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Jun Zhao



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    JCSE01 - Perspectives for Lung Cancer Early Detection (ID 779)

    • Event: WCLC 2018
    • Type: Joint IASLC/CSCO/CAALC Session
    • Track: Screening and Early Detection
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/23/2018, 07:30 - 11:15, Room 202 BD
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      JCSE01.22a - Tislelizumab Combined With Chemotherapy as First-Line Treatment in Chinese Patients With Advanced Lung Cancer (ID 14702)

      11:15 - 11:15  |  Author(s): Jun Zhao

      • Abstract

      Abstract not provided

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-56 - Concurrent Mutations in Chinese Lung Cancer Patients Carrying HER2 Genomic Aberrations (ID 13756)

      16:45 - 18:00  |  Author(s): Jun Zhao

      • Abstract
      • Slides

      Background

      Although human epidermal growth factor receptor 2 (HER2, ERBB2) genomic aberration has been identified as therapeutic targets, clinical trials of HER2-directed therapies have disappointing results in lung cancer. We hypothesize that the concurrent alterations might be one of the reasons, thus the aim of this study was to describe frequent concurrent alterations in Chinese lung cancer patients harboring HER2 mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 147 cancer patients with HER2 mutations were enrolled in the study. Tumor biopsy, ctDNA and pleural effusion samples were collected for detection alterations using hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations of at least 59 genes (59-1021).

      4c3880bb027f159e801041b1021e88e8 Result

      Sixty-two of 147 patients with HER2 genomic aberrations were diagnosed as lung cancer. The HER2 gene was amplified in 11 (18%) patients, whereas HER2 mutations were detected in 48 patients, co-occurrence of HER2 amplification and mutations were in 3 patients. Thirty of the 62 patients (48.39%) had concurrent actionable mutations across 18 genes, which involved in RTK-PIK3CA-mTOR signaling pathways, cell-cycle pathway, DNA repair pathway, RAS-RAF-MAPK pathway and some others (details in table). Moreover, 7 patients had more than 2 concurrent mutations besides HER2 mutation/amplification.

      Table 1. concurrent genetic alterations in HER2-altered lung cancer patients

      Signaling pathway

      Concurrent

      actionable

      mutations

      Number of

      patients

      RTK-PIK3CA-mTOR

      EGFR 11
      PIK3CA 4
      STK11 2
      FBXW7 1
      TSC1 1
      FLCN 1
      C11orf30 1
      Cell-cycle CDKN2A 5
      CCND1 2
      RB1 1
      DNA repair BRCA2 1
      ATM 1
      RAS-RAF-MAPK BRAF 1
      KRAS 1
      Others MDM2 2
      JAK2 2
      SMARCA4 2
      PTCH1 1

      8eea62084ca7e541d918e823422bd82e Conclusion

      Concurrent of actionable genetic alterations in HER2-altered Chinese lung cancer patients was common. The complex molecular profiles elucidate the importance of comprehensive analysis of genetic mutations when considering anti-HER2 targeted therapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-98 - A Phase IIIb Trial of Afatinib in EGFRm+ NSCLC: Analyses of Outcomes in Patients with Brain Metastases or Dose Reductions (ID 12906)

      16:45 - 18:00  |  Author(s): Jun Zhao

      • Abstract

      Background

      We previously reported interim results of a large (n=479) open-label, single-arm Phase IIIb study of afatinib in EGFR TKI-naïve patients with EGFRm+ NSCLC, in a setting similar to ‘real-world’ practice (Wu et al, WCLC, 2017). In this broad population of Asian patients, the tolerability profile of afatinib was predictable and manageable. Adverse events (AEs) were consistent with the LUX-Lung 3, 6 and 7 trials; 3.8% of patients discontinued due to drug-related AEs. Progression-free survival (PFS) and time to symptomatic progression (TTSP) was encouraging, in patients with both common and uncommon EGFR mutations. TTSP data suggested effective treatment beyond progression. Here, we assess the impact of baseline brain metastases and use of dose reductions on efficacy outcomes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with locally advanced/metastatic EGFRm+ NSCLC were recruited in China, Hong Kong, India, Singapore and Taiwan. Afatinib 40mg/day was given until disease progression (investigator-assessed) or lack of tolerability. Treatment-related AEs could be managed by protocol-specified tolerability-guided dose adjustment.

