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Yi-Long Wu

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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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    EP1.14 - Targeted Therapy (ID 204)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.14-49 - A Phase IIIb Open-Label Study of Afatinib in EGFR TKI-Naïve Patients with EGFRm+ NSCLC: Exploratory Biomarker Analysis (Now Available) (ID 1265)

      08:00 - 18:00  |  Author(s): Yi-Long Wu

      • Abstract
      • Slides

      Background

      The safety and efficacy of EGFR TKIs in patients with EGFR mutation-positive (EGFRm+) NSCLC have previously been demonstrated. Here, we present results of a biomarker analysis from a subset of patients in a Phase IIIb study of afatinib in EGFR TKI-naïve patients with locally advanced/metastatic EGFRm+ NSCLC. The aim was to explore the relationship between tumor mutation type, and patients’ response to afatinib in terms of efficacy and tolerability.

      Method

      Patients with EGFR TKI-naïve EGFRm+ NSCLC received 40 mg/day afatinib until lack of clinical benefit (determined by investigator). The primary endpoint was incidence of serious adverse events (SAEs). Secondary endpoints were number of patients with drug-related AEs, and time to symptomatic progression (TTSP). Further endpoints included progression-free survival (PFS). For biomarker analysis, peripheral blood samples were collected during scheduled visits from patients entering the study at Beijing Cancer Hospital. DNA extracted from samples collected at Visit 3 and baseline was analyzed for EGFR and pre-specified non-EGFR mutations, respectively, using an amplification-refractory mutation system.

      Result

      In total, 64 patients were included in the biomarker analysis. Baseline characteristics: Chinese, 100%; female, 70.3%; mean age, 57.4 years; EGFR mutations: L858R, 50%; Del19, 42.2%. All patients experienced ≥1 drug-related AE, most commonly (grouped terms; any grade/≥3): diarrhea (n=63/9, 98.4%/14.1%) and rash or acne (n=52/5, 81.3%/7.8%). SAEs were reported for 15 patients (23.4%), most commonly cerebral infarction (n=3, 4.7%), malignant neoplasm progression, CNS metastases (both n=2, 3.1%). Median TTSP was 13.5 months (95% CI: 10.9, 18.0). At baseline, 19 of 42 patients analyzed (45.2%) had additional non-EGFR mutations; 17 (89.5%) progressed/died. Median PFS was 8.1 months in these patients, versus 12.5 months for patients with EGFR-only mutations (HR, 1.72; 95% CI 0.88, 3.36; p=0.1054). At Visit 3, mutation status had changed from EGFRm+ to EGFR mutation-negative in 33 of 40 patients analyzed (82.5%). Of these, 29 (87.9%) progressed/died; median PFS was 11.0 months versus 5.5 months for patients who remained EGFRm+ (HR, 1.25; 95% CI: 0.47, 3.30; p=0.6556).

      Conclusion

      In this analysis, safety data were consistent with the known safety profile of afatinib. Median PFS was twice as long in patients who became EGFR mutation-negative compared with those who remained EGFRm+; however, the difference was not statistically significant. There was no significant difference in PFS for patients with additional non-EGFR versus those with EGFR-only mutations. This exploratory analysis suggests that afatinib has clinical benefit for patients with EGFRm+ NSCLC across all the subgroups assessed.

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

    • Event: WCLC 2019
    • Type: Joint IASLC-CSCO-CAALC Session
    • Track:
    • Presentations: 3
    • Now Available
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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

      • 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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      JCSE01.22 - 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  |  Author(s): 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  |  Author(s): 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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    MA09 - EGFR & MET (ID 128)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA09.09 - Long-Term Outcomes to Tepotinib Plus Gefitinib in Patients with <i>EGFR</i>-Mutant NSCLC and MET Dysregulation: 18‑Month Follow-Up (Now Available) (ID 1783)

      15:15 - 16:45  |  Presenting Author(s): Yi-Long Wu

      • Abstract
      • Presentation
      • Slides

      Background

      In EGFR-mutant NSCLC, MET amplification may cause resistance to EGFR tyrosine kinase inhibitors (TKIs). In a Phase Ib/II study in EGFR TKI-resistant patients with EGFR-mutant MET+ NSCLC, progression-free survival (PFS) and objective response rate (ORR) after ≥6 months of follow-up were improved with tepotinib (a highly selective MET TKI) plus gefitinib, compared with chemotherapy, particularly in patients with MET amplification. Here we present data at ≥18 months of follow-up.

      Method

      Asian patients with advanced, EGFR+, T790M-, MET+ NSCLC with resistance to prior EGFR TKIs were randomized to receive oral tepotinib 500 mg/day+gefitinib 250 mg/day or ≤6 cycles of cisplatin/carboplatin+pemetrexed chemotherapy±pemetrexed maintenance until confirmed progression, unacceptable toxicity, or withdrawal. Primary endpoint was investigator-assessed PFS. Secondary endpoints included ORR, overall survival (OS) and safety. Subgroup analyses were preplanned in MET IHC3+ and MET amplification populations (NCT01982955).

      Result

      Low recruitment halted full enrolment with 55 of 156 planned patients enrolled.

      As of 12-Dec-2018, median (range) duration of treatment with tepotinib+gefitinib was 21.4 (4.6, 110.9) weeks, with 3 patients still receiving treatment; and with pemetrexed was 18.0 (3.0, 60.4) weeks. 15 patients (62.5%) received ≥4 cisplatin/carboplatin cycles.

      Better outcomes were reported with tepotinib+gefitinib vs chemotherapy (Table), particularly in patients with MET IHC3+ (PFS: HR 0.35 [90% CI 0.17–0.74], OS: 0.32 [0.14–0.75]) or MET amplification (PFS: HR 0.13 [90% CI 0.04–0.43], OS: 0.08 [0.01–0.51]).

      Drug-related grade ≥3 adverse events (AEs) occurred in 17 (54.8%) patients receiving tepotinib+gefitinib and 12 (52.2%) patients receiving chemotherapy. Any-cause AEs leading to discontinuation occurred in 3 (9.7%) patients receiving tepotinib+gefitinib and 1 (4.3%) receiving chemotherapy. Dose reductions due to AEs were reported in 5 (16.1%) vs 4 (17.4%) patients.

      Conclusion

      Tepotinib+gefitinib has durable antitumor activity in patients with EGFR-mutant NSCLC with MET IHC3+ or MET amplification, and was generally well tolerated. MET amplification will be further explored as a biomarker for tepotinib.

      Table: Summary of efficacy data

      Population

      Tepotinib + gefitinib

      Chemotherapy

      HR/OR
      (90% CI)

      Overall MET+*

      Patients, n

      31

      24

      mPFS, months (90% CI)

      4.9 (3.9, 6.9)

      4.4 (4.2, 6.8)

      0.67 (0.35, 1.28)

      mOS, months (90% CI)

      17.3 (12.1, 37.3)

      18.7 (15.9, 20.7)

      0.67 (0.33, 1.37)

      ORR, n (%) [90% CI]

      14 (45.2) [29.7, 61.3]

      8 (33.3) [17.8, 52.1]

      1.99 (0.56, 6.87)

      MET IHC3+

      Patients, n

      19

      15

      mPFS, months (90% CI)

      8.3 (4.1, 21.2)

      4.4 (4.1, 6.8)

      0.35 (0.17, 0.74)

      mOS, months (90% CI)

      37.3 (24.2, 37.3)

      17.9 (12.0, 20.7)

      0.32 (0.14, 0.78)

      ORR, n (%) [90% CI]

      13 (68.4) [47.0, 85.3]

      5 (33.3) [14.2, 57.7]

      4.33 (1.03, 18.33)

      MET amplification†

      Patients, n

      12

      7

      mPFS, months (90% CI)

      21.2 (8.3, NE)

      4.2 (1.4, 7.0)

      0.13 (0.04, 0.43)

      mOS, months (90% CI)

      37.3 (NE, NE)

      13.1 (3.3, NE)

      0.08 (0.01, 0.51)

      ORR, n (%) [90% CI]

      8 (66.7) [39.1, 87.7]

      3 (42.9) [12.9, 77.5]

      2.67 (0.37, 19.56)

      CEP-7, centromere protein 7; CI, confidence interval; EGFR, epidermal growth factor receptor; GCN, gene copy number; HR, hazard ratio; IHC, immunohistochemistry; IRC, independent review committee; ITT, intention to treat; MET, mesenchymal-epithelial transition factor; NE, not estimable; OR, odds ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival

      All efficacy outcomes are investigator-assessed by RECIST v1.1.

      *IHC2+/IHC3+/gene amplification.

      †MET amplification is defined as GCN ≥5 and/or MET/CEP-7 ratio ≥2. 17 of 19 patients with MET amplification have MET overexpression (IHC3+).

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    MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • +

      MA11.02 - KEYNOTE-042 China Study: First-Line Pembrolizumab vs Chemotherapy in Chinese Patients with Advanced NSCLC with PD-L1 TPS ≥1% (Now Available) (ID 1772)

      14:00 - 15:30  |  Presenting Author(s): Yi-Long Wu

      • Abstract
      • Presentation
      • Slides

      Background

      In the global, open-label KEYNOTE-042 study (NCT02220894), pembrolizumab significantly improved OS vs chemotherapy in PD-L1–positive locally advanced/metastatic NSCLC without targetable EGFR/ALK aberrations (HRs: TPS ≥50%, 0.69; ≥20%, 0.77; and ≥1%, 0.81). We present the very first results for Chinese patients enrolled in the KEYNOTE-042 global and China extension (NCT03850444) studies.

