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X. Liu



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    JCES01 - Joint IASLC - Chinese Society for Clinical Oncology - Chinese Alliance Against Lung Cancer Session (ID 413)

    • Event: WCLC 2016
    • Type: Joint Chinese / English Session
    • Track:
    • Presentations: 1
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      JCES01.17 - A Phase I Dose Expansion Study of Epitinib to Evaluate Efficacy and Safety in EGFR Mutation Positive (EGFRm+) NSCLC Patients with Brain Metastasis (ID 7059)

      X. Liu

      • Abstract
      • Slides

      Background:
      A significant portion of patients with non-small cell lung cancer (NSCLC) develop brain metastasis. Patients with brain metastasis suffer from poor prognosis with a median survival of less than 6 months and low quality of life with limited treatment options. First generation EGFR tyrosine kinase inhibitors (EGFR TKIs) have demonstrated significant clinical benefit for patients with EGFR-mutant NSCLC. However, their effect on brain metastasis is limited due to poor drug penetration into the brain. Epitinib is an EGFR TKI designed to improve brain penetration. A Phase I dose escalation study on epitinib has been completed and the recommended Phase 2 dose (RP2D) determined (Y-L Wu, 2016 ASCO). This Phase I dose expansion study was designed to evaluate the efficacy and safety of epitinib in EGFR-mutant NSCLC patients with brain metastasis.

      Methods:
      This is an ongoing open label, multi-center Phase I dose expansion study. EGFR-mutant NSCLC patients with confirmed brain metastasis, either prior EGFR TKI treated or EGFR TKI treatment naïve, were enrolled to receive oral epitinib 160 mg per day. Patients with extra-cranial disease progression while on treatment with an EGFR TKI were excluded. Tumor response was assessed per RECIST 1.1.

      Results:
      As of 31 May, 2016, 27 patients (13 EGFR TKI pretreated, 14 EGFR TKI treatment naïve) have been enrolled and treated with epitinib. The most frequent adverse events (AEs) were skin rash (89%), elevated ALT (41%)/AST (37%), hyper-pigmentation (41%) and diarrhea (30%). The most frequent Grade 3/4 AEs were elevations in ALT (19%), gamma-GGT (11%), AST (7%), hyperbilirubinemia (7%) and skin rash (4%). There have been no Grade 5 AEs to date. Among the 24 efficacy evaluable patients (11 TKI pretreated, 13 TKI naïve), 7 (7/24, 29%) achieved a partial response (PR), including 1 unconfirmed PR. All PRs occurred in EGFR TKI treatment naïve patients (7/13, 53.8%). Of the 24 evaluable patients, 8 (5 EGFR TKI treatment naïve, 3 EGFR TKI pretreated) had measurable brain metastasis (lesion diameter>10 mm per RECIST 1.1) with 2 PRs (both EGFR TKI treatment naïve patients, 2/5, 40%).

      Conclusion:
      Epitinib 160mg per day treatment in EGFR-mutant NSCLC patients with brain metastasis demonstrated clinical activity both extra- and intra-cranial. Epitinib was well tolerated. The data to date appears encouraging and warrants further development of epitinib.

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    MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA08.07 - Prospective Sequential Counts of Total CTC or cKIT+CTC in Advanced NSCLC with 1st Line Chemotherapy (POLICE) (Now Available) (ID 5857)

      X. Liu

      • Abstract
      • Presentation
      • Slides

      Background:
      Circulating tumor cells (CTCs) have been reported prognostic and predictive in non-small cell lung cancer (NSCLC) and a few of other cancer types. In 1[st] line setting, whether EPCAM[+]CK[+]CD45[-] CTC and/or stem cell-like cKIT[+]EPCAM[+ ]CK[+]CD45[-] CTC enumeration and dynamic changes can be prognostic and/or predictive to standard chemotherapy need further investigation in Chinese patients with NSCLC.

