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Li Zhang



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    GR 01 - What to Do at the Time of Progression on Targeted Therapy (ID 520)

    • Event: WCLC 2017
    • Type: Grand Rounds
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      GR 01.03 - First-Line Management of EGFR Mutant NSCLC (ID 7628)

      11:00 - 12:30  |  Presenting Author(s): Li Zhang

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Lung cancer is still the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) remains the predominant form of the disease, with majority of patients being diagnosed at advanced stages. The survival benefit offered by chemotherapy regimens has reached a therapeutic plateau. Fortunately, mutation-specific targeted therapies directed against “actionable” genetic alterations have significantly improved the prognosis of advanced NSCLC. Epidermal growth factor receptor (EGFR) mutation is the most common targetable genetic alteration in NSCLC. The prevalence of EGFR mutations range from 10% in Caucasians, to 60% in never-smoking, Asian, adenocarcinoma patients. This presentation will focus on the first-line management of EGFR mutant NSCLC. Overview of EGFR-TKIs Nine large randomised controlled studies have established the superiority of EGFR tyrosine kinase inhibitors (EGFR-TKIs) against chemotherapy as first-line treatment in NSCLC harboring EGFR mutations in terms of progression-free survival (PFS), objective response rate (ORR) and quality of life (QoL) (Table 1). Several studies suggest there is no significant difference in efficacy between gefitinib and erlotinib. LUX-lung 7 (afatinib) and ACHER 1050 (dacomitinib) are two randomised head-to head trials comparing second-generation EGFR-TKIs to gefitinib, respectively. Although PFS is significantly improved with second-generation TKIs, the increased rates of grade 3 or higher adverse events such as rash and diarrhea result in more dose modification with second-generation TKIs. FLAURA study, which assesses the efficacy of third-generation EGFR-TKI osimertinib versus first-generation EGFR-TKIs as first-line treatment, has been accomplished recently. This trial may establish the role of osimertinib as first-line treatment for EGFR mutant NSCLC. Management of uncommon mutations Exon 19 deletion and L858R mutation account for about 90% of all EGFR mutations. The remaining 10% of EGFR mutations (uncommon mutations) are a heterogeneous group of molecular alterations. Results of retrospective studies and case reports of first-generation EGFR-TKIs show inconsistent responses in this population. According to the post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6, objective responses to afatinib are observed in certain types of uncommon mutations such as G719X (77.8%), L861Q (56.3%), and S768I (100%). However, Patients with de-novo Thr790Met and exon 20 insertion mutations are insensitive to afatinib. Jonathan Riess and colleagues report that osimertinib has in vivo activity across multiple exon 20 insertion mutations in preclinical study. Thus osimertinib warrants further study in patients with exon 20 insertion mutations. Combination treatment strategies Combinations of EGFR-TKIs with chemotherapy, anti-angiogenetic therapy, and immunotherapy have been explored in clinical trials. JMIT study is a randomized phase II trial comparing addition of pemetrexed to gefitinib with gefitinib alone as first-line therapy in EGFR mutant NSCLC. PFS was significantly longer with pemetrexed+gefitinib than with gefitinib (15.8 months vs 10.9 months; hazard ratio [HR], 0.68; 95% CI, 0.48 to 0.96; P = 0.029). According to JO25567 study, combination of erlotinib with bevacizumab also significantly prolongs PFS than erlotinib. Several phase III trials evaluating combination of EGFR-TKIs with anti-angiogenetic therapy are ongoing. Attention should be paid to adverse events such as interstitial lung disease when EGFR-TKIs are used with immunotherapy. Management of brain metastases Brain metastases is a major challenge when managing EGFR mutant NSCLC as up to 40% of patients would develop central nervous system (CNS) metastases during the course of their disease. Novel EGFR-TKIs provide new strategies for brain metastases treatment. AZD3759 is a CNS penetrable and reversible EGFR-TKI. The phase I study (BLOOM) of AZD3759 in TKI naïve EGFR mutant NSCLC with CNS metastases is reported in 2017 ASCO annual meeting. Intracranial response is observed in 83% of patients with measurable brain metastases lesions at baseline. The extracranial anti-tumor efficacy of AZD3759 is also promising. 13 out of 18 patients with extracranial lesions have confirmed objective response. CNS response to osimertinib in patients with T790M-positive advanced NSCLC from AURA3 study is also presented in 2017 ASCO annual meeting. In 30 patients with more than one measurable CNS metastases, the intracranial response is 70%. The median CNS PFS with osimertinib is 11.7 months. Furthermore, osimertinib shows encouraging activity in patients with leptomeningeal metastases. Table 1. First-line treatment of EGFR mutant NSCLC: EGFR-TKIs vs. Chemotherapy

