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J. Wolf

Moderator of

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    MO18 - NSCLC - Targeted Therapies IV (ID 116)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 13
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      MO18.01 - An analysis of the relationship of clinical activity to baseline EGFR status, PD-L1 expression and prior treatment history in patients with non-small cell lung cancer (NSCLC) following PD-L1 blockade with MPDL3280A (anti-PDL1) (ID 2347)

      16:15 - 16:20  |  Author(s): L. Horn, R.S. Herbst, D. Spigel, S.N. Gettinger, M.S. Gordon, A. Hollebecque, L. Gandhi, E. Felip, R. Heist, A. Mokatrin, M. Kowanetz, D. Waterkamp, G. Fine, J. Soria

      • Abstract
      • Presentation
      • Slides

      Background
      NSCLC may utilize PD-L1 overexpression to escape immune surveillance. This mechanism has been suggested by recent clinical studies showing that NSCLC can respond to PD-L1/PD-1 blockade. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, aims to restore tumor-specific T-cell immunity by blocking PD-L1 from binding to its receptors, PD-1 and B7.1.

      Methods
      Patients received MPDL3280A IV q3w for up to 1 year in a Phase I dose escalation/expansion study. Objective response rate (ORR) was assessed by RECIST v1.1 and included unconfirmed/confirmed responses. EGFR and KRAS status was initially assessed locally by investigators. Archival tissue was analyzed centrally for PD-L1 expression by IHC.

      Results
      As of Feb 1, 2013, 52 NSCLC patients were evaluable for safety and treated at doses of 0.03-20 mg/kg. The median age of patients was 61 years (range, 24-83). 17 (33%) of patients were ECOG PS 0 and 35 (67%) of patients were ECOG PS 1. Prior treatments included surgery (89%), radiotherapy (54%) and systemic therapy (98%). 15% of patients received 1 prior regimen, 21% received 2 and 62% received ≥3. Additionally, 14%, 62% and 25% of patients were EGFR-mutation positive, EGFR WT and EGFR status unknown/undetermined, respectively, and 12%, 40% and 48% of patients were KRAS-mutation positive, KRAS WT and KRAS status unknown/undetermined, respectively. Patients received treatment with MPDL3280A for a median duration of 106 days (range 1-450). Treatment-related Gr3/4 AEs occurred in 12% of patients, including fatigue (4%) and hypoxia (4%). 1 patient experienced a Gr3/4 immune-related AE (Gr3 hyperglycemia). No Gr3-5 pneumonitis or diarrhea was reported. 41 NSCLC patients first dosed at 1-20 mg/kg prior to Aug 1, 2012, were evaluable for efficacy. An ORR of 22% (9/41) was observed in patients (squamous [n=9]/nonsquamous [n=31]) with a duration of response range of 1+ to 214+ days. Additional patients had nonconventional responses after apparent radiographic progression but were considered to have progressive disease in this analysis. All responses were ongoing or improving at data cutoff. The 24-week PFS was 46%. ORR by patient characteristics was also examined. The ORR for patients with ≤2 prior therapies was 23% (4/17) and 23% (5/22) for patients with >2 prior therapies. Additionally, the response for former/current smokers was 23% (8/35) versus 17% (1/6) for never smokers. Between EGFR-mutation positive and EGFR WT patients, the ORRs also did not differ (25% [1/4] and 19% [5/26], respectively). In contrast, PD-L1 status was associated with ORR response as patients with PD-L1–positive tumors had an ORR of 80% (4/5) and patients with PD-L1–negative tumors had an ORR of 14% (4/28). Updated data, including responses by KRAS status, will be presented.

      Conclusion
      Treatment with MPDL3280A was generally well tolerated, with no cases of Gr3-5 pneumonitis. Rapid and durable responses were observed, including in an EGFR-mutation positive patient. Responses to MPDL3280A did not appear influenced by the number of prior treatment regimens but did appear to be associated with PD-L1 tumor status. Additional studies have been initiated in NSCLC.