      Methods:
      A prospective study on the CTC enumeration in advanced NSCLC with 1st line chemotherapy (POLICE) was started by China Thoracic Oncology Group (CTONG). Patients with NSCLC naïve for systemic regimens were enrolled since August 2013. CTCs were detected by Cell Search Platform and identified as positive for EPCAM[+]CK[+]CD45[-] phenotype. CD117 (cKIT) marker was added to test the frequency of stem cell-like cKIT[+]EPCAM[+]CK[+]CD45[- ]CTCs. Primary endpoints were CTC counts and its correlation with first line therapy.

      Results:
      Totally 180 patients were enrolled. In 174 case total CTC and cKIT[+]CTC positive (cutoff >=1) rates were 38.5% (67/172) vs 14.3% (24/168), 21.8% (31/142) vs 6.3% (9/142), 13.7% (13/95) vs 6.4% (6/94) and 40.4% (38/94) vs 15.0% (13/93) at time-points of baseline, after first-cycle-chemo, after four-cycles-chemo and disease progression. At time immediately after first-cycle-chemo, patients in CTC=0 group got statistically higher ORR (29.0% VS 7.1%, P=0.017) and DCR (74.2% VS 42.9%, P=0.002) than in CTC>=1 group. At time after four-cycles-chemo, patients in CTC=0 group got statistically higher DCR (88.3% VS 58.3%, P=0.026) than in CTC>=1 group. At time either after first-cycle-chemo or after four-cycles-chemo, patients in CTC>=1 group got worse PFS (5.7m VS 4.0m, P=0.025; 6.3m VS 4.0m, P=0.001 ) than in CTC=0 group. At time after first-cycle-chemo, patients in groups cKIT[+]CTC>=1 and cKIT[-]CTC>=1 got worse PFSs (3.1m vs 4.0m vs 5.7m, P=0.001) and worse DCRs (44.4% vs 42.1% vs 73.9%, P=0.009) than in CTC=0 group. For 142 patients categorized into three groups of dynamic CTC decrease (17), CTC unchanged (82), and CTC increase (43), there were significant differences in terms of DCR (71.8% vs 71.6% vs 33.3%, P=0.018) and PFS (5.2m vs 5.6m vs 3.1m, P=0.037).

      Conclusion:
      In first line setting of advanced NSCLC, at time-points after first-cycle-chemo other than baseline, total CTC or cKIT[+]CTC counts could be predictive for worse DCR or PFS. CTC increase from baseline to after-first-cycle-chemo might be a strong signal for the inefficacy of first line chemotherapy in the NSCLC patients.

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    OA11 - Angiogenesis in Advanced Lung Cancer (ID 387)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      OA11.03 - A Randomized, Multi-Center, Double-Blind Phase II Study of Fruquintinib in Patients with Advanced Non-Small Cell Lung Cancer (Now Available) (ID 4571)

      X. Liu

      • Abstract
      • Presentation
      • Slides

      Background:
      Targeting the tumor microenvironment, such as tumor angiogenesis, has led to the successful development and approval of a number of targeted therapies thereby changing the standard of care for many types of cancer. However, treatment options are limited in third-line non-small cell lung cancer (NSCLC) patients. Fruquintinib is a potent and highly selective oral kinase inhibitor targeting vascular endothelial growth factor receptors and is currently in late stage development for multiple cancers. This Phase II study was designed to evaluate the efficacy and safety of fruquintinib in third-line NSCLC patients (NCT02590965).

      Methods:
      A total of 91 patients were randomized to receive best supportive care (BSC) plus fruquintinib or BSC plus placebo in a 2:1 ratio from 12 Chinese clinical centers. Fruquintinib initial dose was 5 mg once daily and treatment was given in every 4-week cycle (3 weeks treatment followed by 1 week off). The primary objective was to compare progression free survival (PFS) between the two treatment groups. Secondary efficacy parameters included objective response rate (ORR), disease control rate (DCR), overall survival (OS). Tumor response was assessed per RECIST 1.1.

