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J.C. Yang



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    MINI 09 - Drug Resistance (ID 107)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI09.03 - Characterization of Afatinib or EGFR T790M Specific Inhibitor (WZ8040 or AZD9291) Resistant Lung Cancer Cells (PC9) (ID 1065)

      16:45 - 18:15  |  Author(s): J.C. Yang

      • Abstract
      • Presentation
      • Slides

      Background:
      Non-small cell lung cancer patients harboring epidermal growth factor receptor (EGFR) mutation respond well to EGFR tyrosine kinase inhibitors (TKI). However, all patients develop resistance to EGFR TKI after long term use. EGFR T790M mutation can be found in about half of the resistant re-biopsy tumors. Afatinib is an irreversible EGFR TKI with in vitro activity against resistant T790M mutation. However, afatinib has little activity in EGFR TKI resistant patients whose tumors developed T790M mutation. A novel alinino-pyrimidine based WZ8040 has been developed to specifically inhibit phosphorylation of EGFR with T790M mutation and not on wild type EGFR. Similar compounds such as CO1686 or AZD9291 has demonstrated high activity against T790M mutations. We plan to develop afatinib or AZD9291, WZ8040 resistant PC9 cells to study afatinib or AZD9291 resistance.

      Methods:
      PC9 cells were grown in culture media containing escalating concentrations of afatinib, WZ8040 or AZD9291. When cells can grow in high concentrations of drugs, cells were cloned, expanded and grew in drug-free media for more than two weeks to obtain stable afatinib, WZ8040 or AZD9291 resistant clones. Gefitinib, afatinib, WZ8040, AZD9291. Cells viability were determined by surforodamine bromide method. PC9 parental and EGFR TKI resistant cells were treated with gefitnib, afatinib, WZ8040 or AZD9291 for one hour and EGFR, AKT, ERK phosphorylation were determined by Western blot. DNA repair capacity were compared between sensitive and resistant cells after exposure of cells to ultraviolet light and measured by pGL3-luciferase plasmid transfection methods. Epithelial mesenchyma transition of these cells were tested by snail, slug, vimentin and E-cadherin western blot. Autophagy was measured by LC3-II levels by Western blot. EGFR exon 18-21 sequence of each clones were determined by Sanger’s direct sequencing.

      Results:
      We developed afatinib resistant PC9 cells, PC9/AFAb2, PC9/AFAc3 and WZ8040 resistant PC9/WZd7, PC9/WZf6. PC9/AFA cells were more than 100-fold resistant to afatinib and PC9/WZ cells were more than 50-fold resistant to WZ8040. 10nM of afatinib treatment inhibits EGF-induced EGFR, AKT and EKR phosphorylation in PC9 cells, but phosphorylation of these kinases were only partially inhibited in PC9/AFA cells. Phosphorylation was completely blocked at 100nM afatinib. MEK inhibitor plus afatinib did not reverse resistance to afatinib in PC9/AFA cells. On the other hand, WZ8040 or AZD9291 alone completely reversed resistance in PC9/AFA cells. EGFR, AKT and ERK phosphorylation can be blocked by 100nM WZ8040 in PC9 and PC9/WZd7 cells. However, it is curious that phosphorylation of these proteins can be inhibited by 100nM gefitinib as well. EGFR T790M mutation was only detected in PC9/AFA cells and not in PC9/gef, PC9/WZ cells. None of the PC9/WZ cells have EGFR C797S mutation. We did not detect any other EGFR resistance mechanism in PC9/AFA cells. Other of comparing EMT, autophagy and DNA repair capacity of PC9 and their resistant cells are ongoing.

      Conclusion:
      We developed multiple gefitinib, afatinib, WZ8040, AZD9291 resistant PC9 cells. Only afatinib resistant cells develop EGFR T790M. We demonstrated that EGFR T790M was the predominant resistant mechanism in PC9/AFA cells. The characteristics of PC9/WZ and PC9/AZD9291 are still under investigation.

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    MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 3
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      MINI16.06 - AZD9291 in Pre-Treated T790M Positive Advanced NSCLC: AURA Study Phase II Extension Cohort (ID 943)

      16:45 - 18:15  |  Author(s): J.C. Yang

      • Abstract
      • Presentation
      • Slides

      Background:
      AZD9291 is an oral, potent, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), selective for both EGFR-TKI-sensitizing (EGFRm) and T790M resistance mutations. The Phase I AURA study was a dose escalation/expansion study in patients with EGFRm positive advanced non-small cell lung cancer (NSCLC) who had progressed after EGFR‑TKI treatment. The 80 mg once daily (qd) dose was chosen for further evaluation in a Phase II extension cohort of the AURA study, and in an additional Phase II study (AURA2). Here we report efficacy and safety of AZD9291 from the AURA study Phase II extension cohort (NCT01802632) in patients pre-treated with EGFR-TKI and with centrally confirmed T790M positive advanced NSCLC.

      Methods:
      Eligible patients had measurable disease, World Health Organization performance status (WHO PS) 0 or 1, and acceptable organ function; stable brain metastases were allowed. A mandatory tumor sample was taken after disease progression on the most recent line of therapy, for prospective confirmation of T790M positive status by central laboratory testing (cobas™ EGFR Mutation Test). Patients received AZD9291 at 80 mg qd until disease progression. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 (assessed by independent central review, ICR). Secondary objectives included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), investigator-assessed ORR, and safety. Planned enrollment was 175 patients to give an estimate of the ORR with 95% CI within ±8%. Data cut-off was January 9, 2015 after all patients should have undergone the second tumor assessment.

      Results:
      201 patients were dosed in the extension cohort of the study; two patients without measurable disease at baseline by ICR were excluded from the evaluable-for-response set. By central testing, EGFR mutation subtypes were: T790M, 98%; Ex19del, 71%; L858R, 25%; other, 3%. Median age was 62 years; female, 66%; Asian, 57%; WHO PS 0/1/2, 34%/66%/1%; second/≥third-line, 30%/70%. At the data cut-off, median treatment exposure was 4.9 months and 168 patients remain on treatment. ORR by ICR was 58% (115/199; 95% CI 51, 65) and DCR was 92% (95% CI 87, 95). ORRs were similar across lines of therapy (second-line, 59.0% [36/61] vs ≥third-line, 57.2% [79/138]). Investigator-assessed ORR was 68% (137/201; 95% CI 61, 75). Median DoR and median PFS have not been reached (maturity 2% and 21%, respectively). The most common all-causality adverse events (AEs) were diarrhea, 41% (0.5% Gr≥3) and grouped rash terms 37% (0.5% Gr≥3); 42 (21%) patients experienced Gr≥3 AEs. Interstitial lung disease grouped terms were reported in five (2.5%) patients, one of which was fatal (0.5%) and considered possibly causally related to AZD9291 by the investigator. Eight patients (4%) discontinued treatment due to an AE. Updated results from a later data cut-off will be available for presentation.