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      MO18.02 - Preliminary clinical safety and activity of MK-3475 monotherapy for the treatment of previously treated patients with non-small cell lung cancer (NSCLC) (ID 2416)

      16:20 - 16:25  |  Author(s): E.B. Garon, A. Balmanoukian, O. Hamid, R. Hui, L. Gandhi, N. Leighl, M.A. Gubens, J. Goldman, G.M. Lubiniecki, J. Lunceford, K. Gergich, N. Rizvi

      • Abstract
      • Presentation
      • Slides

      Background
      Currently approved cytotoxic chemotherapies for previously treated patients with NSCLC demonstrate few objective responses, which are generally of short duration, with limited impact on progression-free survival and overall survival. Programmed death-1 (PD-1) is an inhibitory T-cell co-receptor whose activation by interaction with its ligands, PD-L1 or PD-L2, can lead to suppression of antitumor immunity. Preclinical and clinical data indicate that this pathway is important in NSCLC.MK-3475 is a humanized monoclonal IgG4 antibody against PD-1.

      Methods
      MK-3475 was administered at 10 mg/kg every three weeks to patients with NSCLC previously treated with two systemic regimens. At least one measurable tumor lesion, ECOG performance status of zero or one, and adequate laboratory function were required for eligibility. A new tumor biopsy no earlier than 60 days before the first dose of MK-3475 was required for study entry. Imaging assessments per investigators were performed every nine weeks until confirmed disease progression utilizing the immune-related response criteria (irRC). Independent central review of images was assessed with RECIST v1.1. PD-L1 expression on the pretreatment tumor sample was determined by immunohistochemistry. A cut-point associated with the Youden Index of the receiver-operating characteristic curve for PD-L1 staining was identified.

      Results
      Between April 2012 and September 2012, thirty-eight patients were enrolled. Median age was 63 years (range, 34-85 years), with 42% men and 42% with an ECOG performance status of zero. Previously treated, stable brain metastases were allowed and were present in 10%. Seven patients had an EGFR mutation, eight patients had a KRAS mutation, and one patient had an ALK gene rearrangement in their tumor. Fifty percent of patients experienced drug-related adverse events; the most common were fatigue, rash, and pruritus (16% each). The incidence of diarrhea was 13% (only grade 1 or 2 reported). One case of a drug-related grade 3-4 adverse event (grade 3 pulmonary edema: 3%) was seen. There were no drug-related fatalities. Using investigator-assessed irRC, the objective response rate (ORR; confirmed and unconfirmed) was 24%, including squamous and nonsquamous subtypes. Similar results were obtained using RECIST v1.1, yielding an ORR (confirmed and unconfirmed) of 21%. Most responses by irRC were observed by the time of first planned assessment at Week 9. The median duration of response by irRC has not been reached, with a median duration of follow-up of 9 months (minimum, 6 months). As of June 2013, seven of the nine responding patients by irRC continue on therapy. Pretreatment tumor PD-L1 expression was a statistically significant predictor of response. In patients with evaluable tumor PD-L1 expression, all confirmed responses by RECIST v1.1 (and irRC) occurred in patients with tumors strongly positive for PD-L1.

      Conclusion
      MK-3475 is generally well tolerated in previously treated patients with advanced NSCLC and provides durable objective responses. An additional cohort of patients whose tumors express PD-L1 is enrolling; preliminary safety and efficacy data, including PFS and OS, will be reported further at the World Conference on Lung Cancer 2013.

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      MO18.03 - Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with non-small cell lung cancer (NSCLC): overall survival and long-term safety in a phase 1 trial (ID 2356)

      16:25 - 16:30  |  Author(s): J.R. Brahmer, L. Horn, S.J. Antonia, D. Spigel, L. Gandhi, L.V. Sequist, V. Sankar, C.M. Ahlers, J.M. Wigginton, G. Kollia, A. Gupta, S.N. Gettinger

      • Abstract
      • Presentation
      • Slides

      Background
      Blockade of programmed death-1 (PD-1), a co-inhibitory receptor expressed by activated T cells, can overcome immune resistance and mediate tumor regression (Topalian S, et al. New Engl J Med. 2012;366:2443-54). We present long-term safety and efficacy outcomes from a phase 1 study of nivolumab, a fully human IgG4 PD-1 receptor blocking monoclonal antibody, in patients with advanced NSCLC.

      Methods
      NSCLC patients enrolled between 2008–2012 received nivolumab 1, 3, and 10 mg/kg IV Q2W on either dose escalation or subsequent expansion cohorts. Tumors were assessed (RECIST 1.0) after each 4-dose cycle. Protocol was amended (Jan. 23, 2012) to explore nivolumab’s potential to deliver prolonged overall survival (OS) for the initial and expansion cohorts and the overall population.