      Trial TKI PFS (month) OS
      TKI Chemo HR (95%CI) HR (95%CI)
      IPASS Gefitinib 9.5 6.3 0.48 (0.36-0.64) 0.78 (0.50-1.20)
      First Signal Gefitinib 8.4 6.7 0.61 (0.31-1.22) 0.82 (0.352-1.922)
      NEJ002 Gefitinib 10.8 5.4 0.322 (0.236-0.438) 0.88 (0.634-1.241)
      WJTOG3405 Gefitinib 9.6 6.6 0.52 (0.378-0.715) 1.185 (0.767-1.829)
      OPTIMAL Erlotinib 13.1 4.6 0.16 (0.10-0.26) 1.19 (0.83-1.71)
      ENSURE Erlotinib 11.0 5.5 0.34 (0.22-0.51) 0.91 (0.63-1.31)
      EURTAC Erlotinib 9.7 5.2 0.37 (0.25-0.54) 0.80 (0.47-1.37)
      Lux-lung 3 Afatinib 11.1 6.9 0.58 (0.43-0.78) 0.88 (0.66-1.17)
      Lux-lung 6 Afatinib 11.0 5.6 0.29 (0.20-0.33) 0.93 (0.72-1.22)


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    MA 08 - Supportive Care and Communication (ID 669)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Nursing/Palliative Care/Ethics
    • Presentations: 1
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      MA 08.02 - Efficacy of Single-Dose NEPA versus 3-Day Aprepitant Regimen for Prevention of CINV: A Phase 3 Lung Cancer Subset Analysis (ID 8460)

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

      • Abstract
      • Presentation
      • Slides

      Background:
      Cisplatin, a systemic treatment component for many lung cancer types, is highly emetogenic (HEC). The guideline-recommended antiemetic combination for patients receiving HEC includes a NK~1~ receptor antagonist (NK~1~RA), a 5-HT~3~RA, and dexamethasone (DEX). NEPA is the first oral fixed combination of an NK~1~RA (netupitant) and a 5-HT~3~RA (palonosetron). The approval of oral NEPA was based on studies demonstrating superior prevention of chemotherapy-induced nausea and vomiting (CINV) over oral palonosetron; an intravenous formulation of NEPA is under FDA evaluation. A new Phase 3 study in Asia has reached its primary objective: a single day oral dose of NEPA is non-inferior to a 3-day regimen of aprepitant (APR) and granisetron (GRAN) [both combined with DEX] in preventing CINV in patients receiving cisplatin. This post-hoc analysis explores the efficacy of NEPA vs APR/GRAN within the lung cancer subset of that study.

      Method:
      Chemotherapy-naïve lung cancer patients in this double-blind, parallel group study received either a single oral dose of NEPA prior to cisplatin-based HEC or a 3-day regimen of APR/GRAN, both with oral DEX on days 1-4. Efficacy endpoints were complete response (CR: no emesis/no rescue medication), no emesis, and no significant nausea (<25 mm on 100 mm visual analog scale) during the acute (0-24h), delayed (25-120h) and overall (0-120h) phases post-chemotherapy. The risk difference for NEPA – APR/GRAN and associated 95% confidence intervals (CIs) were analyzed for each endpoint using the Cochran-Mantel-Haenszel test.

      Result:
      542 (65%) of the 828 patients had lung cancer. Mean age was 56.1; 73% males. Response rates were comparable for both arms during the acute phase, and favored NEPA in delayed phase (Table). Figure 1



      Conclusion:
      As a fixed oral combination of an NK~1~RA and 5HT~3~RA in a single capsule/cycle, NEPA offers a convenient and effective prophylactic antiemetic in lung cancer patients receiving cisplatin-based HEC regimens.

