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Caicun Zhou



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    EP1.04 - Immuno-oncology (ID 194)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.04-40 - Extra-Thoracic Metastasis Indicated Worse Clinical Efficacy on Immune Checkpoint Inhibitors in Chinese Advanced NSCLC Patients (Now Available) (ID 995)

      08:00 - 18:00  |  Author(s): Caicun Zhou

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitors (ICIs) have demonstrated inspiring effectiveness against lots of cancer types, including non-small-cell lung cancer (NSCLC). However, the individual therapeutic response varies and heterogeneous. The purpose of this study was to investigate the association of different metastatic sites with clinical outcomes after ICIs monotherapy in Chinese advanced NSCLC patients.

      Method

      We retrospectively analyzed all patients receiving more than two circles of ICIs monotherapy (anti-programmed death 1 or anti-PD-L1) in Shanghai pulmonary hospital from January 2016 to December 2018. Detailed clinical characteristics, metastasis status and progress-free survival (PFS, calculated from the first day receiving ICIs until the disease progressed) was recorded.

      Result

      76 patients were enrolled in this study. 10 of them received immunotherapy in the first-line and 46 of them in the second-line. The rate of extra-thoracic metastasis was 50% (38/76), including brain metastasis (10/38), liver metastasis (11/38), bone marrow metastasis (30/38), adrenal metastasis (4/38), extra-thoracic lymph node metastasis (10/38) and others (5/38). Patients with extra-thoracic metastasis had a significantly shorter PFS than those without (median PFS 4.20 VS 7.10months; hazard ratio [HR] 1.939, 95% CI 1.221-3.389; p=0.0072). In subgroup analysis, patients with brain metastasis, liver metastasis or bone marrow metastasis showed significantly shorter PFS than those without (3.35 vs 4.60m, p=0.0499; 2.50 vs 4.60m, p=0.0007; 3.70 vs 5.80m, p=0.0003 respectively). The disease control rate (DCR) is numerically lower in patients with extra-thoracic metastasis (66.7% vs 80%) comparing with those without, even though not statistically significant.

      Conclusion

      The current study suggested that advanced NSCLC patients with extra-thoracic metastasis indicated worse clinical outcomes on ICIs monotherapy and more clinical strategies should be considered to improving treatment efficacy for them.

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    MA04 - Models and Biomarkers (ID 122)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Biology
    • Presentations: 1
    • Now Available
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      MA04.02 - Molecular Profiling of Adenocarcinoma and Squamous Cell Lung Cancer at Single Cell Resolution (Now Available) (ID 1358)

      13:30 - 15:00  |  Author(s): Caicun Zhou

      • Abstract
      • Presentation
      • Slides

      Background

      Adenocarcinoma and squamous are two main subgroups of lung cancer: adenocarcinoma (ADC) accounts for 30-50% and squamous cell carcinoma (SCC) accounts for nearly 30% of all cases respectively. ADC and SCC have different pathological phenotypes and respond differently to various therapies, including immunotherapy. However, the underlying molecular mechanism of such differentiated drug responses still needs to be further characterized.

      Method

      To achieve high resolution of both tumor cells and their tumor microenvironment (TME), we used single cell RNA sequencing method to characterize ADC and SCC tumors from Stage IV NSCLC patients. Tissue biopsy samples from 21 patients (12 patients with ADC, 9 with SCC) were collected. For each sample, single cell RNA sequencing was performed on an average of 1930 cells. A graph-based clustering approach was used to classify cells into different cell types based on their gene expression patterns. The cellular subtypes of both cancer cells and TME in ADC and SCC samples were analyzed.

      Result

      ADC and SCC show distinct patterns at single cell resolution. Cancer cells from all ADC patients form two closely related clusters, while cancer cells from SCC patients show high intra-and inter-patient heterogeneity. Gene Ontology (GO) analysis demonstrated that ADC samples are enriched in genes of neutrophil degranulation and activation, while SCCs are enriched in genes related to epidermal cell differentiation and glutathione metabolic process. Genes related to cancer progression and metastasis, such as LSD1 and FASCIN, are normally expressed at higher level in SCC than in ADC. Furthermore, ADC samples contain higher percentage of a specific myeloid cell population, while SCC has higher percentage of fibroblasts, demonstrating the difference also in TMEs of ACD versus SCC.

      Conclusion

      The significantly higher level of heterogeneity for SCC can be a possible reason for poor responses to standard lung cancer therapies, including immunotherapy. Accurate characterization of SCC with single cell resolution could hold the key to more effective therapeutic strategies.

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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
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      MA11.06 - A PII Study of Toripalimab, a PD-1 mAb, in Combination with Chemotherapy in EGFR+ Advanced NSCLC Patients Failed to Prior EGFR TKI Therapies (Now Available) (ID 1160)

      14:00 - 15:30  |  Author(s): Caicun Zhou

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR TKI is the standard 1st line therapy for the patients (pts) with advanced NSCLC harboring EGFR mutations. While PD-1 checkpoint blockade has become an integral component of disease management for EGFR wild type NSCLC pts at various settings, platinum-based chemotherapy is still the standard of care for EGFR mutated NSCLC pts who progress after EGFR targeting therapy. Early attempts to combine EGFR TKI with checkpoint blockade had resulted in exacerbated immune related toxicity in the lung. Here we aimed to prospectively evaluate toripalimab, a humanized PD-1 mAb approved for 2nd line treatment of melanoma, in combination with chemotherapy to treat EGFR mutated NSCLC pts after failure of EGFR targeting therapy.

