 - Pilot Study on the Tumor Immune Microenvironment Between Non-Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC) (ID 3434)

      07:00 - 11:15  |  Presenting Author(s): Qian Chu  |  Author(s): Wei Zhang, Xun Yuan, Xue Wang, Shanshan Huang, Jingyao Tu, Fangfang Liu, Jin Li, Jing Li, Yuan Chen

      • Abstract

      Abstract
      Background
      Tumor immune microenvironment plays an important role in immunotherapy and prognosis. However, the differences and the clinical significance between non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) is still largely unknown.

      Methods
      Resected lung cancer FFPE specimens and matched peripheral blood mononuclear cells (PBMC) from six patients with NSCLC (three adenocarcinoma, three squamous cell carcinoma) and three patients with SCLC were collected. All of the nine patients underwent stage III disease. Tumor mutation burden (TMB) was evaluated by hybridization capture based next-generation sequencing with 1021 cancer associated genes. Tumor infiltrating lymphocytes (TILs) were assessed by immunohistochemistry using multiple immune markers and meanwhile the intratumoral T-cell repertoires were analyzed via high-throughput sequencing of TCR β-chain.

      Results
      Typical EGFR mutations in adenocarcinoma (2 in 3), NSCLC and RB1 mutations in SCLC (3 in 3) were observed. SCLC patients showed significantly higher TMB than NSCLC. Regarding to the tumor immune microenviroment, SCLC tumors exhibited lower infiltration of CD3+ and CD8+ TILs (P< 0.05). Furthermore, we found that SCLC patients tended to have lower TCR Shannon index (P= 0.167) and higher Clonality index (P= 0.095). Interestingly, patients with higher Shannon index exhibited better Overall Survival (OS) while Clonality was potentially associated with decreased OS. However, further study with more patients is needed to confirm the results.

      Conclusion
      Tumor immune microenvironment varies between NSCLC and SCLC patients. Specifically, less prevalent and lower diversity of TILs were observed in SCLCs. This might potentially influence survival outcomes.

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      JCSE01.21 - Changes of Peripheral Blood sPD-L1 in Patients with Small Cell Lung Cancer During Chemotherapy and Its Clinical Significance (ID 3435)

      07:00 - 11:15  |  Presenting Author(s): Hao Tian  |  Author(s): Xiaoyan Kang, Lin Yang, Haibo Zhu, Wei Guo, Xia Song

      • Abstract

      Abstract
      Background
      As a new immunotherapeutic target, the inhibitors of programmed death 1 (PD-1) and programmed death ligand-1 (PD-L1) pathway have been used to treat a variety of tumors including small cell lung cancer (SCLC). However, the biomarkers now used to predict the efficacy of SCLC immunological checkpoint inhibitors are still in the exploratory phase. The aim of this prospective study was to investigate the prevalence and prognostic roles of soluble PD-L1(sPD-L1 ) protein in the blood of patients with lung cancer.

      Methods
      A total of 94 patients with SCLC who were diagnosed by histopathology or cytopathology between March 2018 to November 2018 were enrolled. Blood samples plasma were collected at the time of diagnosis. 17 samples of healthy subjects matching in sex and age from the Health care Center of the hospital were also studied as control. The level of sPD-L1 protein in the blood was measured using an enzyme-linked immunosorbent assay (ELISA). And the correlation of sPD-L1 expression with tumor stage, distant metastasis, and pro gastrin releasing peptide (ProGRP) was analyzed.

      Results
      Expression of sPD-L1 in SCLC patients was significantly higher than healthy people(P<0.05).A cut-off value of 1.362ng/ml was distinguished in patients according to Receiver operating characteristic curve (ROC). Dynamic changes of sPD-L1 are associated with progressive disease(PD)a, partial response(PR)a and stable disease(SD)b in SCLC patients(a P<0.01,b P>0.05).The expression of sPD-L1 in serum was positively correlated with ProGRP.



      Conclusion
      Our results indicated that changes of plasma SPD-L1 levels in SCLC patients are associated with prognosis. Plasma sPD-L1 protein is a great biomarker in SCLC and may play an important role in sifting the beneficiaries of immunotherapy.