      Conclusion:
      In the AURA study Phase II extension cohort, AZD9291 80 mg qd demonstrates clinical activity, manageable tolerability, and a low discontinuation rate in patients with centrally confirmed EGFR T790M positive advanced NSCLC that has progressed on or after EGFR‑TKI treatment. These data provide further validation of the results from the Phase I study cohorts.

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      MINI16.07 - AZD9291 in Treatment-Naïve EGFRm Advanced NSCLC: AURA First-Line Cohort (ID 1232)

      16:45 - 18:15  |  Author(s): J.C. Yang

      • Abstract
      • Presentation
      • Slides

      Background:
      AZD9291 is an oral, potent, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) selective for both EGFR-sensitizing (EGFRm) and T790M resistance mutations. It has shown anticancer activity and manageable tolerability in patients with EGFRm advanced NSCLC that had progressed after EGFR‑TKI treatment.

      Methods:
      In this first-line expansion cohort (AURA, NCT01802632), patients received AZD9291 at 80 or 160 mg/day, in sequential dose groups. EGFRm status was determined locally and/or by central testing using the cobas EGFR Mutation Test. Other inclusion criteria included measurable disease, World Health Organization performance status (WHO PS) 0 or 1, and acceptable organ function; stable brain metastases were allowed. Safety, tolerability, and anticancer activity were assessed in these cohorts, to evaluate AZD9291 in the first-line treatment setting. The data cut-off was December 2, 2014.

      Results:
      Sixty treatment-naïve patients were enrolled; 30 patients in each dose group (80 or 160 mg/day). By central testing, EGFR mutation subtypes were: L858R 40%; exon 19 deletion, 37%; other EGFR-sensitizing mutations, 3%; and T790M, 8%. Baseline median age was 63.5 years; 25% of patients were male; 57%/43% had WHO PS 0/1, respectively; 72% were Asian and 23% Caucasian. Median treatment exposure at the 80 and 160 mg dose levels was 260 and 171 days, respectively. Fifty-two out of 60 patients remained on treatment at the data cut-off. Anticancer activity of AZD9291 is shown in Table 1. One-third (33%) of patients experienced Grade ≥3 adverse events; two patients had Grade 3 diarrhea and one patient had Grade 3 skin rash. New data from a 2015 data cut of the AURA first-line expansion will be available for presentation.

      Table 1. Anticancer activity findings in AURA first-line expansion
      Endpoint Finding
      Objective response rate:
      Overall 70% (95% CI 57, 81)
      AZD9291 80 mg/160 mg 60%/80%
      Disease control rate:
      Overall 97% (95% CI 89, 100)
      AZD9291 80 mg/160 mg 93%/100%
      Progression-free survival:
      Median Not yet reached
      3-month/6-month 93%/87%
      Events to date 7/60 (12% mature)


      Conclusion:
      AZD9291 has a manageable tolerability profile and is associated with promising anticancer activity in treatment-naïve patients with EGFRm advanced NSCLC. A Phase III study (FLAURA, NCT02296125) has been initiated to assess the efficacy and safety of AZD9291 in comparison with a standard-of-care EGFR-TKI (gefitinib or erlotinib) in the first-line setting.

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      MINI16.09 - Design, Execution, and Preliminary Biomarker Results from Paired Tumor Biopsy Cohorts of the AZD9291 AURA Trial (ID 941)

      16:45 - 18:15  |  Author(s): J.C. Yang

      • Abstract
      • Slides

      Background:
      Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) exhibits sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib; however, acquired resistance eventually develops in most patients. The most common mechanism of TKI resistance is a second-site mutation in the EGFR kinase domain, T790M. AZD9291 is an oral, potent, irreversible EGFR-TKI with potency against both T790M resistance and sensitizing EGFR mutations. In the ongoing Phase I AURA study (NCT01802632), AZD9291 induced durable responses in patients with acquired resistance to EGFR-TKIs. We report results of paired biopsy cohorts of the AURA trial, reviewing modulation of key molecular biomarkers of AZD9291 activity in patient tumor samples.

      Methods:
      Two cohorts of patients on the AURA trial were consented for collection of paired tumor biopsies. These patients had a pre-study tumor biopsy with T790M positive tumor status confirmed by central laboratory EGFR testing (Cobas™ EGFR Mutation Test). Following 8 to 15 days of once daily AZD9291 treatment (80 or 160 mg), a post-dose tumor biopsy was obtained. Baseline and post-dose tumor tissue was processed for routine histology and pathologic evaluation. More than 100 viable tumor cells per sample were required for subsequent biomarker scoring. Formalin-fixed paraffin-embedded tumor biopsies were profiled by immunohistochemistry with a suite of key pathway and tumor-relevant markers (phospho[p]-EGFR, pERK, pAKT, pS6, PD-L1, CD8). Matching plasma pharmacokinetic samples were also obtained for PK-PD correlations.

      Results:
      As of February 2015, 58 potential patients with an evaluable baseline biopsy were identified as candidates for post-dose biopsy collection. Sixteen of these patients did not proceed to an on-study biopsy as the identified lesions had regressed too substantially or were no longer considered suitable for re-biopsy, one patient was medically excluded from re-biopsy, and one patient’s sample was not available. In total, 40 patients supplied matched pre- and on-treatment biopsies. As of March 2015, paired tumor samples were available for QC from 26 of these 40 patients. Ten of these 26 biopsy specimens subsequently failed QC due to inadequate tumor content, leaving 16 paired tumor samples available for biomarker analyses, of which five have thus far been evaluated. AZD9291 treatment resulted in the inhibition of EGFR pathway components in the majority of post-treatment tumor biopsies. Tissue biomarker analyses are ongoing and updated data on evaluable biopsy pairs will be reported at the time of the congress.

      Conclusion:
      The completion of a paired biopsy cohort within the AURA trial was challenging due to the rapid onset of anti-tumor effects of AZD9291. Approximately 29% (17/58) of potentially eligible patients were unsuitable for the post-dose biopsy procedure due to tumor regression and 38% (10/26) of available post-dose biopsies were found to contain too little tumor for analysis. In the evaluable tumor pairs, pharmacodynamic modulation of the EGFR pathway was evident. Further biomarker analyses, including evidence of modulation of immune system markers, may help inform future combination strategies.