      Method

      This is a phase II, multicenter, open-label, single-arm study for pts with EGFR activating mutations who have failed prior EGFR-TKI therapies without T790M mutation or failed osimertinib treatment. Pts were treated with 240mg or 360mg fixed dose toripalimab once every 3 weeks in combination with carboplatin and pemetrexed for up to 6 cycles, followed by toripalimab plus pemetrexed maintenance therapy until disease progression or intolerable toxicity. Primary endpoint was objective response rate (ORR) at week 12 as assessed by investigator per RECIST v1.1 once every 6 weeks. Secondary endpoints were safety, ORR, DOR, DCR, TTR, PFS, OS, PK and immunogenicity.

      Result

      f14_2_1_3_pub.png

      Forty pts were enrolled from Apr 25, 2018 to March 22, 2019 with 52.5% female pts and a median age of 57.5. 57.5% pts harbored EGFR exon19 deletion while 42.5% pts had exon21 L858R mutation. Only 1 pt had T790M mutation who progressed after osimertinib treatment. In ITT population, 13 confirmed partial response (PR) and 22 stable disease (SD) were observed at week 12 for a 32.5% ORR. As of Jul 25 2019, among 40 pts, 20 confirmed PR and 15 SD were observed for a 50% ORR (95% CI, 33.8% to 66.2%) and an 87.5% DCR (95% CI, 73.2% to 95.8%). Median progression free survival (PFS) was 7.0 months, and median duration of response (DOR) was 7.0 months. Treatment emergent adverse events (TEAE) occurred in 39 (97.5%) of the pts, grade 3 or higher events occurred in 25 (62.5%) of pts including two deaths. Most common AE included leukopenia, neutropenia, thrombocytopenia, anemia, nausea, and loss of appetite. Treatment discontinuation due to AE occurred in 4 (10%) of the pts.

      Conclusion

      Anti-PD-1 mAb, toripalimab in combination with carboplatin and pemetrexed has shown a promising anti-tumor efficacy with a tolerable safety profile for advanced NSCLC patients with EGFR mutated who progressed after EGFR TKI therapies. Pts will be continuously monitored for safety and efficacy readouts (DOR, PFS and OS). A phase III registration study will be initiated in May 2019.

      (Clinical trial information: NCT03513666)

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    OA04 - Immuno Combinations and the Role of TMB (ID 126)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      OA04.03 - A Randomized Phase 3 Study of Camrelizumab plus Chemotherapy as 1<sup>st</sup> Line Therapy for Advanced/Metastatic Non-Squamous Non-Small Cell Lung Cancer (Now Available) (ID 1682)

      15:15 - 16:45  |  Presenting Author(s): Caicun Zhou

      • Abstract
      • Presentation
      • Slides

      Background

      Platinum-based chemotherapy remains 1st line therapy for advanced non-small cell lung cancer (NSCLC) without oncogenic drivers in China. Camrelizumab (SHR-1210, a potent anti‒PD-1 monoclonal antibody) has shown promising activity in multiple malignancies. Here, we report interim analysis results on efficacy and safety of camrelizumab plus carboplatin/pemetrexed as 1st line treatment in Chinese advanced/metastatic non-squamous NSCLC patients with negative oncogenic drivers.

      Method

      In this open-label, randomized, multicenter phase 3 study (SHR-1210-303), patients with advanced/metastatic, non-squamous NSCLC with negative EGFR or ALK were stratified by sex and smoking history (≥ 400/year versus ˂ 400/year) and were randomly assigned (1:1) to receive 4 to 6 cycles of carboplatin (AUC=5) plus pemetrexed (500 mg/m2) with or without camrelizumab (200 mg), followed by pemetrexed with or without camrelizumab as maintenance therapy up to disease progression or intolerable toxicity. Treatment was given every 3 weeks. Crossover to camrelizumab monotherapy was permitted for patients in the chemotherapy arm who had confirmed disease progression. The primary endpoint was PFS per blinded independent central review according to RECIST v1.1. Secondary endpoints included ORR, DCR, DoR and OS. Data of subgroup analysis will be reported. Clinical Trials.gov number: NCT03134872.

      Result

      Between May 12, 2017 and Jun 6, 2018, 419 patients were randomized, among whom 205 received camrelizumab plus chemotherapy and 207 received chemotherapy treatment. After a median follow-up of 11.9 months, median PFS was 11.3 months (95% CI 9.5‒not reached) in camrelizumab plus chemotherapy arm and 8.3 months (95% CI 6.0‒9.7) in chemotherapy arm (HR 0.61 [95% CI 0.46‒0.80], p=0.0002). ORR, DCR, DoR and OS with camrelizumab plus chemotherapy were superior to chemotherapy (Table 1). Grade 3/4 adverse events occurred in 66.8% of patients in camrelizumab plus chemotherapy arm and 51.2% of patients in chemotherapy arm. There were 5 treatment-related deaths in camrelizumab plus chemotherapy arm and 4 in chemotherapy arm.