      4c3880bb027f159e801041b1021e88e8 Result

      At data cut-off (13 Feb 2017), patient characteristics were as follows: median age, 59.0 years; female, 52.4%; EGFR mutations: Del19+/-L858R+/-uncommon, 86.0%; uncommon only, 14.0%; ECOG PS0, 19.8%; PS1, 78.1%. Prior chemotherapy lines: 0, 59.7%; 1, 30.1%; ≥2, 10.2%.

      Overall, dose reductions from 40mg/day to 30mg/day occurred in 119 patients (25%). Incidences of the most frequently reported AEs before and after dose reduction were (any grade): diarrhea, 96/51%; rash/acne, 69/58%; stomatitis, 65/42%; (≥grade 3) diarrhea, 27/4%; rash/acne, 24/11%; stomatitis, 11/5%. A total of 96 patients had a dose reduction during the first six months; median PFS in this subgroup was 14.1 months (95% CI: 10.0–19.3) versus 11.33 (10.7–13.6) months in those who remained on the starting dose (n=383); HR=1.37 (1.01–1.85), p=0.041. Median TTSP was 17.7 (13.5–23.7) and 14.7 (12.7–17.0) months, respectively; HR=1.26 (0.92–1.72), p=0.15.

      Among 92 patients (19.2%) with brain metastases at baseline, median PFS was 10.9 (8.3–14.3) months, versus 12.4 (10.8–13.9) months in those without metastases (n=387); HR=1.23 (0.91–1.65), p=0.18. Median TTSP was 14.8 (12.7–20.7) and 15.4 (12.9–18.0) months, respectively; HR=1.0 (0.71–1.40), p=1.0.

      8eea62084ca7e541d918e823422bd82e Conclusion

      These findings demonstrate that tolerability-guided dose adjustment of afatinib is an effective measure to reduce treatment-related AEs, while maintaining therapeutic efficacy. TTSP was similar between patients with and without brain metastasis. This is additional evidence for the efficacy of afatinib in patients with brain metastases.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.04-36 - Tislelizumab Combined With Chemotherapy as First-Line Treatment in Chinese Patients With Advanced Lung Cancer (ID 12092)

      16:45 - 18:00  |  Author(s): Jun Zhao

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitors have shown efficacy in patients with NSCLC as monotherapy and in combination with chemotherapy. Tislelizumab is a humanized IgG4 monoclonal antibody to PD‑1 specifically engineered to minimize FcϒR binding on macrophages, possibly minimizing negative interactions with other immune cells. In a phase 1 study, tislelizumab was generally well tolerated and showed antitumor activity; 200mg IV Q3W was established as the recommended dose.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This multi-arm phase 2 study, consisting of safety run-in and dose-extension phases, assessed tislelizumab in combination with platinum-based chemotherapy (by tumor histology) as a potential first-line treatment for Chinese patients with lung cancer. All patients received tislelizumab at 200mg Q3W in combination with 4–6 cycles of platinum-doublet until disease progression. Nonsquamous (nsq) NSCLC patients received pemetrexed + platinum Q3W for 4 cycles followed by pemetrexed maintenance, while squamous (sq) NSCLC patients received paclitaxel + platinum (A) or gemcitabine + platinum (B) Q3W, and small-cell lung cancer (SCLC) patients received etoposide + platinum Q3W. Tumor response (RECIST v1.1) and safety/tolerability were evaluated.

