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Li Zhang



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    MA02 - Improving Outcomes for Patients with Lung Cancer (ID 895)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 201 BD
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      MA02.05 - A Double-Blind, Randomized, Placebo-Controlled Phase 3 Noninferiority Study of Darbepoetin Alfa for Anemia in Advanced NSCLC (ID 13816)

      11:00 - 11:05  |  Author(s): Li Zhang

      • Abstract
      • Presentation
      • Slides

      Background

      The effect of erythropoiesis-stimulating agents on overall survival (OS) in patients with chemotherapy-induced anemia has long been debated. This study (NCT00858364) evaluated noninferiority of darbepoetin alfa (DAR) versus placebo for OS and progression-free survival (PFS) in anemic patients with NSCLC treated to a 12.0-g/dL hemoglobin ceiling.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Adults with stage IV NSCLC expected to receive ≥2 cycles of myelosuppressive chemotherapy, life expectancy >6 months, ECOG 0–1, and hemoglobin ≤11.0 g/dL were randomized 2:1 to DAR (500 µg SC) or placebo Q3W. Patients were stratified by region, histology, and hemoglobin. Primary endpoint was OS; a Cox proportional hazards model, stratified by randomization factors, was used to evaluate noninferiority (margin based on upper confidence limit [CL] for hazard ratio [HR] ˂1.15). Secondary endpoints were PFS (noninferiority) and incidence of transfusions or hemoglobin ≤8.0 g/dL from week 5 to end of efficacy treatment period (EOETP).

      4c3880bb027f159e801041b1021e88e8 Result

      4161 patients were screened, 2549 enrolled, and 2516 included in the primary analysis set: 1680 randomized to DAR and 836 to placebo. The study was stopped early per independent DMC recommendation. Patients were well matched between arms for age (mean 61.8 years), sex (66.0% male), and race (47.5% white). DAR was noninferior to placebo for OS (HRadj 0.92; 95%CL 0.83–1.01) and PFS (HRadj 0.95; 95%CL 0.87–1.04). DAR was superior to placebo for transfusion or hemoglobin ≤8.0 g/dL from week 5 to EOETP (OR 0.70; 95%CL 0.57–0.86; P<0.001). Objective tumor response was similar between arms (DAR 36.2%; placebo 32.6%). Incidence of serious adverse events was the same in both arms (31.1%). No unexpected adverse events or cases of antibody-mediated PRCA were observed (Table).

      DAR (n=1685)

      %

      Placebo (n=833)

      %
      All treatment-emergent adverse events 84.5 86.3
      Serious adverse events 31.1 31.1
      Fatal adverse events 12.2 13.6
      Adverse events leading to discontinuation of blinded drug 2.8 4.2
      Adverse events of interest (standardized MedDRA query)
      CNS vascular disorders 1.5 1.0
      Hypersensitivity 10.6 9.0
      Severe cutaneous adverse reactions 2.1 1.3
      Embolic and thrombotic events 5.3 4.1

      8eea62084ca7e541d918e823422bd82e Conclusion

      DAR dosed to a 12.0-g/dL hemoglobin ceiling was noninferior to placebo for OS and PFS and significantly reduced odds of transfusion or hemoglobin ≤8.0 g/dL in anemic patients with NSCLC receiving myelosuppressive chemotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    OA13 - Therapeutics and Radiation for Small Cell Lung Cancer (ID 927)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 203 BD
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      OA13.06 - Final Report of a Prospective Randomized Study on Thoracic Radiotherapy Target Volumes in Limited-stage Small Cell Lung Cancer with Radiation Dosimetric and Pathologic Analyses (ID 11970)

      11:25 - 11:35  |  Author(s): Li Zhang

      • Abstract
      • Presentation
      • Slides

      Background

      The interim analysis of our prospective trial, which compared irradiation to pre-chemotherapy or post-chemotherapy tumour extent while application of involved field radiotherapy (IFRT) for limited-stage small cell lung cancer (SCLC), showed that reduced field did not result in increased local/regional out-field recurrence. This report presents the final results of the clinical study with radiation dosimetric and pathologic analysis as interpretations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Chemotherapy consisted of 4 to 6 cycles of etoposide and cisplatin (EP). After 2 cycles of EP, patients were randomly assigned to receive thoracic radiotherapy (TRT) to either the post- or pre-chemotherapy tumour extent as study arm or control. TRT was administered concurrently with cycle 3 chemotherapy. IFRT was applied for both arms. The lymph node regions (groups 1 to 10) were contoured in treatment planning system. The intentional or incidental radiation doses to each lymph node regions were recorded. Patients with stage T1-2N0-1M0 SCLC received radical lobectomy. The minimal distances between microscopic nidus and the edge of gross tumor were measured. The clinical target volume of the primary tumor (CTV-T) was defined as the margins covering 95% of microscopic disease extension.