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    MINI 17 - WT EGFR, Angiogenesis and OMD (ID 131)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI17.01 - Maintenance with Gefitinib/Pemetrexed (G/P) or P After Induction P/Platinum for Stage IV Lung Adenocarcinoma with No Sensitizing EGFR Mutation (ID 608)

      16:45 - 18:15  |  Author(s): J.C. Yang

      • Abstract
      • Presentation
      • Slides

      Background:
      We have proposed that synergistic epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-chemotherapeutic interaction in lung cancer cells has 3 essentials: no platinum, cells not or no more sensitive to EGFR-TKI, and using a synergistic chemo partner, e.g., pemetrexed (P) (Tsai, et al. Lung Cancer 82:305, 2013).

      Methods:
      GENIUS study (NCT01579630) was a phase II, multicenter, randomized, open-label prospective trial comparing maintenance G/P versus P in patients with metastatic lung adenocarcinoma (mLADC) harboring no sensitizing EGFR mutations (sEGFRm) detected by high sensitivity methods following a 4-cycle P/Platinum induction therapy in frontline setting. Patients with no disease progression (PD) were 1:1 randomized to receive P (500 mg/m[2], 3-week cycle) ± G (250 mg, daily) until PD or treatment failure, and stratified by study site and response. The primary endpoint was progression free survival (PFS) by both independent radiologist review (IRR) and investigator assessment (IA), secondary endpoints included time to treatment failure (TTF), overall survival (OS), safety and toxicity profile.

      Results:
      Between 03/2011 and 11/2013, 55 patients were randomized, G/P 26, P 29. Baseline characteristics were balanced between arms (age 57; female 42%; never smoker 55%; ECOG1 91%; ≥2 metastatic sites 38.2%; ALK+ 16%). Median follow-up was 20.4 mo. Median cycle of treatment was G/P 9.5 (range 1-32) and P 4 (2-21). Median PFS was substantially longer for G/P than P, both by IRR (3 deemed as PD at randomization were excluded; n = 25 v 27): 8.4 v 3.8 mo; HR [95% CI] 0.42 [0.23-0.79]; p = 0.0057, and by IA: 8.7 v 2.9 mo; HR 0.38 [0.21-0.70], p = 0.0013. Response with induction therapy, age, and smoker had interactions with treatment for PFS. Median TTF: 7.0 v 2.9 mo; HR 0.46 [0.25-0.83], p = 0.0085. OS was also better for G/P than P by IRR (undefined v 29.3 mo; HR 0.44 [0.20-0.97]; p = 0.037) and IA (undefined v 21.7 mo; HR 0.46 [0.22-0.97]; p = 0.038). There were more treatment-related diarrhea, liver and skin toxicities on G/P v P, but generally mild. Two G/P patients were off-study due to liver toxicity.

      Conclusion:
      This proof of concept ph 2 study first demonstrated survival benefit of EGFR-TKI plus chemo in the maintenance phase of frontline treatment for patients with mLADC harboring no sEGFRm. This strategy deserves phase III study to confirm.

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    MINI 30 - New Kinase Targets (ID 157)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI30.06 - Activity of AUY922 in NSCLC Patients With EGFR Exon 20 Insertions (ID 1744)

      18:30 - 20:00  |  Author(s): J.C. Yang

      • Abstract
      • Presentation
      • Slides

      Background:
      EGFR exon 20 insertions (ins20) represent a rare subtype (4%) of EGFR mutations and are refractory to EGFR-specific tyrosine kinase inhibitors (TKIs). No effective targeted therapies exist for patients (pts) with ins20; median PFS on the irreversible EGFR TKI Afatinib is 2.8 months (mos). Based on a durable RECIST partial response (PR) to AUY922, a Heat Shock Protein 90 (Hsp90) inhibitor, observed in an EGFR ins20 patient in a previous study (NCT01124864), we designed a phase II investigator-initiated trial to assess the activity of AUY922 in NSCLC pts with EGFR ins20. Since pts with these mutations are rare, we identified other international investigators who have treated ins20 patients with AUY922. Here, we present the results of a pooled international experience of 21 patients with EGFR ins20 treated with AUY922 in the United States, Taiwan and the Netherlands.

      Methods:
      A total of 21 patients with EGFR in20 are included in this analysis. 14 were treated on a single-arm, multi-center, open-label study of AUY922 in advanced NSCLC pts with EGFR ins20 mutations in the US (NCT01854034). Five were treated on a multicenter Taiwanese trial of AUY922 across a variety of molecular NSCLC subtypes (NCT01922583) and two were treated on a compassionate-use basis in the Netherlands. The starting dose of AUY922 was 70mg/m2 IV weekly for all patients.

      Results:
      21 pts, including 14 females and 7 males, average age 55 (range, 27-75) were included in this analysis. The median number of prior therapies was 2 (range, 1-6.) 6 pts received a prior EGFR TKI; none responded to TKI monotherapy. The most common AUY922-related toxicities were grade 1-2 visual changes (18/21; 86%) diarrhea (18/21; 86%) and fatigue (15/21; 71%). The only treatment-related grade 3 toxicities was hypertension (2/21; 1%) and AST elevation (1/21; 0.5%). There was one death on study, related to pre-existing comorbidity/unrelated to AUY922. Among the 21 patients treated, 5 achieved a partial response by RECIST 1.1 (ORR 24%) (Figure 1.) The median PFS estimate is 3.9 mos (95% CI, 2.9 to 10.7.) 6 patients remain on treatment at the time of abstract submission. Updated results and correlation with specific ins20 mutations will be presented. Figure 1



      Conclusion:
      This international experience suggests that AUY922 may be an active therapy for advanced NSCLC pts with EGFR ins20 mutations with an ORR 24% and median PFS 3.9 mo. AUY922 is generally well-tolerated, though reversible low-grade ocular toxicity is common. Further study of AUY922 in this population is warranted.

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    MS 26 - Genomic Alterations and Drug Targets in Small Cell Lung Cancer (ID 44)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MS26.01 - Genomic Alterations (ID 1963)