      4c3880bb027f159e801041b1021e88e8 Result

      As of 21 Feb 2018, 48 patients (median age, 62 years [range: 36–75], 71% male, 71% current/former smokers) received tislelizumab treatment (median, 3 cycles [range: 1–7]); 44 patients remain on the study. Across the four cohorts, confirmed and unconfirmed partial responses were observed in 13 and 9 patients, respectively (Table). The most frequent AEs were chemotherapy-related hematologic toxicities. The most commonly reported grade ≥3 treatment-related AEs were neutropenia (20.8%) and anemia (12.5%); the most common grade 3 immune-related AEs were pyrexia (6.3%) and rash (6.3%). One sq‑NSCLC patient experienced a fatal myocarditis/myositis following one cycle of paclitaxel/cisplatin; all other treatment-related AEs were managed/resolved by study-drug interruption (n=15) or discontinuation (n=4) and appropriate treatment.

      Best Overall Response (Patients With ≥1 Post-Baseline Tumor Assessment)

      nsq-NSCLC (n=9)

      sq-NSCLC [A] (n=12 )

      sq-NSCLC [B] (n=5 )

      SCLC (n=8)

      Total

      (N=34)

      PR

      4 (44.4)

      9 (75)

      4 (80)

      5 (62.5)

      22 (64.7)

      Confirmed PR

      1 (11.1)

      4 (33.3)

      4 (80)

      4 (50)

      13 (38.2)

      Unconfirmed PR

      3 (33.3)

      5 (41.7)

      0 (0)

      1 (12.5)

      9 (26.5)

      SD

      3 (33.3)

      2 (16.7)

      1 (20)

      2 (25)

      8 (23.5)

      PD

      1 (11.1)

      0 (0)

      0 (0)

      1 (12.5)

      2 (5.9)

      NE

      1 (11.1)

      1 (8.3)

      0 (0)

      0 (0)

      2 (5.9)

      Data presented as n (%).

      Abbreviations: nsq-NSCLC, non-squamous non-small cell lung cancer; NE, not evaluable; PD, progressive disease; PR, partial response; SCLC, small cell lung cancer; SD, stable disease; sq-NSCLC, squamous non-small cell lung cancer.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Tislelizumab, in combination with platinum doublets, demonstrated preliminary antitumor activity and was generally well tolerated in patients with advanced lung cancer.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.13-08 - Distribution, Differences in Clinical Characteristics and Resistance Mechanism of ALK Variants in Chinese Lung Cancer Patients. (ID 13678)

      16:45 - 18:00  |  Author(s): Jun Zhao

      • Abstract
      • Slides

      Background

      ALK rearrangements are established targetable drivers in NSCLC. Recent reports indicate differential progression-free survival to ALK inhibitors according to specific EML4-ALK variant.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 172 unique Chinese lung cancer patients with tumors harboring ALK rearrangements (ALK+) were enrolled in the study from 2016 to 2018. ALK+ were detected by Ventana, FISH, or next-generation sequencing based ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations across at least 59 genes (59-1021). Tissue biopsy was the first choice for NGS mutation profiling, and ctDNA or pleural effusion testing was used as an alternative.

      4c3880bb027f159e801041b1021e88e8 Result

      Of these 172 cases, the median diagnosis age was 50 (range 24-78), 58% were female, 90% was NSCLC. Of the 147 ALK+ cases detected by NGS, we identified 65 (44%) EML4-ALK v1 (E13; A20), 18 (12%) EML4-ALK v2 (E20; A20), 43 (29%) EML4-ALK v3 (E6; A20), 13 (9%) other EML4-ALK, and 8 (5%) non-EML4-ALK rearrangements. 2 new fusion genes were found in non EML4-ALK rearrangements (SRBD1-ALK (EX20; EX20) and CLIP4-ALK (EX9; EX20)), and the CLIP4-ALK patient’s tissue was also ALK positive by Ventana. V1 found a higher proportion of pleural effusion at baseline than non-v1 (12% v.s.5%). Mutation profiling by NGS were performed after disease progression in 55 patients treated with crizotinib. mPFS was 8.1 months, no significant difference existed between v1 and v3 (P=0.69). But the presence of known ALK resistance mechanisms was significantly higher in v3 as compared to non-v3 (67% v.s. 27%, P=0.038).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Next generation sequencing allows for detection of the specific ALK fusion partner and variants, increases the understanding of the biology of ALK+ NSCLC, and may have value to foretell potential mechanisms of resistance.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 4
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.01-100 - Different Genetic Mutations Enriched in Circulating Tumor DNA Predict Different Metastatic Sites in Lung Adenocarcinoma Patients (ID 13636)

      16:45 - 18:00  |  Author(s): Jun Zhao

      • Abstract

      Background

      The mutation map of the lung adenocarcinoma is clear. However, differences of genetic mutations related to metastatic sites have not been addressed before and remain to be explored. Identification of mutation signature may help to predict metastasis.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed 353 ctDNA samples from lung adenocarcinoma patients with definite metastasis at our institute. Somatic mutation profiles were analyzed using hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations of 59 genes.