      Table 1. Responses per blinded independent central review and overall survival in the total study population

      Camrelizumab plus chemotherapy

      (n=205)

      Chemotherapy alone

      (n=207)
      p-value
      Objective response rate 60.0% (53.0‒66.8) 39.1% (32.4‒46.1) p<0.0001
      Disease control rate 87.3% (82.0‒91.6) 74.4% (67.9‒80.2) p=0.0009
      Duration of response (months) 17.6 (11.6‒NR) 9.9 (8.5‒13.8) p=0.0356
      Overall survival (months) NR (17.1‒NR) 20.9 (14.2‒NR) p=0.0272
      Data are shown in % (95% CI) or median (95% CI). NR: not reached.

      Conclusion

      First-line camrelizumab plus chemotherapy shows substantial clinical benefit in patients with advanced/metastatic non-squamous NSCLC with negative EGFR or ALK in terms of PFS, ORR, and OS and acceptable safety profiles. The combination should become novel standard 1st line therapy for this population.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 3
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-121 - Superior Outcomes of 1<sup>st</sup> Line EGFR TKI in Next-Generation Sequencing Identified Uncommon EGFR Exon 19delins Mutation Non-Small Cell Lung Cancer (ID 2953)

      09:45 - 18:00  |  Author(s): Caicun Zhou

      • Abstract

      Background

      First line EGFR-TKI showed promising efficacy on EGFR mutant advanced non-small cell lung cancers (NSCLC). However, the response duration time differs with different mutation variants. The aim of our study was to evaluate the efficacy and resistance mechanism of first-line EGFR TKI in NSCLC patients with uncommon mutation of EGFR 19del mutations.

      Method

      Among 1530 lung cancer patients who received detection of next generation sequencing (NGS) from Jan, 2015 to Aug, 2018, 49 gefitinib or erlotinib treated EGFR exon 19delins mutant advanced NSCLC patients received NGS of 168 genes panel using tumor tissue in baseline was enrolled in this study for cohort A. Using Propensity Score Matching (Ratio of 1:2), 98 patients carrying EGFR sensitive mutation of EGFR exon19del (745-760del) were set as cohort B. EGFR exon 19delins mutation variants in cohort A, clinical outcomes and resistance mechanism for both cohorts were also been evaluated.

      Result

      figure 1, pfs of cohort a and b..jpgIn cohort A, 19 EGFR exon 19delins variants were detected and 10 variants were novel. Among exon 19 delins variants, L747-A750delinsP and L747-A753delinsS were the domain variants, contributing to 24.5% (12/49) and 22.5% (11/49) respectively. In cohort A, 38 patients were evaluated with progress disease and 11 patients were ongoing current treatments. In cohort B, 73 patients were evaluated with progress disease and 36 patients were ongoing current treatments. There was no difference between cohort A and B for base characteristics, treatment drugs and response rate. The median PFS of cohort A and B was 19.0 months vs. 12.0 months (p=0.006). In all the 19del variants, the mPFS of L747-A750delinsP subtype was significantly prolong for 21 months (p=0.03). All the progress disease patients received re-biopsy and NGS detection. T790M was defined as the domain acquired resistance mechanism, contributing to 26.3% in cohort A and 45.2% in cohort B, followed by pathology transformation (5.3% vs 4.1%) and MET amplification (5.3% vs 4.1%).

      Conclusion

      Our results indicated that patients with EGFR exon 19delins mutation presented with significantly better outcomes for first line EGFR-TKI. Dominate resistant mechanism were still for EGFR exon 20T790M but significantly be decreased in uncommon EGFR mutations.

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      P1.01-22 - Investigation of Acquired Resistance for EGFR-TKI Plus Bevacizumab as 1st Line Treatment in Patients with EGFR Sensitive Mutant NSCLC (ID 2852)

      09:45 - 18:00  |  Author(s): Caicun Zhou

      • Abstract

      Background

      The progression-free survival (PFS) advantage of EGFR-TKI plus Bevacizumab (A+T) over standard TKI monotherapy (T) in the 1st line treatment of EGFR mutant non-small cell lung cancer (NSCLC) has been confirmed in prospective clinical trials. However, the acquired resistance mechanism which impacts the subsequent management was poorly understood. We did the first analysis to unveil it using next generation sequencing (NGS).

      Method

      256 EGFR sensitive mutant (EGFR 19del and L858R) NSCLC patients received NGS of 168 genes panel of tumor tissue in baseline from Jan, 2015 to Aug, 2018 was enrolled in this study. 60 patients treated with A+T were recognized as cohort A. Using Propensity Score Matching (Ratio of 1:2), 120 patients treated with single T were chosen as cohort B. Clinical outcomes and resistance mechanism (also by the 168 genes NGS panel) were evaluated.