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      JCSE01.22 - Tumor Microenvironment Is Associated with Efficacy of PD-1/PD-L1 Inhibitors in Patients with Primary Pulmonary Lymphoepithelioma-Like Cancer (ID 3436)

      07:00 - 11:15  |  Presenting Author(s): Xu-Chao Zhang  |  Author(s): Kai Yin, Zhi Xie, Zhi Yi Lv, Jin-Ji Yang, Xue-Ning Yang, Qing Zhou, Wen-Zhao Zhong, Lin-Lin Li, Hui-Bo Feng, Wei-Bang Guo, Dan-Xia Lu, Yu Chen, Wen-Qing Yan, Yi-Long Wu

      • Abstract
      • Slides

      Abstract
      Background
      Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is Epstein-Barr (EB) virus related subtype of non-small-cell lung cancer. Evidence of immunotherapy in LELC is scarce. The role of immune markers in tumor microenvironment and their relation with the efficacy of PD-1/PD-L1 inhibitors in LELC remain poorly explored.Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is Epstein-Barr (EB) virus related subtype of non-small-cell lung cancer. Evidence of immunotherapy in LELC is scarce. The role of immune markers in tumor microenvironment and their relation with the efficacy of PD-1/PD-L1 inhibitors in LELC remain poorly explored.

      Methods
      A total of seventeen patients treated with PD-1/PD-L1 inhibitors in Guangdong Lung Cancer Institute were enrolled. We detected multiple immune markers including PD-L1, IDO1, TIM3, LAG3, CD4 and CD8 by immunohistochemistry in eleven of these patients. Dynamic changes of the checkpoint biomarkers in two patients (#10 and #11) treated with PD-1 inhibitors were analyzed. Tumors with 1% TPS (tumor proportion staining) were defined as PD-L1 positive. H-score of PD-L1, IDO1, TIM3 and LAG3 was calculated by multiplying percentage of positively stained cells and intensity score (0, absent; 1, weak; 2, moderate; 3, strong). For CD4 and CD8, the H-score equals the percentage of staining positive lymphocytes among all nucleated cells.

      Results
      In the 17 patients, most of them suffered from lines of chemotherapy (only two patients (2/17, 11.8%) received PD-1/PD-L1 inhibitors as the first line therapy). There are eight males and nine females. The median age was 47 years (range from 13 to 63). All of them were stage IIIB and IV. Thirteen of seventeen patients received single agent PD-1/PD-L1 inhibitor. PD-1/PD-L1 inhibitor showed an 82.4% disease control rate and 17.6% objective response rate. The median progression free survival was 7.4 months. The overall survival was not reached. Biomarkers of IDO1, LAG3, and TIM3 were not mutually exclusive with PD-L1, and could be highly expressed in responder patients to PD1/PD-L1 inhibitors. Notably, TIM3 expression was up-regulated at disease progression in two patients treated with PD-1 inhibitor.



      Conclusion
      PD-1/PD-L1 inhibitors had preliminary good activity, and TIM3 up-regulation might be a mechanism of resistance to PD-1 inhibitors in advanced pulmonary LELC.

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      JCSE01.23 - Specific TP53 Mutation Subtypes as Biomarker for Response to PD-1/L1 Blockade Immunotherapy in NSCLC (ID 3437)

      07:00 - 11:15  |  Presenting Author(s): Hao Sun  |  Author(s): Si-yang Liu, Jia Ying Zhou, Meimei Zheng, Jiao Jiao Huan, Yan Fang Guan, Rui Gao, Xin Yi, Yi-Long Wu

      • Abstract
      • Slides

      Abstract
      Background
      Although TP53 co-mutation with KRAS have been proved to have predictive value for response to PD-1/L1 blockades, not all TP53 mutations are equal in this context. TP53 subtypes as independent factors to predict the response to PD-1/L1 blockade have not yet reported.

      Methods
      We performed an integrated analysis on the multiple-dimensional data types including genomic and clinical data from cohorts of NSCLC public (240 from MSK database) and local databases (224 patient with PD-L1 IHC score, 1986 NSCLC with TMB data). Durable clinical benefit (DCB) was defined as partial response/stable disease that lasted more than 6 months.