      Method

      The global and extension studies were designed identically. Patients were randomized 1:1 (stratified by ECOG PS 0/1, squamous/nonsquamous histology, and TPS ≥50%/1‒49%) to up to 35 cycles of pembrolizumab 200 mg Q3W or up to 6 cycles of paclitaxel/pemetrexed + carboplatin with optional pemetrexed maintenance (nonsquamous only). Primary endpoints were OS in patients with PD-L1 TPS ≥50%, ≥20%, and ≥1%. No alpha was allocated to the China extension analysis. Overall, ~350 patients from China will be enrolled including 140 patients with TPS ≥50%, to determine the OS effect of pembrolizumab and consistency across outcomes in Chinese patients.

      Result

      As of September 4, 2018, 262 Chinese patients with PD-L1–positive (TPS ≥1%) NSCLC were enrolled (global, n=92; China extension, n=170) and randomized to pembrolizumab (n=128) or chemotherapy (n=134). 146 patients (55.7%) had PD-L1 TPS ≥50%; 204 (77.9%) had PD-L1 TPS ≥20%. After median (range) follow-up of 11.3 (0.1‒23.2) months, 32 patients (25.0%) were still receiving pembrolizumab and 6 (4.8%) were receiving pemetrexed maintenance. Pembrolizumab improved OS vs chemotherapy in patients with PD-L1 TPS ≥50%, ≥20%, and ≥1% (Table). Among patients who received ≥1 dose of pembrolizumab (n=128) or chemotherapy (n=125), grade 3–5 drug-related AEs occurred in 17% vs 68%, respectively.

      Overall Survival

      n

      Median (95% CI), mo

      HR (95% CI)

      PD-L1 TPS ≥50%

      Pembrolizumab

      72

      20.0 (15.5–NR)

      0.62 (0.38–1.00)

      Chemotherapy

      74

      14.0 (10.0–17.9)

      PD-L1 TPS ≥20%

      Pembrolizumab

      101

      20.0 (17.4–NR)

      0.62 (0.41–0.95)

      Chemotherapy

      103

      13.7 (10.1–17.9)

      PD-L1 TPS ≥1%

      Pembrolizumab

      128

      20.0 (17.4–NR)

      0.65 (0.45–0.94)

      Chemotherapy

      134

      13.7 (10.1–17.9)

      PD-L1 TPS 1–49%a

      Pembrolizumab

      56

      19.9 (11.9–NR)

      0.69 (0.40–1.20)

      Chemotherapy

      60

      10.7 (8.3–20.9)

      NR, not reached. aExploratory analysis.
      Conclusion

      Pembrolizumab monotherapy improved OS with a favorable safety profile vs platinum-based chemotherapy as first-line therapy in Chinese patients with locally advanced/metastatic NSCLC without sensitizing EGFR/ALK aberrations and a PD-L1 TPS ≥1%. Findings are consistent with the global study primary endpoints, supporting first-line use of pembrolizumab for PD-L1–expressing advanced/metastatic NSCLC in China.

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    MA13 - Going Back to the Roots! (ID 139)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • +

      MA13.11 - A Randomized Phase III Study of Cisplatin-Polymeric Micelle Paclitaxel vs Cisplatin-Solvent-Based Paclitaxel in 1st Line Advanced NSCLC (Now Available) (ID 696)

      14:00 - 15:30  |  Presenting Author(s): Yi-Long Wu

      • Abstract
      • Presentation
      • Slides

      Background

      Cisplatin-sb-Pac is the one of current standard of chemotherapy in aNSCLC, It produced 15% to 32% objective response rate (ORR) and 7.9 to 10.6 months of median overall survival (OS). Alternative nab-paclitaxel to sb-Pac only increased ORR but not improved progression-free survival (PFS) and OS. Thus the unmet medical need for new chemo regimen remains.

      Method

      From May 2015 to Jan 2018 448 untreated patients (pts) with stage IIIB to IV NSCLC from 24 sites were randomly assigned 2:1 to receive 230 mg/m2 pm-Pac and cisplatin 70 mg/m2 on day 1 of a 3-week cycle, and then dose escalation of pm-Pac to 300 mg/m2 from the second cycle if no prespecified toxic effects observed or 175 mg/m2 sb-Pac plus cisplatin 70 mg/m2 once every 3 weeks. Pts were stratified by stage and histology. The primary end point was ORR by Independent review committee (IRC) and Investigator (INV) in the intent-to-treat population. The second endpoints included PFS, OS and safety. Data cutoff was Jan 26, 2019.

      Result

      300 pts were assigned to pm-Pac and 148 to sb-Pac. Baseline characteristic were balance in both arms. Nonsquamous carcinoma (non-squ) and stage IV were 57.3% and 81.0% in pm-Pac and 58.1% and 81.8% in sb-Pac respectively. 73.2% pts in pm-Pac arm escalated their dose to 300mg/m2, 0.7% down to 184mg/m2. ORR and PFS in pm-Pac were significant better than that in sb-Pac (table 1). OS was immature. For histology subgroup the ORR was 58.6% v 37.1% (P=0.0054) in squamous carcinoma (Squ) and 44.2% v 18.6% (P<0.0001) in non-squ. Grade ≥3 AEs was 80.0% for pm-Pac and 79.7% for sb-Pac. No new safety issues were identified.

      Conclusion

      The phase 3 trial met its primary endpoint. pm-Pac significantly improved ORR and PFS than sb-Pac, and pm-Pac regimen should be a new standard chemo for aNSCLC. (NCT 02667743).

      Tab. Efficacies comparison between pm-Pac and sb-Pac

      pm-Pac

      sb-Pac

      P value

      ORR % (95% CI)

      IRC

      INV

      50.3 (44.5-56.1)

      52.0 (46.2-57.8)

      26.4 (19.5-34.2)

      28.4 (21.3-36.4)

      <0.0001

      <0.0001

      PFS (months)

      6.4 (6.2-6.9)

      5.3 (4.6-6.0)

      HR 0.66 (0.52-0.84), P=0.0006

      OS at 12 months

      67.3%

      61.8%

      -

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    MS04 - New Systemic Adjuvant/Neo-Adjuvant Strategies in Early Stage Lung Cancer: Targeted Therapy and I/O (ID 67)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
    • +

      MS04.01 - EGFR TKIs for Resected EGFRmut NSCLC (Now Available) (ID 3455)

      15:15 - 16:45  |  Presenting Author(s): Yi-Long Wu

      • Abstract
      • Presentation
      • Slides

      Abstract

      Adjuvant chemotherapy became the standard treatment for resected stage 2-3 non-small cell lung cancer (NSCLC). It increased overall survival (OS) by 5% at 5 years, and resected NSCLC was considered "curable disease." Stage II to IIIA resected NSCLC is heterogeneous. The 5-year survival was only 40% -50%. There is a huge medical need to improve the long-term survival for these patients whose cancers are destined to recur after surgery.

      BR.19, the first trial to evaluate an EGFR TKI (gefinitib) in the adjuvant setting, and the subsequent RADIANT trial, which compared erlotinib to placebo, were not designed specifically for patients with EGFR mutations. Thus, these two adjuvant TKIs failed to show meaningful benefits.1,2 The ADJUVANT trial, first randomized phase 3 trial compared gefitinib with doublet chemotherapy for stage 2 and 3 (N1N2) resected EGFR mutant NSCLC. The results showed that adjuvant gefitinib significant improved disease-free survival (DFS). HR for recurrence was 0.60 with 28.7 months in gefitinib vs 18.0 months in chemotherapy3. Subsequently the EVAN -- another Chinese phase 2 trial confirmed that adjuvant erlotinib was superior to chemotherapy in DFS4. SELLECT trial from American once again confirmed that adjuvant EGFR TKI improved DFS5. The both Chinese adjuvant trials targeted the patients with the highest risk of recurrence and are more likely to respond to EGFR TKIs in patients harboring an EGFR mutation. Unlike BR.31 and RADIAN EGFR TKIs were used following adjuvant chemotherapy. the ADJUVANT trial was a direct comparison of adjuvant TKIs with Vinorelbine plus cisplatin instead of comparing TKIs with placebo after chemotherapy, as evaluated in the BR.19 and RADIANT trials. Compliance with adjuvant TKIs (95.5%) was better than that with chemotherapy (78.4%) in ADJUVANT trial. This means that patients receiving adjuvant TKIs were more likely to complete treatment than patients receiving standard chemotherapy. The design of ADJUVANT is different from RADIANT, and the hypothesis of the two trials designs is different. The ADJUVANT study was created to test whether an EGFR TKI might be a viable treatment alternative to chemotherapy in the adjuvant setting, specifically in EGFR mutant (+) NSCLC. In this situation, using DFS as the primary endpoint was rational. The U.S. Food and Drug Administration has stated that a prolonged delay in the development of metastatic disease is an objective and a clinically relevant outcome and that agents can be approved based on metastasis-free survival (MFS) if substantial effects on this endpoint are demonstrated and the safety profile is acceptable.6 In addition, after adjuvant gefitinib or erlotinib, patients with disease recurrence still have the opportunity to be re-challenged with TKIs. And the median duration of treatment approximates the DFS in a de novo advanced EGFR-mutant population.7

      Recently Zhong et al reported a phase 2 trial on neo-adjuvant setting for EGFR mutant stage 3A resectable NSCLC. Of 386 patients screened, 72 were randomized to treatment. The ORR for neoadjuvant erlotinib versus GC chemotherapy was 54·1% versus 34·3% (p=0·092). pCR was 10·7% vs 0. Median DFS was significantly longer with erlotinib (21·5 months) versus GC chemotherapy (11·9 months; HR 0·42; 95% CI, 0·23–0·76; p=0·003)8. The results of neo-adjuvant EGFR TKI treatment in CTONG 1103 was similar to adjuvant EGFR TKI in CTONG 1104. The difference of DFS comparing with chemotherapy in both trials are 10 months. Definitely EGFR TKIs could be safely and effectively used in early resected NSCLC.

