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Y.-. Wu

Moderator of

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    SC15 - Clinical Trials: How to Set Priorities? (ID 339)

    • Event: WCLC 2016
    • Type: Science Session
    • Track: Trial Design/Statistics
    • Presentations: 6
    • Now Available
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      SC15.01 - The American Perspective (Now Available) (ID 6658)

      S.S. Ramalingam

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The treatment of lung cancer has changed dramatically in the past few years. From a time when treatment decisions were made without regard to histology or genotype, an era of personalized therapy, at least for a subset of patients with lung cancer, is a reality. The treatment of EGFR mutation-positive patients with EGFR inhibitors has resulted in significant improvements in outcomes over standard chemotherapy. Similarly, for patients with ALK- and ROS1-positive non-small cell lung cancer (NSCLC), targeted therapies have proven to be superior. However, for patients with KRAS mutations, which are seen in approximately 25-30% of lung adenocarcinomas, there is no effective targeted therapy option. For nearly 70% of patients with NSCLC, systemic chemotherapy remains the standard approach. The emergence of immune-checkpoint inhibitors has resulted in considerable change in the treatment algorithm for advanced NSCLC. These agents are now preferred salvage therapy after progression following platinum-based chemotherapy. As immunotherapy moves to the first-line therapy setting for advanced NSCLC, it is anticipated that at least 25-30% of the patients without a driver mutation will be treated with immune-checkpoint inhibitors. All of these exciting developments call for careful evaluation of ongoing and planned clinical trials, so that appropriate new priorities are established. The newly established NCI National Clinical Trials Network (NCTN) includes all the adult cancer cooperative groups (ALLIANCE, ECOG-ACRIN, SWOG, & NRG Oncology) is actively engaged in conducting the new generation of clinical trials for lung cancer. Despite, the success with targeted agents in advanced stage NSCLC, patients do not achieve a cure. Using these agents in early stage NSCLC provides the best chance for a cure. The ALCHEMIST study has been launched by the NCTN to evaluate personalized adjuvant therapy for early stage NSCLC. In this study, patients with early-stage lung cancer (stages IB, II and IIIA) are treated with systemic chemotherapy after surgical resection, as per standard of care. Subsequently, their tumor is subjected to molecular testing. Patients with ALK-positive disease are randomized to treatment with crizotinib or placebo. Patients with EGFR mutations are randomized to erlotinib or placebo. Patients who are negative for EGFR and ALK, are randomized to nivolumab or observation. These studies will evaluate the effect of the personalized adjuvant therapy on overall survival and disease-free survival. Another ongoing effort is to understand the therapeutic value of targeted strategies in patients with advanced stage squamous cell lung cancer. The lung-MAP study enrolls patients with advanced stage squamous NSCLC. Following next-gen sequencing, patients with selected targets are treated with an appropriate targeted agent. The study includes a phase 2 component, which can be rapidly adapted to phase 3 if a agent demonstrates the pre-defined level of efficacy. This trial is also designed to accelerate the development of treatments leading to full approval by the FDA by shortening timelines. These individualized treatment approaches based on genotype are likely to answer important questions in a definitive manner. As immunotherapy becomes integrated in the standard treatment paradigms, considerable changes are also warranted for patients without driver mutations. For a subset of patients, as immunotherapy becomes the first line treatment in the advanced stage disease setting, the role of platinum-based chemotherapy in the second line needs to be investigated. It is also important to evaluate the need for continued immunotherapy after disease progression when patients are switched to chemotherapy. Another key question relates to the duration of therapy for patients receiving immune checkpoint inhibitors. Appropriately designed trials to understand the optimum duration of therapy will optimize benefits, reduce toxicity, and decrease cost. Combination strategies using immune checkpoint inhibitors with chemotherapy and other targeted agents is also an important area of priority. The role of biomarkers to select therapy is another critical research priority. We should also make efforts to improve the percentage of patients enrolled to clinical trials. A major reason for this is the stringent eligibility criteria that excludes a significant proportion of patients in order to select the ‘fittest’ candidates for clinical trials. While this is certainly appropriate in early phase drug development, if patients enrolled in clinical trials do not represent the ‘real-world’ patient population, the applicability of the results are limited. The next wave of clinical trials should also take into consideration the impact of new treatments on the overall cost of care and the clinical significance of improvements in efficacy. The national Cooperative groups in the United States are committed to a collaborative approach to address key research questions and improve outcomes for lung cancer.

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      SC15.02 - The European Perspective (Now Available) (ID 6659)

      R. Stahel

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      SC15.03 - The Chinese Perspective (Now Available) (ID 6660)

      Y.-. Wu

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      SC15.04 - The Japanese Perspective (Now Available) (ID 6661)

      Y. Ohe

      • Abstract
      • Presentation
      • Slides

      Abstract:
       In Japan, several cooperative study groups, such as Japan Clinical Oncology Group (JCOG), West Japan Oncology Group (WJOG), North East Japan Study Group (NEJ), Thoracic Oncology Research Group (TORG), Tokyo Cooperative Cooperative Oncology Group (TCOG), Oncology Group in Kyushu (LOGiK), Okayama Lung Cancer Study Group (OLCSG) and so on are conducting investigator initiated cooperative clinical studies for lung cancer. Phase 3 studies are mainly conducted by JCOG, WJOG and NEJ. JCOG and WJOG are conducting intergroup phase 3 studies for lung cancer. More recently, multi-group phase 3 studies are also started.  JCOG is a multicenter clinical study group for cancer treatment fully funded by the national research grants in Japan. The goal of the JCOG is to establish effective standard treatments for various types of malignant tumors by conducting nationwide multicenter clinical trials, and to improve the quality and outcome of the management of cancer patients. JCOG consists of 16 subgroups and JCOG Lung Cancer Study Group (JCOG-LCSG) consists of 44 institutions, was established in 1982. JCOG also have JCOG Lung Cancer Surgical Study Group (JCOG-LCSSG) established in 1986.  Only JCOG is supported by no industries but National Cancer Center and grants of Japan Agency for Medical Research and Development (AMED). Thus, JCOG studies are conducting completely independent from pharmaceutical companies. Other groups are supported by mainly pharmaceutical companies and grants of AMED. JCOG-LCSG has been conducting many randomized trials for small cell lung cancer and elderly non-small cell lung cancer. In case of JCOG-LCSG, protocol concepts are discussing in the group meeting held every 3 months. The protocol concept agreed in the group meeting will discuss in JCOG Protocol Review Committee and finally approved by JCOG Steering Committee. Kawano Y, Okamoto I, Fukuda H, et al. Current status and future perspectives of cooperative study groups for lung cancer in Japan. Respir Investig 52: 339-347, 2014.

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      SC15.05 - The South American Perspective (Now Available) (ID 6662)

      G. Castro

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      SC15.06 - Q&A (Now Available) (ID 6885)

      • Abstract
      • Presentation

      Abstract not provided

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Author of

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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: 4
    • Now Available
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      JCES01.02 - Welcome and Introduction (Now Available) (ID 6810)

      Y.-. Wu

      • Abstract
      • Presentation

      Abstract not provided

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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)

      Y.-. Wu

      • 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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      JCES01.18 - Dual Positive PD-L1 and CD8+ TIL Represents a Predominant Subtype in NSCLC and Correlates with Augmented Immunogenicity (ID 7060)

      Y.-. Wu

      • Abstract
      • Slides

      Background:
      Recent studies have identified that the degree of tumor infiltrating lymphocyte (TIL) infiltration and PD-L1 expression in the tumor microenvironment (TME) are significantly correlated with the clinical outcomes of anti-PD-1/PD-L1 therapies. Here we conducted this study to verify the distribution of PD-L1/CD8[+] TIL expression and its clinical significance in non-small cell carcinoma (NSCLC). Potential mechanism predicted for PD-1 blockade was explored in depth as well.

      Methods:
      Immunohistochemistry was performed to detect PD-L1 and CD8 expression in NSCLC. The Kaplan–Meier (KM) survival curve was used to estimate disease free survival (DFS) and overall survival (OS). Gene Set Enrichment Analysis (GSEA) was used to determine potentially relevant gene expression signatures.

      Results:
      288 cases with stage I-IIIA NSCLC were evaluated for PD-L1 and CD8+ TIL staining. Dual positive PD-L1 and CD8 (PD-L1+/CD8+) represents a predominant subtype in NSCLC, accounting for 36.5% (105/288), followed by PD-L1-/CD8- (24.3%, 70/288), PD-L1-/CD8+ (26.0%, 75/288) and PD-L1+/CD8- (13.2%, 38/288). Survival analysis of DFS (p=0.031) and OS (p=0.002) showed a significant difference between four subgroups. Furthermore, we analyzed the correlation between expression types of PDL1/CD8 and mutation burden and angtigen presentation. We can identified dual positive PD-L1 and CD8 was significant with increased mutation burden (p<0.001), high frequency of mismatch repair (MMR) related gene mutation. More interestingly, tumor with dual positive PD-L1 and CD8 manifested a remarkable activated angtigen presentation and T cell receptor signature compared with other subgroups.