      4c3880bb027f159e801041b1021e88e8 Result

      Between June, 2002 and January, 2017, 159 and 150 patients were randomly assigned to study arm or control. The 1-, 3-, and 5-year local/regional progression free probability were 79.4%, 60.1% and 60.1% respectively in the study arm versus 79.8%, 64.5%, and 57.3% in the control (p=0.73). The median overall survival (OS) time was 22.1 months in the study arm (95% CI, 18.2-26.0) and 26.9 months (95% CI, 23.5-30.3) in the control, the 1-, 3-, 5-, and 7-year OS rates were 81.1%, 31.6%, 23.9% and 22.2% respectively in the study arm versus 85.3%, 36.6%, 26.1% and 20.0% in the control arm (p=0.51). A total of 1680 lymph node regions in 105 patients were contoured. The lymph node regions that received incidental radiation doses over 30Gy were: 7, 3P, 4L, 6, 4R, 5 and 2L. Eight patients were enrolled in the pathologic evaluation of CTV-T. The median range of CTV-T in patients received or did not receive neoadjuvant chemotherapy were 0.4mm and 1.7mm respectively, a margin of 1.4mm and 10.2mm could cover 95% of microscopic nidus extension respectively (p=0.00).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Irradiating post-chemotherapy tumour extent and applicant of IFRT didn't increase local/regional failure, and the OS difference wasn't statistically significant between the two arms. TRT could be limited to post-chemotherapy tumour extent, while IFRT could be routinely applied for limited-stage SCLC patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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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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      P1.01-109 - Phase I Study of Apatinib Plus Gefitinib as First-Line Therapy in Patients with EGFR Mutant Advanced Non-Small Cell Lung Cancer (ID 13616)

      16:45 - 18:00  |  Author(s): Li Zhang

      • Abstract
      • Slides

      Background

      EGFR-TKI plus bevacizumab (anti-VEGF) has brought significant progression-free survival (PFS) improvement for advanced NSCLC patients (pts) as first-line therapy compared to EGFR-TKI alone (16.0 vs. 9.7 months, HR 0.41, Lancet Oncol, 15(11):1236-1244). Apatinib, a TKI that selectively inhibits VEGFR-2, has shown strong antitumor activity in both preclinical and clinical studies in NSCLC. This phase I study aims to evaluate the safety and efficacy of Gefitinib plus Apatinib in the first line setting.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Treatment-naïve advanced NSCLC pts with EGFR 19 Del or 21 L858R mutation were eligible. Two prespecified groups were designed: Cohort 1: Apatinib 500mg QD PO + Gefitinib 250mg QD PO; Cohort 2: Apatinib 250mg QD PO + Gefitinib 250mg QD PO. Pharmacokinetics (PK) profile of Apatinib plus Gefitinib was also evaluated. 6 pts in each cohort should be enrolled for PK analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      From July 2016 to April 2017, 12 pts were enrolled. Most common AEs were rash (91.7%, 11/12), diarrhea (66.7%, 8/12), proteinuria (58.3%, 7/12), hypertension (25.0%, 3/12), and hand-foot-skin reaction (8.3%, 1/12). And most of AEs were grade 1-2. SAE was observed in 1 case with grade 3 hypertension (8.3%). The PK parameters in this combination setting were similar to those of single agent from the previous literature reports (Table 1). Among all evaluable patients, ORR was 83.3% (10/12), and DCR was 91.7% (11/12). Median PFS was 19.0 months (95% CI 0.0–43.9) in the Apatinib (500mg) + Gefitinib group and 13.4 months (13.0–13.8) in the Apatinib (250mg) + Gefitinib group (P=0.657).

      Table 1. Pharmacokinetic parameters (geometric mean, SD) of apatinib and gefitinib

      Apatinib 250mg Apatinib 500mg Gefitinib 250mg
      Cmax (ng/ml) 446(283) 499(257) 468(28)
      Cmaxmulti (ng/ml) 415(184) 603(438) 469(134)
      Tmax (h) 2.6(1.0) 2.8(1.9) 3.9(1.2)
      AUC0-24 (ng·h/ml) 3315(2367) 4155(2564) 3330(852)
      AUC0-24multi(ng·h/ml) 4875(4439) 4914(3898) 8132(2311)
      8eea62084ca7e541d918e823422bd82e Conclusion

      Apatinib (500mg) in combination with Gefitinib (250mg) shows a manageable tolerability profile and prolonged PFS tendency for EGFR-mutant NSCLC patients in first-line treatment setting. Clinical trial information: NCT02824458

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.01-110 - Three Specific HER2 Mutations Predict Favorable Outcomes in Advanced Lung Cancer Patients Treated with Afatinib (ID 12862)

      16:45 - 18:00  |  Author(s): Li Zhang

      • Abstract
      • Slides

      Background

      HER2 mutation is a potential therapeutic target for non-small cell lung cancer (NSCLC). However, HER2-targeting therapies including trastuzumab, afatinib and T-DM1 show limited and inconsistent efficacies in HER2-mutant NSCLC, suggesting its heterogeneity and the need to refine patient selection strategy for this population.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To investigate the efficacy of afatinib in HER2-mutant NSCLC and develop NGS (next generation sequencing)-based patient selection strategy, we reviewed afatinib-treated, HER2-mutant advanced NSCLC in 8 different institutions across China. HER2 status of all included cases were tested using NGS. Patients with EGFR/ALK co-mutations were excluded. The primary endpoint was investigator-assessed objective response rate (ORR) using RECIST v1.1. The secondary endpoint was progression-free survival (PFS). Adopting the binomial exact method (one-sided type I error=10%, power=80%, P0=20%, P1=30%), at least 21 patients were needed.

