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Yi Xin



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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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      P1.04-34 - Study on Treatment of Stage IV Solid Tumors with Mutant Neoantigen Specific T Cells (ID 12833)

      16:45 - 18:00  |  Author(s): Yi Xin

      • Abstract
      • Slides

      Background

      As an important tumor immunotherapy, the specificity and efficiency of PD1 inhibitor is not yet satisfactory. The treatment of solid tumor with mutant neoantigen specific T (Nas-T) cells developed in this study is an adoptive cell therapy which is specific for each patient. The aim is to explore the difference in safety and efficacy between Nas-T cells and PD1 inhibitors, and to evaluate the charateristic of immune repertoire (IR) as predictive biomarker.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total number of 11 patients with advanced solid tumors who failed after multiline treatments were recruited. They were treated with Nas-T cells, PD1 inhibitors and BSC; other 11 patients were treated with PD1 inhibitors and BSC as control. Peripheral blood was collected at baseline and per cycle (21-28d) respectively. Multiple PCR and NGS on TCR beta chain was used to detect IR.

      4c3880bb027f159e801041b1021e88e8 Result

      pfs and indexes of ir.jpg

      PFS of two groups had a statistical significance (P<0.05), suggesting Nas-T cells prolong patients' PFS. The safety was analyzed from routine blood urine stool test, coagulation function, liver and kidney function. There was no significant difference at baseline (P>0.05). Compared with C group, total protein and albumin in T group had a transient decrease in 3rd, 4th and 5th follow-up respectively (P<0.05), however, It can be recovered autonomously before 6th cycle.

      Three indexes were examined to illuminate the diversity and clonality of IR. Compared to baseline, T cell repertoir of non-responders and responders after 1st cycle showed significant changes: Shannon 1.14 vs 0.97, P=0.048; Evenness 3.90 vs 0.85, P=0.004; Clonality 1.20 vs 0.70, P=0.017. Elevated Clonality may indicate amplification of tumor specific T cells which could recognize mutant neoantigen specifically.

      8eea62084ca7e541d918e823422bd82e Conclusion

      The combined immunotherapy of Nas-T cells and PD1 inhibitors is more effective than PD1 inhibitor alone in prolonging the PFS, and has a good safety. IR Clonality change shows its potential as a predictive biomarker.

      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: 2
    • 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): Yi Xin

      • 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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      P1.13-18 - Exploring the Resistance Mechanism of Osimertinib and Monitoring the Treatment Response Using Plasma ctDNA in Chinese NSCLC Patients (ID 13297)

      16:45 - 18:00  |  Author(s): Yi Xin

      • Abstract
      • Slides

      Background

      Osimertinib (AZD9291; Tagrisso) is a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) known to be effective for patients harboring the EGFR-T790M variant, which is accounts for more than half of the acquired resistance mechanisms to the first generation EGFR-TKIs. However, limited osimertinib resistance-mechanism was reported. Study on potential osimertinib-resistance mechanisms in advanced NSCLC is necessary.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This study enrolled eight T790M-positive (tissue validated) patients, treated with osimertinib after first generation EGFR-TKI (Erlotinib, Gefitinib, Icotinib) resistance and progressed rapidly. Serial plasma samples were collected until disease progressed. Plasma DNA was extracted and sequenced by target-capture deep sequencing of 1021 previously annotated genes related to solid tumors. Clonal EGFR T790M mutation was defined if mutation was in the cluster with the highest mean variated allele frequency with PyClone, and otherwise subclonal EGFR T790M mutation. Molecular tumor burden index (mTBI) was calculated with the mean variant allele frequency of mutations in trunk clonal population.

      4c3880bb027f159e801041b1021e88e8 Result

      The median progression-free survival (PFS) of these eight rapidly-progressed patients was 3.82 months [95% CI 2.05-5.01] .Targeted capture sequencing of pretreatment ctDNA showed all of the eight patients (100%) were EGFR-positive (Exon19del [n=6] and L858R [n=2]), and seven patients (88%) harbored EGFR T790M mutation, except for the only one patient (P006) who showed an extremely low level of ctDNA. During the Osimertinib treatment, five patients (63%) had osimertinib resistance-related mutations: EGFR C797S (in cis position), G724S, KRAS G12D, PIK3CA E542K, EGFR amplification, and ERBB2 amplification. Among them, two patients had more than one resistance mechanisms: patient P034 had EGFR G724S, KRAS G12D and EGFR amplification, simultaneously; patient P013 had amplification in both EGFR and ERBB2. Other potential resistance mechanisms were identified including EGFR T751I and K754E mutations in P002 and ERBB2 S603 in P013. Notably, the only one patient (P004) who had not been detected to have any known osimertinib resistance mechanism but progressed in 3 months, was demonstrated to harbor a subclonal EGFR T790M mutation by analysis of ctDNA clonal structure. Serial ctDNA monitoring showed mTBI increased when disease progressed in 88% (7/8) patients, except P006, whose mutation were negative at second (stable disease) and third (progressed disease) therapeutic evaluations due to the extremely low level of ctDNA.

      8eea62084ca7e541d918e823422bd82e Conclusion

      This study presented comprehensive the resistance mechanism of osimertinib progressed rapidly in ctDNA including multiple mechanisms co-occurred in same patient. Serial monitoring of plasma ctDNA may be a promising approach to explore resistance mechanism and monitored the treatment response of third generation EGFR-TKI.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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