      Conclusion:
      Dual positive PD-L1 and CD8 was identified as a predominant subtype in NSCLC and correlates with increased immunogenicity. These findings provide the evidence that combined analysis of PD-L1 and CD8 in NSCLC may be a promising way to predict PD-1 blockade immunotherapy.

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      JCES01.24 - Molecular Mechanism of Transformation from Adenocarcinoma to Small-Cell Lung Cancer after EGFR-TKI (ID 7066)

      Y.-. Wu

      • Abstract
      • Slides

      Background:
      In patients with advanced non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutations, EGFR-tyrosine kinase inhibitors (TKIs) are recommended as first-line treatment due to favorable clinical efficacy. However, acquired resistance inevitably develops after median progression-free survival (PFS) of 9-14 months. Among the mechanisms of acquired resistance, small-cell lung cancer (SCLC) transformation was reported to account for nearly 5%. However, the molecular details underlying this histological change and resistance to EGFR-TKI therapy remain unclear.

      Methods:
      15 out of 233 (6.4%) patients were confirmed to develop SCLC transformation after failure to EGFR-TKI. We analyzed the clinical parameters of these patients by using chi-square test and Kaplan-Meier analysis. To explore gene alterations that might contribute to SCLC transformation, next generation sequencing (NGS) was performed on four pairs of matched pre- and post-transformation tumor tissue samples. We further performed NGS on 11 matched circulating tumor DNA (ctDNA) to explore the potential mechanism of resistance to EGFR-TKI.

      Results:
      The median age of SCLC transformed patients was 53 years. 93.3% (14/15) patients harbored EGFR exon19 deletion. The median PFS and overall survival (OS) of SCLC-transformed patients treated with EGFR-TKI compared to those without transformation were 11.7 versus 11.9 months (P=0.473) and 29.4 versus 24.3 months (P=0.664), respectively. All 4 patients developed loss of heterozygosity of TP53/RB1 after transformation. Besides, increased copy number of five proto-oncogenes were identified in post-transformation tissue samples. Three patients developed EGFR T790M mutation in the post-transformation ctDNA rather than their tissue samples.

      Conclusion:
      SCLC transformation was commonly seen in patients harboring EGFR exon 19 deletion. The clinical outcomes of TKI and OS in SCLC transformed patients were similar to non-transformed patients. The loss of heterozygosity of TP53 and RB1along with increased copy number of proto-oncogenes may lead to the SCLC transformation. The mechanisms of acquired resistance to TKI during SCLC transformation might be the emergence of classic drug resistance mutations, which was undetectable due to the intra-tumor heterogeneity.

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    MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 2
    • Now Available
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      MA08.03 - Osimertinib vs Platinum-Pemetrexed for T790M-Mutation Positive Advanced NSCLC (AURA3): Plasma ctDNA Analysis (Now Available) (ID 4733)

      Y.-. Wu

      • Abstract
      • Presentation
      • Slides

      Background:
      AURA3 (NCT02151981) is a Phase III, open-label, randomised study assessing the efficacy and safety of osimertinib, a T790M directed EGFR-TKI, vs platinum-based doublet chemotherapy in patients with EGFR T790M-positive advanced NSCLC, whose tumours progressed on previous EGFR-TKI therapy. Concordance between plasma and tissue testing, and efficacy outcomes by baseline plasma T790M status, were evaluated.

      Methods:
      Eligible patients were randomised 2:1 to osimertinib 80 mg orally once daily or platinum-pemetrexed (pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC5) every three weeks for up to six cycles. Patients were tumour tissue T790M-positive (by cobas[®] EGFR Mutation Test v2) from a biopsy after disease progression prior to study entry. Blood samples were taken at baseline for retrospective analysis of T790M mutation status by plasma ctDNA using the cobas[®] EGFR Mutation Test v2.

      Results:
      Concordance data are reported in the table. Within the intent-to-treat (ITT) population (n=419), patients plasma T790M-positive and randomised to treatment (n=172) had markedly improved progression-free survival (PFS) by investigator assessment (IA) with osimertinib vs platinum-pemetrexed: hazard ratio 0.42 (95% CI: 0.29, 0.61); median 8.2 vs 4.2 months. Objective response rate (ORR) by IA was also distinctly improved with osimertinib vs platinum-pemetrexed: 77% vs 39% (odds ratio 4.96 [95% CI: 2.49, 10.15]; p<0.001). This is consistent with the ITT population: PFS hazard ratio 0.30 (95% CI: 0.23, 0.41); p<0.001 (median 10.1 vs 4.4 months); ORR 71% vs 31% (odds ratio 5.39 [95% CI: 3.47, 8.48]; p<0.001). Figure 1



      Conclusion:
      In plasma T790M-positive patients the clinical benefit of osimertinib was superior to platinum-pemetrexed, consistent with the ITT T790M-positive population selected by tumour tissue test. PFS with osimertinib was similar regardless of selection by tissue or plasma T790M-positive status. Based on these, and AURA Phase II data, routine biopsy testing is recommended for patients with a plasma T790M-negative test where feasible.

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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)

      Y.-. Wu

      • 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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    MA15 - Immunotherapy Prediction (ID 400)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
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      MA15.10 - Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma (ID 4885)

      Y.-. Wu

      • Abstract
      • Slides

      Background:
      Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non-small cell lung cancer (NSCLC), the factors that predict which subtype patients will be responsive to checkpoint blockade remains elusive. This study was sought to identify the potential biomarkers that predicted response to PD-1 blockade immunotherapy in lung adenocarcinoma.

      Methods:
      We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic and clinical data from cohorts of both lung adenocarcinoma public database including The Cancer Genome Atlas (TCGA), GEO repository (GSE72094) and Broad dataset, and clinical immunotherapeutic patients in our center. Gene Set Enrichment Analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups.

      Results:
      We observed distinct function of TP53 and KRAS mutation in regulating immune tumor microenvironment (TME). It is TP53 mutation but not KRAS mutation in lung adenocarcinoma that significantly increased expression of immune checkpoints, facilitated CD8+T cell infiltration and activated T-effector and interferon-γ (IFN-γ) signature. Interestingly, TP53 and KRAS co-mutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1+/CD8A+. More importantly, TP53 or KRAS mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that TP53 or KRAS mutation altered a group of genes involved in cell cycle regulating, DNA replication and damage repair. Finally, clinical immunotherapeutic data were further confirmed that TP53 or KRAS mutation lung adenocarcinoma patients, especially those with co-occurring TP53/KRAS mutations, showed remarkable clinical benefit to PD-1 blockade immunotherapy. Figure 1



      Conclusion:
      This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding PD-1 blockade immunotherapy.

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    MA16 - Novel Strategies in Targeted Therapy (ID 407)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
    • Now Available
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      MA16.06 - Phase I/II Study of AC0010, Mutant-Selective EGFR Inhibitor, in Non-Small Cell Lung Cancer (NSCLC) Patients with EGFR T790M Mutation (Now Available) (ID 5117)

      Y.-. Wu

      • Abstract
      • Presentation
      • Slides

      Background:
      AC0010 was designed specifically to inhibit EGFR active mutations and the T790M acquired resistant mutation. The purpose of the study is to determine the safety, antitumor activity and recommended phase II dose of AC0010 in T790M-postitive NSCLC patients after the first generation EGFR TKIs treatment.

      Methods:
      This is a dose escalation and expansion phase I/II study. Oral AC0010 was administered on a 28-day cycle with the starting dose at 50 mg BID. In any given dose cohort, if 1 out of 3 patients was evaluated as PR at the first cycle, and no DLT determined, up to 20 patients will be enrolled. Plasma samples were collected to evaluate pharmacokinetics of AC0010. T790M in biopsy samples was detected by a central laboratory. NCT02330367.