      The treatment paradigm for early resectable NSCLC is evolving. Similar to advanced NSCLC early stage NSCLC should be divided to driver mutation or wild type NSCLC. For wild NSCLC check point blockade should be tested in peri-operation. For driver mutation NSCLC TKIs including EGFRi or ALKi even other rare mutation should be tested.

      Some issues should be evaluated. One issue is how to select populations more precisely for adjuvant or neo-adjuvant treatment. Whether circulating tumor DNA (ctDNA) could serve as biomarker of minimal residual disease (MRD) and how to monitor it9? Second issue is what is the primary endpoint for neo-adjuvant or adjuvant treatment in NSCLC? Apparent OS is rational but the trial will last a long time even beyond 10 years. The third issue is how to choose neo-adjuvant or adjuvant treatment for recectable NSCLC either clinical trial or clinical practice. For personalized adjuvant treatment in the future, we need to identify patients precisely and match the appropriate treatment with appropriate patient.

      References:

      1. Goss GD, O'Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol. 2013;31(27):3320-3326.

      2. Kelly K, Altorki NK, Eberhardt WE, et al. Adjuvant Erlotinib Versus Placebo in Patients With Stage IB-IIIA Non-Small-Cell Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2015;33(34):4007-4014.

      3. Zhong W-Z, Wang Q, Mao W-M, et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II–IIIA (N1–N2) EGFR -mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol. 2018;19(1):139-148

      4. Yue D, Xu SD, Wang Q, et al. Erlotinib verse vinorebine plus cisplatin as adjuvant therapy in Chinese patitents with stage 3A EGFR mutantion-positive non-small-cell lung cancer (EVAN): a randomised, open-lable. phase 2 trial. Lancet Res Med 2018; 6(11):863-873

      5. Pennell NA, Neal JW, Chaft JE, et al. SELECT: A Phase II Trial of Adjuvant Erlotinib in Patients With Resected Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer. J Clin Oncol. 2019;37(2):97-104.

      6. Mauguen A, Pignon JP, Burdett S, et al. Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: a re-analysis of meta-analyses of individual patients' data. Lancet Oncol. 2013;14(7):619-626.

      7. Oxnard GR, Janjigian YY, Arcila ME, et al. Maintained sensitivity to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer recurring after adjuvant erlotinib or gefitinib. Clin Cancer Res. 2011;17(19):6322-6328

      8. Zhong WZ, Chen KN, Chen C, et al. Erlotinib verse gemcitabine plus cisplatin as neoadjuvant treatment for stage IIIA-N2 EGFR-mutant NSCLC (EMERGING-CTONG 1103): a randomized phase II study, J Clin Oncol 2019 in press.

      9. Ng TL, Camidge DR. Lung cancer's real adjuvant EGFR targeted therapy questions. Lancet Oncol. 2018;19(1):15-17.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 6
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-104 - Survivals in ROS1-Rearranged Advanced Non-Small-Cell Lung Cancer Treated with First-Line Crizotinib (ID 1735)

      09:45 - 18:00  |  Author(s): Yi-Long Wu

      • Abstract
      • Slides

      Background

      The c-ros oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC) can be treated effectively with crizotinib, a tyrosine kinase inhibitor (TKI) of anaplastic lymphoma kinase (ALK), ROS1, and mesenchymal-epithelial transition (MET). However, few studies have investigated on survivals in ROS1-rearranged advanced NSCLC patients treated with first-line crizotinib.

      Method

      We retrospectively analyzed clinicopathological and survival data of ROS1-rearranged patients with advanced NSCLC treated with crizotinib between August 2013 and January 2019 at the Guangdong Provincial People's Hospital. ROS1 rearrangements were detected by Reverse Transcription-Ploymerase Chain Reaction(RT/PCR),Fluorescence in situhybridization (FISH), or Next-generation Sequencing (NGS) . Overall survival (OS) and progression-free survival (PFS) were compared between first-line crizotinib, chemotherapy followed by crizotinib and first-line chemotherapy without any subsequent targeted therapy.

      Result

      Among totally 40 patients with ROS1-rearranged advanced NSCLC, 29 were treated with crizotinib (16 with first-line; 13 with second- or further-line), and 11 were not treated with crizotinib at data cutoff (April 4, 2019). Median OS was significantly prolonged in patients with first-line crizotinib (N=16) than those with first-line chemotherapy followed by subsequent crizotinib (N=9), not reached vs. 27.1 months, P=0.042. However, there was no significant difference in median PFS between the two groups, 16.3 vs. 5.7 months, P=0.054. Meanwhile, first-line crizotinib (N=16) was significantly superior to first-line chemotherapy without any subsequent targeted therapy (N=8) in both median OS (not reached vs. 9.1 months, P=0.024) and PFS (16.3 vs. 4.8 months, P=0.017).

      Conclusion

      First-line crizotinib prolongs survivals than chemotherapy for patients with ROS1-rearranged advanced NSCLC.

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      P1.01-28 - Mutational Heterogeneity Between Primary Pulmonary Cancer Lesions and Matched Brain Metastases (Now Available) (ID 3133)

      09:45 - 18:00  |  Author(s): Yi-Long Wu

      • Abstract
      • Slides

      Background

      Brain metastasis (BM) is a severe and common lethal condition in non-small cell lung cancer patients. A few data have been reported about the molecular landscape of genomic alterations in BM of non-small cell lung cancer (NSCLC). Yet little is known about molecular heterogeneity and evolution process during the cancer metastases from lung to brain. We seek to profile the genomic alterations in paired specimens of primary lung lesions (PL) versus brain metastasis (BM).

      Method

      Paired specimens of thirteen patients with BM were collected. MassARRAY LungCarta (26 genes) and Next Generation Sequencing (NGS, 285 genes) assays were performed to generate genomic profiles.

      Result

      Thirteen patients were aged mean 58 (range 40-74), 10 adenocarcinoma and 2 squamous carcinoma and 1 small cell lung cancer, 9 males and 4 females, 5 smokers and 8 non-smokers, 7 stage IV, 3 stage III, 2 stage II and 1 stage I. By LungCarta test, we detected 6 EGFRm (1 concurrent STK11, 1 concurrent TP53), 2 KRASm, 1 STK11m cases and 4 wild type primary lung cancers. All corresponding BM lesions harbored the same mutations of EGFR, KRAS, TP53 and STK11, and additional EGFR T790M in 1 EGFR mutated case. By NGS test, in 9 patients all above mutations were detected along with additional genomic alterations. There were average mutated 9 genes in primary lung lesions and 13 mutated genes in BM. Common altered genes in PL included EGFR, KRAS, TP53, STK11, NF2, ARID1B and ATM. Shared mutated genes between PL and BM had EGFR, KRAS, TP53, KMT2C and etc. BM specific altered genes included ARID1A, SMARCA4, ATM, ATR, EPHA5, RB1, KMT2C, LRP1B, and SETD2, etc. Notably, genes involved in the chromatin remodeling or modification and cell cycle pathways were enriched in BM.

      Conclusion

      There were heterogeneous molecular alterations between PL and BM of NSCLC. Differential genes involved in the chromatin remodeling and modification and cell cycle checkpoint may be highly related to the process of BM, suggesting future therapeutic development on these potential molecular targets.

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      P1.01-61 - A Phase II Umbrella Study of Camrelizumab in Different PD-L1 Expression Cohorts in Pre-Treated Advanced/Metastatic Non-Small Cell Lung Cancer (ID 1633)

      09:45 - 18:00  |  Presenting Author(s): Yi-Long Wu

      • 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.

      Method

      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).

      Result

      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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      P1.01-81 - A New Prognostic Index Combines the Metabolic Response and RECIST 1.1 to Evaluate the Therapeutic Response in Patients with Lung Cancer (ID 752)

      09:45 - 18:00  |  Author(s): Yi-Long Wu

      • Abstract
      • Slides

      Background

      Response Evaluation Criteria in Solid Tumors (RECIST) is occasionally insufficient for evaluation. We propose a new prognostic index (NPI) that combines the standardized uptake value (SUV), metabolic tumor volume (MTV) and RECIST.

      Method

      In total, 163 patients with lung cancer who underwent positron emission tomography-computed tomography prior to and after treatment were included. We formulated the NPI by estimating the hazard ratios of overall survival for ∆MTV, ∆SUVmax and ∆D (tumor size based on RECIST). Then the regression coefficients were used, which gave rise to the HRs, as weights to formulate the new prognostic index (NPI). Progression-free survival (PFS) and overall survival (OS) were compared between RECIST and the NPI.

      Result

      ROC curve analysis identified two cutoff values based on the NPI (≤-44.0% and >40.4%) to discriminate partial remission (NPR), stable disease (NSD) and progressive disease (NPD). The concordance rate between RECIST and NPI was 74.2% (κ = 0.572, P<0.001). Based on RECIST, survival analysis did not discriminate significantly on either PFS or OS between the PR, SD and PD groups. However, according to the NPI, PFS and OS differed significantly between the NPR, NSD, and NPD groups (training set: PFS, P = 0.007; OS, P = 0.027; validation set: PFS, P = 0.003; OS, P = 0.044). In total, 83 patients with SD were reclassified based on the NPI (20 with NPR, 57 with NSD, 6 with NPD), and the patients reclassified as NPR showed prolonged PFS (P = 0.004) and OS (P = 0.026) compared with those in the NSD+NPD group.wclc图形.jpg

      Conclusion

      The NPI shows superiority for evaluation of the therapeutic response and survival for patients with lung cancer, especially in the assessment of SD patients based on RECIST.