      14:15 - 15:45  |  Author(s): J.C. Yang

      • Abstract
      • Presentation

      Abstract:
      Genomic Alterations and Drug Targets in Small Cell Lung Cancer Over the past 15 years, we have made a lot of advances in the treatment of non small cell lung cancer (NSCLC). However, the treatment paradigm for small cell lung cancer (SCLC) remains the same as 30 years ago, e.g., concurrent chemoradiotherapy for limited stage SCLC and chemotherapy for extensive stage SCLC. The successful introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for the treatment of lung cancer patients has helped us understand the underlying genomic alterations in responding patients and the biology of tumor cells harboring EGFR mutations. In contrast to the successful story of EGFR TKIs in NSCLC treatment leading to the discovery of EGFR mutations in responding patients, the discovery of EML4-ALK fusion in NSCLC has led to the successful treatment of crizotinib in patients harboring this mutation. Crizotinib was designed to inhibit cMET but was developed successfully as an ALK inhibitor for those patients. Further genomic analysis of lung adenocarcinoma patients disclosed that some specific recurrent mutations in EGFR, HER2, KRAS, NRAS, BRAF, cMET, EML4-ALK, ROS1, RET fusions etc. were found in patients. However, each patient only harbored one mutation. Specific inhibitors are very effective in the treatment of lung adenocarcinoma patients harboring corresponding targeted mutations. Thus, driver mutation or oncogene addiction hypothesis was built through genomic analysis of lung adenocarcinoma patients and clinical observations of successful targeted therapy treatment. Several targeted therapies have been tested in a small scale of advanced stage SCLC patients. None of the studies showed any signal of anticancer activity in years. Thus, radiotherapy and chemotherapy remain the effective treatment for SCLC. Current technique allowed us to examine cancer genome in detail. The information can be used to predict clinical usage of certain targeted therapy. Genomic analysis of SCLC may open a door for us to understand the basic differences between NSCLC and SCLC and ponder the ineffectiveness of targeted therapy in SCLC. Genomic alterations of SCLC cells were first described in 1980s by observation of chromosome aberrations. Frequent deletion of 3p was first observed by Peng-Whang J et al. The most frequent reported genetic alterations in SCLC cells were inactivting mutations of TP53, RB1, PTEN, mutations in PIK3CA, EGFR and KRAS, amplification of myc family, EGFR and BCL2 as well as loss of RASSF1A, PTEN and FHIT. Those genomic alterations were examined through small series of samples and target gene examinations. Systemic approach to explore the multitude and magnitude of genomic alterations in SCLC was only possible with recent next generation sequencing technology and the application of bioinformatics to analyze the vast amount of data generated from the samples. Rudin et al. have collected 36 primary human SCLC and normal tissue pairs and 17 matched SCLC and lymphoblastoid cell lines and examined the exome, transcriptome and copy number alterations. In 4 primary tumors and 23 SCLC cell lines, the authors identified 22 significant mutated genes. In the exome of 42 SCLC tumor normal tissue pairs, they identified 26406 somatic mutations. 30% of them resulted in protein alterations. An average of 175 protein-altering single nucleotide variants was calculated per patient. G-to-T transversions were the predominant mutation, followed by G-to-A and A-to-G transition mutations signify that these mutations were related to tobacco smoke carcinogens. In the whole genome analysis of one patient, 286 protein-altering changes were found. Frequent altered genes included genes encoding for kinases, G-protein-coupled receptors and chromatin-modifying proteins. The authors found that SOX2 mutation or amplification was frequently found in its series. SOX2 expression may play some crucial roles in SCLC cells, such as maintenance of pluripotency of stem cells property. In addition, the authors also discovered several non-recurrent fusion genes from RNA-seq data. The roles of these fusion proteins in SCLC are less well understood. But some of those fusion proteins seem to result in activating kinases. Peifer M et al. sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes. They discovered inactivation of TP53, RB1 and recurrent mutations in CREBBP, EP300 and MLL genes. Additional findings included mutations in PTEN, SLIT2, EPHA7 and FGFR1 amplification. They concluded that histone modification is a major feature of SCLC. Both comprehensive genomic studies disclosed similar gene alterations such as TP53 and RB1 are the important signatures of SCLC genomic alterations. However, an individual analysis pointed out at different angles, for example, SOX2 or histone modification. The different results of two series reflected that only a limited number of samples were tested, interpatient heterogeneity may be huge and more genomic studies should be performed in the future. When major genomic alterations were compared among lung adenocarcinoma, squamous cell carcinoma and SCLC, alterations of TP53, CDKN2A, PIK3CA and PTEN were commonly found in all three types of lung cancer. FGFR1 and SOX2 alterations were found in SCLC and squamous cell carcinoma, whereas KEAP1 alterations was detected in both squamous cell carcinoma and adenocarcinoma. Recently, transformation from adenocarcinoma to SCLC was detected in a minority of patients with EGFR mutations who have received EGFR TKIs and developed resistance. Typical EGFR mutations can be found in untreated SCLC patients, especially in east Asian ethnic patients. Occasionally mixed SCLC and adenocarcinoma were described under light microscopy. Some of those patients harbor EGFR mutations. Unfortunately, EGFR TKI was usually not effective in the treatment of such patients, it suggested that alterations of the transcriptional factors contributed SCLC phenotype being more dominant and only chemotherapy was effective to control the progression of the disease. The heterogeneous nature of genomic alterations in SCLC suggested that targeted therapy may be difficult to be successful in SCLC treatment. None of the altered genes seems to be the dominant driver. On the other hand, RB1 and myc, genes altered easily that are not the good targets for current targeted therapy. Thus, genomic analysis of SCLC further indicated that the combination of targeted therapy may not be useful. It may have to combine targeted therapy and chemotherapy to obtain better anti-cancer activity. However, patient selection may be needed according to the genomic findings and pathway predictions. The hyper mutational genomic background was a good predictor for immune checkpoint inhibitor therapy. However, in a recent report in American Society of Clinical Oncology Meeting suggested that only a low response rate was noted in SCLC treated with immune checkpoint inhibitors. More genomic, immune studies and clinical trials are needed to advance the treatment of SCLC in the future.

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    ORAL 16 - Clinical Care of Lung Cancer and Advanced Biopsies (ID 115)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL16.05 - Retrospective Analysis of ctDNA EGFR Mutations in the Phase III, Randomized IMPRESS Study (ID 2106)

      10:45 - 12:15  |  Author(s): J.C. Yang

      • Abstract
      • Presentation
      • Slides

      Background:
      The majority of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer respond to first-line EGFR-tyrosine kinase inhibitors (EGFR-TKIs, e.g. gefitinib) but nearly all eventually acquire resistance. The most common mechanism of acquired resistance is a second-site mutation in the EGFR kinase domain, T790M. The phase III, double-blind IMPRESS study evaluated the efficacy and safety of continuing gefitinib plus pemetrexed/cisplatin versus placebo plus pemetrexed/cisplatin in patients with acquired resistance to first-line gefitinib. Study results did not support the continuation of gefitinib after disease progression (by RECIST criteria) when platinum-based doublet chemotherapy is used as second-line therapy. Here we report the results of a retrospective biomarker analysis of plasma circulating free, tumor-derived DNA (ctDNA) from patients in IMPRESS, including T790M profiling, to help understand the IMPRESS clinical trial outcome.

      Methods:
      Plasma samples for ctDNA isolation were collected at baseline and discontinuation from 151 randomized, non-Chinese patients in IMPRESS (58% of overall IMPRESS population). ctDNA levels of T790M, L858R, and Exon19 deletions were detected using both a quantitative emulsion (BEAMing) digital PCR assay (Sysmex[®]) and a qualitative QIAGEN[®] Therascreen ARMS assay (baseline only). Local EGFR tumor tissue (diagnostic) results were available for 133/151 patients. Mutation concordance rates between tissue and baseline plasma results, and comparisons between the two plasma detection methods, were calculated.