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    MA 11 - Emerging Diagnostic/Biomarkers in NSCLC (ID 668)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA 11.03 - Gefitinib as First-Line Treatment of Plasma CtDNA EGFR Mutation-Positive NSCLC Detected by DdPCR: BENEFIT Study (CTONG1405) (ID 9278)

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

      • Abstract
      • Presentation
      • Slides

      Background:
      EGFR mutations in plasma circulating free tumor-derived DNA (ctDNA) as a predictor of EGFR TKI efficacy in patients with NSCLC requires validation in prospective studies. The large, prospective Phase II, single-arm, multicenter BENEFIT study (CTONG1405; NCT02282267) validated the efficacy of first-line gefitinib in EGFR mutation-positive NSCLC detected in plasma ctDNA using droplet digital PCR (ddPCR).

      Method:
      Patients with stage IV lung adenocarcinoma and plasma ctDNA EGFR-sensitizing mutations (exon 19 del or exon 21 L858R; by ddPCR) received first-line gefitinib (250 mg once-daily) until progressive disease (PD). Blood samples were collected every 8 weeks for dynamic EGFR analysis until PD. Primary endpoint was ORR. Secondary endpoints included PFS, DCR (Week 8), and analysis of baseline ctDNA samples by next-generation sequencing (NGS).

      Result:
      From December 2014-January 2016, 426 patients from 15 Chinese centers were screened: 391 had matched tissue and blood samples; 188 had ctDNA EGFR mutation-positive NSCLC and received gefitinib; and 183 had ≥1 post-baseline tumor assessment and plasma samples every 8 weeks until PD. At data cutoff (January 31, 2017), 152 patients had progressed. ORR was 72.1% (95% CI 65.0%,78.5%); DCR (Week 8) was 92.3% (95% CI 87.5%,95.8%); and median PFS was 9.5 months (95% CI 9.07,11.04). PFS was significantly shorter in the subgroup with baseline ctDNA de novo T790M mutations (5.0%, n=9) versus the EGFR-sensitizing mutations subgroup (5.6 vs 9.6 months, HR=2.60; 95% CI 1.32,5.12, p=0.004). In patients with Week 8 on-treatment plasma samples (n=167), the subgroup who showed EGFR mutation clearance in ctDNA by ddPCR (88%, 147/167) had longer PFS compared with those who did not (11.0 vs 2.1 months, HR=7.28; 95% CI 4.35,12.18, p<0.0001). The median time to emergence of acquired T790M mutation in plasma was 7.6 months. The T790M-positive rate increased from Week 24 (15.7%) to Week 48 (32.6%), with a corresponding increase in PD rate (24.7% at Week 24, 56.9% at Week 48). Among 180 patients with baseline NGS data, 21 (11.7%) harbored aberrations in additional oncogenic drivers (MET, ERBB2, KRAS, BRAF, RET, or ROS1) and tumor suppressors (TP53, RB1, and PTEN). This subgroup had worse PFS versus those with EGFR-sensitizing mutations alone (3.9 vs 13.0 months, HR=2.83; 95% CI 1.65,4.87, p=0.00016).

      Conclusion:
      The BENEFIT study prospectively demonstrated that ctDNA-based EGFR mutation detection can be used to select patients for treatment with first-line gefitinib. Dynamic alterations in EGFR mutations could be used to predict efficacy and disease progression, ahead of radiological results.