      Results:
      As of 10 Jul 2016, 136 patients have been treated across 7 cohorts (50, 100, 150, 200, 250, 300, and 350 mg BID). At the 30 Jun 2016 cutoff, 124 pts were evaluable. MTD has not been reached. The most common adverse events (AE) regardless of study drug relationship were diarrhea (38%), rash (26%) and ALT/AST elevation. Most AEs were grade 1 and 2. The most common Grade 3/4 drug-related AE was diarrhea (2%) rash (2%) and ALT/AST elevation (4%, 2%). All patients with AEs of the grade 3/4 were recovered after either stopped the treatment or reduced the dose. As of the cutoff date, there is no Grade 2,3 hyperglycemia, and grade 3 QTc prolongation. RECIST responses were observed at all dose levels except 50 mg BID. Amongst 124 evaluable patients in all cohorts, ORR (including unconfirmed responses) and disease control rate (DCR) was 44% and 85% respectively. In the dose cohorts between 150 mg BID and 300 mg BID (n=95 pts), the ORR and DCR were 51% and 89%. PK shows rapid absorption with a T~max~ of 2-4h and a median T1/2 of 8 h. At 300 mg BID, total 32 patients were treated and ORR and DCR are 53% and 90% respectively. Based on the efficacy, safety and PK results, the 300 mg BID was selected as RP2D. The phase II, AEGIS-1 study has started.The Phase II result will be presented.

      Conclusion:
      AC0010 shows a safe profile and antitumor activity against T790M mt NSCLC. Phase II, AEGIS-1 study is ongoing to evaluate therapeutic outcomes as a second line treatment for T790M positive NSCLC patients. Clinical trial information: NCT02330367

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    MA17 - Genetic Drivers (ID 409)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Biology/Pathology
    • Presentations: 1
    • Now Available
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      MA17.05 - Evolutionary Trajectories of Molecular Progression in Different Subtypes of Primary Lung Adenocarcinomas (Now Available) (ID 5712)

      Y.-. Wu

      • Abstract
      • Presentation
      • Slides

      Background:
      Morphological and genetic heterogeneity predict prognostics, impede continuous responses to systemic regimens and foster inevitable treatment failure. But how morphological and genetic features evolve in tumorigenesis still remains controversial.

      Methods:
      Single(n=1112) and multiple(n=91) primary adenocarcinoma patients receiving surgeries with specific prominent subtypes were screened. Six patients with mixed ground glass opacities and maximum cross-sections of primary tumors were randomly selected. Intra-tumoral regions with different subtypes and imaging densities related to relative distributions, were resected for target region sequencing and further molecular evolutionary analyses.

      Results:
      Clinical data revealed certain preferences of driver gene mutations and discrepant survival benefits. Driver gene heterogeneity was higher in multiple primary lung cancers(51.7%, 15/29) than single ones(1.4%, 1/70). Copy number alterations implied more consistence within the same subtype and tended to be higher in lepidic subtype. Somatic nucleotide variants revealed highest homogeneity between different regions within the same tumor lesion. Sequencing data indicated larger fractions of geographically ubiquitous mutations than pathologically ones, and higher mutation frequencies of shared mutations in the lepidic than acinar subtype. Phylogenetic trees exhibited higher geographically private mutation burdens of lepidic than acinar region in lesions with mixed subtypes; while in lesions with the same subtype, the central region bore higher mutation burdens than in the periphery, implying a linear accumulation of genetic mutations. Functional analyses of private mutations verified that lepidic subtypes promoted intracellular organism and structure development, promoting growth and proliferation. Acinar subtypes lead to metabolic and signaling transduction pathway. Preferences of divergent pathway alterations delineated branched evolutions from low to higher grade subtypes. Figure 1



      Conclusion:
      We propose a model that the same morphological subtype evolves with a linear accumulation and mixed subtypes in branched evolutionary trajectories with preferences to pathway alterations. Couple with relatively geological distributions of different subtypes, tumor microenvironment might contribute more to genetic instability and thus tumor evolutions.

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    OA07 - Lymph Node Metastases and Other Prognostic Factors for Local Spread (ID 376)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Surgery
    • Presentations: 1
    • Now Available
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      OA07.04 - Discussant for OA07.01, OA07.02, OA07.03 (Now Available) (ID 7075)

      Y.-. Wu

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA09 - Locally Advanced NSCLC: Innovative Treatment Strategies (ID 384)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Locally Advanced NSCLC
    • Presentations: 1
    • Now Available
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      OA09.03 - Randomized Controlled Study Comparing Adjuvant versus Neo-Adjuvant Chemotherapy  in Resectable Stage IB to IIIA NSCLC (Now Available) (ID 5843)

      Y.-. Wu

      • Abstract
      • Presentation
      • Slides

      Background:
      Adjuvant chemotherapy is the standard of care for completely resected stage II-IIIa non-small cell lung cancer (NSCLC). A few trials suggest that neoadjuvant chemotherapy is a promising strategy for resectable NSCLC. Indirect comparison meta-analysis of adjuvant versus neoadjuvant therapy showed no difference in survival. This study was conducted to determine the difference of disease-free survival(DFS) between adjuvant chemotherapy and neoadjuvant chemotherapy among patients with resectable NSCLC.

      Methods:
      Patients with clinical stage IB-IIIA NSCLC were eligible. Patients were randomly assigned to 3 cycles adjuvant DC (Docetaxel: 75mg/m2, Carboplatin:AUC=5 on day 1, every 3wk) after completely resection (lobectomy or pneomonectomy with mediastinal lymphnode dissection, or 3 cycles neoadjuvant DC at the same schedule followed by surgery 3-6 wk after chemotherapy. The primary end point was 3 years DFS; secondary end points were 3ys and 5ys Overall Survival(OS) and Safety. Planned sample size is 410. The trail was early closed because slowly accrued.

      Results:
      Between March 2006 and May 2011,198 patients from 8 Institute were randomized to neoadjuvant arm (97 cases) or adjuvant arm (101 cases). The median age was 58, male accounted for 80.3%, Adenocarcinoma 48.5%, stage Ib, II a, II b and IIIa were 32.5%, 12.2%, 28.4% and 26.9% respectively. Two arms were balanced. 100% cases received neoadjuvant chemotherapy and 87.4% finished the planned adjuvant chemotherapy. No unexpected toxicities were seen and 41.2% of patients experienced grade 3-4 neutropenia. In neoadjuvant arm, the ORR was 34% and 12.4% patients developed PD. No difference in postoperative complication was found between two arms. Survival analysis show in Table 1.Figure 1



      Conclusion:
      Adjuvant or neo-adjuvant chemotherapy with docetaxel plus carboplatin in resectable clinical stage IB-IIIA NSCLC are feasible and safe. The final results showed no difference in 3ys DFS and OS between two arms. Long term survival in Adjuvant arm show the tendency of superior to neoadjuvant arm.

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    P1.05 - Poster Session with Presenters Present (ID 457)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Early Stage NSCLC
    • Presentations: 2
    • Now Available
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      P1.05-046 - Randomized Study of Adjuvant Docetaxel vs. Observation for Completely Resected StageⅠB-Ⅲa NSCLC with 11 Years' Median Follow-Up (ID 5722)

      Y.-. Wu

      • Abstract

      Background:
      Although previous meta-analyses have verified the significance of adjuvant chemotherapy, the role of adjuvant carbopatin plus docetaxel(DC) among patients with completely resected NSCLC with long periods of follow-up remains unclear.

      Methods:
      Eligible patients were randomly assigned to 4 cycles of DC or observation after complete resection. The primary end point was DFS; secondary ones were OS, the toxicity and safety of drugs. An increase of 15% in 1-year survival rate (observation arm 70%) with a sample size of 270 patients was considered significant.

      Results:
      This trial was suspended prematurely in June 2005 due to the negative survival benefits from chemotherapy in stage IB patients in the JBR10 trial. 82 patients were enrolled between 2002 to 2005(43 and 39 in each arm).Two arms were well-balanced on age, gender, histology, smoking history and staging. Median follow-up was 11 years(10.5-13y). DFS was marginally significantly longer in DC arm than observation (10.4 vs. 3.7y; HR=0.58; 95% CI, 0.33-1.03; P=0.06), as was 5-year DFS rates(63% vs. 41%, P=0.057). No statistical significance existed in OS (NR vs. 7.1y; P=0.103) or 5-year survival rates(76% vs. 61%; P=0.148). Multivariable analysis revealed patients receiving adjuvant DC(HR=0.54,95%CI 0.30-0.96,P=0.036) and with stage IB disease(HR=0.34,95%CI, 0.19-0.61,P<0.001) bore lower recurrence risk. In DC arm, 84% of patients received at least one cycle of DC, and 53% of patients finished four. Grades 3 adverse events occurred in 5%(2/43) in chemotherapy group. The time-varying endpoints showed adjuvant DC could delay the recurrence and mortality in the first postoperative 5ys, while two arms tended to be equivalent after 5ys. Figure 1



      Conclusion:
      This is the first randomized trial used DC as adjuvant chemotherapy suggesting a potentially significant role for completely resected early stage NSCLC with safety and compliance. Additionally, at least 10ys’ follow-up for each patient was vital to investigate the long-term time-varying recurrence and mortality pattern.