      Results
      The presence of mutant TP53 was associated with longer median progression free survival (mPFS) in NSCLC taking PD-1/L1 blockade therapy compared with TP53 wild-type group in the MSK-cohort (4.3 vs2.6 months, P=0.0027, HR=0.6409, 95%CI, 0.49 to 0.88). TP53 frameshift seemed to predict longer mPFS (6.6 months, P=0.0159, HR= 0.41, 95%CI, 0.26 to 0.65) than TP53 wild-type, TP53 missense (mPFS=4.27 months, P=0.17) and TP53 nonsense status (mPFS=2.7 months, P=0.002).NSCLC with TP53 frameshift mutation had a 52.9% rate of DCB, which was higher than TP53 missense (34.4%) and nonsense (21.1%) group. Besides, in the MSK cohort, five of six patients with TP53 truncated mutation in proline-rich (PR) domain (residues 58--101) achieved DCB, and one patient achieved 5.5 months of PFS and did not progress. Fractions of PD-L1 low-positive (1% - 49%) and PD-L1 high-positive (≥50%) tumors between each TP53 mutation subtype and wild-type groups are analyzed based on local data. The TP53 mutation rate was significantly higher in NSCLC with PD-L1 score >50% (P=0.004). But NSCLC with TP53 frameshift showed lower fractions of PD-L1 high-positive (12.5%, 2/16) compared with TP53 missense group (27.5%, 33/120) and TP53 nonsense group (25.8%, 8/31). PD-L1 low-positive rate is also lower in TP53 frameshift group (25.0%, 4/16) than TP53 missense (30.8%, 37/120) and nonsense group (29.0%, 9/31). Among 1986 NSCLC patients with TMB data, each TP53 mutation subtype is associated with significantly higher TMB than TP53 wildtype, especially among NSCLC with TP53 truncated mutation in PR domain (median TMB= 9 mut/Mbs). But no significant difference was found between TP53 mutation subtypes in TMB.



      Conclusion
      ​​​​​​Our study demonstrated heterogeneity among TP53 mutations in predicting the response to PD-1/L1 blockade therapy. TP53 frameshift mutation may contribute to better PD-1/L1 blockade therapy response beyond PD-1/L1 IHC status. And the truncated TP53 mutation in PR domain may contribute to DCB.

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      JCSE01.24 - Dynamic Changes of Plasma PD-L1 mRNA Expression Predict Response to Anti-PD-1/Anti-PD-L1 Treatment in Malignancies (ID 3438)

      07:00 - 11:15  |  Presenting Author(s): Jianguo Sun  |  Author(s): Qiao Yang, Mingjing Chen, Jiaoyang Gu, Linpeng Zheng, Yongxin Yu, Feng Li, Luping Zhang, Kai Niu

      • Abstract
      • Slides

      Abstract
      Background
      PD-L1 expression in malignant tumor tissues is a rational biomarker to predict the efficacy and prognosis of anti-PD-1/anti-PD-L1 treatment, but few studies focus on the role of blood PD-L1 expression.

      Methods
      Fifty-one paired tissue samples and blood samples, as well as clinicopathologic features, were collected from patients with diverse malignancies to investigate the correlation among tissue PD-L1 (tPD-L1) expression, plasma PD-L1 mRNA expression, soluble PD-L1 (sPD-L1) expression and clinicopathologic features. Tissue PD-L1 were measured by immunohistochemistry. PD-L1 mRNA and self-designed plasma inner reference PLACON were measured by quantitative real-time PCR. Soluble PD-L1 were detected by ELISA kit. Then, dynamic changes of blood PD-L1 expression (at baseline and within 2 months) were measured to evaluate the efficacy of patients with malignancies (n=24) who received anti-PD-1/anti-PD-L1 treatment.

      Results
      Moderate correlation between tPD-L1 and PD-L1 mRNA (r=0.62, P<0.001), weak correlation between tPD-L1 and sPD-L1 (r=0.37, P=0.007) and weak correlation between PD-L1 mRNA and sPD-L1 (r=0.32, P=0.02) were found. Most clinicopathologic features had no significant correlation with PD-L1 mRNA and sPD-L1 expression. Interestingly, patients without metastasis had higher PD-L1 mRNA and sPD-L1 expression than counterparts. Further, patients with over 2.03-fold PD-L1 mRNA increase (n=11) during treatment experienced improved progression-free survival (PFS) than those with less than 2.03-fold increase (n=13), these patients also had higher best overall response (bOR) rate (45.45% vs. 7.69%). By comparison, the dynamic changes of sPD-L1 expression had no significant correlation with PFS and bOR.



      Conclusion
      Our study demonstrates that plasma PD-L1 mRNA expression was significantly correlated with tissue PD-L1 expression, and provides proof for the application of plasma PD-L1 mRNA as a predictor for anti-PD-1/anti-PD-L1 treatment.