      Results:
      Baseline ctDNA EGFR mutation results were obtained for >99% (150/151) of patients. Using BEAMing, sensitivity and specificity between baseline plasma EGFR sensitizing mutations and local EGFR tumor tests were 78% (69/89) and 98% (42/43), respectively, for Exon19 deletions, and 82% (31/38) and 97% (91/94) for L858R. The T790M detection rate in baseline plasma samples using BEAMing was 56% (84/150). The Therascreen ARMS assay demonstrated a significantly reduced T790M detection rate of 13% (20/150). Likewise, the sensitivity of the Therascreen ARMS assay with respect to tissue for EGFR sensitizing mutations was also reduced compared with BEAMing: Exon 19: 54% (48/89), L858R: 47% (18/38), though the specificity remained near 100%. In the 97 evaluable plasma samples collected at discontinuation, T790M was detected by BEAMing in 52% (50/97) of patients. When compared with matched baseline plasma, 11 patients had newly acquired T790M mutation at discontinuation while T790M reverted to undetectable in 14 patients. Full plasma profiling data from the complete IMPRESS clinical study population (including 108 patients from China) and correlative analyses of plasma EGFR mutation status with clinical outcome (progression-free survival, overall survival, objective response rate) will be presented.

      Conclusion:
      In IMPRESS, T790M was detectable with BEAMing digital PCR in the baseline ctDNA samples of 56% of evaluable patients, a rate comparable to similar mutation analyses in this same second-line, EGFR-TKI-failed setting. EGFR mutation detection in plasma using the Therascreen ARMS assay demonstrated comparable specificity to BEAMing but reduced sensitivity. The T790M detection rate afforded by the BEAMing technology will allow for a comprehensive assessment of correlations between clinical outcome in IMPRESS and EGFR mutational status.

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    ORAL 17 - EGFR Mutant Lung Cancer (ID 116)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 2
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      ORAL17.02 - Randomized Trial of Gefitinib with and without Pemetrexed as First-Line Therapy in East-Asian Patients with Advanced NS NSCLC with EGFR Mutations (ID 1319)

      10:45 - 12:15  |  Author(s): J.C. Yang

      • Abstract
      • Presentation
      • Slides

      Background:
      Pemetrexed (P) is the standard of care for non-squamous non-small cell lung cancer (NS NSCLC), whereas epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib (G), are the standard of care for advanced NSCLC with EGFR mutations. Clinical and nonclinical studies have demonstrated synergistic effects of EGFR TKIs and P. Based on these observations, the efficacy and safety of G+P was compared with G monotherapy in patients with NS NSCLC positive for activating EGFR mutations.

      Methods:
      The primary objective of this randomized, multicenter, open-label, parallel-arm, phase 2 East-Asian study was to assess whether G+P prolongs progression-free survival (PFS) versus G alone. Secondary endpoints included overall survival (OS), overall response rate, disease control rate, time to progressive disease, duration of response, and treatment-emergent adverse events (TEAEs). Eligible patients had stage IV NS NSCLC with activating EGFR mutations, were chemonaïve, and had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. Patients were randomized in a 2:1 ratio (G+P:G). Dosing schedule was concurrent G (250 mg/day) and P (500 mg/m[2] every 3 weeks) in the G+P arm and G monotherapy (250 mg/day) in the G arm. Treatment continued until progression or unacceptable toxicity. The primary endpoint was analyzed after 144 events, which provided 70% power at a 1-sided 20% significance level, assuming a true hazard ratio (HR) of 0.79.

      Results:
      Between February 2012 and August 2013, 191 patients were randomized and treated (G+P: N=126; G: N=65). Patients were mostly female (64.4%) with a mean age of 62 years; most were never-smokers (67.0%), had confirmed stage IV disease (84.8%), and ECOG PS of 1 (68.6%). Overall, 55.0% had exon 19 deletions, 39.3% had exon 21 L858R mutations, and 5.8% had other activating EGFR mutations. Baseline characteristics were balanced between treatment arms. Patients in the G+P arm received 96.3% and 92.9% of the planned mean dose of G and P, respectively; patients in the G arm received 97.9% of the planned mean dose of G. Median PFS for G+P (15.8 months) was significantly longer than for G (10.9 months); HR=0.68; 95% confidence interval 0.48, 0.96; 1-sided P=0.014; 2-sided P=0.029. OS data are immature and will be reported at study completion. The incidence of grade 3/4 study drug-related TEAEs was significantly higher for G+P (42.1%) than for G (18.5%); P=0.001. The most common study drug-related TEAEs for G+P were diarrhea (44.4%), aspartate aminotransferase increased (41.3%), and dermatitis acneiform and alanine aminotransferase increased (38.1% for each), and for G were diarrhea (47.7%), dermatitis acneiform (43.1%), and dry skin (35.4%). The proportion of treatment discontinuations due to TEAEs was 16.7% in the G+P arm and 9.2% in the G arm; 2 patients (G+P arm) died due to study drug-related adverse events.

      Conclusion:
      The combination of G+P led to a significant improvement in PFS compared with G monotherapy for East-Asian patients with EGFR mutation-positive NS NSCLC, and met the primary study endpoint. The incidence of grade 3/4 study drug-related AEs was higher for G+P than for G. ClinicalTrials.gov identifier: NCT01469000.

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      ORAL17.08 - Gefitinib/Chemotherapy vs Chemotherapy in EGFR Mutation-Positive NSCLC Resistant to First-Line Gefitinib: IMPRESS T790M Subgroup Analysis (ID 3287)

      10:45 - 12:15  |  Author(s): J.C. Yang

      • Abstract
      • Presentation
      • Slides

      Background:
      Exon 20 T790M mutation is the most common cause of acquired resistance to first-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs). The IMPRESS study (NCT01544179; Phase III, double-blind IRESSA[TM ]Mutation Positive Multicentre Treatment Beyond ProgRESsion Study; Lancet Oncology: in press) reported no statistically significant difference in progression-free survival (PFS; primary endpoint) between gefitinib plus cisplatin/pemetrexed (cis/pem) (G) vs placebo plus cis/pem (P) in patients with acquired resistance to first-line gefitinib (hazard ratio [HR] 0.86; 95% confidence interval [CI] 0.65–1.13; p=0.273; median PFS 5.4 months in both arms) and other secondary endpoints. Among the subgroup analyses performed for IMPRESS, the most noticeable difference was observed by T790M status as tested via plasma circulating free tumor-derived DNA (ctDNA).