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      P1.01-82 - The Different Frequencies and Genetic Profiles of Histologic Transformation After Different EGFR-TKIs in EGFR-Mutant Adenocarcinomas (ID 418)

      09:45 - 18:00  |  Author(s): Yi-Long Wu

      • Abstract
      • Slides

      Background

      Histologic transformation is a mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor(TKIs) in EGFR-mutant non-small cell lung cancers（NSCLCs）. Those adenocarcinomas with histologic transformation usually underwent poor prognosis. However, few studies have focused on the different occurrence rates and genetic profiles between EGFR-mutant adenocarcinomas treated with different generations of EGFR-TKIs.

      Method

      Pathology was confirmed in 345 EGFR-mutant patients at baseline and recurrence. Among these patients，235 patients were treated with gefitinib or erlotinib，54 with afatinib and 56 with osimertinib. But only 11 patients with sufficient tumor specimens could be evaluated for the genetic profiles by next-generation sequencing (NGS). Demographics, disease features, and outcomes of these patients were analyzed.

      Result

      The frequency of these EGFR-mutant adenocarcinomas with histologic transformation after the treatment of different generation TKIs were quite different. The frequency of gefitinib/erlotinib group was 7.2% (17/235)，while the others were 5.6%（3/54, afatinib group）and 17.9%（10/56, osimertinib group）. The median progression free survival （PFS）to EGFR-TKIs of those patients were 12.2 months（gefitinib/erlotinib group）, 5.3 months （afatinib group）and 7.7 months（osimertinib group） respectively. Four adenocarcinomas treated with gefitinib/erlotinib all harbored TP53 mutations at baseline. One adenocarcinoma treated with afatinib was founded to have acquired MET amplification and transformed to small-cell lung cancer meanwhile. Moreover, the PFS of one patient to afatinib was just 3 months and her genetic profile at baseline was characterized by Rb1, TP53, and PIK3CA mutations. There were 3 patients treated with osimertinib underwent histologic transformation from adenocarcinomas to squamous carcinoma. One patient after progressive disease of osimertinib did not have enough tissue to detect NGS，and her blood NGS result just showed EGFR L858R and T790M mutation. The tissue NGS result of the second patient showed EGFR p.Glu746-Ala750 deletion, EGFR T790M and C797S mutations, CDK4/ CCND1/ EGFR/ KRAS amplifications. The second patient received the chemotherapy of pemetrexed+ carboplatin + bevacizumab and the best response was partial response. The third patient take palbociclib and osimertinib meanwhile and his symptoms improved with the tissue NGS of EGFR T790M mutation and CDK4/ MDM2/ EGFR amplifications. They were characterized by EGFR amplification and CDK4 amplification. The others transform from adenocarcinomas to small cell cancers or neuroendocrine tumors were seem to harbor with TP53, Rb1 and PIK3CA mutations.

      Conclusion

      It seems more common in some subtypes that the EGFR-mutant adenocarcinomas treated with osimertinib undergo histologic transformation. The genetic profiles vary greatly between transformation to squamous carcinomas and transformation to small-cell cancers/neuroendocrine tumors in EGFR-mutant adenocarcinomas treated with osimertinib. Further verification is needed.

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      P1.01-85 - Treatment for Advanced NSCLC with EGFR Mutations and De Novo MET Amplification/Overexpression (ID 2190)

      09:45 - 18:00  |  Author(s): Yi-Long Wu

      • Abstract
      • Slides

      Background

      Combination of epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) tyrosine kinase inhibitors (TKIs) are effective in advanced non-small-cell lung cancer (NSCLC) patients harboring EGFR mutation and acquired MET-amplification. However, there are few reports about treatments of patients with EGFR mutation and de novo MET amplification/ overexpression.

      Method

      We retrospectively screened 88 consecutive advanced NSCLC patients harboring EGFR mutation and de novo MET amplification/overexpression at Guangdong Provincial People's Hospital of China from January, 2014 to December, 2018. Among them, a total of 41 patients receiving first-line targeted therapy were included and stratified into EGFR-driven, MET-driven and EGFR/MET co-driven groups illustrated respectively in Table 1.

      Table 1. Classification of advanced NSCLC with EGFR mutation and MET overexpression/amplification.
      Group EGFR mutation MET overexpression/amplification Response to first-line TKI
      EGFR-driven Exon 19 deletion or exon 21 L858R mutation (tested by next generation sequencing (NGS) or amplification refractory mutation system (ARMS) or polymerase chain reaction (PCR)).

      Overexpression: strong intensity staining was in more than 50% of tumor cells (tested by immunohistochemistry (IHC)).

      Amplification: CNG≥5, or MET/centromeric portion of chormosome 7 ratio≥2.2, with an additional criterion of focal amplification was in more than 10% of tumor cells (tested by fluorescence in situ hybridization (FISH)).

      		 PFS＞3 months, best response is complete response (CR)/partial response (PR)/stable disease (SD); not receiving MET-TKIs in later-line treatment, or had MET-TKIs but PFS≤3 months.
      MET-driven PFS≤3 months, receive MET-TKIs monotherapy or MET-TKIs plus EGFR-TKIs in later-line treatment and PFS＞3months, or PFS≤3 months，but with acquired mechanism to MET.
      EGFR/MET co-driven Response to EGFR-TKIs at least one time, receiving EGFR-TKIs plus MET-TKIs in later-line treatment and PFS＞3 months, or PFS≤3 months, but with acquired mechanism to MET.

      Result

      Among enrolled patients, 40 of them received first-line first-generation EGFR-TKIs while 1 treated with MET-TKI. Twenty-eight received targeted therapy in the later-line treatments after resistance. Thirty-one (75.6%), 5 (12.2%) and 5 (12.2%) patients were classified into EGFR-driven, MET-driven and EGFR/MET co-driven groups. Median progression-free survival (PFS) was 12.1, 1.0 and 5.3 months respectively in the first-line setting. Objective response rates were 58.1%, 0.0% and 20.0% (P=0.028) respectively. Among 28 patients receiving subsequent targeted therapies, 58.1% (18/31), 100.0% (5/5) and 100.0% (5/5) were EGFR-driven, MET-driven and EGFR/MET co-driven respectively. Median PFS was 7.0, 6.5 and 10.3 months for the EGFR-driven group receiving subsequent EGFR-TKIs, the MET-driven group receiving MET-TKIs with or without EGFR-TKIs, and the EGFR/MET co-driven group treating with EGFR-TKIs plus MET-TKIs respectively (P=0.399). Also, no significant difference was observed in overall survival for these 28 patients (33.8 vs. 11.8 vs. 27.9 months, P=0.098).

      Conclusion

      Subsequent individualized targeted therapy or co-targeted therapies might favor clinical outcomes for both MET-driven and EGFR/MET co-driven patients with advanced NSCLC after resistance to first-line EGFR-TKIs.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-42 - Tumor Microenvironment Is Associated with Efficacy of PD-1/PD-L1 Inhibitors in Patients with Primary Pulmonary Lymphoepithelioma-Like Cancer (Now Available) (ID 651)

      09:45 - 18:00  |  Author(s): Yi-Long Wu

      • Abstract
      • Slides

      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.

      Method

      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.

      Result

      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.

      ll.jpg

      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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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 4
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-13 - EGFR Amplification Mediates Resistance to Third-Generation EGFR TKIs and in Vitro Validation of Combination Strategies to Overcome Resistance (Now Available) (ID 762)

      09:45 - 18:00  |  Author(s): Yi-Long Wu

      • Abstract
      • Slides

      Background

      As a concurrent genomic alteration in EGFR-mutant NSCLC, whether all detected EGFR amplification serve as a driver of resistance to third-generation EGFR-TKIs remains controversial. Furthermore, which subtype of EGFR amplification-mediated resistance is actionable has been poorly elucidated. Our study aims to investigate the driver role of EGFR amplification in mediating resistance to third-generation EGFR TKIs and potential strategy to overcome resistance mediated by EGFR amplification.

      Method

      44 resistance samples from 32 patients who experienced disease progression from to a third-generation EGFR TKI abivertinib in Guangdong Lung Cancer Institute underwent NGS-based genomic profiling (data cutoff: october 30, 2018). FISH analysis of tissue samples from patients with EGFR amplification detected by NGS was performed. Different alleles of EGFR over-expressed PC9GR cell line models was established. Cell proliferation assay and western blot were performed to determine the sensitivity of these cell lines to third-generation EGFR TKI abivertinib and osimertinib, and to screen for potential strategies to overcome resistance mediated by EGFR amplification.

      Result

      Upon abivertinib progression, 27 patients provided plasma samples (six patients also provided paired samples from the progression sites) and five patients only provided samples from the progression sites for NGS. A heterogeneous landscape of resistance to abivertinib was observed with EGFR amplification being the most frequent, observed in 11 (34%) patients (Figure 1) , and considered a putative resistance mechanism in seven (22%) patients. FISH analysis of 3 patients who had available tissue samples further confirmed the presence of EGFR amplification detected by NGS. We established 3 different EGFR-overexpressed PC9GR cell lines by lentivirus transfection of Del 19 EGFR, Del19/T790M EGFR and wild-type EGFR. Among them, introduction of wild-type EGFR resulted in significantly loss of cellular sensitivity to abivertinib and osimertinib under EGF stimulation, but retains sensitivity to combination treatment of abivertinib and afatinib. In addition, abivertinib plus nimotuzumab also demonstrated preliminary inhibitory effect on phosphorylation of EGFR downstream pathway in wild-type EGFR overexpressed PC9GR. Finally, abivertinib plus nimotuzumab or afatinib in is effective and tolerable in treating 2 patients who developed EGFR amplification-mediated resistance to abivertinib. One of them experienced a long-term benefit from the combination treatments with an overall progression-free survival of 23 months.

      fig 1. egfr amp as the most frequent resistance mechanism to abivertinib.jpg

      Conclusion

      Wild-type EGFR amplification mediates resistance to third-generation EGFR TKIs and could be overcome by combination treatments. Future studies need to more precisely determine the presence of wild-type EGFR amplification in third-generation EGFR TKIs resistant setting.