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      JCSE01.25 - TP53/KMT2C Co-Mutation as a Novel Biomarker for Immunotherapy in Non-Small Cell Lung Cancer Patients (ID 3862)

      07:00 - 11:15  |  Presenting Author(s): Qing Zhou  |  Author(s): Xiaoxiao Peng, Wenjing Wang, Weifeng Wang, Lin Zhang, Kai Wang, Shiyue Zhang

      • Abstract
      • Slides

      Abstract
      Background
      Immune checkpoint inhibitors (ICIs) have shown remarkable antitumor effects in non-small cell lung cancer (NSCLC), however only a subset of patients respond. Genomic alterations (GAs) detected by targeted next-generation sequencing (NGS) is increasingly used in clinical practice, but its correlation with recognized immune biomarkers and predictive value for ICIs response in NSCLC is unclear.

      Methods
      FFPE tumor and matched blood samples of 637 NSCLC patients (84 squamous cell and 553 non-squamous cell) were collected for targeted NGS panel sequencing from December 2017 to January 2019. GAs including single nucleotide variations, short and long insertions/deletions, copy number variations and gene rearrangements were assessed. TMB high (TMB-H) was defined as ≥10 muts/Mb. Positive PD-L1 expression was defined as ≥1% of tumor cells with membranous staining (22C3/28-8, DAKO). Genomic data and ICIs treatment outcome from a 240 NSCLC patient cohort was derived from cBioPortal (MSKCC, J Clin Oncol 2018).

      Results
      In 637 NSCLC patients, the prevalence of PD-L1≥1% was 26.5% and the median TMB was 4.6 muts/Mb (IQR, 2.3-10). Recurrent TP53, KRAS, LRP1B and KEAP1 mutations were significantly correlated with higher TMB (p value). TP53, KRAS and KEAP1 mutations were significantly enriched in the TMB-H/PD-L1+ subset while STK11 mutations were enriched in TMB-H/PD-L1- subset (p value). KMT2C, also known as MLL3, belongs to the mixed‐lineage leukemia (MLL) family of histone methyltransferases and its GAs was found in 5% of our cohort. Tumors with KMT2C and TP53 co-mutations (co-MUT) had a significantly higher TMB (15.1 muts/Mb) than TP53/KMT2C single-MUT (8.7 muts/Mb) and TP53/KMT2C co-WT (3.1 muts/Mb) tumors. Moreover, TMB-H/PD-L1+ subset was enriched in KMT2C and TP53 co-MUT (25%) comparing to TP53/KMT2C single-MUT (14.7%) and TP53/KMT2C co-WT (3.3%) tumors. Survival analysis from public clinical trials confirmed that patients with TP53/KMT2C co-MUT had remarkable clinical benefit to ICIs in both progression free survival (PFS) and durable clinical benefit (DCB). The median PFS was 7.3, 4.2 and 2.5 months for TP53/KMT2C co-MUT, TP53/KMT2C single-MUT and TP53/KMT2C co-WT patients, respectively (p=0.0032). TP53/KMT2C co-MUT was an independent variable of PFS (TP53/KMT2C co-MUT vs. TP53/KMT2C co-WT, HR: 0.47, 95%CI: 0.25-0.89, p=0.0199). Furthermore, TP53 with KMT2C or KRAS co-MUT expanded the patient population benefiting from ICIs (mPFS = 7.2 months, p=0.00042; DCB = 51.2%, p= 0.0195).

      Conclusion
      This study provides evidence that TP53/KMT2C co-MUT may serve as a predictive biomarker for ICIs in NSCLC. GAs detected by targeted NGS could illuminate insight for immunotherapy.

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      JCSE01.26 - PD-1 Inhibitor Plus Chemotherapy as 2nd/Subsequent Line Setting Demonstrate Superior Efficacy over PD-1 Inhibitor Alone in Pts of Advanced NSCLC (ID 3863)

      07:00 - 11:15  |  Presenting Author(s): Shengxiang Ren  |  Author(s): Yiwei Liu, Fei Zhou, Tao Jiang, Chunxia Su, Xiaoxia Chen, Caicun Zhou

      • Abstract
      • Slides

      Abstract
      Background
      PD-1/PD-L1 inhibitors have become standard of care as the 2nd-line setting and also approved as 1st line setting when combined with doublet chemotherapy in patients with advanced NSCLC. This study aims to compare the efficacy of PD-1 inhibitor plus chemotherapy with PD-1 inhibitor alone as 2nd/subsequent lines setting in patients with advanced NSCLC

      Methods
      Patients who received PD-1 inhibitor monotherapy or PD-1 inhibitor plus chemotherapy as 2nd/subsequent lines setting in Shanghai Pulmonary Hospital, Tongji University were retrospectively collected. Detailed clinicopathologic characteristics and therapeutic outcomes were analysis.