      Methods:
      Patients (age ≥18 years [Japan ≥20 years], chemotherapy-naïve, locally advanced/metastatic NSCLC with an activating EGFR mutation, prior disease progression on first-line gefitinib) from 71 centers (Europe/Asia Pacific) were randomized to G or P (gefitinib 250 mg/day or placebo, plus cis 75 mg/m[2]/pem 500 mg/m[2]). For biomarker analysis, consenting randomized patients provided 10-mL blood samples (at Visit 1 [baseline], 4, 6; then every 6 weeks and at discontinuation) from which to obtain ctDNA. ctDNA levels of EGFR mutations, including T790M, were detected using a quantitative emulsion (BEAMing) digital PCR assay (Sysmex[®]) conducted at a central laboratory (positivity defined as ≥0.02% mutant DNA fraction).

      Results:
      Data are reported for plasma samples from baseline visits (serial data will be available in the future). Blood samples were available for all 261 randomized patients, of whom T790M status was known for 247 (93.2%): T790M mutation-positive n=142 (57.5%; G=81, P=61) and T790M mutation negative n=105 (42.5%; G=46, P=59). Median PFS for the T790M mutation-positive subgroup was 4.6 vs 5.3 months for G and P, respectively (HR 0.97, 95% CI 0.67 to 1.42, p=0.8829). Median PFS for the T790M mutation-negative subgroup was 6.7 vs 5.4 months for G and P, respectively (HR 0.67, 95% CI 0.43 to 1.03, p=0.0745). See Table for additional study endpoints.

      Conclusion:
      Following acquired resistance to first-line gefitinib, these data suggest there were two distinct patient populations defined by T790M genotype. For plasma T790M-positive, gefitinib should not be continued when platinum-based doublet chemotherapy is used as second-line therapy. For plasma T790M-negative, continuation of gefitinib in combination with platinum-based doublet chemotherapy may offer clinical benefit, which would require further confirmation in a prospective randomized study.

      IMPRESS subgroup populations (plasma)
      T790M mutation-positive N=142 T790M mutation-negative N=105
      ORR, % (G vs P) 28.4 vs 39.3 p=0.282 37.0 vs 27.1 p=0.171
      DCR, % (G vs P) 81.5 vs 77.0 p=0.5175 93.5 vs 83.1 p=0.0895
      OS, HR (95% CI)* 2.16 (1.26, 3.82) p=0.0067 0.83 (0.36, 1.85) p=0.6644
      Plasma BEAMing PCR (compared with tumor), % (n/N)
      Exon 19 Deletions L858R
      Sensitivity 73.8 (124/168) 81.6 (62/76)
      Specificity 96.7 (89/92) 95.3 (161/169)
      Concordance 81.9 (213/260) 91.0 (224/247)
      *OS immature, follow up ongoing G: gefitinib plus cisplatin/pemetrexed; P: placebo plus cisplatin/pemetrexed ORR, objective response rate; DCR, disease control rate; OS, overall survival


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    ORAL 33 - ALK (ID 145)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      ORAL33.05 - Pooled Analysis of CNS Response to Alectinib in Two Studies of Pre-Treated ALK+ NSCLC (ID 1219)

      16:45 - 18:15  |  Author(s): J.C. Yang

      • Abstract
      • Presentation
      • Slides

      Background:
      The central nervous system (CNS) is a frequent site of progression in ALK+ NSCLC patients treated with crizotinib, thus good CNS efficacy is of crucial importance for new ALK inhibitors. Two recent phase II studies examined the efficacy and safety of alectinib in patients with ALK+ NSCLC who progressed after crizotinib; data from both studies were pooled to further examine the efficacy of alectinib in the CNS.

      Methods:
      Both phase II, single-arm, multicenter studies enrolled ALK+ NSCLC patients previously treated with crizotinib. One study was conducted in North America only (NP28761; NCT01871805), the other was global (NP28673; NCT01801111). All patients received 600mg oral alectinib twice daily. A primary endpoint of both studies was objective response rate (ORR) by independent review committee (IRC) and key secondary endpoints included CNS ORR by IRC and CNS duration of response (DOR). Response was determined according to RECIST v1.1. All patients underwent imaging at baseline to assess CNS metastases.

      Results:
      The pooled analysis population comprised 225 patients (n=87 from NP28761 and n=138 from NP28673); baseline characteristics were similar to each study population, with most patients being non-smokers, <65 years old with ECOG performance status 0/1. Median follow-up was 27.7 weeks. Fifty patients had measurable CNS disease at baseline (MD) while a further 85 had non-measurable disease (NMD) at baseline; both groups together (M+NMD) comprised 135 patients, 60% of the overall study population. In the MD group, 34 patients (68%) had received prior radiotherapy, but 24 of them had completed that radiotherapy >6 months prior to starting alectinib. For the M+NMD group, 94 patients (70%) had received prior radiotherapy, with 55 completing this >6 months prior to starting alectinib. In the MD group, 30/50 patients had a CNS response (60.0%; 95% CI 45.2–73.6%), with 7 complete responses (CR; 14.0%) and a CNS DCR of 90.0% (78.2–96.7%). In the M+NMD group, 22 additional patients had a CR (29/135; 21.5%), giving a CNS ORR of 38.5% (30.3–47.3%), with a CNS DCR of 85.2% (78.1–90.7%). Complete responses were seen in patients with and without prior radiotherapy. Median CNS DOR after only 17% of events in both groups was 7.6 months (5.8–7.6) in the MD group (n=30) and 7.6 months (5.8–10.3) in the M+NMD group (n=52), which is similar to the systemic DOR reported in both studies (Ou et al, ASCO 2015; Gandhi et al, ASCO 2015). Tolerability was also similar to the overall study population.

      Conclusion:
      Alectinib showed promising efficacy in the CNS in ALK+ NSCLC patients previously treated with crizotinib, achieving a complete response rate of 22% and a DCR of 85%, irrespective of prior radiotherapy. The CNS response was sustained for an equivalent duration to the systemic response, suggesting that alectinib could provide an effective treatment for patients with ALK+ NSCLC while actively targeting CNS metastases. The ongoing phase III clinical studies will assess the systemic and CNS efficacy of alectinib versus crizotinib as front-line therapy for ALK+ NSCLC patients.