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    P1.04 - Clinical Design, Statistics and Clinical Trials (ID 690)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Clinical Design, Statistics and Clinical Trials
    • Presentations: 1
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      P1.04-010 - CheckMate 870: An Open-label Safety Study of Nivolumab in Previously Treated Patients With Non-Small Cell Lung Cancer in Asia (ID 8231)

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

      • Abstract
      • Slides

      Background:
      Programmed death-1 (PD-1) is an immune checkpoint receptor that attenuates T-cell activation by binding to its ligands, PD-L1 and PD-L2, which are expressed on tumor cells. Nivolumab, an anti–PD-1 antibody, showed durable antitumor activity and a favorable safety profile compared with docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC) in 2 global phase 3 studies (CheckMate 017 and CheckMate 057). Data from these trials led to the approval of weight-based nivolumab 3 mg/kg administered as a 60-minute infusion every 2 weeks (Q2W) in previously treated patients with NSCLC. Data from exposure-response simulations indicated that flat-dose nivolumab 240 mg Q2W has comparable pharmacokinetic, safety, and efficacy profiles to the weight-based dose, and data from CheckMate 153 demonstrated that nivolumab 3 mg/kg can be safely infused over 30 minutes. CheckMate 078 is an ongoing phase 3 registrational trial evaluating second-line nivolumab 3 mg/kg as 60-minute infusions Q2W versus docetaxel in patients with advanced NSCLC in a predominantly Chinese population. CheckMate 078 excludes patients with hepatitis B virus (HBV) infection, which represent a clinically relevant subgroup of patients in Asia; approximately 15% of patients with lung cancer in China are seropositive for HBV surface antigens. CheckMate 870 is an open-label, single-arm phase 3b study evaluating the safety and tolerability of flat-dose nivolumab 240 mg infused over 30 minutes Q2W in Asian patients with advanced or metastatic NSCLC, with or without HBV infection.

      Method:
      Approximately 400 patients in Asia with advanced or metastatic NSCLC and disease progression during or after 1 prior systemic platinum-based therapy will be enrolled; those with EGFR mutations (maximum of 40 patients) or ALK translocations should have received 2 prior systemic treatments including a tyrosine kinase inhibitor and chemotherapy. Nivolumab will be administered 240 mg over 30 minutes Q2W until disease progression or unacceptable toxicity, for a maximum of 24 months. Nivolumab may be reinitiated for subsequent disease progression and administered for up to 1 additional year. The primary objective is to evaluate the safety and tolerability of nivolumab in non–HBV-infected patients with NSCLC. The secondary objective is to assess safety and tolerability in all patients and in HBV-infected patients. Exploratory objectives include efficacy, patient-reported outcomes, health care resource utilization and direct medical costs, biomarker characterization in all patients, and viral load change and HBV reactivation rate in HBV-infected patients.

      Result:
      Section not applicable

      Conclusion:
      Section not applicable

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    P1.14 - Radiotherapy (ID 700)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Radiotherapy
    • Presentations: 1
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      P1.14-011 - An Esophagus-Sparing Technique to Limit Radiation Esophagitis in Locally Advanced NSCLC Treated by SIB-IMRT and Concurrent Chemotherapy  (ID 8090)

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

      • Abstract
      • Slides

      Background:
      To investigate the incidence of radiation esophagitis (RE) and tumor local control using esophagus sparing technique in locally advanced non-small cell lung cancer (LANSCLC) treated by simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT) and concurrent chemotherapy.

      Method:
      Ninety-five patients with stage IIIA/B NSCLC who received definitive SIB-IMRT and concurrent chemotherapy had been divided into two groups: 1.with esophagus sparing technique; 2.without esophagus sparing technique. Chi-square test was performed to compare sex, clinical stage, histology, concurrent chemotherapy, RE and nutrition status between two groups. T-test was used to compare the dosimetric parameters. Overall survival (OS) and loco-regional failure free survival (LRFS) were calculated by the Kaplan–Meier method and compared by a log-rank test.

      Result:
      There were 50 patients in the esophagus sparing group and 45 in the non-sparing group. The incidence of severe RE (Grade 3-5) was significantly lower in patients with esophagus sparing technique (p = 0.000). Patients in esophagus sparing group had better nutrition status (p = 0.029). With a median follow-up of 23 months (range 0-37 months), the 3-year OS of all the patients was 33.4%. OS time was found to be longer in the esophagus-sparing group (32 vs. 27 months, p= 0.010). LRFS was comparable between two groups (29 vs. 24 months, p=0.960).