      Result

      Newly present alterations in cohort A % N
      EGFR amp 3.2% 1
      MET amp 3.2% 1
      MET amp+EGFR amp+TP53 3.2% 1
      RB1 3.2% 1
      RB1+TP53 3.2% 1
      RB1+TP53+EGFR amp 3.2% 1
      SMAD4 3.2% 1
      T790M 22.6% 7
      T790M+BRAF V600E 3.2% 1
      T790M+EGFR exon 18 p.V834L+TP53 3.2% 1
      T790M+TP53 6.5% 2
      TP 53 16.1% 5
      unknown 25.8% 8
      Total 1 31
      Newly present alterations in cohort B % N
      EGFR amp 6.8% 7
      EGFR exon 7 p.T263P 1.0% 1
      EGFR exon18 p.G724S 1.0% 1
      ERBB2 amp 1.0% 1
      KRAS 1.0% 1
      MET amp 4.9% 5
      MET skipping 1.0% 1
      RET+KRAS 1.0% 1
      SCLC 2.9% 3
      T790M 37.9% 39
      T790M+BRAF V600E 1.0% 1
      T790M+EGFR amp 8.7% 9
      T790M+MET amp 1.9% 2
      T790M+TP53 1.9% 2
      TP53 4.9% 5
      TP53+RB1 1.0% 1
      unknown 22.3% 23
      Total 1 103

      There was no different for clinical characteristics between Cohort A and B. Comparing with single T, A+T significantly prolonged the medium PFS (16.5m vs.12.0m, HR=0.7, p=0.001). A+T significantly increased the overall response rate (95% vs 74.2%, p<0.05). Until Jan 2019, 31 patients in cohort A, 103 patients in cohort B were evaluated with progressed disease and received tissue re-biopsy for NGS with the same 168 genes panel. In cohort B, T790M was defined as the domain acquired resistance mechanism, contributing to 51.5% (53/103) of progressed patients, followed by EGFR amplification 15.5% (16/103), MET amplification 6.8% (7/103), TP53 mutations 6.8% (7/103) and small cell lung cancer transformation 2.9% (3/103). However, in cohort A, although T790M was also defined as the domain acquired resistance mechanism, the mutation ratio was decreased to 35.5% (11/31), followed by TP53 mutations 29.0% (9/31), RB1 mutations 9.7% (3/31), EGFR amplification 9.7% (3/31), MET amplification 6.5% (2/31), and novel SMAD4 mutations 3.2% (1/31), EGFR uncommon mutation (p.V834L) 3.2% (1/31).

      Conclusion

      Treatment of 1st line A+T significantly extends the time to progression and increases the response rate with acceptable safety profile. The dominant acquired resistance mechanism retained in T790M but with lower probability. SMAD4 mutation and EGFR p.V834L were considered as novel resistant mechanism to A+T.

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      P1.01-62 - Association of Baseline Pulmonary Fibrosis with the Outcome of PD-1 Inhibitor in Patients with Advanced Non-Small Cell Lung Cancer (ID 2942)

      09:45 - 18:00  |  Author(s): Caicun Zhou

      • Abstract

      Background

      PD-1/PD-L1 inhibitors have become standard care for previously treated advanced non-small cell lung cancer (NSCLC). However, not all patients are suitable for the immunotherapy. This study aimed to investigate the efficacy and safety of PD-1/PD-L1 inhibitors in patients with advanced NSCLC and pre-existing pulmonary fibrosis (PF).

      Method

      Patients who had a NSCLC diagnosis, received anti-PD-1/PD-L1 monotherapy and had baseline chest HRCT screen at Shanghai Pulmonary Hospital, Tongji University were retrospectively collected from January 2016 to February 2019. The pre-existence of PF was identified by reviewing baseline chest imaging. Baseline clinicopathologic characteristics, treatment outcomes and immune-related pneumonitis were collected.

      Result

      116 patients were included with 61 age < 65. Among them, 97 (83.6%) were male, 76 (65.5%) were smoker, 51 (44%) were squamous, 61 (52.6%) received anti-PD-1 monotherapy (Pembolizumab n=62, Nivolumab n=28) as 2nd line setting, 28 (24.1%) had PF prior to PD-1 inhibitors. Baseline characteristics such as age, gender, ECOG PS, smoking history, pathology are similar between patients with or without PF. Patients with PF had a comparable response (ORR: 25% vs 15.9%, p=0.277, figure A), disease control (DCR: 60.7% vs 48.9%, p=0.274, figure B) and PFS (median 2.5 vs 2.8 months, p=0.950). The incidence of immune-related pneumonitis in the entire cohort was 9.2%, which was numerally higher in PF group (17.9% vs 6.8%, p=0.172, figure C). No death from immune-related pneumonitis occurred.

      fig.jpg

      Conclusion

      NSCLC patients with pre-existing PF showed comparable response to PD-1 inhibitors but a higher incidence to immune-related pneumonitis.