      Results
      From January 2016 to February 2019, 148 patients who meet the criteria were included. Among them, 116 were in PD-1 inhibitor monotherapy group and 32 were in PD-1 inhibitor plus chemotherapy group. Chemotherapy regimens were pemetrexed(n=9), docetaxel(n=2), nab-paclitaxel(n=18) and gemcitabine(n=3). The baseline characteristics such as age, gender, smoking status, histology, PD-1 mono-antibodies, line of therapy were similar in the 2 groups. Combination group showed a favorable ORR (28.1% vs. 13.8%, p=0.055) and a significantly longer PFS(median 4.9 vs 2.5 months, p=0.005) compared with ICI monotherapy. Overall survial (OS) data was immature in the cutoff date of follow up. In the subgroup of 96 patients (monotherapy group n=69/ Combination group n=27) who were included as 2nd line setting, PD-1 inhibitor plus chemotherapy had significantly higher ORR(ORR:33.3% vs 18.8%, p=0.129) and longer PFS(median PFS: 4.9 vs 2.9 months, p=0.041).



      Conclusion
      PD-1 inhibitor plus chemotherapy as 2nd/subsequent lines setting demonstrated superior efficacy over PD-1 inhibitor alone in patients with advanced NSCLC.

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      JCSE01.28 - Changes of Brain Structure in Advanced NSCLC Patients Receiving EGFR-TKIs: Dynamic Analysis Based on Series MRI Images (ID 3865)

      07:00 - 11:15  |  Presenting Author(s): Chunli Luo  |  Author(s): Beisheng Yang, Xiaojuan Zhou, Lin Zhou, Ying Zhou, Jiang Zhu, Meijuan Huang, Feng Peng, Yongmei Liu, Yongsheng Wang, Zhiping Li, You Lu, Su Lui, Youling Gong

      • Abstract
      • Slides

      Abstract
      Background
      EGFR-TKI was the standard care for metastatic NSCLC patients harboring positive EGFR mutation, which might inhibit EGF signaling pathway and consequently have effect on differentiation, maturation and rehabilitation of neural cells. For the first time, we evaluated the dynamic changes of white matter lesion (WML) and gray matter volume (GMV) among such patients based on series of MRI images.

      Methods
      We retrospectively identified 778 patients with pathologically diagnosed advanced NSCLC receiving first-generation EGFR-TKIs in our hospital from 2010 to 2017, and 75 patients without brain metastasis and else comorbidity (hypertension, etc.) were analyzed. The modified Scheltens visual scale were performed to evaluate the changes of WML based on the series (baseline, 12 months' point and 24 months' point) of MRI images, and CBM (cluster-based morphometry) method based on SPM12 were adopted to identify GMV loss. The statistical methods were performed using SPSS software 22.0.

      Results
      During the 24-month EGFR-TKI treatment, the patient's WML visual scores showed a progressive worsen. Comparing to the baseline (6.680±3.636), the scores were significantly changed at the 12 months' point (8.650±3.857; Mean scores increasing 1.973, 95% CI 1.595-2.352, p<0.001) and changed more obviously at the 24 months' point (10.110±3.854; Mean scores increasing 3.427, 95% CI 2.979-3.874, p<0.001), respectively. Also, the significant GMV loss were found in subregions of the right occipital lobe (mean decrease 76.714, 95% CI 40.739-112.690), left occipital lobe (mean decrease 93.476, 95% CI 37.483-149.469) and left basal ganglia (mean decrease 37.571, 95% CI 21.576-53.567), respectively (all p<0.005, the cluster level FDR<0.05).

      Conclusion
      Dynamic structural analysis of series brain MRI images showed the significant worsen of the WML and GMV loss in patients with advanced NSCLC receiving EGFR-TKIs chronically. Perspective studies are warranted to verify its impact on the cognitive deficiency and hypomnesis among these patients in future.

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    P1.09 - Pathology (ID 173)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.09-12 - In-Situ Hybridization Visual Scoring of Epigenetic Imprinting Genes Improves Early Diagnosis and Grading of Lung Cancers (Now Available) (ID 1504)

      09:45 - 18:00  |  Author(s): Chunxue Bai

      • Abstract
      • Slides

      Background

      Pathologists rely on cellular morphology to determine cancer diagnosis. However earlier grades (dysplasia) and stages (Carcinoma-in-situ) of cancers which are most treatable have less obvious changes. Epigenetic changes occur at most stages of carcinogenesis, but the application of epigenetic testing in cancer diagnosis is limited. Imprinted genes are normally silenced in one of two parental alleles, but is reportedly reversed in carcinogenesis, with expression of biallelic (Loss of Imprinting-LOI) or multiallelic (Copy Number Variations-CNV) expression (Figure 1A). We present here a novel visual and quantitative approach targeting imprinted genes involved in lung cancer development and progression.