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      P1.14-31 - Lack of Association Between BIM Deletion Polymorphism and Clinical Efficacy of EGFR-TKIs in NSCLC Based on NGS (Now Available) (ID 2154)

      09:45 - 18:00  |  Author(s): Yi-Long Wu

      • Abstract
      • Slides

      Background

      BIM deletion polymorphisms are most common in Asian population, with an incidence of 12-16% in lung cancer patients with EGFR mutations. Previous studies showed BIM deletion polymorphisms could predict poor treatment response to EGFR-TKIs, owing to loss function in mediating apoptosis of tumor cells. Recently, available data on BIM is inconsistent on its predictive role and we don’t know if NGS could bring us something new.

      Method

      Data were pooled from clinical trial CTONG0901 and local database in our hospital (GLCI). 194 and 117 EGFR mutant patients with IIIB-IV NSCLC are enrolled for survival analysis in the two cohorts, respectively. BIM status of all these patients were confirmed by NGS. 28 patients have baseline NGS results with 168 genes panel.

      Result

      The incidence of BIM deletion polymorphism in patients with EGFR mutation was 11.3% (22/194) and 17.6% (26/148) in CTONG0901 and GLCI, respectively. In CTONG0901, median PFS of patients treated with erlotinib or gefitinib between BIM deletion polymorphism and BIM wild type is 10.47m versus 11.17m (P=0.59). Median OS is 20.5m versus 20.47m (P=0.82). In GLCI, median PFS between BIM deletion polymorphism and BIM wild type is 10.13m versus 12.87m (P=0.33). Median OS is 58.5m versus 54.97m (P=0.82). No survival differences on PFS and OS present in the two cohorts. 28 patients with baseline NGS were analyzed from two cohorts. Three patients with MET amplification, ALK rearrangement and PD-L1 expression (20%+++) are lower than median PFS (8.63m). Two patients with MET amplification are around median PFS.

      figure.jpg

      Conclusion

      In our study, BIM deletion polymorphism has no relationship with the efficacy of EGFR-TKIs in CTONG0901. The result is confirmed in our local database. Outcomes of NGS showed that combined molecular variations, such as MET amplification, ALK rearrangement and PD-L1 expression seems more important to the prediction of EGFR-TKIs on NSCLC patients.

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      P1.14-39 - Acquired ALK Rearrangement in EGFR-Mutant Lung Adenocarcinoma Treated with EGFR TKIs (ID 1784)

      09:45 - 18:00  |  Author(s): Yi-Long Wu

      • Abstract
      • Slides

      Background

      Few studies have been reported on acquired anaplastic lymphoma kinase (ALK) rearrangement in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma patients with EGFR tyrosine kinase inhibitors (TKIs).

      Method

      EGFR-mutant lung adenocarcinoma patients were screened after resistance to EGFR TKIs from September 2017 to December 2018 at the Guangdong Lung Cancer Institute. Both EGFR mutation and ALK rearrangement were tested by next-generation sequencing (NGS). Acquired ALK rearrangement was defined as positive ALK rearrangement after resistance to EGFR TKIs, but negative result detected by NGS at the baseline of EGFR TKI treatments.

      Result

      Totally 320 patients were tested by NGS after resistance to EGFR TKIs ( 175, 42 and 103 with first-, second- and third-generation EGFR-TKIs respectively). Frequency of acquired ALK rearrangement was 1.14% (2/175), 2.38% (1/42) and 1.94% (2/103) in patients treated with first-, second- and third-generation EGFR TKIs respectively. The fusion partners of ALK were EML4 in 2 patients, CLIP4 (1), NPM1 (1) and PIBF1 (1). Non-EML4-ALK fusion accounted for 60%. One with acquired EML4-ALK achieved minor response with osimertinib plus crizotinib. One with acquired NPM1-ALK achieved partial response with erlotinib plus crizotinib. Unfortunately, one with acquired CLIP4-ALK fusion and BRAF V600E mutation did not respond to ensartinib single agent. One with acquired PIBF1-ALK had no clinical benefit with osimertinib plus alectinib. Finally, one with acquired EML4-ALK died shortly without any treatment due to poor performance status.

      Conclusion

      The frequency of acquired ALK rearrangement is similar in EGFR-mutant lung adenocarcinomas after resistance to the first-, second-, or third-generation EGFR TKIs. The majority of acquired ALK-fusion partners are non-EML4. Combination of EGFR TKIs and ALK inhibitors might be a strategy to overcome such resistance.

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      P1.14-62 - Afatinib in EGFR TKI-Naïve Patients with EGFR Mutation-Positive NSCLC: Combined Analysis of Two Single-Arm Phase IIIb Studies (ID 1338)

      09:45 - 18:00  |  Author(s): Yi-Long Wu

      • Abstract
      • Slides

      Background

      First-line afatinib significantly improved progression-free survival (PFS) compared with platinum-doublet chemotherapy in patients with EGFR mutation-positive (EGFRm+; including uncommon mutations) NSCLC in two Phase III studies (LUX-Lung 3: median 11.1 vs 6.9 months, hazard ratio [HR]=0.58; p=0.001; LUX-Lung 6: 11.0 vs 5.6 months, HR=0.28; p<0.0001). First-line afatinib also significantly improved PFS compared with gefitinib in the Phase IIb LUX-Lung 7 study (11.0 vs 10.9 months, HR=0.73; p=0.017). However, some patients still receive chemotherapy as a first-line treatment choice in clinical practice. Here, we report a combined analysis of outcomes from two large Phase IIIb studies of afatinib in EGFR TKI-naïve patients treated in a setting similar to real-world practice.

      Method

      In both studies, EGFR TKI-naïve, including chemotherapy-pretreated, patients with locally advanced or metastatic EGFRm+ NSCLC received 40 mg/day afatinib until progressive disease or lack of tolerability (dose reduction was permitted [minimum: 20 mg/day]). Study 1 enrolled patients across eight European countries, and Russia, Israel and Australia; Study 2 enrolled patients from centres in China, Hong Kong, India, Singapore, and Taiwan. Interim (Study 1; data cut-off: 30 April 2018) and final (Study 2; data cut-off: 06 July 2018) data were used for this combined analysis of time to symptomatic progression (TTSP), PFS, objective response, and safety.

      Result

      A total of 1020 patients were treated with afatinib (female: 59%; Asian/White/other: 54%/46%/<1%; median age [range]: 61 years [25–89]; ECOG PS 0/1/2: 26%/69%/5%; common/uncommon EGFR mutations: 82%/18%; treatment line 1st/2nd/≥3rd: 69%/23%/8%; presence of brain metastases: 18%). Overall, median TTSP was 14.6 months (95% confidence interval [CI]: 13.8–15.8 months); median PFS was 12.9 months (95% CI: 11.6–13.7 months). Objective response rate was 52.7%. Adverse events (AEs; all grade/grade ≥3) occurred in 1012/556 (99%/55%) patients; serious AEs were reported in 366 patients (36%). The most common grade ≥3 AEs were diarrhoea (14%) and rash (9%). Any-cause AEs leading to dose reduction were reported in 412 (40%) patients. Treatment discontinuation due to afatinib-related AEs occurred in 54 patients (5%).

      Conclusion

      In this combined analysis of two large, prospective ‘real-world’ afatinib studies in EGFR TKI-naïve patient populations, which included patients treated with afatinib in later lines, patients with ECOG PS 2, patients with brain metastases, and patients with uncommon mutations, safety data were consistent with previous results seen in the LUX-Lung 3, 6, and 7 studies. Efficacy findings are also encouraging, with a median TTSP of 14.6 months.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 4
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-79 - Afatinib in EGFR Mutation-Positive (EGFRm+) NSCLC Harbouring Uncommon Mutations: Experience in ‘Real-World’ Clinical Practice (ID 1282)

      10:15 - 18:15  |  Presenting Author(s): Yi-Long Wu

      • Abstract
      • Slides

      Background

      Approximately 10–12% of patients with EGFRm+ NSCLC have tumors harboring uncommon EGFR mutations. Preclinical data indicate that the ErbB family blocker, afatinib, has broader inhibitory activity against uncommon mutations, including compound mutations, compared with first-generation EGFR TKIs.1,2 Post-hoc analysis of the LUX-Lung 2, 3, and 6 trials3 demonstrated that afatinib is active against certain uncommon EGFR mutations. The objective response rate (ORR) with afatinib against G719X (n=18), L861Q (n=16), and S768I (n=8) single/compound mutations was 78%, 56%, and 100%, respectively. Patients with exon 18–21 uncommon mutations had progression-free survival (PFS) and overall survival of 10.7 and 19.4 months, respectively. The aim of this analysis was to explore the sensitivity of uncommon EGFR mutations to afatinib in a broader ‘real-world’ patient population.

      Method

      We undertook a pooled analysis of data from an Asian phase IIIB trial (NCT01953913) and a German non-interventional study (NCT02047903) that assessed afatinib in patients with EGFR TKI-naïve EGFRm+ NSCLC. Tumour response was based on investigator review, and PFS was calculated by Kaplan–Meier methodology.