      4c3880bb027f159e801041b1021e88e8 Result

      All the samples were divided into 2 groups based on the distance of the metastases: 165 samples was in the distal metastasis group including bone or liver metastases; 188 samples was in the proximal group, including lung, pleural or thoracic lymph node metastasis. The gene mutation number of the distal metastasis is higher than the proximal metastasis (4.92 vs 3.85, P=0.031). Gene mutations for each group are shown in the figure below. Similar to the genetic profiling of lung adenocarcinoma in COMIC database, the most frequently mutated genes were EGFR and TP53 in two groups. But the frequency mutation of NTRK1 in proximal metastasis group is three times more than that of the distal metastasis group (11/188, 5.9% vs 3/165,1.8%). And the frequency of ALK mutation in the distal metastasis group is two times more than that of the proximal metastasis group (10/165, 6.1% vs 6/188, 3.2%). Moreover, for the top 9 frequently mutant genes, there was 78% overlap in the two groups. However, the overlap with COSMIC database was 55% for distal metastasis group and 44% for the proximal metastasis.

      Distant metastasis group

      Proximal metastasis group

      COSMIC database

      gene

      Mutation frequency

      gene

      Mutation frequency

      gene

      Mutation frequency

      1

      EGFR

      70.30%

      EGFR

      73.94%

      EGFR

      31%

      2

      TP53

      60.61%

      TP53

      61.17%

      TP53

      31%

      3

      KRAS

      11.52%

      ERBB2

      9.04%

      KRAS

      18%

      4

      RB1

      10.30%

      KRAS

      9.04%

      STK11

      8%

      5

      NF1

      9.70%

      RB1

      7.45%

      CDKN2A

      7%

      6

      ERBB2

      7.88%

      NF1

      7.40%

      SMARCA4

      6%

      7

      APC

      6.67%

      APC

      6.91%

      NF1

      6%

      8

      ALK

      6.06%

      PIK3CA

      6.38%

      ATM

      5%

      9

      ATM

      6.06%

      RET

      5.85%

      KDR

      5%

      10

      PIK3CA

      6.06%

      NTRK1

      5.85%

      8eea62084ca7e541d918e823422bd82e Conclusion

      Lung adenocarcinoma patients with ALK mutation are more likely to have distant metastasis. While the patients with NTRK1 mutation are more likely to have proximal metastasis.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-101 - Dynamic Monitoring of Gene Alterations with ctDNA by NGS for EGFR Mutated Lung Adenocarcinoma Treated with Gefitinib in BENEFIT Study (CTONG 1405) (ID 14347)

      16:45 - 18:00  |  Author(s): Jun Zhao

      • Abstract

      Background

      Blood-based cell-free tumor DNA (ctDNA) could be dynamically monitored to provide gene alterations during EGFR-TKI treatment, which might offer critical clue for prognosis and clinical treatment decision. Here we reported the dynamic gene alterations monitoring using next generation sequencing (NGS) in BENEFIT study to explore the mechanisms of different responses and resistances to EGFR-TKI in EGFR-sensitizing-mutated lung-adenocarcinoma (LADC) patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with systemic treatment-naïve, stage IV LADC and EGFR-sensitizing-mutation in ctDNA were enrolled to receive gefitinib. Blood samples were dynamically obtained at baseline, every 8 weeks and at disease progression (PD). The dynamic analysis of quantity of ctDNA, multiple driver genes and tumor suppressors were investigated with NGS (Nextseq500 sequencer, consisting of critical exons/introns of 168 genes), and were correlated with efficacy and resistance.