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    P1.03 - Biology (ID 161)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.03-50 - Type- and Stage-Specific Genomic Profiles in East Asian Lung Cancer Patients with No TKI-Related Driver Gene Mutations     (ID 1196)

      09:45 - 18:00  |  Author(s): Caicun Zhou

      • Abstract

      Background

      It is widely accepted that the development of advanced lung cancer or distant metastases rely on driver gene mutations, but the carcinogenesis of lung cancers without key driver gene mutations has not been fully understood. The genomic landscape of lung adenocarcinoma (LADC), lung squamous cell carcinoma (LUSC) and small cell lung cancer (SCLC) without TKI-related driver gene mutations in East Asian has not been well investigated. Systematic study of these subtypes may identify biomarkers to distinguish different types and find novel tractable targets for therapy. We have therefore studied the genomic profiles of these types of lung cancers to identify type-specific and stage-specific gene mutations.

      Method

      32 LADC patients, 43 LUSC patients and 26 SCLC patients with no TKI-related driver gene (EGFR, ALK, ROS1, RET, BRAF, C-MET, HER2) mutations were included in this study. Genomic profiles were determined with lung cancer tissue by whole-exome sequencing (WES). Sequencing data were analyzed with R packages and statistics was performed with SPSS 20.

      Result

      In 101 patients enrolled, TP53, TTN, MUC4, ZFHX4 and CSMD3 mutations were commonly detected in all 3 types of lung cancer, and TP53 was the commonest mutated gene. Markedly, KRAS mutations were found only in LADC, and CSMD1 mutations were more frequent in LUSC, whereas RB1 mutations were observed exclusively in SCLC. LRP1B and RYR2 mutations were found more frequently at late stages. Copy number variations (CNV) in TERT, RICTOR and FGFR1 were seen in all 3 subtypes. The PIK3CA copy number gain was commonly seen in LUSC and SCLC other than that in LADC. In contrast, the CDKN2A copy-number loss was found in LADC and LUSC, but not in SCLC. The PTEN copy number loss was only identified in LUSC. No significant differences in TMB were observed among these 3 subtypes of lung cancer. However, statistical significance in TMB was attained between non-small cell lung cancer (NSCLC) and SCLC (P=0.022) in stage Ⅳ patients when the cut-off of TMB was set to 4.5 muts/MB.

      subtype.jpg

      Conclusion

      Results from this genomic study confirmed the mutual and exclusive gene variations (including gene mutations and copy number variations) in 3 subtypes of lung cancer. It showed that gene variations were associated with lung cancer subtypes in patients with no TKI-related driver gene mutations. These findings might detecte subtype-specific biomarkers to assist histological-based diagnosis, and help to identify potential type-specific targets for lung cancer therapy.

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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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      P1.04-57 - Metronomic Dosing of Chemotherapy Alters Antitumor Immunity and Synergizes with PD-1/PD-L1 Inhibition in Non-Small Cell Lung Cancer (Now Available) (ID 1216)

      09:45 - 18:00  |  Author(s): Caicun Zhou

      • Abstract
      • Slides

      Background

      The combination of immune checkpoint blockade with chemotherapy is currently under investigation as a promising strategy for the treatment of non-small cell lung cancer. Although it has been reported that metronomic dosing of cisplatin can be immune stimulating, the impact of its combination with anti-PD-1/PD-L1 immunotherapy for the treatment of lung cancer remains to be evaluated. Therefore, the current study aimed to explore whether combining low-dose continuous chemotherapy and anti-PD-L1 treatment can induce synergistic antitumor effect by enhancing antitumor immune response in murine lung cancer.

      Method

      We evaluated the antitumor effects of conventional dose of cisplatin and low-dose metronomic dose of cisplatin as monotherapy or in combination with anti-PD-L1 monoclonal antibody in a murine lung cancer model using Lewis lung cancer cells (LLC). And the changes of immune components in tumor were tested in different treatment groups by flow cytometry and immunohistochemistry.

      Result

      tumor.jpg

      The results showed that low-dose metronomic use of cisplatin could eradicate Foxp3+ regulatory T cells (Tregs) and myeloid derived suppressive cells (MDSCs). Furthermore, combining low-dose cisplatin and anti-PD-L1 therapy could not only increase the inflitration of CD8+ T cells ,especially IFN-γ+CD8+ T cells , but also significantly reduce the expression of PD-1 and PD-L1. In a syngeneic mouse model of NSCLC, we observed that concurrent use of low-dose cisplatin and anti–PD-L1 delayed tumor growth and enhanced survival.

      Conclusion

      Low-dose continuous cisplatin treatment can modify tumor immune microenvironment by eliminating immunosuppressive components like Tregs and MDSCs and enhance antitumor immune response, which can be enhanced by PD-1/PD-L1 blockade and therefore induced a synergistic anti-tumor effect.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-30 - Hepatitis B Infection or Aminotransferase Increase Associate with Poor Outcome of Anti-PD-1 Monotherapy in Patients with Advanced NSCLC (ID 2508)

      10:15 - 18:15  |  Author(s): Caicun Zhou

      • Abstract

      Background

      Previous study demonstrated that the existence of liver metastases at the commencement of immunotherapy was associated with poor response. Since hepatitis B infection and liver dysfunction were higher prevalent in China, this study aimed to investigate the efficacy and safety of PD-1/PD-L1 inhibitor in Chinese NSCLC patients with hepatitis B infection or liver dysfunction.