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      P1.05-072 - Predictors and Patterns of Lymph Node Metastasis in Small Peripheral Non Small Cell Lung Cancer (Now Available) (ID 4268)

      Y.-. Wu

      • Abstract
      • Slides

      Background:
      Lobectomy is the standard treatment of early stage non-small cell lung cancer (NSCLC) and wheather sublobar resection is appropriate for small peripheral small NSCLC or not is unclear. PET-CT is a powerful imaging modality for the detection of lymph node metastasis with a relatively low false-negative rate. We identified predictors and patterns to identify false-negative N(+) disease in PET-CT.

      Methods:
      A total of 435 consecutive cN0 peripheral NSCLC underwent curative-intent resections following PET-CT scans from January 2008 to December 2014 in our hospital, we analysed patients’ clinicopathological data retrospectively. 171 patients with tumour size≤2cm were enrolled to identify predictors and patterns of lymph node metastases by multivariable analysis. The cut‑off values, sensitivity and specificity for the predictors were calculated using a receiver operating characteristic curve. The patterns of lymph node metastases were also analysed.

      Results:
      In total, 9.4% (16/171) PET-CT-diagnosed N0 NSCLC cases were pathologically N1/N2 disease. The preoperative CEA was a unique independent risk factor for lymph node metastasis (OR = 0.914, 95 CI% = 0.85–0.98, P = 0.009). According to ROC curve, we divided the patients into two groups by CEA: the N(+) rates in the CEA ≤1.67 and CEA> 1.67 groups were 1.6% (1/64) and 14.0% (15/107), respectively (P =0.007). In 16 patients with lymph node metastasis, 7 were N1 disease, and 6 out of 9 N2 diseases were skip N2 disease. 93.5%(15/16) lymph node metastases were found in adenocarcinoma and 11 of them were single station metastases. The metastases rates in solid and subsolid lesions were 12.8%(16/125) and 0%(0/46)(P=0.007), retrospectively. Solid/mucinous/ micropapillary predominant adenocarcinoma were associated with LN metastases(31.2% vs 7.1%, P=0.01).

      Conclusion:
      The preoperative CEA was an independent risk factor for lymph node metastases in cN0 NSCLC with T ≤ 2cm. In patients with CEA>1.67, sublobar resection should be avoided before thorough lymph node sampling that include intrapulmonary lymph node while patients with CEA ≤ 1.67 may be candidate for sublobar resection, especially in GGO lesions. In patients with solid/mucinous/ micropapillary predominant adenocarcinoma, sublobar resection should be avoided due to high LN metastases rate.

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    P1.07 - Poster Session with Presenters Present (ID 459)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
    • Now Available
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      P1.07-038 - Typical Morphological Features Revealed Unfavorable Survival Benefits in High-Grade Neuroendocrine Carcinomas (Now Available) (ID 5718)

      Y.-. Wu

      • Abstract
      • Slides

      Background:
      The 2015 WHO classification of lung cancer has proposed an revision about high-grade neuroendocrine carcinomas(HGNEC). Neuroendocrine(NE) markers are necessary for differentiations in cases lacing in typically morphological features, but their roles in survival benefits remain unclear.

      Methods:
      A total of 700 consecutive patients diagnosed with pNET were re-diagnosed during 2008 to 2015 and 632 were HGNECs. NE markers, such as Syn(synaptophysin), CgA(chromogranin A) and CD56, were stained by immunohistochemistry(IHC) if morphological features were not enough for diagnoses.

      Results:
      Four were excluded due to clinical identification of transformation from adenocarcinomas to SCLC. Nine HGNECs were previously diagnosed with AC. TTF1 stained 77.4%(459/593) HGNEC patients, of which 50.6% in LCNEC, 80.9% in SCLC and 62.5% in poorly differentiated HGNEC(P<0.001). Syn staining(94.1%, 571/607) were not statistically significant in three groups(89.1% vs. 94.6% vs. 100.0%, respectively; P=0.30). The same situation was in CgA(52.6%, 319/607), with a frequency of positive staining as 46.9%, 53.6% and 25.0%(P=0.26), respectively in three diagnoses. The number of positive NE markers were generally balanced(P=0.62). Cases with zero to three positive NE markers indicated marginal significant differences of overall survival(OS)(P=0.05). Meanwhile, no differences of mOS existed in positive and negative staining of Syn(14.7 vs. 32.53 mons, P=0.14) or CgA(14.6 vs. 15.9 mons, P=0.82); but patients with typical morphological features for diagnose and thus without IHC staining Syn or CgA (mOS, 9.13mons) bore significantly poorest OS benefits than those with positive(Syn, HR=2.71, 95%CI=1.24-5.86, P=0.01; CgA, HR=2.72, 95%CI=1.25-5.92, P=0.01) or negative(Syn, HR=3.44, 95%CI=1.39-8.52, P<0.01; CgA, HR=2.76, 95%CI=1.26-6.05, P=0.01) staining. The same condition occurred especially inⅠto Ⅲa patients(P<0.01). Figure 1



      Conclusion:
      The number of positive NE markers were necessary for precise diagnoses but not significant for survival benefits. Typical morphological features of NE tumor cells were unfavorable factors for OS. Further studies are imperative to identify its crucial role in HGNEC patients.

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

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 3
    • 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)

      Y.-. Wu

      • 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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      P2.03b-041 - Cerebrospinal Fluid Tumor Cells for Diagnosis of Leptomeningeal Metastases in Non-Small Cell Lung Cancer (Now Available) (ID 4479)

      Y.-. Wu

      • Abstract
      • Slides

      Background:
      The diagnosis of leptomeningeal metastases (LM) relied on tumor cells found in cerebrospinal fluid (CSF) and/or typical magnetic resonance imaging (MRI) findings, but both lack sensitivity. The CellSearch Assay™ had been validated to detect CTCs for follow-ups of cancer patients, and we adapted it to identify CSF tumor cells (CSFTCs) in non-small cell lung cancer (NSCLC) with suspected LM, and moreover detected their gene statuses of epidermal growth factor receptor (EGFR).

      Methods:
      Twenty-one NSCLC patients with suspicious LM had CSF analyzed through both traditional Thinprep cytologic test (TCT) and CellSearch, and peripheral blood were detected for circulating tumor cells (CTCs) in fourteen patients. The statuses of EGFR were tested in primary tissues of all twenty-one patients and in CSFTCs of eight patients.

      Results:
      All twenty-one patients were identified as LM, CSFTCs were captured by CellSearch in twenty patients (median 969 CSFTCs/ 7.5 mL, range: 27-14888), while CTCs were captured in only five patients (median 2 CTCs/7.5 mL, range: 2-4), which were much lower than CSFTCs. The sensitivity of CellSearch was 95.2%, while that of TCT from the same CSF puncture was 57.1%, and that of MRI was 52.4%, and that of combined MRI and TCT was 90.5%. Moreover, the specificity of CSFTCs was 100%. Among eight patients with EGFR tested in CSFTCs, six patients matched with primary tissues and resistant gene T790M was identified in two cases.Figure 1



      Conclusion:
      Cerebrospinal fluid tumor cells could be more sensitive and effective to diagnose LM, and may serve as the potential way of liquid biopsy for EGFR mutation in NSCLC with LM.

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      P2.03b-043 - Peripheral Blood CD45RA+ CCR7+ Naive T Cells Were Correlated with Prognosis in Non-Small Cell Lung Cancer Patients (Now Available) (ID 5999)

      Y.-. Wu

      • Abstract
      • Slides

      Background:
      CD45RA+ CCR7+ naive T cells were reported to generate effectors possessed the high potent cytotoxic activity and low level of "exhaustion" T cells in vitro. However the relationship between frequency of naïve T cells in peripheral blood and prognosis in non-small cell lung cancer (NSCLC) is not clear. In order to elucidate this relationship, we first analyzed the frequency of CD45RA+ CCR7+ naïve T cell in peripheral blood of healthy population and patients with NSCLC.

      Methods:
      The frequency of CD45RA+ CCR7+ naïve T cells was calculated by flow cytometry from healthy volunteers and NSCLC patients. The correlation of naive T cell frequency and overall survival (OS) of NSCLC patients who were treated with tyrosine kinase inhibitors (TKIs) or chemotherapy was statistically analyzed.