      4c3880bb027f159e801041b1021e88e8 Result

      Totally 181 LADC patients with EGFR-sensitizing-mutation (exon-19-deletion and exon-21-L858R-point-mutation) provided sufficient blood samples for NGS analysis at baseline, of which 143 patients obtained at least four timepoints of dynamic blood sample collection until PD (baseline, 8 weeks, 8 weeks before PD and PD). At baseline, 180 of patients (99.4%) were confirmed as EGFR-sensitizing-mutation with NGS (92 EGFR-19-deletion and 88 EGFR-L858R-point-mutation) including 44 (24.3%) EGFR-amplification, 116 (64%) TP53-mutation, or other known oncogenic drivers including MET (N=5, 2.8%), ERBB2 (N=7,3.9%), KRAS (N=6, 3.3%), BRAF (N=2, 1.2%), RET (N=1, 0.6%), ROS1 (N=1, 0.6%), or EGFR-T790M (N=4, 2.2%), which was correlated with poor efficacy compared with those with only EGFR-sensitizing-mutation (PFS 4.7 months [m] vs. 13.2m , p=0.002). Additionally, tumor suppressor genes exhibiting cumulative effect to poor prognosis: PFS for 164 patients with TP53&RB1&PTEN-mutation≤1 was 11.1m, while for 16 patients with TP53&RB1&PTEN-mutation>1,PFS was 4.7 m, p<0.0001. To cut-off date, 117 patients had PD, among them, 63 (54%) patients acquired EGFR-T790M-mutation presented as dominant resistance mechanism besides MET-amplification/ERBB2-amplification/ERBB2-S310F (N=16, 14%), RET fusion/splice (N=2, 1.7%), ROS1-C2336F-mutation (N=1, 0.9%), RB1-nonsense-mutation (N=2, 1.7%), TP53-Y205S-mutation (N=1, 0.9%) and TP53-Y205S-mutation accompanied with FGFR1-amplification (N=1, 0.9%). The remaining resistance mechanisms (31%) were unknown. Patients with only T790M-mutation had a significantly longer PFS (11.5m) compared with patients obtaining other acquired resistant mechanisms (3.0m). Interestingly, seventy-five (53.2%) patients had molecular progression before radiographic progression, and the median time difference was 8.7 weeks.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Dynamic alterations of multi-drivers and suppressors together with EGFR-sensitizing-mutation and T790M-mutation could separate LADC into different subgroups with distinguished molecular features, which may play a vital role during EGFR-TKI treatment for resistance-predicting, and initial/subsequent treatment decision-making.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-107 - Analysis of Mutation Detection by ctDNA on the Basis of Metastatic Sites in Lung Adenocarcinoma Patients (ID 13635)

      16:45 - 18:00  |  Author(s): Jun Zhao

      • Abstract

      Background

      Circulating tumor DNA (ctDNA) testing represents a powerful tool to detect gene alterations in patients. However, differences in mutation detected by ctDNA related to metastatic sites in lung cancer have not been addressed before and remain to be explored.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed 317 ctDNA samples from 310 lung adenocarcinoma patients with definite metastasis at our institute. Somatic mutation profiles were analyzed using hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations of 1021 genes.

      4c3880bb027f159e801041b1021e88e8 Result

      Patients were divided into two groups according to metastatic sites. Any case with metastasis to the bone, liver or adrenal gland falls into the major organ metastasis group, while any case with metastasis to the lung, pleura or lymph node belongs to the local metastasis group. No genetic alteration was detected in 14 (11.5%) of 122 samples in the major organ group and 35 (17.9%) of 195 in the local group. And distant metastasis is associated with more mutations on average detected by ctDNA (5.26 for the major organ group vs 3.72 for the local group; p=0.0039). As for genes involved, the most common mutated ones are EGFR and TP53 for both groups, with an overall mutation rate being 40.6% and 33.2% respectively. And just as average gene alterations mentioned above, the mutation rates of EGFR and TP53 are much higher in the major organ group (49.6% vs 35.2% for EGFR; 43.6% vs 26.9% for TP53). Besides, mutations of NF1, MLL3, KRAS and KEAP1 are more frequent in the major organ group while mutation rate of PIK3CA is slightly higher in the local group (Table).