      Conclusion:
      Esophagus-sparing technique is an effective and essential method to limit RE in LANSCLC treated by SIB-IMRT and concurrent chemotherapy. Reducing severe RE when escalating radiation fraction size may help to achieve higher local control and better general performance status.

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    P2.04 - Clinical Design, Statistics and Clinical Trials (ID 705)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Clinical Design, Statistics and Clinical Trials
    • Presentations: 1
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      P2.04-003 - Phase II Trial of X-396 (Ensartinib) for Chinese Patients with ALK (+) Non–Small-Cell Lung Cancer Who Progressed on Crizotinib (ID 8849)

      09:30 - 16:00  |  Presenting Author(s): Li Zhang

      • Abstract

      Background:
      Crizotinib has been established as the standard first-line treatment for patients with ALK-rearranged non-small-cell lung cancer. However, despite its superiority to chemotherapy, resistance occurs within approximately 12 months. New ALK-inhibitors are needed to overcome the resistance to crizotinib and to increase drug penetration to CNS. X-396 (ensartinib) is a novel, potent ALK tyrosine kinase inhibitor (TKI). Its phase I/II study showed X-396 is well-tolerated with favorable anti-tumor activities in both ALK TKI-naïve and crizotinib-resistant NSCLC patients, as well as patients with CNS metastases. The recommended phase II dose (RP2D) was established at 225 mg, once daily.

      Method:
      A phase II, multi-center study is evaluating the efficacy and safety of single-agent X-396 in Chinese patients with ALK (+) non–small-cell lung cancer after progression on crizotinib. Eligible patients will have documentation of a positive ALK rearrangement and progression on crizotinib. X-396 225 mg is orally administered until disease progression or intolerable toxicity. The primary endpoint is RECIST 1.1 response rate. Secondary endpoints include PFS, duration of response, and safety. The sample size is calculated using the test for inequality method, assuming that X396 have an ORR of 50% in patients with ALK-positive NSCLC, 15% higher than that from existing second-line therapy. Therefore, up to 144 patients will be enrolled with a significance level and power of 5% and 90%, respectively. Recruitment will be started on September, 2017.

      Result:
      Section not applicable

      Conclusion:
      Section not applicable

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    P2.14 - Radiotherapy (ID 715)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Radiotherapy
    • Presentations: 1
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      P2.14-004 - Comparable Local Controls after Twice-Daily and Once-Daily Chest Radiotherapy in Extensive Stage Small Cell Lung Cancer (ID 8788)

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

      • Abstract

      Background:
      The optimal radiation schedule for small cell lung cancer (SCLC) has not yet fully established. This study was designed to compare the clinical outcomes between twice- and once-daily radiotherapy in the treatment of SCLC.

      Method:
      One hundred and twenty-four consecutive patients diagnosed with extensive stage SCLC and treated with chemoradiotherapy were retrospectively reviewed. Either twice-daily hyper-fractionated irradiation (45 Gy/30 fractions/BID), or alternative schedules, including hypo-fractionated (45 Gy/15 fractions/QD) or conventionally fractionated (50 Gy/25 fractions/QD or 60 Gy/30 fractions/QD) radiation was delivered, with etoposide and platinum prescribed concurrently or sequentially. Local controls and overall survivals were calculated and compared between twice- and once-daily schedules based on Kaplan-Meier method. Toxicities were record according to Common Terminology Criteria Adverse Events.

      Result:
      There were 67 and 57 patients received twice- and once-daily chest radiotherapy, respectively. With a median follow-up of 27 and 24 months, the local control rates were reported 64.2% and 63.2%. The 2-year estimated local progression-free survival rates were similar (61.6% vs 61.0%, p=0.90). Progressive disease identified three months after radiotherapy was correlated to increased local failure (p=0.026). There was no difference between the incidences of grade 3-4 toxicities between twice- and once-daily schedules (23.9% vs 12.3%, p=0.16).

      Conclusion:
      Either twice- (45 Gy/30 fractions/BID) or once-daily (45 Gy/15 fractions/QD, 50 Gy/25 fractions/QD, 60 Gy/30 fractions/QD) radiation schedule could be considered in the treatment of SCLC, resulting in comparable local control and toxicities.