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L. Zhang



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    MA 12 - Circumventing EGFR Resistance (ID 665)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA 12.09 - EGFR T790M Co-Exist with Sensitive Mutation in the Same Cell Group in Lung Adenocarcinoma Patients (ID 9414)

      11:00 - 12:30  |  Author(s): L. Zhang

      • Abstract
      • Presentation
      • Slides

      Background:
      EGFR TKI therapy has improved lung adenocarcinoma patients’ prognosis tremendously, but almost all of the patients inevitably develop acquired resistance, and EGFR T790M mutation is the major contributors. T790M restores the EGFR tyrosine kinase domain affinity to ATP, and therefore gefitinib is displaced from the binding pocket, and the ‘driving’ signal for proliferation is switched on again. Previous work has shown that after TKI therapy, lung adenocarcinoma patients kept the sensitive mutation and acquired resistance mutation simultaneously by sequencing methods or in vitro cell line experiments. Whether the two different type mutations are in the same cell group or in two different cell groups is unknown. None of them has observed what was happening in the tumor cells after TKI therapy.

      Method:
      RNA in situ hybridization methods was employed to examined EGFR T790M and L858R mutation in lung adenocarcinoma cancer tissues which was obtained before and after TKI therapy. EGFR expression was examined by immunohistochemistry. EGFR mutation were detected by ARMS PCR methods.

      Result:
      Twenty five patients were enrolled in this study which were divided into 3 groups. Group 1: 5 patients who had concurrent primary T790M and sensitive EGFR mutation. Group 2: 14 patients who acquired T790M mutation after receiving TKI therapy. Among them, 6 patients had biopsy tissues before and after TKI therapy. 8 patients only own tissues after TKI therapy. Group 3: 6 patients who had sensitive EGFR mutation and received TKI therapy, but re-biopsy tissues didn’t had EGFR T790M. We found that the results of RNA ISH and ARMS PCR methods was identical in the majority of the examined tissues. Only one repeated biopsy tissue didn’t identify EGFR T790M after TKI therapy by PCR in group 3, while the RNA ISH method detected T790M in this tissue which contain only 150 tumor cells. In the serial cut slides, we observed that T790M and L858R mutations were in the same cell group, not only in the primary resistance cases, but also in the acquired resistance cases. For the two cases which had tissues available after receiving third generation TKI therapy, we observed that T790M disappeared in the repeated biopsy specimen, leaving the sensitive mutation which existed from the beginning.

      Conclusion:
      In the primary and acquired resistance tissues, EGFR sensitive mutation and T790M co-exist in the same cell groups. EGFR sensitive mutation is a trunk and drive mutation, while T790M is a passenger mutation during the treatment process by TKI therapy.

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    P2.03 - Chemotherapy/Targeted Therapy (ID 704)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 2
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      P2.03-041 - The Concentration of Avitinib in Cerebrospinal Fluid and Its Efficacy and Safety in NSCLC Patients with T790M Mutation (ID 9458)

      09:30 - 16:00  |  Author(s): L. Zhang

      • Abstract
      • Slides

      Background:
      Avitinib is an oral, potent, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor selective for T790M resistance mutations. We report the safety, the intracranial/extracranial efficacy, and the blood brain barrier (BBB) penetration rate of Avitinib in non-small cell lung cancer(NSCLC) patients with EGFR T790m mutation. The data come from Peking Union Medical College hospital-a single center of the Phase 1, open-label, multicenter study (NCT02330367).

      Method:
      NSCLC Patients with acquired EGFR T790m (+) were enrolled. Patients were orally administered with dose escalating from 150 mg to 300 mg twice daily for 28-continuous-day cycles until disease progression. Blood (2mL) and cerebrospinal fluid (CSF) samples (2ml) were collected for concentration analysis on day 29 in available patients with brain metastases (BM). Tumor response was assessed on day 29 and then every 8 weeks.

      Result:
      Sixteen patients were included. Nine patients had asymptomatic BM, and all the nine patients had more than 3 BM lesions. The most frequent adverse events were the elevated hepatic transaminases (10/16, 62.5%) and diarrhea (5/16, 31.3%), Most were mild and reversible. 9 Patients (56.3%) achieved Partial Response (PR), 6 (37.5%) achieved Stable Disease (SD). Median Progress Free Survival (PFS) was 247 days (95%CI: 154.8-339.2), and the Median Overall Survival (OS) was 536 days (95%CI: 363.6-708.4). Of the 7 evaluable BM patients, the median intracranial PFS was 142 days (95% CI 31.1-252.9), with two patients progressed first in intracranial disease, while five patients had concurrent intracranial and extracranial progression after avitinib treatment. The cytologic analysis of CSF showed one meningeal metastases who accepted intrathecal injection with methotrexate and dexamethasone later. The blood and CSF analysis of 5 BM patients showed the BBB penetration rate were 0.046%-0.146% (Table).