      4c3880bb027f159e801041b1021e88e8 Result

      As of 30 January 2018, a total of 23 afatinib-treated, HER2-mutant NSCLC patients were identified. Among 16 evaluable patients, 4 patients achieved partial responses (PR; ORR=25%), 7 achieved stable diseases (SD) and 5 had disease progression (PD) within 6 weeks. Median PFS (mPFS) for patients achieving disease control (n=11; 69%) was 9.53 months (range: 1.77-11.97). Two of the four partial responders had p.G778_P780dup, one had p.Y772_A775dup and one had p.G776delinVC. Same mutations were detected in five other patients. Patients harboring the three specific HER2 mutations (p.G776delinsVC (n=3); p.Y772_A775dup (n=3); p.G778_P780dup (n=2)) had marginally higher ORR (ORR=50%, P=0.077) and longer PFS (mPFS=9.53m, P=0.057) than those carrying other types of HER2 mutations (n=8: ORR=0%, mPFS=1.80m) (Figure 1). TP53 co-mutation was observed in 6 patients, who showed similar responses to afatinib (PR=2, SD=2, PD=2) comparing to patients without co-occurring TP53 (n=10: PR=2, SD=5, PD=3).figure 1.tif

      8eea62084ca7e541d918e823422bd82e Conclusion

      HER2-mutant NSCLC represents a heterogenous group of diseases. Although afatinib failed to show the expected ORR in the overall population, patients harboring three specific HER2 mutations may still benefit from afatinib treatment.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.15 - Treatment in the Real World - Support, Survivorship, Systems Research (Not CME Accredited Session) (ID 947)

    • 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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      P1.15-17 - Risk Factors of Local Recurrence in EGFR-Mutant Stage III-pN2 Adenocarcinoma After Complete Resection: A Multi-Center Real-World Cohort Study (ID 12740)

      16:45 - 18:00  |  Author(s): Li Zhang

      • Abstract

      Background

      Postoperative radiotherapy (PORT) of complete resected stage IIIA non-small cell lung cancer with N2 nodal involvement remained contentious. Our previous study suggested low locoregional recurrences in epidermal growth factor receptor (EGFR) mutant patients. We sought to launch a multi-center large cohort study to evaluate the risk factors of locoregional recurrence in R0 resected EGFR mutant III-pN2 patients without PORT, producing evidence for the design of adjuvant regimens.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Three-hundred and fifty-nine consecutive patients with complete resected, pathological approved stage III-pN2 lung adenocarcinoma with sensitive EGFR mutation (exon 19 or exon 21) have been investigated. Patients were excluded if they received induction therapy (7.5%) or PORT (9.6%). Three hundred cases have been analyzed. Clinicopathologic characteristics, pretreatment work-ups, EGFR mutant status and patterns of failure were documented. Patients were sub-staged by the International Association for the Study of Lung Cancer (IASLC)/ the Union for International Cancer Control (UICC) 7th classification on N2 disease. Risk factors of locoregional recurrence-free survival (LRFS) were evaluated by univariate and multivariate analyses.

      4c3880bb027f159e801041b1021e88e8 Result

      According to IASLC/UICC 7th classification, there were 198 (66.0%) patients with unforeseen N2 (N2a), 36 (12.0%) with minimal/single station N2 (N2b), 41 (13.7%) with selectively centrally located N2 (N2c) and 25 (8.3%) with bulky and/or multilevel N2 (N2d). After surgery, 70 (23.3%) patients were treated with adjuvant tyrosine-kinase inhibitors (TKIs), while other 230 (76.7%) were free from adjuvant TKIs. With median follow-up of 28.5 (range:6-133) months, the 2-year LRFS, distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were 88.3%, 65.3%, 57.7% and 89.7%. Ultimately, 15.7% (47/300) patients developed locoregional recurrences. Distant metastasis was the predominant failure pattern. Multivariate analysis indicated that N2d disease (HR: 2.65, p=0.030) and extranodal extension (HR: 3.48, p<0.001) were risk factors of LRFS.

      8eea62084ca7e541d918e823422bd82e Conclusion

      R0 resected stage III-pN2 NSCLC patients with sensitive EGFR mutation (exon 19 or exon 21) tended to present limited N2 disease and low locoregional recurrences. Patients without bulky N2, multilevel N2, and extranodal extension might be refrained from PORT. Further studies evaluating the optimal radiotherapy approach for completely resected N2-positive NSCLC are required for validation.

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