      Results:
      105 healthy volunteers (age rank 23-85year-old) and 137 NSCLC patients (age rank 33-86year-old) were enrolled in our study from 2013 October 1st to 2015 December 1st. Our results showed that the frequency of peripheral blood naïve T cells in NSCLC patients’ (Mean=17.8±5.7%) was significantly lower than that in healthy subjects’ (Mean=31.2±5.2%) (p<0.05). The frequency of naïve T cell was negatively correlated with the frequency of PD-1+CD8+ T cells (R[2]=0.1111, p<0.001) in peripheral blood of NSCLC patients, whereas, which was positively associated with the immune activity of CD8+ T cells and with the frequency of lymphoid stem cells or lymphoid progenitor cells in peripheral bloods (R[2]=0.1521, p<0.001). In the patients who were treated with TKIs,mOS in the group of high frequency of naïve T cells (>17.8%) was not reached, while that of group with low frequency (17.8%) was 19.0m (HR=0.3057, 95% CI 0.1127- 0.8291, p=0.0199). In patients who were administered chemotherapy, the mOS in the naïve T cells low frequency group was 12.0m, but in the high frequency group the median OS was undefined (HR=0.3286, 95% CI 0.1100 0.9817, p=0.0463).

      Conclusion:
      Our study shows that the CD45RA+ CCR7+ naïve T cells in peripheral blood closely related with immune response, and the frequency of naïve T cells in peripheral blood is positively associated with prognosis of NSCLC, which can be worked as a valuable prognostic factor for NSCLC patients.

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    P2.06 - Poster Session with Presenters Present (ID 467)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
    • Presentations: 1
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      P2.06-020 - A Open-Label Randomised Controlled Trial of First-Line Genexol-PM/ CrEL-Based Paclitaxel plus Cisplatin in Advanced NSCLC Patients (ID 4569)

      Y.-. Wu

      • Abstract

      Background:
      Genexol-PM is a novel Cremophor EL(CrEL)-free polymeric micelle formation of paclitaxel.This multicentre study was designed to compare Genexol-PM and CrEL-based paclitaxel in combination with cisplatin in terms of efficacy and safety as first-line therapy in advanced non-small cell lung cancer.

      Methods:
      Chemonaive patients aged from 18 to 70 years with histologically or cytologically confirmed, locally advanced, metastatic or recurrent advanced NSCLC and an ECOG performance status of 0–1 were randomised 2:1 to the treatment group (Genexol-PM+ cisplatin ) and the controll group (paclitaxel+cisplatin) .Patients were treated with Genexol-PM 230mg/m2 intravenously without premedication or paclitaxel 175mg/m2 intravenously with premedication plus cisplatin 70mg/m2 on day 1 of a 3-week cycle for up to six cycles. Intrapatient dose escalation of Genexol-PM to 300mg/m2 was carried out in treatment group from the second cycle if the prespecified toxic effects were not observed after the first cycle.

      Results:
      170 patients were randomised into the study. PFS and OS data are not yet mature.

      Conclusion:
      This multicentre study is in progress.

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    P3.02a - Poster Session with Presenters Present (ID 470)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 4
    • Now Available
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      P3.02a-012 - Patient-Reported Symptoms and Quality of Life (QoL) in East Asian Patients with ALK+ NSCLC Treated with Crizotinib vs Chemotherapy (Now Available) (ID 5170)

      Y.-. Wu

      • Abstract
      • Slides

      Background:
      The phase 3 study PROFILE 1014 showed a superior outcome of crizotinib over pemetrexed-cisplatin/carboplatin (PCC) in ALK+ NSCLC.[1] PROFILE 1029 is an ongoing phase 3 study of similar design (NCT01639001) conducted in an East Asian population in China, Hong Kong, Malaysia, Taiwan, and Thailand. Here, we present findings on patient-reported symptoms and QoL.

      Methods:
      Patients with previously untreated, ALK+ advanced NSCLC were randomized 1:1 (stratification: ECOG PS 0 or 1 vs 2) to crizotinib 250 mg PO BID or pemetrexed 500 mg/m[2] with cisplatin 75 mg/m[2] or carboplatin to an AUC of 5–6 mg·min/mL, IV Q3W for ≤6 cycles. The EORTC QLQ-C30 and lung cancer-specific module (QLQ-LC13) questionnaires were completed at baseline, days 1, 7, and 15 of Cycle 1, day 1 of each subsequent cycle, and at end-of-treatment or withdrawal. Mixed model analyses were used to evaluate changes from baseline and between treatment arms.

      Results:
      Patients, who received crizotinib (n=103) had significantly longer median time to deterioration (TTD) for chest pain, dyspnea, or cough compared to PCC (n=98) (2.8 mo [95% CI: 1.4, 6.9] vs 0.3 mo [95% CI: 0.3, 0.5], respectively; HR=0.432 [95% CI: 0.307, 0.610]; P<0.0001). Crizotinib treatment, compared to PCC, was associated with a significantly greater change from baseline in global QoL and physical, role, cognitive, and social functioning (Table). QLQ-C30 results demonstrated that crizotinib-treated patients experienced either improvement or reduced worsening of most symptoms compared to PCC-treated patients. QLQ-LC13 data showed improvement or reduced worsening across all symptoms for crizotinib, relative to PCC. Figure 1



      Conclusion:
      Crizotinib treatment significantly delayed TTD of lung cancer symptoms (chest pain, cough, dyspnea). Crizotinib was associated with significantly greater improvements from baseline in key patient-reported lung cancer symptoms and global QoL, compared with PCC. Reference: 1. Solomon BJ, et al. J Clin Oncol. 2016 [Epub ahead of print].

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      P3.02a-014 - Patient Reported General Health Status in a Study of Crizotinib Versus Chemotherapy in Patients With Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 5169)

      Y.-. Wu

      • Abstract
      • Slides

      Background:
      Patients with advanced NSCLC typically experience symptoms compromising their quality of life (QoL), making this an important therapeutic goal. PROFILE 1029 (NCT01639001) is an ongoing open-label, Phase 3 study in East Asian patients with previously untreated, ALK+ advanced NSCLC in China, Hong Kong, Malaysia, Taiwan, and Thailand. Patient-reported health status outcomes are presented.

      Methods:
      Patients were randomized 1:1 (stratification: ECOG PS 0 or 1, 2) to crizotinib 250 mg PO BID or pemetrexed 500 mg/m[2] IV with either cisplatin 75 mg/m[2] or carboplatin (PCC) to achieve an AUC of 5–6 mg·min/mL, IV q3w for ≤6 cycles. Health status assessed using the EuroQoL 5D (EQ-5D) was a secondary endpoint of the study. The EQ-5D, consisting of a visual analogue scale (VAS) score ranging from 0 (worst imaginable health state) to 100 (best imaginable health state) and a descriptive measure (no, some or extreme) of problems in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, was to be completed at baseline and on day 1 of each cycle until treatment termination or withdrawal. The data were analyzed using a mixed model analysis.

      Results:
      The proportion of patients completing at least one question on the EQ-5D questionnaire ranged from 97.6% to 100% for crizotinib-treated patients over 42 cycles of treatment and from 98.0% to 100% for PCC-treated patients over a maximum of 6 cycles of treatment. The estimated overall change from baseline in the EQ-5D VAS was 3.4209 (95% confidence interval [CI]:1.20, 5.64) for crizotinib and ‑0.4927 (95% CI: -2.75, 1.77) for PCC. The difference between crizotinib and PCC was 3.9136 (95% CI: 0.85, 6.98; P<0.05). The estimated overall change from baseline in the EQ-5D utility score was 0.0502 (95% CI: 0.02, 0.08) for crizotinib and 0.0077 (95% CI: -0.02, 0.04) for PCC. The difference in utility score changes for crizotinib versus PCC was 0.0425 (95% CI: 0.00, 0.08; P<0.05). End of treatment descriptive results showed no deterioration from baseline across most EQ-5D dimensions.

      Conclusion:
      A statistically significantly (p-value <0.05) greater improvement from baseline in general health status, as assessed by the EQ-5D VAS and utility scores, was observed for crizotinib-treated patients compared with PCC-treated patients.

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      P3.02a-020 - Clinical Failure to Crizotinib in Patients with Anaplastic Lymphoma Kinase-Positive Advanced Non-Small-Cell Lung Cancers (Now Available) (ID 4523)

      Y.-. Wu

      • Abstract
      • Slides

      Background:
      Crizotinib, as the standard treatment for use in first-line treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC), showed superiority over platinum-based chemotherapy in advanced ALK-positive lung adenocarcinoma.Undoubtedly, the resistance to crizotinib is a current bottleneck which limits its clinical application. However, there are few reports about clinical failure to crizotinib, especially the correlation between the failure patterns of crizotinib and survival benefit.

      Methods:
      Totally,171 ALK-positive NSCLC patients treated with crizotinib were reviewed at the Guangdong General Hospital in China from October 2010 to July 2016.The status of ALK rearrangement was assessed by Lysis ALK Break Apart fluorescence in situ hybridization,reverse transcription polymerase chain reaction, or Ventana ALK immunohistochemistry.Chi-square test and Kapla-Meier survival curve were used to analyze the results statistically.