      Result

      Fifty-four patients were identified with tumours harbouring uncommon mutations, including L861Q (n=13), S768I (n=3), G719X (n=23), and other (n=8); 21 patients had compound mutations. Baseline characteristics were: male, 59%; median age (range), 63.5 (35‒79) years; Eastern Cooperative Oncology group performance status 0 or 1/>1, 93%/6%. The combined ORR for evaluable patients with L861Q, S768I, or G719X was 59% (20/34), and the disease control rate was 91% (30/34); ORR and DCR in patients with compound mutations was 47% (9/19) and 89% (17/19), respectively. Overall, median PFS in patients with L861Q, S768I, or G719X was 10.7 months; median PFS in patients with compound mutations was 7.3 months.

      Conclusion

      In this ‘real-world’ cohort of patients with EGFRm+ NSCLC, afatinib was active against uncommon mutations known to be less responsive to reversible EGFR TKIs. These data are in line with the LUX-Lung trials and support the use of afatinib in patients with non-resistant EGFR mutations.

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      P2.01-80 - Clinical Outcomes in Advanced EGFR-Mutant NSCLC Patients Treated with First-Generation EGFR TKIs Followed by Subsequent Osimertinib (ID 1732)

      10:15 - 18:15  |  Author(s): Yi-Long Wu

      • Abstract
      • Slides

      Background

      Treatment with first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) plus subsequent osimertinib is standard of care for advanced (EGFR)-mutant non-small cell lung cancer (NSCLC) harboring T790M mutation. However, few data are available that have assessed the cumulative survival benefit of sequential EGFR TKIs in patients with EGFR-mutant NSCLC with T790M mutations in ‘real-world’ clinical practice.

      Method

      We retrospectively identified advanced EGFR-mutant NSCLC patients treated with first-line EGFR TKIs plus subsequent osimertinib between January 27th, 2015 and December 1st, 2018 at our institute. Clinical outcomes were analyzed. Subsequent genetic profiling was performed at the time of progression by next-generation sequencing (NGS). The primary endpoint was overall survival (OS) calculated from first-line treatment start to death or the last follow-up, and the secondary endpoint was progression-free survival (PFS) with osimertinib defined as the time from the first dose of osimertinib to disease progression or death. Primary resistance to osimertinib was defined as PFS≤4 months for T790M-mutant patients treated with osimertinib. The last follow-up time was January 27th, 2019. Median follow-up time was 52.0 months (range, 9.0~108.0 months).

      Result

      Among 117 eligible patients treated with first-line EGFR TKIs plus subsequent osimertinib, 96 had T790M mutation and 21 showed negative T790M mutation or unknown status at the baseline of osimertinib treatment,. Median OS was significantly prolonged in T790M-mutant patients than those with negative/unknown T790M mutation (58.0 vs. 28.3 months, p＜0.001). However, there was no significant difference in median PFS with osimertinib between the two groups. Furthermore, there was no significant difference in both median OS and PFS with osimertinib between the non-brain metastatic and brain metastatic groups (median OS, 58.0 vs. 54.8 months, p=0.840; median PFS, 11.8 vs. 9.1 months, p=0.145). Median OS was significantly shortened in patients (N=20) with primary resistance to osimertinib than those (N=72) with PFS＞4 months (38.2 vs 54.8 months, p=0.027).

      Conclusion

      In real-world clinical practice, treatment with first-generation EGFR TKIs plus subsequent osimertinib for T790M-mutant patients can significantly prolong OS than those with negative/unknown T790M mutation. However, survivals are similar between the patients with and without brain metastases at the baseline of osimertinib. OS is significantly shorter in those with primary resistance to osimertinib.

      Non-brain metastasis at the baseline

      (n=55)

      Brain metastasis at the baseline

      (n=41)

      P-value

      Osimertinib PFS≤4m

      (n=20)

      Osimertinib PFS＞4m

      (n=72)

      P-value

      Sex

      Male

      21 (38.2%)

      20 (48.8%)

      0.299

      7 (35.0%)

      32 (44.4%)

      0.450

      Femal

      Age,years

      ≤55

      ＞55

      34 (61.8%)

      19(34.5%)

      36(65.5%)

      21 (51.2%)

      18(43.9%)

      23(56.1%)

      0.357

      13 (65.0%)

      9 (45.0%)

      11(55.0%)

      40 (55.6%)

      27(37.5%)

      45(62.5%)

      0.543

      ECOG PS

      0-1

      54(98,2%)

      38(92.7%)

      0.000

      20(100%)

      68(94.4%)

      0.281

      2-4

      1(1.8%)

      3(7.3%)

      0(0%)

      4(5.6%)

      Histology

      adenocarcinoma

      53 (96.4%)

      41 (100%)

      0.217

      18 (90.0%)

      72 (100%)

      0.007

      non-adenocarcinoma

      2 (3.6%)

      0 (0%)

      2 (10.0%)

      0 (0%)

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      P2.01-88 - Molecular Alterations in Cerebrospinal Fluid Predict Clinical Outcomes of Central Nervous System Metastases in Lung Cancer (ID 1511)

      10:15 - 18:15  |  Author(s): Yi-Long Wu

      • Abstract
      • Slides

      Background

      Cerebrospinal fluid (CSF) has been proven as good media for genetic profiling of central nervous system (CNS) metastases. However, the association of genetic alterations in CSF and clinical outcomes remains elusive.

      Method

      A total of 94 lung cancer patients with CNS metastases underwent lumbar puncture. Circulating tumor DNA were extracted from CSF and profiled by next-generation sequencing. The effect of genetic alterations in CSF on survival and treatment outcomes were evaluated.

      Result

      The most common genes seen in CSF were EGFR, TP53, MET, CDKN2A, MYC, NTRK1 and CDK6. Kaplan-Meier survival analysis indicated that CDK4, CDK6, FGFR1, MET and MYC alterations, which were also characterized by more copy number changes, were associated with poor survival. Multivariate analysis found only MET (HR, 2.01; 95% CI, 1.15 to 3.52) and MYC alterations (HR, 2.31; 95% CI, 1.27 to 4.21) were correlated to poor OS. Forty-two patients harbored high n-CNVs (defined as the number of genes with copy number variations >2) while 50 patients carried low n-CNVs (defined as the number of genes with copy number variations <=2). Median overall survival (OS) of patients with high n-CNVs in CSF was 14.9 months (95% CI, 9.2 to 25.8 months), significantly shorter than those with low n-CNVs (21.6 months, 95% CI, 17.9 months to not reached (NR); HR, 1.9; 95% CI, 1.11 to 3.24; P=0.016). Patients with high n-CNVs and MET and MYC CNVs (copy number variations) were associated with the poorest OS. Osimertinib significantly prolonged OS only among patients with high n-CNVs (with vs. without osimertinib, 25.8 vs. 9.2 months; P=0.004). Among T790M negative patients, high n-CNVs seemed to positively associate with better response to osimertinib (OS with vs. without osimertinib, 23 vs. 7.8 months; P=0.058). Further analysis indicated that EGFR and FGFR1 CNV were the most significant factors associated with OS benefit from osimertinib among the high n-CNVs group (P=0.014; P=0.02). TP53_LOH and Wnt pathway alterations were significantly more prevalent in the high n-CNVs group than in the low n-CNVs group (P=0.016, P=0.006). With regard to clinical characteristics, higher performance status score (HR, 2.06; 95% CI, 1.38 to 3.07; P=0.0004) and occurrence of extracranial metastases (HR, 3.21; 95% CI, 1.25 to 8.24; P=0.015) suggested poor OS.

      figure 300dpi.jpg

      Conclusion

      While genetic profiles in CSF, like high n-CNVs as well as MET and MYC CNV were related to poor prognosis, patients with high n-CNVs, especially those with EGFR or FGFR1 CNV might benefit more from osimertinib, further supporting CSF as liquid biopsy of CNS metastases in lung cancer.

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      P2.01-99 - A Phase IIIb Open-Label Study of Afatinib in EGFR TKI-Naïve Patients with EGFR Mutation-Positive NSCLC: Final Analysis (ID 1671)

      10:15 - 18:15  |  Presenting Author(s): Yi-Long Wu

      • Abstract
      • Slides

      Background

      The safety and efficacy of afatinib, an orally administered irreversible EGFR TKI, have been demonstrated in patients with EGFR mutation-positive (EGFRm+) NSCLC in several Phase III clinical trials. However, prospective evidence supporting the clinical benefit of afatinib in the real-world setting is limited. Here, we report final data from a Phase IIIb open-label, multicenter trial evaluating safety and efficacy of afatinib in EGFR TKI-naïve Asian patients with locally advanced/metastatic EGFRm+ NSCLC, in a setting similar to real-world practice.

      Method

      EGFR TKI-naïve patients with locally advanced/metastatic EGFRm+ NSCLC were recruited from 34 sites in China, Hong Kong, India, Singapore, and Taiwan. Patients received 40 mg/day afatinib. Dose reduction to minimum 20 mg/day was permitted. Treatment continued until lack of clinical benefit as determined by the investigator. The primary and secondary safety endpoints were number of patients with serious adverse events (SAEs), and number of patients with drug-related AEs, respectively. The secondary efficacy endpoint was time to symptomatic progression (TTSP). Further endpoints included progression free survival (PFS), objective response, and duration of disease control.