      Table. Some mutated genes detected by ctDNA

      major organ metastasis (117)

      local metastasis (193)

      EGFR

      58 (49.6%)

      68 (35.2%)

      TP53

      51 (43.6%)

      52 (26.9%)

      KRAS

      9 (7.7%)

      7 (3.6%)

      MLL3

      9 (7.7%)

      6 (3.1%)

      NF1

      9 (7.7%)

      3 (1.6%)

      ERBB2

      5 (4.3%)

      6 (3.1%)

      PIK3CA

      3 (2.6%)

      7 (3.6%)

      KEAP1

      7 (6.0%)

      3 (1.6%)

      8eea62084ca7e541d918e823422bd82e Conclusion

      More gene alterations were detected by sequencing of ctDNA in patients of lung adenocarcinoma with major organ metastasis compared to those with only local metastasis.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P2.01-117 - Concurrent Gene Alterations in Treatment-Naïve EGFR-Mutant Advanced Non-Small Cell Lung Cancer (ID 13102)

      16:45 - 18:00  |  Author(s): Jun Zhao

      • Abstract
      • Slides

      Background

      EGFR-TKIs is the standard first line treatment for EGFR-mutant advanced non-small-cell lung cancer (NSCLC). However, 20% to 30% of patients who receive EGFR-TKIs exhibit primary resistance. The gene alterations in treatment-naïve EGFR-mutant advanced NSCLC should be better explored.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively reviewed gene test results of 980 treatment-naïve advanced NSCLC samples in our institute. Tumor biopsy, ctDNA, pleural effusion or cerebrospinal fluid samples were analyzed using hybridization capture-based NGS ER-seq method, white blood cells as control, which enables simultaneously assess single-nucleotide variants (SNV), insertions/deletions (indel), rearrangements and somatic copy-number(CNV) variation at least 59 genes (range 59-1021 genes).

      4c3880bb027f159e801041b1021e88e8 Result

      Three hundreds and eighty one cases with EGFR sensitive mutation were identified, 358 adenocarcinoma, 7 squamous cell carcinoma, 1 adenosquamous carcinoma and 15 NSCLC. Among the patients, 88 patients (23.1%) harbored concurrent actionable mutations with EGFR, which 43 were exon 19 deletion, 37 were L858R and 8 were uncommon EGFR mutations. One patient had co-occurring L858R, T790M and CDKN2A frameshift mutation. The actionable mutations were from 23 genes, which involved in cellular signaling pathways, and some genes had been reported associated with EGFR-TKIs resistance (details in table). Except the actionable mutations, TP53 mutations were detected in 225 samples (59.1%, 225/381), which 35.1% (79/225) in exon8. Bcl-2–like 11(BIM) deletion were detected in 31 (8.1%, 31/381) white blood cells.

      Signaling Pathways

      Concurrent gene alterations

      Frequency(N=88)

      Cell cycle*

      CDKN2A

      3.9%

      CDK4

      2.1%

      CCNE1

      0.8%

      CCND1

      0.8%

      CCND3

      0.3%

      PI3K/AKT/mTOR*

      PIK3CA

      2.9%

      PTEN

      1.3%

      TSC1/2

      1.0%

      AKT2

      0.3%

      NF1

      0.3%

      RTKs*

      MET

      0.8%

      HER2

      0.8%

      FGFR2

      0.3%

      FGFR3-TACC3

      0.3%

      Ras/Raf/MAPK*

      KRAS

      0.8%

      Homologous Recombination Repair pathway

      BRCA2(sc+gm)

      0.8%

      BRCA1(sc)

      0.5%

      ATM

      0.5%

      PALB2

      0.3%

      Others

      CTNNB1

      2.9%

      MDM2

      2.4%

      SMARCA4

      0.8%

      JAK2

      0.5%

      sc, somatic mutation;

      gm, germline mutation;