      Results:
      Among enrolled patients,47.5%(81/171) gained secondary resistance,10.5%(18/171) had primary resistance and 4 patients stopped taking crizotinib because of the occurrence of unacceptable toxicities including anasarca,ventricular tachycardia and hepatic insufficiency. Moreover,49 patients had no progression,in which 2 patients had taken crizotinib more than 5 years uninterruptedly.In the patients with secondary resistance (n=81),46 were male and 63 were never smokers.Brain metastases occurred in 27.1%(22/81) at the baseline,half of which(11/22) still had brain progression after the treatment of crizotinib.On the contrary,21 patients without brain metastases at the baseline were evaluated at disease progression because of brain metastases.We classified patients with secondary resistance into several categories according to the failure patterns of crizotinib, such as dramatic,gradual and local progression.There were 47(58.0%), 2(2.5%) and 32(39.5%) patients for dramatic, gradual and local progression respectively.The patients with dramatic progression had an inferior progression-free survival with crizotinib to those with gradual and local progression (9.8 vs 11.9 months),which did not achieve statistical significance.The post progression survival(PPS) of dramatic progression group is 10.4 months.The PPS of other group is 20.5 months comparatively.Patients with dramatic progression showed shorter overall survival when compared with other patients (26.7 vs 41.0 months, P=0.042).

      Conclusion:
      Dramatic progression was prevalent in ALK-positive lung adenocarcinoma beyond failure to crizotinib, and predicted poor overall survival.

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      P3.02a-025 - PROs With Ceritinib Versus Chemotherapy in Patients With Previously Untreated ALK-rearranged Nonsquamous NSCLC (ASCEND-4) (ID 5128)

      Y.-. Wu

      • Abstract

      Background:
      Here, we present the patient-reported outcomes (PROs) of ceritinib versus chemotherapy as first-line treatment for advanced ALK+ NSCLC.

      Methods:
      Untreated, ALK+, advanced, nonsquamous NSCLC patients (N=376) were randomized (1:1) to ceritinib 750 mg/day (n=189) or chemotherapy (n=187; [pemetrexed 500 mg/m[2 ]plus cisplatin 75 mg/m[2] or carboplatin AUC 5-6] for 4 cycles followed by maintenance pemetrexed). PROs were assessed using EORTC quality-of-life questionnaire (QLQ-C30), the lung cancer module (QLQ-LC13), Lung Cancer Symptom Scale (LCSS), and EQ-5D.

      Results:
      Median treatment exposure was 66.4 weeks for ceritinib and 26.9 weeks for chemotherapy. PRO compliance was high, ≥80% at most timepoints. Ceritinib significantly prolonged time to deterioration of lung cancer-specific symptoms (pain, dyspnea, and cough) versus chemotherapy in both LCSS and QLQ-LC13 instruments (composite endpoints for LCSS, HR=0.61 [0.41, 0.90]; and QLQ-LC13, HR=0.48 [0.34, 0.69]). Time to deterioration in LC13 questionnaire was significantly longer with ceritinib versus chemotherapy (23.6 [20.7, NE] vs 12.6 [8.9, 14.9] months) (Table). In the QLQ-C30 instrument, 4 of 5 functional domains and 6 of 9 symptom scales improved with ceritinib (P< 0.05); 2 scales related to gastrointestinal symptoms indicated deterioration for ceritinib. In agreement with most other scales showing symptom improvement, ceritinib demonstrated significant improvements in Global Health Status/QoL in the same instrument (QLQ-C30, P<0.001) as well as for EQ-5D-5L index (P<0.001) and EQ-5D-5L VAS (P<0.05 from cycle 13 until 49). Figure 1



      Conclusion:
      Untreated ALK+ NSCLC patients experienced significantly greater improvements in lung cancer-specific symptoms on treatment with ceritinib. General health status was significantly improved with ceritinib versus chemotherapy. Overall, PRO results from all 4 instruments independently showed improvements highlighting the consistency and robustness of these findings.

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    P3.02b - Poster Session with Presenters Present (ID 494)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 5
    • Now Available
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      P3.02b-016 - An Exploration Study of Mechanisms Underlying Primary Resistance to EGFR-TKIs in Patients Harboring TKI-Sensitive EGFR Mutations (Now Available) (ID 4280)

      Y.-. Wu

      • Abstract
      • Slides

      Background:
      Primary resistance to EGFR-TKIs was generally defined as disease progression in less than 3 months without any evidence of objective response. Although possible mechanisms have been investigated in several preclinical and retrospective studies, little is known about the molecular backgrounds of primary resistance.

      Methods:
      Random Sample of Cases was used to screen TKI-sensitive patients to match with the primary resistant patients on the basis of clinical characteristics (smoking history, EGFR mutations etc.). DNA was extracted from the tumor and their matched normal material. The paired-end whole exome sequencing (WES) of DNA was performed on the Illumina HiSeq 2500 sequencing platform.

      Results:
      Totally, five patients exhibiting primary resistance to EGFR-TKIs were enrolled and each was randomly matched with one patient possessing TKI sensitivity (Table1). The mean depth of the WES was 100x. The mean number of nonsynonymous SNV per sample was 195 (range 97 to 348) in TKI-resistant group versus 84 (range 60 to 101) in TKI-sensitive group (P=0.059). Consistent with the initial result of Sanger sequencing, all 10 patients were found with EGFR sensitizing mutations (exon 19 deletions or L858R point mutation in exon 21), but no T790M mutation; the resistance group present with a lower EGFR mutant allele frequency than the sensitive group. Next generation sequencing of TKI-resistant specimens detected KRAS amplification (CN~tumor ~/ CN~normal ~= 2.6) in one of five patients, and MET amplification (CN~tumor ~/ CN~normal ~= 2.3) in another one. The recurrent mutation genes included FAT4, RBM10, TANC2, ACAN, PPFIA2, UBR4, XIRP2 and PRAMEF1. Figure 1



      Conclusion:
      Next-generation sequencing offers more complete genomic analysis to understand the mechanism of differential responses to EGFR-TKIs, which can lead to more precision therapy. KRAS amplification appears to be a newly mechanism underlying primary resistance to EGFR-TKIs in patients harboring TKI-sensitive EGFR mutations. However, it needs to be validated in a larger cohort.

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      P3.02b-059 - The Role of Epidermal Growth Factor Receptor in the Onset of Skeletal Related Events in Non-Small Cell Lung Cancer (Now Available) (ID 6042)

      Y.-. Wu

      • Abstract
      • Slides

      Background:
      Bone metastasis is frequent in non-small cell lung cancer (NSCLC) patients, and subsequent skeletal related events (SREs) adversely deteriorate life quality and survival. Patients harboring sensitive epidermal growth factor receptor (EGFR) mutation experience a prolonged life expectancy. However, it is unclear whether survival enhancement in NSCLC patients with sensitive EGFR mutation may encounter an increase in the onset of SREs or not. Also, it is still unknown whether time to SREs is impacted by EGFR mutation status. In this study, we evaluated the impact of EGFR mutation status and other clinic-pathological variables on the incidence of SREs and on survival outcomes of SREs in stage IV NSCLC patients.

      Methods:
      We conducted a retrospective study of medical records from patients who were diagnosed stage IV NSCLC in a single institute. EGFR mutation status, and other clinical-pathological variables, bone metastasis outcomes and survival data were collected and statistically analyzed.

      Results:
      410 patients with evident bone metastasis were enrolled in the study. 49.0% patients were detected with sensitive EGFR mutation, and 29.0% were prophylactically administered bisphosphonate. 42.7% experienced at least one SRE, the most common type of which was palliative radiotherapy. Patient harboring sensitive EGFR mutation hold a lower incidence of SREs than patients who were detected with wild type EGFR (37.3% vs 47.8%, p=0.031), and patients who received bisphosphonate confronted a lower incidence of SRE comparing with patients who didn’t receive bisphosphonate prophylactically (36.1% vs 45.4%, p=0.087). Median time from bone metastasis to first SRE was two months longer in patients with EGFR mutation, comparing to patients with wild type EGFR, with a marginal significance (5.0m vs 3.0m, p=0.08). The administration of bisphosphonate delayed the median time to first SRE for 5 months (7.0m vs 2.0m, p=0.037). In multivariate analysis using a Cox proportion model, wild type EGFR (HR=1.559, 95%CI 1.081-2.249), multiple bone lesions (HR= 1.991, 95%CI 1.217-3.258), mixed type bone lesions (HR=2.144, 95%CI 1.085-4.238) were independent risk factors of survival post first SRE, while a smoking history (HR=1.428, p=0.053) was shown marginally significant with an impaired survival post first SRE.