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    P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 3
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      P1.01-076 - TIGER-1: A Phase 2/3 Study of First Line Rociletinib or Erlotinib in EGFR-Mutant NSCLC (ID 944)

      09:30 - 17:00  |  Author(s): J.C. Yang

      • Abstract

      Background:
      Activating EGFR mutations including the L858R mutation and exon 19 deletions (del19) are key drivers of non-small cell lung cancer (NSCLC) in 10%–15% of patients of European and 30%–35% of Asian descent.[1] Acquired resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib can be driven by additional EGFR mutations, with exon 20 T790M accounting for 50%–60% of cases.[2] Rociletinib (CO-1686) was designed to inhibit T790M as well as L858R and del19 while sparing wild-type EGFR and has demonstrated response rates up to 67% in patients with T790M mutations who had progressed on first or later line EGFR inhibitor therapy. Rociletinib continues to be well tolerated by patients in ongoing studies.[3] Given that T790M mutated subclones commonly emerge during treatment with existing EGFR inhibitors, early targeting of T790M along with initial activating mutations is a rational approach to delay progression.

      Methods:
      TIGER-1 (NCT02186301) is a randomized, open label study of rociletinib vs erlotinib in patients with mutant EGFR NSCLC. Patients with histologically or cytologically confirmed metastatic or unresectable locally advanced treatment-naive NSCLC (no prior therapy in the metastatic setting and no CNS disease), with documentation of ≥1 activating EGFR mutation (excluding exon 20 insertions) and biopsy within 60 days will be enrolled in this 2-part study. All patients will be randomized 1:1 to rociletinib (500 mg twice daily) or erlotinib (150 mg once daily) and treated until death, qualifying adverse events or disease progression. Patients will be stratified by sensitizing EGFR mutation (T790M, del19, L858R, or other) and territory (Asian vs non-Asian geography). The same patient eligibility criteria will be used for the Phase 2 and Phase 3 portions of TIGER-1. The phase 2 portion is currently enrolling and will transition to the Phase 3 portion upon enrollment of the 201[st] patient. The maturing Phase 2 dataset will contribute to decision-making rules for the Phase 3 interim analyses. The Phase 3 portion will incorporate larger cohorts; the final sample sizes will be determined by interim analyses where the chances of success will be estimated at pre-planned enrollment milestones. The primary endpoint is PFS; secondary efficacy endpoints include objective response rate, duration of response, disease control rate and overall survival. Safety will be assessed via standard adverse event reporting. PFS and OS will be summarized with Kaplan-Meier plots. The stratified log-rank and hazard ratio will compare PFS distributions for rociletinib- vs erlotinib-treated patients. Enrollment is ongoing. 1. Herbst R et al. N Engl J Med. 2008 2. Yu H et al. Clin Cancer Res. 2013 3. Sequist LV J Clin Oncol. 2014

      Results:
      Not applicable

      Conclusion:
      Not applicable

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      P1.01-079 - Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone as First-Line Therapy for NSCLC (ID 2993)

      09:30 - 17:00  |  Author(s): J.C. Yang

      • Abstract
      • Slides

      Background:
      Platinum doublet chemotherapy with or without bevacizumab is the standard first-line therapy for patients with advanced NSCLC without EGFR sensitizing mutations or ALK rearrangement. Pembrolizumab (MK-3475), a humanized monoclonal antibody against PD-1 designed to block the interaction of PD-1 with its ligands PD-L1 and PD-L2, has shown efficacy and a manageable toxicity profile in patients with NSCLC treated at doses ranging from 2 mg/kg every 3 weeks to 10 mg/kg every 2 weeks. In 45 patients with treatment-naive advanced NSCLC treated in KEYNOTE-001, single-agent pembrolizumab has demonstrated a response rate of 26%.

      Methods:
      KEYNOTE-021 (ClinicalTrials.gov, NCT02039674) is an international, open-label, multi-arm, phase 1/2 trial of pembrolizumab for advanced NSCLC. After establishing the safety and tolerability of pembrolizumab plus carboplatin and pemetrexed in phase 1, a randomized phase 2 cohort comparing the efficacy of pembrolizumab plus carboplatin and pemetrexed with that of carboplatin and pemetrexed has been initiated. Key eligibility criteria for this cohort are previously untreated stage IIIB/IV nonsquamous NSCLC, no sensitizing EGFR mutation or ALK rearrangement, and ECOG PS 0-1. Patients will be randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg Q3W plus carboplatin and pemetrexed at standard doses or carboplatin and pemetrexed alone. Randomization will be stratified by PD-L1 expression determined by immunohistochemistry at a central laboratory (positive [membranous expression in ≥1% of tumor cells] vs negative). Pembrolizumab will be given for 24 months or until progression, intolerable toxicity, or investigator decision. Pembrolizumab may be continued beyond radiographic progression in eligible patients. Carboplatin and pemetrexed will be given for 4 cycles followed by maintenance pemetrexed, alone or with pembrolizumab. Patients allocated to the chemotherapy-alone arm who experience progression may cross over to the pembrolizumab arm of the study. AEs will be monitored throughout treatment and for 30 days thereafter. Response will be assessed every 6 weeks for the first 18 weeks, then every 9 weeks in year 1 and every 12 weeks in year 2. Survival follow-up will occur every 3 months after discontinuation of study treatment. Primary end point is progression-free survival (RECIST v1.1, central review); secondary end points include overall survival, objective response rate, and correlation of PD-L1 expression with antitumor activity. This cohort is currently enrolling patients.

      Results:
      Not applicable.

      Conclusion:
      Not applicable.

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      P1.01-086 - TIGER-3: A Phase 3 Open-Label, Randomized Study of Rociletinib vs Chemotherapy in NSCLC (ID 949)

      09:30 - 17:00  |  Author(s): J.C. Yang

      • Abstract
      • Slides

      Background:
      Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) that has demonstrated efficacy against the activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. TIGER-X, a Phase I/II dose-ranging trial, has provided evidence that rociletinib is associated with durable response and is well tolerated in patients with NSCLC and positive T790M status following progression on a TKI.[1 ]Efficacy has also been noted for patients with T790M negative status in TIGER-X.[2] TIGER-3 is designed to investigate single agent rociletinib vs chemotherapy in patients who have failed EGFR therapy and platinum-based doublet chemotherapy, which is a setting of acquired resistance and high unmet need for targeted therapeutic options. TIGER-3 will evaluate patients with T790M positive and negative status based on tumor biopsies and plasma, and biomarkers of response and/or resistance.