      Result

      In total, 541 patients received afatinib. Baseline characteristics were representative of patients with EGFRm+ NSCLC (median age, 59 years; female, 52.9%; never smoked, 69.3%; EGFR mutations, common [Del19/L858R]/uncommon: 88.2% [48.2%/40.5%]/11.8%; ECOG performance status 0/1, 18.3%/79.7%; brain metastases, 19%). SAEs were reported in 164 patients (30.3%). 34 patients (6.3%) had drug-related SAEs, most commonly (grouped terms): diarrhea (1.8%), stomatitis (0.7%), and vomiting (0.7%). Drug-related AEs (DRAEs) of any grade were reported in 528 patients (97.6%). AEs leading to dose reduction occurred in 154 patients (28.5%); TRAEs leading to treatment discontinuation were reported in 17 patients (3.1%). Three patients experienced DRAEs leading to death (decreased appetite, dyspnea, and respiratory failure). Median TTSP was 14.0 months (95% confidence interval [CI]: 12.9, 15.9) and median PFS was 12.1 months (95% CI: 11.0, 13.6). Objective responses were reported in 312 patients (57.7%) by week 52; the median duration of response was 12.2 months (95% CI: 11.0, 13.5). 483 patients (89.3%) achieved disease control of median duration 13.6 months (95% CI: 12.1, 14.4).

      Conclusion

      Safety data for afatinib in this patient population were consistent with previously reported data, with no new safety signals. AEs were manageable and did not lead to discontinuation in most patients. This study also demonstrated the efficacy and clinical benefit of afatinib in Asian patients with locally advanced or metastatic EGFRm+ NSCLC in a near real-world setting.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-32 - Metastatic Lymph Nodes as High Immunogenicity Media for Perioperative Immunotherapy in Locally Advanced NSCLC (ID 289)

      10:15 - 18:15  |  Author(s): Yi-Long Wu

      • Abstract
      • Slides

      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).

      Method

      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).

      Result

      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.

      all.png

      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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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-38 - Tumor-Associated Neutrophils as a Potential Predictor for Early Recurrence in Resectable I-IIIA Lung Adenocarcinoma (Now Available) (ID 1509)

      10:15 - 18:15  |  Author(s): Yi-Long Wu

      • Abstract
      • Slides

      Background

      A recurrence of the early-stage non-small cell lung cancer (NSCLC) is usually unpredictable by clinical features alone. It has been appreciated that the high degree of infiltrated neutrophils is significantly associated with poor patient outcome in NSCLC.

      Method

      Transcriptional profiles and clinical information of 484 primary lung adenocarcinoma (ADC) subjects were retrieved from Gene Expression Omnibus (GEO). An additional cohort of mRNA expression, somatic mutations, and clinical data of 398 ADC were obtained from The Cancer Genome Atlas (TCGA). CIBERSORT algorithm was employed to infer the relative proportions of 22 sorts of leukocytes in each tumor using gene-expression profiles. Patients were stratified into two groups by the fraction of neutrophils using an optimal cutoff value (0.01) obtained with the "survminer" algorithm in R. We further investigated comprehensively the molecular differences between the high- and low-neutrophils patients.

      Result

      A significantly higher rate of 1-year recurrence was found in the high-neutrophils compared with the low-neutrophils group in both training (GEO,19.5% vs 6.1%) and validation (TCGA, 27.3% vs 19.0%) cohorts. However only in training cohort the patients with high neutrophils experienced a poorer recurrence-free survival (HR 1.95, 95% CI 1.47-2.51, P< 0.0001). The two groups were not only distinguished by clinical behaviors, but presented characteristic mutation genes and mutation patterns. EGFR and BRAF were more frequently mutated in low-neutrophils patients, whereas in high-neutrophils patients the most common mutation was found in STK11. Yet such molecular distinction was more pronounced in ADC with high tumor mutation load (TMB >=10). Gene Set Enrichment Analysis (GSEA) suggested that the common mutant genes in high-neutrophils patients were involved in the TP53 signaling, cell cycle pathways or associated with molecular functions including chemokine production and CD4 activation, while the common mutant genes in low-neutrophils patients were linked to RAS signaling pathway. Interestingly, we observed immune scene accompanied with good prognosis of ADC and concordant with limited infiltration of neutrophils, for instance high infiltration of B memory cells, resting memory CD4+T cells, resting mast cells and CD8+T cells.

      Conclusion

      Our findings suggested that local neutrophils are one of important components which are determinant for early recurrence of ADC, and it might serve as a simple predictor. Further research is warranted to identify the molecular mechanisms that neutrophils employed to exert, directly or indirectly, the regulatory effect on ADC progression.

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    P2.09 - Pathology (ID 174)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.09-35 - Proposal to Revise VENTANA ALK Scoring Interpretation Guide for Non-Small Cell Lung Carcinoma: Interpretation of ALK Heterogeneity (Now Available) (ID 831)

      10:15 - 18:15  |  Author(s): Yi-Long Wu

      • Abstract
      • Slides

      Background

      A small number of non-small cell lung cancer (NSCLC) cases showed heterogeneity of anaplastic lymphoma kinase (ALK) by VENTANA immunohistochemistry (IHC) in clinical practice. According to the ALK Scoring Interpretation Guide for VENTANA anti-ALK (D5F3), the presence of strong granular cytoplasmic staining in tumor cells (any percentage of positive tumor cells) is called positive for ALK. However, we know little about ALK heterogeneous cases. Multiple detection platforms are used to analyze molecular variability and pathological features in anticipation of clinical treatment decisions for such cases.

      Method

      A total of 2228 NSCLC cases with successful ALK IHC (VENTANA, D5F3, Roche) detection in Guangdong Provincial People`s Hospital were recruited between January 2012 and April 2018. Positive and negative system control and a negative agent control were established for each case. ALK IHC positivity was defined as the presence of strong granular cytoplasmic staining in 100% tumor cells; ALK IHC heterogeneity as the presence of strong granular cytoplasmic staining in 1-99% tumor cells; ALK IHC negativity as no tumor cells show strong granular cytoplasmic staining. Fluorescence in-situ hybridization (FISH) (Vysis ALK Break Apart FISH Probe Kit, Abbott) and next-generation sequencing (NGS) (OseqTMLung Cancer Gene Detection, BGI, China) was performed for cases showed ALK (D5F3) IHC heterogeneity.

      Result

      ALK (D5F3) double-blind review analysis showed 201 (9.0%) ALK-positive cases, 10 (0.4%) ALK-heterogeneous cases, and 2017 (90.5%) ALK-negative cases. The heterogeneity cases included 2 large cell neuroendocrine carcinomas, 1 lymphoid epithelioid carcinoma, and 7 squamous cell carcinomas. The percentages of tumor cells with strong granular cytoplasmic staining were 1% to 30%. The ALK FISH break apart signal of these ten cases were 0% to 12%, indicating ALK FISH negativity. Nine ALK-heterogeneous cases were successfully detected by NGS, and no ALKgene variations (including gene fusion, copy number variation, insertion/deletion or single nucleotide variation) were found. Immunohistochemical staining showed that some ALK-heterogeneous cases showed neuroendocrine differentiation.

      Table. Comparison of IHC, FISH and NGS results of the ALK-heterogeneous cases.

      ALK

      IHC

      ALK

      FISH

      ALK

      FISH

      ALK

      NGS

      ALK

      NGS
      Case No. Gender Age Biopsy/surgery Diagnosis

      Tumor cell

      content

      		 Strong positive staining tumor cells Break apart signal Interpretation result ALK fusion ALK INDEL/SNV/CNV 8thTNM
      1 M 69 Wedge resection Large cell neuroendocrine carcinoma 70% 2% 0% Negative Negative Negative pT1bN0M0
      2 M 55 Lobectomy Large cell neuroendocrine carcinoma 85% 20% 4% Negative Negative Negative pT2bN0M0
      3 F 33 Lobectomy Lymphoid epithelioid carcinoma 60% 5% 0% Negative Negative Negative pT3N0M0
      4 M 68 Lobectomy Squamous cell carcinoma 70% 5% 6% Negative Negative Negative pT3N0M0
      5 M 69 Lobectomy Squamous cell carcinoma 70% 5% 12% Negative Negative Negative

      pT2aN0M0
      6 M 52 Lobectomy Squamous cell carcinoma 80% 1% 0% Negative Negative Negative pT2aN1M0
      7 M 73 Lobectomy Squamous cell carcinoma 90% 5% 2% Negative Negative Negative pT3N0M0
      8 M 70 Lobectomy Squamous cell carcinoma 80% 5% 4% Negative Negative Negative pT2bN1M0
      9 M 69 Biopsy Squamous cell carcinoma 85% 15% 0% Negative Negative Negative sT3N1M0
      10 M 60 Biopsy Squamous cell carcinoma 85% 30% 0% Negative NA NA cT2bN3M0

      Abbreviations: INDEL, insertion and deletion; SNV, single nucleotide variation; CNV, copy number variation; NA, NGS was not performed due to insufficient tumor tissues.

      Conclusion

      Multi-platform detection of ALK-heterogeneous cases did not show evidence of ALKgene variation, and the effect of ALK-TKI treatment was unknown. therefore, the VENTANA ALK scoring interpretation guide for non-small cell lung carcinoma should be revised. It is recommended that ALK-heterogeneous cases be defined as ALK (D5F3) uncertain equivocal cases. The molecular pathology report should clearly state that the clinical significance is unclear, and it is recommended to conduct further testing by FISH or NGS.

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 3
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-49 - Molecular Characteristics of HER2 Mutations in Non-Small Cell Lung Cancer (Now Available) (ID 2859)

      10:15 - 18:15  |  Author(s): Yi-Long Wu

      • Abstract
      • Slides

      Background

      Earlier clinical trials targeting on HER2 exon 20 mutations show promising results. However, target therapy also had shown a favorable effect on non-tyrosine kinase domain (non-TKD) mutations in preliminary studies and case report, while no systemic study was reported about non-TKD mutations in HER2. Hence, The study aims to comprehensively outline the mutation landscape of HER2 in NSCLC.