      Conclusion:
      This retrospective study shows that EGFR mutation has a propensity to impact the onset of SRE and prolong survival post first SRE in patients with stage IV NSCLC. For patients with higher risks to experience SREs, bisphosphonate is an alternative to impede the process.

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      P3.02b-095 - Tracing Spatiotemporal T790M Heterogeneity in Patients with EGFR-Mutant Advanced NSCLC after Acquired Resistance to EGFR TKIs (Now Available) (ID 6057)

      Y.-. Wu

      • Abstract
      • Slides

      Background:
      With the marketing of osimertinib, epidermal growth factor receptor (EGFR) T790M mutation has become a clinically significant biomarker for advanced EGFR-mutant non-small-cell lung cancer (NSCLC) after acquired resistance to previous EGFR TKIs. However, T790M status might vary spatiotemporally and consequently hinder the initiation and clinical efficacy of third generation EGFR TKIs. Till now, the spatiotemporal traces of T790M under treatment pressure have not been fully elucidated.

      Methods:
      We retrospectively reviewed T790M status and clinical courses of 93 patients who underwent multiple (≥2) rebiopsies after acquired resistance to first or second generation EGFR TKIs from 2010 to 2015 in Guangdong General Hospital. Patients underwent synchronous rebiopsies at the same lesion or paired tissue and plasma rebiopsies were enrolled to evaluate the spatial T790M heterogeneity. Patients received heterochronous rebiopsies at the same lesion or different lesions were enrolled to evaluate the temporal and spatiotemporal T790M heterogeneity respectively.Tissue EGFR detection was performed by SNAPSHOT or Amplification Refractory Mutation System (ARMS). Plasma EGFR was detected by ARMS.

      Results:
      A total of 99 evaluations were performed with 6 of 93 enrolled patients underwent both synchronous and heterochronous rebiopsies. Among 20 patients who underwent synchronous rebiopsies at the same lesion, 13 revealed T790M heterogeneity. Among 17 patients who had paired tissue and plasma rebiopsies, 8 showed T790M heterogeneity. Spatial T790M heterogeneity ratio was 57% (21/37) in general. 33% (10/30) patients who received heterochronous rebiopsies at the same lesion revealed temporal T790M heterogeneity. Spatiotemporal T790M heterogeneity was observed in 53% (17/32) of patients who received heterochronous multiple sites rebiopsies. Of abovementioned patients with heterochronous T790M heterogeneity, T790M status in 67% (18/27) switched from negative to positive after chemotherapy or continuation of EGFR TKIs and in 33% (9/27) switched from positive to negative after chemotherapy or combined regimens of chemotherapy and EGFR TKIs.

      Conclusion:
      T790M status could vary spatiotemporally at a ratio of 33-57% in patients with acquired resistance to previous EGFR TKIs. Repeated rebiopsies both at the same lesion and various lesions might be valued particularly in T790M-negative cases in this subset of patients.

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      P3.02b-096 - Osimertinib (AZD9291) in Asia-Pacific Patients with T790M Mutation-Positive Advanced NSCLC: Open-Label Phase II Study Results (ID 4282)

      Y.-. Wu

      • Abstract

      Background:
      Osimertinib (AZD9291) is an oral, potent, irreversible EGFR-TKI, selective for both EGFR-sensitizing (EGFRm) and T790M resistance mutations. Following positive outcomes from recent Phase I and II trials, osimertinib is now recommended for patients with EGFR T790M mutation-positive advanced non-small cell lung cancer (aNSCLC).

      Methods:
      AURA17 (NCT02442349) is an open-label, single arm, Phase II study investigating the efficacy and safety of osimertinib in an Asia-Pacific patient population with EGFRm T790M mutation-positive locally advanced or metastatic NSCLC, who had progressed following EGFR-TKI therapy or EGFR-TKI and chemotherapy. T790M-positive status was confirmed via central testing of biopsy samples using the cobas[®] EGFR Mutation Test. Inclusion required measureable disease, performance status (PS) 0/1, and acceptable organ function; asymptomatic brain metastases were allowed. Patients received osimertinib 80 mg once daily until disease progression. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 (by blinded independent central review, BICR). Secondary objectives included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival, and safety and tolerability.

      Results:
      As of 4 March 2016 data cut-off, 171 patients were enrolled, with 166 evaluable for response: median age, 60.0 years; female, 69%; Asian, 98%; never smokers, 78%; PS 0/1, 15%/85%; EGFR Exon 19 and L858R mutations, 64% and 34% patients, respectively; second-/≥third-line, 32%/68%; median treatment exposure, 5.6 months. Confirmed ORR and DCR (95% CI) by BICR were 60% (52, 68) and 88% (82, 92), respectively. DoR and PFS are not calculable as data is immature. Causally-related adverse events (AEs) grade ≥3 were reported in eight (5%) patients. AEs leading to dose interruption or dose reduction occurred in seven (4%) and two (1%) patients, respectively. Six (4%) patients discontinued treatment due to AEs, two (1%) causally-related AEs as assessed by investigator. The most commonly reported AEs (%, [grade ≥3]) were diarrhoea (29%, [0]), rashes and acnes (grouped terms) (20%, [0]), and dry skin (grouped terms) (17%, [1%]). Interstitial lung disease-like events were reported in three (2%) patients.

      Conclusion:
      AURA17 demonstrated clinical efficacy of osimertinib in Asia-Pacific patients with EGFR T790M mutation-positive aNSCLC, with an ORR of 60% and DCR of 88% that are comparable to global Phase II trials. Osimertinib was well tolerated, with a low frequency of AEs grade ≥3. No new safety signals were seen and the pattern of AEs was consistent with global studies

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      P3.02b-116 - Molecular Mechanism of Transformation from Adenocarcinoma to Small-Cell Lung Cancer after EGFR-TKI (Now Available) (ID 4983)

      Y.-. Wu

      • Abstract
      • Slides

      Background:
      In patients with advanced non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutations, EGFR-tyrosine kinase inhibitors (TKIs) are recommended as first-line treatment due to favorable clinical efficacy. However, acquired resistance inevitably develops after median progression-free survival (PFS) of 9-14 months. Among the mechanisms of acquired resistance, small-cell lung cancer (SCLC) transformation was reported to account for nearly 5%. However, the molecular details underlying this histological change and resistance to EGFR-TKI therapy remain unclear.

      Methods:
      15 out of 233 (6.4%) patients were confirmed to develop SCLC transformation after failure to EGFR-TKI. We analyzed the clinical parameters of these patients by using chi-square test and Kaplan-Meier analysis. To explore gene alterations that might contribute to SCLC transformation, next generation sequencing (NGS) was performed on four pairs of matched pre- and post-transformation tumor tissue samples. We further performed NGS on 11 matched circulating tumor DNA (ctDNA) to explore the potential mechanism of resistance to EGFR-TKI.

      Results:
      The median age of SCLC transformed patients was 53 years. 93.3% (14/15) patients harbored EGFR exon19 deletion. The median PFS and overall survival (OS) of SCLC-transformed patients treated with EGFR-TKI compared to those without transformation were 11.7 versus 11.9 months (P=0.473) and 29.4 versus 24.3 months (P=0.664), respectively. All 4 patients developed loss of heterozygosity of TP53/RB1 after transformation. Besides, increased copy number of five proto-oncogenes were identified in post-transformation tissue samples. Three patients developed EGFR T790M mutation in the post-transformation ctDNA rather than their tissue samples.

      Conclusion:
      SCLC transformation was commonly seen in patients harboring EGFR exon 19 deletion. The clinical outcomes of TKI and OS in SCLC transformed patients were similar to non-transformed patients. The loss of heterozygosity of TP53 and RB1 along with increased copy number of proto-oncogenes may lead to the SCLC transformation. The mechanisms of acquired resistance to TKI during SCLC transformation might be the emergence of classic drug resistance mutations, which was undetectable due to the intra-tumor heterogeneity.

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    P3.02c - Poster Session with Presenters Present (ID 472)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      P3.02c-060 - Dual Positive PD-L1 and CD8+ TIL Represents a Predominant Subtype in NSCLC and Correlates with Augmented Immunogenicity (Now Available) (ID 4502)

      Y.-. Wu

      • Abstract
      • Slides

      Background:
      Recent studies have identified that the degree of tumor infiltrating lymphocyte (TIL) infiltration and PD-L1 expression in the tumor microenvironment (TME) are significantly correlated with the clinical outcomes of anti-PD-1/PD-L1 therapies. Here we conducted this study to verify the distribution of PD-L1/CD8[+] TIL expression and its clinical significance in non-small cell carcinoma (NSCLC). Potential mechanism predicted for PD-1 blockade was explored in depth as well.