      Method

      The Lisen in-situ hybridization(ISH) targets non-coding introns of imprinted genes to provide a visual and quantitative analysis of malignancy associated changes, unlike bisulfite reduction techniques. Formalin fixed lung cancer and benign lung samples are tested with an epigenetic panel (imprinted genes GNAS, GRB10 and SNRPN) stains. Diagnostic algorithm for a grading model based on LOI, CNV and summed “Total Expression (TE)” counts is developed comparing cancer samples in different stages and benign samples (Figure 1A).

      wclc abstract figure - rex yung.jpg

      Result

      Technicians trained in counting LOI and CNV studied 198 cases of lung samples in a blinded fashion to score LOI, CNV and TE (Figure 1A). These included 29 benign, 20 with Atypical Adenomatous Hyperplasia (peripheral), 11 Adenocarcinoma-in-situ (ADIS), 138 invasive squamous and adenocarcinomas (64 stage 1, 20 stage 2, 54 stages 3&4). A grading model from Grade 0 (benign) to Grade IV (highly malignant) is developed based on the expression pattern of the three genes epigenetic panel to correlate with pathological staging. Grade 0 (benign) corresponds with benign normal, Grade I (malignant potential) corresponds with precancerous AAH, Grade II (limited disease) corresponds to ADIS, Grade III (more invasive) corresponds to stage 1 and 2, and Grade IV (highly invasive) corresponds to stages 3 and 4. (Figure 1B)

      Conclusion

      Imprinted gene detection by ISH staining provides a novel way to visualize and quantify epigenetic changes occurring in earlier stages of lung cancer development. The quantitative grading model can reduce the subjective variation in diagnosis and provide a more precise tool to assist the pathologist. Inclusion of an expanded panel of imprinted genes, studying larger specimen sets and adaptation by automated image analysis hold promise of advancing standardization of early lung cancer diagnosis.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-54 - Imprinted Genes Predict Non-Small Cell Lung Cancer Prognosis (Now Available) (ID 1214)

      10:15 - 18:15  |  Presenting Author(s): Chunxue Bai

      • Abstract
      • Slides

      Background

      Lung cancer (LC) is the leading cause of cancer mortality worldwide, Significant numbers of stage I/II patients after curative surgery present with recurrent and progressive disease. It is critical to identify additional biomarkers to predict prognosis of early stage NSCLC. In carcinogenesis, epigenetic modifications on imprinted genes are changed and lead to biallelic (loss of imprinting, LOI) and multiallelic (copy number variation, CNV) expression. We present here an epigenetic panel involved in NSCLC prognosis.

      Method

      Retrospective study of 123 NSCLC cases with known 5-year survival status. Samples from diagnostic bronchoscopies are subjected to in-situ hybridization targeting non-coding regions to show the expression status of imprinted genes. Total expression (TE), LOI and CNV are counted manually. A statistical model is generated based on the expression status of a 3-imprinting gene epigenetic panel (DCN, PEG10 and SNRPN) to classify the cases. The 5-year survival is used as the only standard for good or poor prognosis.

      Result

      The NSCLS cases can be classified into 4 groups by epigenetic panel. In group A with high expression of DCN, 91.2% (31/34) had poor prognosis, including 8 stage I, 6 stage II, 9 stage III and 8 stage IV. In group B with low expression of DCN and high expression of both PEG10 and SNRPN, 75% (6/8) had poor prognosis. In group C with low expression of DCN and low expression of either or both of PEG10 and SNRPN, 39.5% (30/76) had poor prognosis. In group D with no expression of DCN, PEG10 or SNRPN, 100% (5/5) had good prognosis, even when metastatic and recurrent cases are found, their average survival is more than 8 years.

      Conclusion

      Imprinting Gene epigenetic panel may provide a quantitative assessment of NSCLC prognosis, and complement standard pathologic staging. This explains the poor prognosis of some early stage ca. The prognostic role may help select individual cases for adjuvant therapies. Further studies with expanded epigenetic panel and larger patient sets are planned to refine the classification algorithm, and identify potential predictive biomarkers for specific therapies to advance personalized lung cancer care.

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