      Methods:
      Patients with histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC, with radiological progression on the most recent therapy will be enrolled in this phase 3, randomized, open-label study (NCT02322281). Patients must have documented evidence of a tumor with ≥1 EGFR activating mutations excluding exon 20 insertion, and prior treatment with an EGFR TKI and platinum-containing doublet chemotherapy. Patients will be randomized 1:1 to receive rociletinib twice daily (500 mg) or single agent cytotoxic chemotherapy (investigator choice specified before randomization) until disease progression according to RECIST 1.1. Patients will be stratified by presence or absence of brain metastases, ECOG performance status (0 vs 1), and race (Asian vs non-Asian). The primary endpoint is progression-free survival (PFS). Secondary endpoints include safety, objective response rates, duration of response, disease control rate, and overall survival. Kaplan-Meier methodology will assess time to event variables. The stratified log-rank and the hazard ratio will be used for comparing PFS distributions. Serial assessment of safety will be carried out based on standard adverse event reporting. Planned enrolment is 600 patients; enrolment has been open since March 2015. Sequist LV J Clin Oncol. 2014 Soria J-C EORTC-NCI-AACR 2014

      Results:
      Not applicable

      Conclusion:
      Not applicable

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    P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P2.01-094 - Phase II Trial of Tepotinib/Gefitinib vs Cisplatin/Pemetrexed in T790M-/c-Met+ NSCLC (ID 2105)

      09:30 - 17:00  |  Author(s): J.C. Yang

      • Abstract
      • Slides

      Background:
      The recommended phase II dose of the highly selective c-Met inhibitor tepotinib (MSC2156119J) for use in combination with gefitinib was confirmed as 500 mg/day in the phase Ib part of the current trial, in which patients with gefitinib-resistant locally advanced/metastatic c-Met-positive NSCLC were treated with tepotinib plus gefitinib. This trial demonstrated that the combination regimen is well tolerated and has evidence of antitumor activity that may be associated with c-Met-positive tumor status. These observations suggest that c-Met inhibition may have a role in EGFR tyrosine kinase inhibitor-resistant NSCLC and that a phase II trial is warranted.

      Methods:
      The design of the phase II part of a phase Ib/II trial (NCT01982955) is described. Asian adults with histologically or cytologically confirmed, gefitinib-resistant locally advanced/metastatic NSCLC other than predominantly squamous histology and ECOG PS 0/1 are eligible. Patients must have tumors with documented activating mutations of EGFR. Tumor tissue obtained between documentation of acquired resistance to gefitinib and enrollment must be available. Tumors must be confirmed as being c-Met positive (2+/3+ c-Met protein overexpression by immunohistochemistry using CONFIRM anti-total c-MET [SP44] rabbit MAb [Ventana] or c-Met gene amplification on IQ FISH [Dako] [c-Met:CEP7 ratio ≥2 or <2.0 with >15 c-Met signals/cell in >10% of cells or clusters in >10% of tumor cell nuclei]). EGFR mutation status will be assessed centrally using the therascreen[®] EGFR RGQ PCR Kit (QIAGEN). Patients will be enrolled into different parts of the trial based on tumor T790M status. Patients with c-Met-positive, T790M-negative NSCLC (n=136) will be randomized to tepotinib 500 mg/day p.o. + gefitinib 250 mg/day q3w or cisplatin 75 mg/m[2] + pemetrexed 500 mg/m[2] q3w for up to 6 cycles. Patients with c-Met-positive, T790M-positive NSCLC (n=15) will be treated with tepotinib 500 mg/day p.o. + gefitinib 250 mg/day q3w. The primary objective is to determine whether progression-free survival (PFS) in patients treated with second-line tepotinib combined with gefitinib is superior to that of pemetrexed + cisplatin in patients with c-Met-positive, T790M-negative advanced NSCLC and acquired resistance to first-line gefitinib. The two T790M subgroups will be analyzed separately. An interim analysis of the randomized part of the study is planned when 50% of PFS events have occurred in both arms. Secondary objectives are to evaluate: the safety and tolerability tepotinib combined with gefitinib; the efficacy of tepotinib combined with gefitinib; the antitumor activity of tepotinib combined with gefitinib in patients with c-Met-positive, T790M-positive tumors; and patient-reported outcomes.

      Results:
      not applicable

      Conclusion:
      This randomized phase II trial will provide the first evidence regarding whether tepotinib has a role in the treatment of Asian patients with gefitinib-resistant, c-Met-positive, T790M-negative NSCLC.

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    P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P3.01-011 - Antitumor Activity of Tepotinib plus Gefitinib in Asian Patients with Met+ EGFRm+ NSCLC (ID 763)

      09:30 - 17:00  |  Author(s): J.C. Yang

      • Abstract
      • Slides

      Background:
      c-Met abnormalities are key in resistance to EGFR TKIs in EGFRm+ NSCLC patients (pts). The highly selective c-Met inhibitor tepotinib (MSC2156119J) had promising activity in a phase I trial in pts with advanced solid tumors. We report phase Ib data from a trial evaluating tepotinib + gefitinib in pts with Met+ NSCLC (NCT01982955).

      Methods:
      Asian adults with locally advanced/metastatic NSCLC, Met+ status (2+/3+ c-Met protein overexpression by immunohistochemistry using CONFIRM anti-total c-MET [SP44] rabbit MAb [Ventana] or c-Met gene amplification on IQ FISH [Dako] [c-Met:CEP7 ratio ≥2 or <2.0 with >15 c-Met signals/cell in >10% of cells or clusters in >10% of tumor cell nuclei]) and ECOG PS 0/1 were eligible. EGFR mutation status was assessed using the therascreen[®] EGFR RGQ PCR Kit (QIAGEN). A 3+3 design was used for the phase Ib part; planned recruitment was 15-18 pts, who received tepotinib 300 or 500 mg p.o. + gefitinib 250 mg/d q3w. Primary objective: determine the RP2D of tepotinib for use in combination; secondary objectives: pharmacokinetics, safety, antitumor activity.

      Results:
      14 pts have been enrolled (median age 65 years; male 43%; ECOG PS 0/1 2/12; median prior therapy regimens including an EGFR TKI 3.5). 3 pts received tepotinib 300 mg + gefitinib and 11 tepotinib 500 mg + gefitinib. No DLTs were observed; 4 pts had grade 3/4 treatment-related adverse events (amylase increase [n=3], lipase increase [2], decreased neutrophil count [1]). Best overall response by c-Met status (cut-off Jan 20, 2015) for the 12 evaluable pts is shown in the table. EGFR mutation status for these 12 pts was T790M and L858R mutation (n=2), L858R mutation alone (4), exon 19 deletion (4), no mutation detected using the therascreen[®] kit (2).

      Best overall response (n)
      n=12 Partial response Stable disease Progression
      IHC
      2+ 0 5 2
      3+ 4 0 1
      FISH
      c-Met:CEP7 ratio >2 1 0 0
      ≥5 copies in >50% of cells 3 1 1
      Negative 0 3 2
      Not valid 0 1 0


      Conclusion:
      The RP2D of tepotinib in combination with gefitinib has been confirmed as 500 mg/d in pts with advanced NSCLC. The data show evidence of antitumor activity and that response may be associated with c-Met status. The phase II trial will randomize ≈136 pts with T790M-/c-Met+ tumors who have failed first-line gefitinib to tepotinib 500 mg/d + gefitinib or cisplatin/pemetrexed.

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