      Methods:
      Immunohistochemistry was performed to detect PD-L1 and CD8 expression in NSCLC. The Kaplan–Meier (KM) survival curve was used to estimate disease free survival (DFS) and overall survival (OS). Gene Set Enrichment Analysis (GSEA) was used to determine potentially relevant gene expression signatures.

      Results:
      288 cases with stage I-IIIA NSCLC were evaluated for PD-L1 and CD8+ TIL staining. Dual positive PD-L1 and CD8 (PD-L1+/CD8+) represents a predominant subtype in NSCLC, accounting for 36.5% (105/288), followed by PD-L1-/CD8- (24.3%, 70/288), PD-L1-/CD8+ (26.0%, 75/288) and PD-L1+/CD8- (13.2%, 38/288). Survival analysis of DFS (p=0.031) and OS (p=0.002) showed a significant difference between four subgroups. Furthermore, we analyzed the correlation between expression types of PDL1/CD8 and mutation burden and angtigen presentation. We can identified dual positive PD-L1 and CD8 was significant with increased mutation burden (p<0.001), high frequency of mismatch repair (MMR) related gene mutation. More interestingly, tumor with dual positive PD-L1 and CD8 manifested a remarkable activated angtigen presentation and T cell receptor signature compared with other subgroups. Figure 1



      Conclusion:
      Dual positive PD-L1 and CD8 was identified as a predominant subtype in NSCLC and correlates with increased immunogenicity. These findings provide the evidence that combined analysis of PD-L1 and CD8 in NSCLC may be a promising way to predict PD-1 blockade immunotherapy.

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    PL03 - Presidential Symposium (ID 428)

    • Event: WCLC 2016
    • Type: Plenary
    • Track:
    • Presentations: 3
    • Now Available
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      PL03.03 - Randomised Phase III Study of Osimertinib vs Platinum-Pemetrexed for EGFR T790M-Positive Advanced NSCLC (AURA3) (Abstract under Embargo until December 6, 7:00 CET) (Now Available) (ID 4452)

      Y.-. Wu

      • Abstract
      • Presentation
      • Slides

      Background:
      Osimertinib is a potent, irreversible, CNS active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for sensitising (EGFRm) and T790M resistance mutations. Osimertinib is indicated for the treatment of patients with locally advanced or metastatic EGFR T790M-positive NSCLC. AURA3 (NCT02151981) is a Phase III, open-label, randomised study assessing the efficacy and safety of osimertinib versus platinum-based chemotherapy plus pemetrexed in patients with EGFR T790M-positive advanced NSCLC, whose tumours progressed on first-line EGFR-TKI therapy.

      Methods:
      Eligible patients were ≥18 years with documented EGFRm, radiological disease progression following first-line EGFR-TKI and centrally confirmed T790M-positive (by cobas® EGFR Mutation Test) from a tissue biopsy after disease progression. Asymptomatic, stable CNS metastases were allowed. Patients were randomised 2:1 to osimertinib 80 mg orally, once daily or platinum-pemetrexed (pemetrexed 500 mg/m[2] plus either cisplatin 75 mg/m[2] or carboplatin AUC5) every three weeks for up to six cycles; pemetrexed could be continued as maintenance treatment. Primary endpoint was progression-free survival (PFS) by investigator assessment according to RECIST v1.1; sensitivity analysis was by blinded independent central review (BICR).

      Results:
      A total of 419 patients were randomised to treatment (osimertinib, n=279; platinum-pemetrexed, n=140). Baseline characteristics were generally balanced across treatment groups: female 64%, Asian 65%, never smoker 68%, CNS metastases 34%, EGFR exon 19 deletion 66%. Osimertinib significantly improved PFS compared with platinum-pemetrexed: hazard ratio [HR] 0.30; 95% CI: 0.23, 0.41; p<0.001 (median 10.1 months vs 4.4 months). The result was consistent with PFS analysis by BICR: HR 0.28; 95% CI: 0.20, 0.38; p<0.001 (11.0 months vs 4.2 months). Objective response rate was significantly improved with osimertinib (71%) vs platinum-pemetrexed (31%); odds ratio 5.39 (95% CI: 3.47, 8.48; p<0.001). Median duration of response was 9.7 months (95% CI 8.3, 11.6) with osimertinib and 4.1 months (95% CI 3.0, 5.6) with platinum-pemetrexed. Grade ≥3 causally-related adverse events (AEs) as assessed by the investigator were reported in 6% of patients (n=16) treated with osimertinib and 34% (n=46) treated with platinum-pemetrexed. Most common causally-related AEs in the osimertinib group: diarrhoea (29% [grade ≥3, 1%]), rash (28% [<1%]); in the platinum-pemetrexed group: nausea (47% [3%]), decreased appetite (32% [3%]).

      Conclusion:
      In patients with EGFR T790M-positive advanced NSCLC following progression on EGFR-TKI treatment, osimertinib demonstrated a superior clinically-meaningful efficacy over platinum-pemetrexed, with a 70% reduction in the risk of disease progression, and well-characterised safety profile, establishing the new standard of care for these patients.

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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)

      Y.-. Wu

      • 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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      PL03.07 - First-line Ceritinib Versus Chemotherapy in Patients With ALK-rearranged (ALK+) NSCLC: A Randomized, Phase 3 Study (ASCEND-4) (Abstract under Embargo until December 6, 7:00 CET) (Now Available) (ID 4987)

      Y.-. Wu

      • Abstract
      • Presentation
      • Slides

      Background:
      Here, we report results of ceritinib versus chemotherapy as first-line treatment for advanced ALK+ NSCLC.

      Methods:
      Untreated ALK+ (IHC confirmed), advanced, nonsquamous NSCLC patients (N=376; median age, 54 years) were randomized (1:1) to ceritinib 750 mg/day (n=189 [59 with brain metastases (BM)]) or chemotherapy (n=187 [62 with BM]; [pemetrexed 500 mg/m[2] plus cisplatin 75 mg/m[2] or carboplatin AUC 5-6] for 4 cycles followed by maintenance pemetrexed), stratified by WHO PS (0 vs 1-2), BM at screening, and prior neo-/adjuvant chemotherapy. Crossover from chemotherapy to ceritinib was allowed at progression (n=80 crossed-over).

      Results:
      Median treatment exposure was 66.4 weeks for ceritinib and 26.9 weeks for chemotherapy. Median follow-up duration was 19.7 months (randomization to cut-off date). The study met its primary objective, with ceritinib demonstrating statistically significant improvement in BIRC PFS (RECIST 1.1; median, 16.6 [12.6, 27.2] vs 8.1 months [5.8, 11.1], HR=0.55, P<0.001) versus chemotherapy. OS was immature (HR, 0.73 [0.50, 1.08]; P=0.056) with 42.3% of required events at interim analysis. ORR (BIRC, 72.5% vs 26.7%) and DOR (BIRC, median, 23.9 vs 11.1 months) were also higher with ceritinib versus chemotherapy. Among patients with measurable baseline BM and ≥1 postbaseline assessment, intracranial ORR (BIRC neuroradiologist; modified RECIST v1.1) was higher with ceritinib (72.7% [49.8, 89.3] vs 27.3% [10.7, 50.2]) versus chemotherapy (Table). Most common AEs (>50%) with ceritinib were diarrhea (84.7%), nausea (68.8%), vomiting (66.1%), ALT increase (60.3%), and AST increase (52.9%). Overall, 5.3% ceritinib- and 11.4% chemotherapy-treated patients discontinued due to AEs suspected to be drug-related. Figure 1



      Conclusion:
      First-line ceritinib achieved statistically significant and clinically meaningful improvement in median PFS with an estimated 45% risk reduction in advanced ALK+ NSCLC versus chemotherapy including maintenance. Moreover, ceritinib achieved high and durable systemic responses and high OIRR in patients with measurable BM. Safety profile of ceritinib is consistent with previously reported.

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    PR03 - Press Conference: Accurate Diagnosis (ID 477)

    • Event: WCLC 2016
    • Type: Press Conference
    • Track:
    • Presentations: 1
    • Now Available
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      PR03.03 - BRAIN: A Phase Ⅲ Trial Comparing WBI and Chemotherapy with Icotinib in NSCLC with Brain Metastases Harboring EGFR Mutations (CTONG 1201) (Now Available) (ID 7211)

      Y.-. Wu

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    SC15 - Clinical Trials: How to Set Priorities? (ID 339)

    • Event: WCLC 2016
    • Type: Science Session
    • Track: Trial Design/Statistics
    • Presentations: 1
    • Now Available
    • +

      SC15.03 - The Chinese Perspective (Now Available) (ID 6660)

      Y.-. Wu

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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