      Results:
      As of August 7, 2015, median PFS was 3.8 months for the fruquintinib group comparing with 1.2 months for the placebo group (hazard ratio=0.27, p<0.001). The ORR was 16.4% for the fruquintinib group comparing with 0% for the placebo group (p=0.02). The DCR of the fruquintinib group was significantly higher than that of the placebo group with a difference of 53.8% (36.3, 71.4; 95% CI, p<0.001). OS was not mature and initial analysis revealed 3- and 6-month OS rates of 90.2% and 68.3% for the fruquintinib group, and 73.3% and 58.2% for the placebo group, respectively. Adverse event was reported in 68.9% and 60.0% patients in fruquintinib and placebo group, respectively. The incidence of serious adverse events was 3.3% in the fruquintinib group and 6.7% in the placebo group.

      Conclusion:
      Fruquintinib in third-line NSCLC met the primary efficacy endpoint of PFS and demonstrated superiority in the secondary endpoints of ORR and DCR as compared with placebo. OS has yet to mature. Fruquintinib was generally well tolerated and safety profile consistent with previously reported. These results support further development of fruquintinib in third-line NSCLC patients. A randomized, double-blind, multi-center Phase III registration study was initiated in December 2015 (NCT02691299). Clinical trial information: NCT02590965.

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    P2.03b - Poster Session with Presenters Present (ID 465)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      P2.03b-001 - A Phase I Dose Expansion Study of Epitinib to Evaluate Efficacy and Safety in EGFR Mutation Positive (EGFRm+) NSCLC Patients with Brain Metastasis (Now Available) (ID 4253)

      X. Liu

      • Abstract
      • Slides

      Background:
      A significant portion of patients with non-small cell lung cancer (NSCLC) develop brain metastasis. Patients with brain metastasis suffer from poor prognosis with a median survival of less than 6 months and low quality of life with limited treatment options. First generation EGFR tyrosine kinase inhibitors (EGFR TKIs) have demonstrated significant clinical benefit for patients with EGFR-mutant NSCLC. However, their effect on brain metastasis is limited due to poor drug penetration into the brain. Epitinib is an EGFR TKI designed to improve brain penetration. A Phase I dose escalation study on epitinib has been completed and the recommended Phase 2 dose (RP2D) determined (Y-L Wu, 2016 ASCO). This Phase I dose expansion study was designed to evaluate the efficacy and safety of epitinib in EGFR-mutant NSCLC patients with brain metastasis.

      Methods:
      This is an ongoing open label, multi-center Phase I dose expansion study. EGFR-mutant NSCLC patients with confirmed brain metastasis, either prior EGFR TKI treated or EGFR TKI treatment naïve, were enrolled to receive oral epitinib 160 mg per day. Patients with extra-cranial disease progression while on treatment with an EGFR TKI were excluded. Tumor response was assessed per RECIST 1.1.

      Results:
      As of 31 May, 2016, 27 patients (13 EGFR TKI pretreated, 14 EGFR TKI treatment naïve) have been enrolled and treated with epitinib. The most frequent adverse events (AEs) were skin rash (89%), elevated ALT (41%)/AST (37%), hyper-pigmentation (41%) and diarrhea (30%). The most frequent Grade 3/4 AEs were elevations in ALT (19%), gamma-GGT (11%), AST (7%), hyperbilirubinemia (7%) and skin rash (4%). There have been no Grade 5 AEs to date. Among the 24 efficacy evaluable patients (11 TKI pretreated, 13 TKI naïve), 7 (7/24, 29%) achieved a partial response (PR), including 1 unconfirmed PR. All PRs occurred in EGFR TKI treatment naïve patients (7/13, 53.8%). Of the 24 evaluable patients, 8 (5 EGFR TKI treatment naïve, 3 EGFR TKI pretreated) had measurable brain metastasis (lesion diameter>10 mm per RECIST 1.1) with 2 PRs (both EGFR TKI treatment naïve patients, 2/5, 40%).