      Method

      We retrospectively collected the patients who were diagnosed with non-small cell lung cancer and received anti-PD-1 monotherapy at Shanghai Pulmonary Hospital, Tongji University School of Medicine, China, from January 2016 to February 2019. Detailed clinicopathologic characteristics, therapeutic outcomes, hepatitis biomarker test and liver function test were collected.

      Result

      135 patients were enrolled with 73(54.1%) aged <65 years old. Among them, 113(83.7%) were male, 84(62.2%) were smoker, 57(42.2%) were squamous, 69(44.4%) received anti-PD-1 monotherapy (Pembolizumab n=28, Nivolumab n=21) as 2nd line setting, 5(3.7%) patients had hepatitis B infection and 17(12.6%) had increased ALT or AST. The baseline characteristics such as age, gender, smoking status, histology, PD-1 mono-antibodies, line of therapy was similar between hepatitis infection or liver dysfunction group vs. normal group. Hepatitis infection or liver dysfunction group had a lower ORR (9.5% vs. 17.5%, p=0.553, Figure A), significantly shorter PFS (1.6 months vs. 3.0 months, p<0.050, Figure B) when compared with these patients without. Out of the 22 patients with hepatitis or increase transaminase, 35.7% deteriorated the grading of alanine or aspartate aminotransferase increased. 肝炎肝损final (1).jpg

      Conclusion

      NSCLC patients with hepatitis B infection or increased transaminase showed a high incidence of hepatic disfunction and poor outcome to anti-PD-1 monotherapy.

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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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      P2.03-36 - tTMB and bTMB in East Asian Lung Cancer Patients with No TKI-Related Driver Gene Mutations (ID 1183)

      10:15 - 18:15  |  Author(s): Caicun Zhou

      • Abstract

      Background

      High-level TMB was shown to be correlated with the better response of immunotherapy in lung cancer patients. However, the correlation between tissue tumor mutational burden (tTMB) with the blood tumor mutational burden (bTMB) in lung cancer patients has not been fully defined, and the tTMB and bTMB of East Asian lung cancer patient harboring no TKI-related driver gene mutations remains unexplored. This study aimed to define the tTMB and bTMB in East Asian by whole-exome sequencing (WES) and panel-based sequencing, and interrogate the correlation between gene mutations and TMB in lung cancer patients with no TKI -related driver gene mutations.

      Method

      In this cohort study, 122 primary lung cancer patients without TKI-related driver gene (EGFR, ALK, ROS1, RET, BRAF, C-MET, HER2) mutations were included. tTMB and bTMB were determined by whole-exome sequencing (WES) and a targeted 451-gene panel sequencing. The correlation between any two among the WES-tTMB, the panel-tTMB and the panel-bTMB were determined, and the relationship between gene mutations and tTMB were analyzed. Statistics was performed with the SPSS 20 software.

      Result

      The mean tTMB measured by WES (WES-tTMB), the 451-gene panel (panel-tTMB) and bTMB measured by the 451-gene panel (panel-bTMB) was 4.5, 7.2 and 6.1 mutations/Mb, respectively. Significant correlation was found between panel-tTMB and WES-tTMB (Pearson r=0.76, P<0.001) or panel-bTMB (Pearson r=0.52, P<0.001), but WES-tTMB showed no correlation with panel-bTMB (Pearson r=0.189, P=0.75). The relationship between gene mutations and WES-tTMB was further explored. Patients with p53, TTN, CSMD3, ZFHX4, RYR2 , MUC16, MUC12 and USH2A gene mutations had dramatically higher tTMB (P<0.001), while no significant relationship between CDKN2A or KRAS gene mutations and TMB was identified (p>0.05). In contrast, patients harboring both KRAS and P53 mutations showed significantly higher TMB than those with either gene mutations or no mutations in both genes (P<0.001).

      tmb.jpg

      Conclusion

      Our study suggested that discrepancies exist in TMB measurement using different NGS-based detecting methods with tissue or blood sample types. The cut-off values should be determined based on detecting methods and samples types. Panel-tTMB was stronger correlation with WES-tTMB and panel-bTMB. Gene mutations were correlated with high TMB might be stronger predictors for TMB status in lung cancer patients without TKI-related driver gene mutations. Our observations provided new insights in TMB determination in East Asian lung cancer patients with NGS-based methods in various samples types and might improve the prediction of therapeutic effect and prognosis in future immunotherapy.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-57 - Predictive and Prognostic Value of CTC Monitoring in Advanced NSCLC Patients Treated with Immune Checkpoint Inhibitors (ID 1165)

      10:15 - 18:15  |  Author(s): Caicun Zhou

      • Abstract

      Background

      Immune checkpoint inhibitors (ICI) have recently emerged as a treatment option for selected patients with advanced non-small-cell lung cancer (NSCLC). However, there is a lack of effective biomarker to predict the treatment response and monitor disease progression. In this prospective observational study, we aimed to investigate the predictive and prognostic value of folate receptor-positive circulating tumor cell (FR+CTC), a well-established lung cancer biomarker, in advanced NSCLC patients treated with ICIs.