      patients CSF Con. (ng/ml) Plasma Con. (ng/ml) Per.% Intracranial PFS (days) Extracranial PFS (days)
      1 0.106 231 0.046 566 566
      2 0.425 291 0.146 60 177
      3 0.487 631 0.077 142 142
      4 4.05 2940 0.138 138 138
      5 1.72 1890 0.091 28 28
      6 24 227 10.6[1] 218 218
      7 308 350
      8 550[2] 252
      [1]Her BBB was broken by postocular metasatses. [2]He accepted brain radiotherapy before avitinib, and he also accepted chemotherapy with pemetrexed plus carboplatin plus endostatin after progression from avitinib. He was excluded from the analysis of intracranial PFS.

      Conclusion:
      Avitinib is well tolerated and efficacious in EGFR T790m(+) NSCLC patients. Its concentration in CSF is low, and the penetrability of BBB is weak. The median intracranial PFS for asymptomatic BM is relative short comparing to extracranial disease. Further studies are proceeding.

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      P2.03-050 - The Efficacy of EGFR Tyrosine Kinase Inhibitors in Advanced Non-Small Cell Lung Cancer Harboring G719X Mutation (ID 9927)

      09:30 - 16:00  |  Author(s): L. Zhang

      • Abstract
      • Slides

      Background:
      Few uncommon EGFR mutations existed in NSCLC patients, such as G719X mutation on 18 exon. The best treatment option for G719X mutation is unclear, and it is usually excluded from clinical trials using EGFR TKI therapy. Here we studied the clinical data of patients harboring G719X mutation in real world and their sensitivity to EGFR TKIs.

      Method:
      Between January 2011 and December 2016, we retrospectively collected the clinical data of stage IIIB/IV NSCLC patients harboring G719X mutation at Peking Union Medical College Hospital.

      Result:
      A total of 830 NSCLC patients were found to harbor common sensitive EGFR mutations ( 417 patients harbored 19 exon deletion,413 patients harbored 21 L858 mutation, respectively), while 27 (27/857, 3.15%) patients harbored G719X mutation on 18 Exon, using amplification refractory mutation system (ARMs). 19 (19/27, 70.4%) patients with G719X mutation were treated with EGFR TKIs, 11 (57.9%) with Gefitinib, 5 (26.3%) with Icotinib, and 3 (15.8%) with Erlotinib, respectively. The median age was 58.3 years ( range from 30 to 79 years). There were 11(57.9%) females, and 6 (31.6%) patients with history of heavy smoking. 3 (15.8%) patients had baseline central nervous systemic metastasis. 11(57.9%) patients had unique G719x mutation, while 8 patient had compound mutations (5 patients had G719+20s768I, 2 patients had G719+L861Q, and 1 patient had G719+19del). 9 (47.4%) patients gained PR, 7 (36.8%) patients gained SD, and 3 (15.8%) achieved PD, the ORR was 47.4%, and the DCR was 84.2%. The median PFS was 8.8 months (95% CI: 0.932-16.67). The median PFS of first-line TKI therapy was longer than second-line TKI therapy (10.8months vs. 4.0months respectively), but it didn’t got statistical significance (p=0.226). The median OS was 15.3 months (95%CI: 12.3-18.3), with 6 patients still alive. There were no intolerant adverse effect associating with EGFR TKIs.

      Conclusion:
      These results suggest that EGFR TKI therapy is effective in patients with G719X mutations. EGFR TKI could be a treatment choice better than chemotherapy for patients harboring G719X mutation.

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    P3.03 - Chemotherapy/Targeted Therapy (ID 719)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 2
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      P3.03-006 - Efficiency of Anlotinib as 3rd Line Treatment in Patients with Different EGFR Gene Status, an Exploratory Subgroup Analysis of ALTER0303 Trial (ID 8306)

      09:30 - 16:00  |  Author(s): L. Zhang

      • Abstract
      • Slides

      Background:
      Anlotinib hydrochloride is a novel TKI targeting the VEGFR, FGFR, PDGFR and c-Kit. ALTER0303 trial (NCT02388919), phase III study has demonstrated that Anlotinib significantly prolonged OS and PFS in advanced NSCLC patients as 3[rd] line treatment. Here we report the efficacy of anlotinib in patients with or without EGFR gene mutations from the ALTER0303 trial.

      Method:
      Eligible adult IIIB/IV NSCLC patients who progressed after at least 2 lines of prior therapies were randomized 2:1 to receive Anlotinib or placebo (12 mg QD from day 1 to 14 of a 21-day cycle) till progression. Patients harboring EGFR or ALK mutations must had received previous targeted therapies. Primary endpoint is OS.