      *, genes had been reported associated with EGFR-TKIs resistance

      8eea62084ca7e541d918e823422bd82e Conclusion

      Concurrent gene alterations in treatment-naïve EGFR-mutant advanced NSCLC is common, and mutiple genes are involved. This maybe contribute to the primary resistance to EGFR-TKIs in EGFR-mutant advanced NSCLC. Indicate the importance of multiplex molecular test and further researches of target therapies.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.04-29 - Preliminary Results With Tislelizumab in Chinese Patients With Non-Small Cell Lung Cancer (NSCLC) (ID 11319)

      16:45 - 18:00  |  Author(s): Jun Zhao

      • Abstract
      • Slides

      Background

      NSCLC accounts for 80–85% of all lung cancers and has a poor prognosis at later stages. Immune checkpoint inhibitors have shown efficacy in patients (pts) with advanced NSCLC. Tislelizumab is a humanized IgG4 monoclonal antibody with high affinity/specificity for PD-1. Tislelizumab was specifically engineered to minimize FcϒR binding on macrophages that, based on preclinical evidence, is believed to minimize potentially negative interactions with other immune cells. In a phase 1 study, tislelizumab was generally well tolerated and showed antitumor activity in NSCLC pts; 200 mg IV Q3W was established as the recommended tislelizumab dose.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In the ongoing indication-expansion phase of this study, Chinese pts with histologically confirmed NSCLC were enrolled into PD-L1-high (PD-L1+; 10% tumor cells expressing PD-L1) and PD‑L1‑low (PD-L1) cohorts. Antitumor activity (RECIST v1.1) and safety/tolerability (NCI-CTCAE v4.03) were assessed.

      4c3880bb027f159e801041b1021e88e8 Result

      As of 8 Dec 2017, 42 NSCLC pts (median age 54 yr [range 37–72]) were enrolled; 17 were PD-L1+ and 25 were PD-L1. Most pts were male (69%), former/current smokers (57%), and had received prior therapy (95%). Adenocarcinoma was the most prevalent histology (57%). Median follow-up was 4.5 mo and 23 pts remain on treatment. Of the 39 response-evaluable pts, 4 (n=2/14, PD-L1+; n=2/25, PD-L1) achieved confirmed PR and 20 (n=6/14, PD-L1+; n=14/25, PD‑L1) achieved SD, including 4 (n=2, PD-L1+; n=2, PD‑L1) with unconfirmed PR. Across the study population, ORR was 10% and DCR was 61.5%. ORRs by cohort were 14% (PD‑L1+) and 8% (PD-L1), respectively. Common treatment-related AEs were increased AST (24%), increased ALT (19%), hypothyroidism (12%), and rash (12%). Five grade 3 treatment-related AEs occurred in 4 pts (increased AST [n=2], hyperglycemia, increased ALT, and increased GGT [n=1 each]). No treatment-related grade 5 events were reported.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Tislelizumab was generally well tolerated and demonstrated antitumor activity in previously treated pts with advanced NSCLC. A global phase 3 study (NCT03358875) of tislelizumab vs docetaxel as potential second/third-line therapy in NSCLC pts who progressed after a platinum-based regimen is ongoing.

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    P2.06 - Mesothelioma (Not CME Accredited Session) (ID 955)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.06-39 - Next Generation Sequencing Reveals Genetic Landscape of Malignant Mesothelioma (ID 12702)

      16:45 - 18:00  |  Author(s): Jun Zhao

      • Abstract
      • Slides

      Background

      Malignant mesothelioma (MM) is a rare form of cancer affecting the mesothelium lining. The 5-year survival rate of advanced patients is less than 1% due to the lack of effective medical therapies. To investigate the possibility of targeted therapy for MM patients, a deeper understanding of the genetic basis is required.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We reviewed 26 samples taken from 22 MM patients who underwent genetic testing at our institute from 2016 to the present. Somatic mutation profiles were analyzed using hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations of at least 59 genes (range 59 – 1021 genes).