      Method

      Advanced NSCLC patients with at least one measurable lesion and expected to undergo ICIs treatment were recruited. Peripheral blood samples were collected from each participant at baseline, after each cycle of ICI treatment, and on disease progression. FR+CTCs were enumerated by using negative enrichment and ligand-targeted polymerase chain reaction methods. Treatment efficacy was analyzed according to the iRECIST criteria. The correlation of FR+CTC level and its dynamic changes with radiological responses was evaluated.

      Result

      Of the 35 patients, 17 received first-line treatment, 10 received second-line treatment, and 8 received third-line treatment or above. CTCs were detected (≥8.7FU/3ml) in 80.0% of patients at baseline. The baseline CTC of first-line/second-line therapy patients was significantly higher than that of third-line and above therapy patients (median values 16.68 vs 8.36, P=0.017). Meanwhile, there was no significant difference in baseline CTC values between different pathological subtypes and whether PD-L1 was expressed or not. For the radiological responses, after at least two cycles of ICI treatment, PR, SD, and PD were found in 10, 8, and 4 patients, respectively. The CTC count in the PD group at baseline was significant higher than that of the disease control (PR+SD) group (P=0.033). Similarly, the CTC value after two cycles of ICI treatment in PD group (17.84 ± 7.03) was higher than SD/PR group (12.50 ± 4.94), but not statistically significant (P=0.081). However, the changes of CTCs after one or two cycles of immunotherapy were poorly related to the treatment response (P>0.05), perhaps because of the polarization trend of CTC changes in the PR group after treatment.

      Conclusion

      In sum, these data confirm the predictive significance of CTCs in advanced NSCLC patients treated with immune checkpoint inhibitors. The baseline CTCs value correlated significantly with radiological response. Further studies are needed to confirm whether CTCs can be used as a prognostic factor for advanced non-small cell lung cancer.

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      P2.04-58 - The Correlation Between TMB and Clinical Factors in East Asian Lung Cancer Patients with No TKI-Related Driver Gene-Mutations  (ID 1253)

      10:15 - 18:15  |  Author(s): Caicun Zhou

      • Abstract

      Background

      Clinical factors, such as stage, metastasis, pathological type, age, smoking, gender and tumor mutational burden (TMB), have been reported to correlate with the prognosis of lung cancer (LC). However, it is still unclear how these factors influence the outcomes of patients with no TKI-related driver gene-mutations, and how these factors inter-correlate with each other. The aim of this study was to investigate the inter-correlation of these clinical variables in East Asian LC patients with no TKI-related driver gene-mutations to provide suggestions for patient selection and prognosis prediction.

      Method

      122 primary lung cancer patients without TKI-related driver gene (EGFR, ALK, ROS1, RET, BRAF, C-MET, HER2) mutations were recruited, in which 67 patients were confirmed with stage IV LC. Gene variations were determined in tumor tissue by whole-exome sequencing (WES). SPSS 20 software were used for statistics analysis, and P-values < 0.05 were considered significant.

      Result

      In 122 enrolled patients, 110 (90.2%) were male, 87 (71.3%) had smoking history and 95 (77.9%) were older than 60 years old. Significant differences in TMB were observed between male and female (P <0.05), but not between patients with or without smoking history (P >0.05). Patients older than 60 years old had dramatically higher TMB than those younger than 60 (P <0.05). Gender, smoking history, age, lung cancer subtype were not associated with the occurrence of brain or bone metastases (P >0.05). The mean TMB measured by WES was 4.5 mutations/Mb for all lung cancer patients. It was notable that the ratio of patients with TMB ≤4.5 was 68.2% (15/22) and 41.7% (5/12) for bone and brain metastatic patients, respectively. .Although the difference was not significant (P=0.163), the trend suggests that there may be a metastasis-specific difference in TMB.

      Conclusion

      Result from this exploratory study confirmed the gender preference in patients without TKI-related driver gene mutations. Male and elder patients with higher TMB may be the population that benefits more in immunotherapy. Although clinical the factors were not found to correlate with metastatic sites in this study, larger cohorts may find significant correlation, which could lead to the identification of novel biomarker for patient stratification or selection in therapies.

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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-51 - Dual ALK Fusion Partners as Poor Predictive Marker in First Line Crizotinib Treated ALK Rearranged Non-Small Cell Lung Cancer (ID 2971)

      10:15 - 18:15  |  Author(s): Caicun Zhou

      • Abstract

      Background

      First line crizotinib response duration time differs with different fusion patterns in ALK-rearranged advanced non-small cell lung cancer (NSCLC) patients. Some former researches have elucidate the impact of EML4-ALK variants on crizotinib efficacy, however, there was little data about the efficacy of crizotinib considering different fusion partners including one patient with two or more fusion partners or non-EML4 partners.