      Result:
      Among patients with sensitive EGFR mutations, the PFS was 0.83 months for control arm and 5.57 months for anlotinib arm (p<0.0001, HR=0.15, 95%CI: 0.09-0.24). Accordingly, OS was found 4.43 months longer in anlotinib group (6.27 vs 10.70, p=0.0227, HR=0.59, 95%CI: 0.37-0.93). On the other hand, in the subgroup of patients with wild-type EGFR gene, remarkable advantages in PFS and OS were observed as well. Specifically, PFS in control arm was 1.57 months which is 3.80 months shorter than that in anlotinib group (1.57 vs 5.37, p<0.0001, HR=0.29, 95%CI: 0.22-0.39). As to OS, superiority of 2.40 months was found in anlotinib arm (6.47 vs 8.87, p=0.0282, HR=0.73, 95%CI: 0.55-0.97). In the patients treated with Anlotinib, the most common (≥ 3 grade) and significantly differ from placebo group AEs were hypertension (13.61%), dermal toxicity (3.74%) and hypertriglyceridemia (3.06%). These results indicate that either the patient with EGFR mutation or not, they can both benefit from Anlotinib treatment.

      Conclusion:
      In ALTER0303 trial, significant advances in OS and PFS were found in anlotinib treated patients from both subgroups (sensitive EGFR mutations and wild EGFR gene type), indicating that, independent of the EGFR gene status, anlotinb treatment led to a consistent improvement in OS and PFS for advanced NSCLC patients and may be an appropriate option for this difficult-to-treat population as 3[rd] line treatment.

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      P3.03-017 - Blood Samples NGS for Baseline Molecular Signature of Anotinib Treated Advanced NSCLC Patients in ALTER0303 Trial (ID 9670)

      09:30 - 16:00  |  Author(s): L. Zhang

      • Abstract
      • Slides

      Background:
      Anlotinib hydrochloride, an oral multi-target TKI targeting VEGFR, FGFR, PDGFR and c-Kit, have demonstrated noticeable effects for advanced NSCLC as 3[rd] line treatment in phase III trial (ALTER0303). Anlotinib significantly improved OS (9.63 vs. 6.30 months, p=0.0018, HR=0.68) and PFS (5.37 vs 1.40 months, p<0.0001, HR=0.26) comparing to placebo. Here, we applied ctDNA-based NGS to investigate the association between baseline molecular signature and clinical parameters.

      Method:
      Blood samples were collected from patients who enrolled in Anlotinib arm in ALTER0303 trial. Total of 92 samples were analyzed by capture-based targeted ultra-deep sequencing using a panel consisting of critical exons and introns of 168 NSCLC-related genes for the baseline genetic profiling.

      Result:
      At baseline, ctDNA was detected in 85% samples (78/92), driver mutation was found in 58% (53/92) samples. POM121L12 and CDKN2A mutations showed a tendency of co-occurrence with TP53, and mutually exclusivity was found between KEAP1 and TP53. The correlation between baseline molecular signature and treatment efficacy measured by PFS or best response was also investigated. Maximum mutation allele frequency (MAF) at baseline was inversely correlated with PFS (P=0.006, HR=0.612, 95%CI: 0.402-0.932). Patients achieving SD or PR had a significantly lower MAF comparing to patients having PD as their best response (p=0.018). Tumor mutation burden (TMB) is positively correlated with age (p=0.016) and gender (p=0.01). POM121L12, TP53 and MYC statuses are correlated with metastases burden. Moreover, as an important drive gene, EGFR mutation and/or EGFR amplification was found in 36 patients at baseline. In 27 patients with sensitizing EGFR mutation (L858R or 19 del), no significant differences was found in PFS compare to those without this mutation (n=65) (5.53 vs 5.53 months, p=0.495, HR=1.16, 95%CI: 0.73-1.85). As well, no significant difference was found in PFS between the patients with (n=17) or without EGFR T790M mutation (5.53 vs 5.53 months, p=0.253, HR=1.35, 95%CI: 0.75-2.41). Interestingly, in patients with EGFR amplification (n=10), the PFS is significantly shorter than those with normal EGFR copy number (2.12 vs 5.57 months, p=0.002, HR=2.70, 95%CI: 0.99-7.36). However, a tendency of PFS benefit is still observed in patients with EGFR amplification treated by Anlotinib comparing placebo arm in ALTER0303 (1.40 months).

      Conclusion:
      According to available data, no correlation was found between PFS and EGFR sensitizing mutations or T790M in anlotinib treatment. The negative correlation of EGFR amplification and PFS is still need verification to eliminate the bias caused by the disparity and limitation of samples. A larger scale analysis is ongoing.

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