      Conclusion:
      Epitinib 160mg per day treatment in EGFR-mutant NSCLC patients with brain metastasis demonstrated clinical activity both extra- and intra-cranial. Epitinib was well tolerated. The data to date appears encouraging and warrants further development of epitinib.

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    PL03 - Presidential Symposium (ID 428)

    • Event: WCLC 2016
    • Type: Plenary
    • Track:
    • Presentations: 1
    • Now Available
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      PL03.05 - BRAIN: A Phase Ⅲ Trial Comparing WBI and Chemotherapy with Icotinib in NSCLC with Brain Metastases Harboring EGFR Mutations (CTONG 1201) (Abstract under Embargo until December 6, 7:00 CET) (Now Available) (ID 4570)

      X. Liu

      • Abstract
      • Presentation
      • Slides

      Background:
      Non-small cell lung cancer (NSCLC) with brain metastases (M) had a poor prognosis. Whole brain irradiation (WBI) is a standard of care for this critical medical condition. The median survival is only 4-6 months. Small molecule inhibitors of epidermal growth factor receptor (EGFR) including icotinib achieved very successful results in advanced NSCLC with EGFR mutations. There were no prospective randomized clinical trials to explore the efficacy of EGFR tyrosine kinase inhibitors (TKIs) on brain M.

      Methods:
      Advanced NSCLC with EGFR sensitive mutations and brain M were randomized to WBI plus chemotherapy (chemo) or icotinib. Patients in WBI arm received radiotherapy with 30Gy/3Gy/10 fractions plus concurrent or sequential doublet chemo of 4-6 cycles. Patients in EGFR TKI arm received icotinib 125mg orally tid until disease progression. Icotinib could be continued beyond progression if clinical benefit was observed by the investigator. Crossover to icotinib from WBI could be permitted. Key inclusion criteria were EGFR mutations and radiologically confirmed brain M with at least 3 lesions. The primary endpoint was intracranial progression-free survival (iPFS) by investigator assessments according to RECIST v1.1. The secondary endpoints included objective response rate (ORR), PFS and overall survival (OS). Safety and tolerability were assessed by measuring adverse events (AEs) (CTCAE v4).

      Results:
      From Dec. 2012 to June 2015, 176 patients from 17 sites were randomized to WBI+Chemo arm (N=91) or icotinib arm (N=85). The baseline clinicopathologic factors were balanced between the two groups. Median age was 58, PS 1 was 87.2%, non-smoker 70.9%, adenocarcinoma 96.8%, symptomatic brain M were 16.5%. Icotinib significantly improved median iPFS compared with WBI+chemo: hazard ratio [HR] 0.56; 95% CI: 0.36-0.90; p=0.014 (10.0 vs 4.8 months). Median PFS was 6.8 vs 3.4 months, (HR 0.44, 95% CI 0.31-0.63, P<0.001). Median OS had no significant difference between the arms (18.0 vs 20.5 months, HR 0.93, 95%CI 0.60-1.44, P=0.734). Intracranial ORR was significantly improved with icotinib than WBI+Chemo (67.1% vs 40.9%; p<0.001); Overall ORR was 55.0% vs 11.1% (P<0.001). Grade ≥3 AEs assessed by the investigators were reported in 8.2% (N=7) of patients treated with icotinib and 26.2% (N=28) treated with WBI+Chemo. Most common causally related AEs in the icotinib arm were increased liver transaminase & rash; in the WBI+Chemo arm were hematologic toxicity.

      Conclusion:
      Icotinib demonstrated superior iPFS, PFS and ORR over WBI+Chemo in EGFR mutant advanced NSCLC with brain M, and well-tolerated safety profile. Icotinib would be a treatment option for EGFR mutant patients with brain M (NCT01724801).

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