      4c3880bb027f159e801041b1021e88e8 Result

      The 26 samples included 8 tumor tissue samples, 17 blood samples and 1 ascetic fluid sample. The most frequently mutated genes were TP53 (11/21), followed by NF2 (6), RB1 (4), NF1 (3), FLT1 (3), BAP1 (2), EGFR (2), FAT2 (2), FGFR4 (2), KIT (2), MAP3K1 (2), MLL4 (2), STK11 (2), APC, ATR, BRAF, BRCA2, CDKN2A, ERBB3, FBXW7, MET, KRAS, PIK3CA and so on. Among these mutations, 5 of NF2 mutations and 2 of NF1 mutations were loss-of-function mutations, which suggests the possible sensitivity of mTOR inhibitors administration. Besides, patients with the active or inactive mutations of KRAS, BRAF, CDKN2A, ERBB3, MET and PIK3CA gene might be sensitive to corresponding targeted drugs. MET exon 14 skipping mutation, commonly identified in non-small-cell cancer (NSCLC) patients, had never been reported in MM patients before. c-Met inhibitors such as crizotinib and cabozantinib may be of efficacy for this patient. Apart from predicting therapeutic effectiveness of MEK inhibitors, the detection of KRAS activating mutation may also provide prognostic information.

      8eea62084ca7e541d918e823422bd82e Conclusion

      NGS can identify genetic mutations comprehensively and provide predictive and prognostic implications for MM patients. It is a cost-effective tool to describe the genetic landscape of MM, which will facilitate the development of novel therapeutics for the treatment of MM patients.

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    P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.01-105 - Retrospective Analysis of Efficacy and Safety in Chinese Elderly Patients Treated with Nab-Paclitaxel (Now Available) (ID 12682)

      12:00 - 13:30  |  Author(s): Jun Zhao

      • Abstract
      • Slides

      Background

      Albumin-bound paclitaxel (nab-PC) could benefit advanced non-small cell lung cancer (NSCLC) either in first line or second line. However, the safety and efficacy in Chinese elderly population remains unclear. In this study, we retrospectively analyzed the efficacy and safety of nab-pc in Chinese elderly patients (≥65 year old) from a single cancer center.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively collected data from 75 patients who were treated with weekly nab-paclitaxel (125 or 130 mg/m2d1, d8) from Janurary 2010 to December 31, 2017 in Peking University Cancer Hospital. Among which, 33 patients were non-squamous NSCLC, and 42 patients were squamous NSCLC. Twelve of these patients received nab-paclitaxelas first line treatment (7 of which were combined with carboplatin) and 63 patients received single nab-paclitaxel as latter line treatment.

      4c3880bb027f159e801041b1021e88e8 Result

      Results: Sixty-eight out of 75 patients were available for efficacy evaluation, the overall objective response rate (ORR) was 13.1 (10/68), disease control rate (DCR) was 69.3%(52/68), median progression free survival (PFS) was 5.2 months and overall survival was 12.2 months in the entire population. For fist-line and latter line setting subgroup, the ORR, DCR, PFS and OS were 18.2% and 14.0%; 90.9% and 73.7%; 6.7 months and 5.0 months; 17.7 months and 12.2 months, respectively. For the patients ≥70 years old, the PFS significantly longer compared with patient <70 years old (6.3 months vs. 3.7 months p=0.021; the same trend was observed in OS, however the difference was not significant (13.3 months vs. 10.0 months, p=0.089). For all grade of adverse events (AEs), the most common AEs were leukopenia (37.3%, n=28), anemia (40%, n=30) fatigue (18.7%, n=14) and Peripheral neuritis (17.3%, n=13) which were all manageable, and the incidence of grade 3 were 13.3% (10/75), no grade 4 AEs were found and no AEs related death. Totally 7 patients discontinued treatment because of AEs. And the incidence of AEs was not different among subgroups of patients defined with age (65≤age<70, 70≤age<75 and age≥75).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The efficacy of nab-paclitaxel in Chinese elderly patients was desirable. The toxicity was tolerable and manageable. Patients over 70 may benefit more from nab-paclitaxel. Prospective clinical trials are expected to further confirm the results.

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