      Method

      HER2 profile data (patients, N=5,222) from thirteen NSCLC studies in the cBioPortal for Cancer Genomics was screened. Finally, after excluding duplicated data (n=2,725) and no HER2 profile data (n=563), 1,934 individuals were enrolled in the analysis. The mutation subtype, mutation type, mutation region, biological effect of mutations referred to OncoKB, and HER2 copy number variation were described.

      Result

      4.3% (84/1934) of NSCLC patients were detected with HER2 mutation, and three patients carried double HER2 mutations, totally eighty-seven HER2 mutations were identified in the study. Fifty-three HER2 mutation subtypes were identified, and the most common mutation subtypes were Y772_A775dup (24%, 21/87), S310F (6%, 5/87), G776delinsVC (5%, 4/87) and G778_P780dup (5%, 4/87) respectively. HER2 fusion was identified in 8% (7/87) of mutations with a tendency to concurrent with HER2 copy number increased (5 amplification, 2 copy number gain). As for mutation region, 43% (37/87) of mutations occurred in TKD, while biological effect was not validated in 16% (6/37) of TKD mutations. Notably, biological effect of 56% mutations was inclusive or unknown. In gain of function subset, 82% (31/38) of mutations located at TKD, 13% (5/38) and 5% (2/38) were located at furin-like cysteine rich region and transmembrane domain.

      figure1.jpg

      Conclusion

      Mutation subtypes were diverse in HER2. Though accounting for more than half of HER2 mutations, the effect of non-TKD mutations was fewly understood rather than TKD mutations. Biological effect and clinical implication of non-TKD mutations need to be further investigated in the near future.

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      P2.14-56 - Osimertinib Overcomes Alectinib Resistance Caused by Amphiregulin in a Leptomeningeal Carcinomatosis Model of EML4-ALK Lung Cancer (ID 1543)

      10:15 - 18:15  |  Author(s): Yi-Long Wu

      • Abstract
      • Slides

      Background

      Central nervous system (CNS) metastasis, such as brain metastasis and leptomeningeal carcinomatosis (LMC), occurs in 20–40% of all patients with cancer. Anaplastic lymphoma kinase (ALK) is a clinically validated drug target and ALK rearrangements are found in approximately 3-5% of non-small cell lung cancer (NSCLC). ALK tyrosine kinase inhibitor (TKI) shows dramatic clinical efficacy in ALK-rearranged NSCLC patients, and the second-generation ALK-TKI alectinib is effective against CNS metastasis of ALK-rearranged NSCLC. However, the patients with ALK-rearrangement acquire resistance to alectinib over time and develop recurrent LMC metastasis. This study aimed to clarify the mechanism of resistance to alectinib in LMC and seek a novel therapeutic strategy.

      Method

      Alectinib-resistant cell line (A925L/AR) was established by continuous treatment with alectinib in the LMC mouse model inoculated with the alectinib-sensitive human lung cancer cell line, A925LPE3, which harbors the EML4-ALK gene fusion. The tumor level was measured by in vivo imaging system. To clarify the mechanism of alectinib resistance, tumor cell culture supernatants, patient cerebrospinal fluid (CSF), and patient serum were measured using ELISA kits for EGFR ligands.

      Result

      A925L/AR cells were moderately resistant to various ALK-TKIs, such as alectinib, crizotinib, ceritinib, and lorlatinib, compared with parental cells in vitro. A925L/AR cells acquired resistance through epidermal growth factor receptor (EGFR) activation due to overexpression of its ligand, amphiregulin. EGFR-TKIs and anti-EGFR antibodies re-sensitized A925L/AR cells to alectinib in vitro. In the LMC model with A925L/AR cells, combined treatment with alectinib and an EGFR-TKI, such as erlotinib and osimertinib, successfully controlled LMC progression. Imaging mass spectrometry showed accumulation of EGFR-TKIs in the tumor lesions. Moreover, notably high amphiregulin levels were detected in the cerebrospinal fluid from ALK-rearranged NSCLC patients with alectinib-resistant LMC compared with those in EGFR-mutated NSCLC patients with EGFR-TKI-resistant LMC or patients without LMC.

      Conclusion

      We demonstrated that EML4-ALK lung cancer cells acquired moderate resistance to alectinib in the leptomeningeal space due to amphiregulin-triggered EGFR activation. Moreover, combined use of alectinib and EGFR-TKIs, including the third-generation inhibitor osimertinib, could overcome resistance in the LMC model. Our findings may provide rationale for clinical trials to investigate the effects of novel therapies dual-targeting ALK and EGFR in ALK-rearranged NSCLC with alectinib-resistant LMC.

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      P2.14-60 - Afatinib in EGFR Mutation-Positive NSCLC: Activity in Patients with Brain Metastases, and Impact on CNS Progression/Spread (ID 1664)

      10:15 - 18:15  |  Author(s): Yi-Long Wu

      • Abstract
      • Slides

      Background

      In the LUX-Lung 3 and 6 trials, first-line afatinib significantly improved progression-free survival (PFS) versus chemotherapy in patients with EGFR mutation-positive (EGFRm+) NSCLC and baseline brain metastases (hazard ratio [HR], 0.50; P=0.0297).1 In LUX-Lung 7, similar PFS improvement with afatinib versus gefitinib was observed in patients with, and without, brain metastases (HR, 0.76 and 0.74; Pint=0.93).2 The aims of this study were to assess: i) the impact of afatinib on central nervous system (CNS) progression or metastatic spread in LUX-Lung 3, 6, and 7; ii) efficacy of afatinib in patients with brain metastases in a similar setting to ‘real-world’ practice.

      Method

      Competing risk analysis of CNS/non-CNS progression or death was performed in patients who received afatinib in LUX-Lung 3, 6, and 7, based on the cumulative frequency of the event of interest versus the competing risk event. Separate analysis was performed of an Asian phase IIIb study, which assessed afatinib in a broad population of EGFR TKI-naïve patients with EGFRm+ NSCLC (NCT01953913).3 PFS and time-to-symptomatic progression (TTSP) in patients with baseline brain metastases were calculated by Kaplan–Meier methodology.

      Result

      In patients with baseline brain metastases receiving afatinib in LUX-Lung 3 and 6 (n=48; median follow-up: 10.3 months), the risk of CNS progression was 40% lower than the risk of extracranial progression; 31.3%/52.1% of patients had CNS/non-CNS progression, respectively. In patients without baseline brain metastases receiving afatinib in LUX-Lung 3, 6, and 7 (n=485; median follow-up: 13.0 months), the risk of de novo CNS/non-CNS progression was 6.4%/78.4%. Cumulative risk of CNS/non-CNS progression was 1.3%/17.2% at 6 months and 2.6%/41.2% at 12 months. In the Asian phase IIIb study, there was no difference in PFS (median 10.9 vs 12.4 months; P=0.18) or TTSP (median 14.8 vs 15.4 months; P=1.0) between patients with (n=92) or without (n=387) brain metastases.

      Conclusion

      Competing risk analyses of LUX-Lung 3, 6, and 7 suggest that afatinib delays the onset/progression of brain metastases. Real-world data are consistent with LUX-Lung 3, 6, and 7, and support the use of afatinib in patients with EGFRm+ NSCLC and baseline brain metastases.

      1. Schuler, M. et al. J Thorac Oncol 2016;11:380‒90

      2. Park, K. et al. Lancet Oncol 2016;17:577‒89

      3. Wu YL, et al. J Thorac Oncol 2017;12(suppl 2):abstract P3.01-036

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    P2.17 - Treatment of Early Stage/Localized Disease (ID 189)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.17-16 - Genomic Heterogeneity and Evolutionary Trajectory in Multifocal Synchronous Lung Cancer (ID 2082)

      10:15 - 18:15  |  Author(s): Yi-Long Wu

      • Abstract
      • Slides

      Background

      Multifocal synchronous lung cancer (MSLC) presented as coexistence of multiple tumor lesions that share an identical germline genetic background and environmental exposure in individual patients. Along with the improved resolution of cross-sectional imaging, multiple types of ground glass opacities (GGOs) have been detected in increasing frequency as well as solid nodules even in an unique patient. However the molecular origins and relationships among the synchronous lesions remain unclear.

      Method

      10 treatment-naive MSLC patients were retrospectively collected while 25 tissue samples were performed whole exosome sequencing. In addition, we constructed phylogenetic trees to estimate the ancestral relationships of individual foci.

      Result

      79 somatic mutations in average were identified in MSLC tissues. The most significant mutated gene EGFR has been detected in 10 samples from 7 patients in our cohort. Tumor mutation burden as was significantly higher in IAC lesions than AIS/MIA ones. The mutation spectra of single-nucleotide variations (SNVs) were fairly consistent across the same histologic type even from different patients. Compared to AIS/MIA, IAC samples displayed a preponderance of A>T/T>A transition (Ti) while less frequency of A>C/T>G transversion (Tv). However few share mutations were located by pair of lesions in individual patients. Distinct genomic profiles suggested all were primary tumours. WNT pathway was enriched in AIS/MIA lesions exclusively while IAC appeared TGFβ/TP53 pathway mutation associated with cell proliferation and apoptosis.

      图1.jpg

      组图2.jpg

      Conclusion

      Even in the same individual patient different lung cancer lesions may be driven by distinct genomic profiles so that each presented its own evolutionary trajectory. A deeper understanding of tumorigenesis is still in need to improve the diagnosis and treatment of MSLC.

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