      Method

      150 patients with NGS-identified ALK-rearranged NSCLC from March 2014 to July 2018 in Hunan Cancer Hospital were enrolled in this study. Among them, 112 patients received crizotinib as first-line treatment. Efficacy of crizotinib was evaluated and categorized according to different fusion partners.

      Result

      Among 150 advanced NSCLC patients with NGS-identified ALK-rearranged, 181 fusion partners were detected including 43 novel fusion partners. 122 patients (81.3%) were identified with single ALK fusion partners, 28 patients (18.7%) were identified with dual or triple ALK fusion partner patients. Among 112 patients received first line crizotinib treatment, 89 patients were identified with single fusion partner (79 for EML4, 10 for non-EML4). 23 patients were identified with dual fusion partner (20 patients with dual fusion partners, 3 patients with triple fusion partners). The overall response rate (ORR) was 85.2% and the median progression-free survival time (mPFS) was 11.7 months. The frequency of brain metastasis was high in dual fusion partner patients. Patients with dual ALK fusion partners have a significantly shorter mPFS compared with patients carrying single ALK fusion partner (6.1m vs. 12.0m, p=0.001). Patients with EML4 partners have a significantly longer mPFS compared with patients carrying non-EML4 fusion partners (12.6m vs. 6.1m, p=0.004).

      Fusion partners EML4-ALK fusion variants Number of patient Percentage of patient(%)
      C9orf3-ALK   2 1.3%
      CLIP1-ALK   1 0.7%
      CYBRD1-ALK 1 0.7%
      DEFA5-ALK   1 0.7%
      EML4-ALK V1 31 20.7%
      EML4-ALK V2 10 6.7%
      EML4-ALK V3 47 31.3%
      EML4-ALK V5 11 7.3%
      EML4-ALK V7 3 2.0%
      EML4-ALK E3:A20 1 0.7%
      EML4-ALK E7:A20 1 0.7%
      EML4-ALK,APOB-ALKE V5 1 0.7%
      EML4-ALK,ATXN1-ALK V7 1 0.7%
      EML4-ALK,BIRC6-AS2-ALK V3 1 0.7%
      EML4-ALK,C1QC-ALK V3 2 1.3%
      EML4-ALK,COL22A1-ALK V3 1 0.7%
      EML4-ALK,COL22A1-ALK V1 1 0.7%
      EML4-ALK,DIRC3-AS1-ALK,CDC42EP3-ALK V3 1 0.7%
      EML4-ALK,EHBP1-ALK V3 1 0.7%
      EML4-ALK,FLJ14082-ALK V3 1 0.7%
      EML4-ALK,LBH-ALK V1 1 0.7%
      EML4-ALK,LINC00486-ALK V3 1 0.7%
      EML4-ALK,LINC01121-ALK V1 1 0.7%
      EML4-ALK,LOC102467222-ALK V3 1 0.7%
      EML4-ALK,LOC388942-ALK V1 1 0.7%
      EML4-ALK,LOC388942-ALK, V3 1 0.7%
      EML4-ALK,LRRTM4-ALK V3 1 0.7%
      EML4-ALK,MBOAT2-ALK V2 1 0.7%
      EML4-ALK,MTA3-ALK,SP3-ALK V1 1 0.7%
      EML4-ALK,MYH7-ALK V2 1 0.7%
      EML4-ALK,PDE6D-ALK V1 1 0.7%
      EML4-ALK,QPCT-ALK V1 1 0.7%
      EML4-ALK,RC3H2-ALK V1 1 0.7%
      EML4-ALK,SGPP2-ALK V3 1 0.7%
      EML4-ALK,SIX3-AS1-ALK V2 1 0.7%
      EML4-ALK,SRBD1-ALK V3 1 0.7%
      EML4-ALK,THADA-ALK V3 1 0.7%
      EML4-ALK,TSPYL6-ALK,ABCG8-ALK V3 1 0.7%
      FAM179A-ALK   1 0.7%
      GBE1-ALK   1 0.7%
      KLC1-ALK   1 0.7%
      LOC388942-ALK   1 0.7%
      NCOA1-ALK   1 0.7%
      RP11-433C9.2-ALK   1 0.7%
      RPSA-ALK   1 0.7%
      SLC8A1-ALK   1 0.7%
      STRN-ALK   1 0.7%
      THADA-ALK   1 0.7%
      UBXN2A-ALK   1 0.7%
      USP34-ALK   1 0.7%
      WDR37-ALK   1 0.7%

      figure 1 pfs in dual and single fusion partner patients(a), eml4 and non-eml4 fusion partner patients..jpg

      Conclusion

      Efficacy of first-line crizotinib in ALK-rearranged NSCLC patients differs based on different ALK fusion partners. Dual ALK fusion partners were poor prognostic factors in first-line crizotinib treatment NSCLC. It also correlated with more brain metastasis compared with single fusion partners.