      Results
      129 pretreated NSCLC patients (non-squamous [n=74], squamous [n=54], unknown histology [n=1]) were treated as of March 2013. Responses (CR/PR) occurred in 22 patients (17%) and were durable (estimated median response duration, 74.0 weeks [6.1+, 133.9+]), and ongoing in 55% (12/22) of patients. The highest objective response rate (ORR) was at 3 mg/kg (24%) across NSCLC histologies. Responses were rapid; 50% of patients (11/22) demonstrated response at first tumor assessment (8 weeks). Among 12 responders who discontinued therapy for reasons other than disease progression, 3 responded for ≥24 weeks post therapy discontinuation, and all 3 had not progressed at the time of this analysis. An additional 6 of the 122 patients (5%) demonstrated unconventional “immune-related” responses (based on target lesions), but were not included among responders. Survival benefit was demonstrated by 1-year and 2-year landmark OS rates (42% and 14%; Table). Median OS was 9.6 months across doses and 14.9 months at 3 mg/kg across histologies. Median OS across doses was similar for squamous/non-squamous patients. Any grade drug-related select adverse events (AEs) occurred in 41% (53/129) of patients (grade 3/4 select AEs, 5% [6/129]); most common being skin (16%), gastrointestinal (12%), and pulmonary (7%). Any grade drug-related pneumonitis occurred in 6% (8/129) of patients (grade 3/4 pneumonitis, 2% [3/129]), resulting in 2 deaths early in the trial, leading to increased emphasis on management algorithms. Characteristics and management of nivolumab-related pneumonitis will be summarized.

      Cohort Dose, mg/kg ORR[a] no. of patients/total no. of patients (%) [95% CI] Estimated median response duration, wk (range) Median OS,[b] mo (95% CI) OS rate, % (95% CI); patients at risk, n
      1 y 2 y
      NSCLC (n=129)[c] All doses 22/129 (17.1) [11.0, 24.7] 74.0 (6.1+, 133.9+) 9.6 (7.8, 12.4) 42 (33, 51); 43 14 (4, 24); 5
      1 1/33 (3.0) [0.1, 15.8] 63.9 (63.9, 63.9) 9.2 (5.6, 11.1)
      3 9/37 (24.3) [11.8, 41.2] NR (16.1+, 133.9+) 14.9 (9.5, NE)
      10 12/59 (20.3) [11.0, 32.8] 83.1 (6.1+, 117.1+) 9.2 (5.2, 12.4)
      Initial cohort (n=19) All doses 9.6 (4.5, 19.8) 42 (20, 64); 8 26 (7, 46); 5
      Expansion cohort (n=110) All doses 9.9 (7.8, 12.5) 42 (32, 51); 35
      Squamous (n=54) All doses 9/54 (16.7) [7.9, 29.3] NR (16.1, 133.9+) 9.2 (7.3, 12.5) 39 (25, 53); 16
      1 0/15 0 8.0 (2.6, 13.3)
      3 4/18 (22.2) [6.4, 47.6] NR (16.1, 133.9+) 9.5 (6.7, NE)
      10 5/21 (23.8) [8.2, 47.2] 83.1 (16.1, 117+) 10.5 (7.8, 12.5)
      Non-squamous (n=74) All doses 13/74 (17.6) [9.7, 28.2] 63.9 (6.1+, 74.0+) 10.1 (7.2, 13.7) 43 (31, 54); 26
      1 1/18 (5.6) [0.1, 27.3] 63.9 (63.9, 63.9) 9.9 (5.6, 22.7)
      3 5/19 (26.3) [9.1, 51.2] 74.0 (24.3, 74.0+) 18.2 (10.3, 18.2)
      10 7/37 (18.9) [8.0, 35.2] NR (6.1+, 65.7+) 7.4 (4.6, 12.4)
      [a]ORR = ([CR + PR] ÷ n) × 100.[b]OS estimates after 1 year reflect censoring and shorter follow-up for patients enrolling later in the study.[c]Non-squamous (n=74), squamous (n=54), and unknown histology (n=1) NE = not estimable; NR = not reached.

      Conclusion
      In advanced NSCLC patients, nivolumab produced durable responses and survival benefit (1-year OS rate, 42%), with a long-term safety profile acceptable for the outpatient setting, supporting ongoing development in phase 3 trials with survival endpoints. Additional follow-up on patient survival will be presented at the time of the meeting.

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      MO18.04 - MUC1-targeted dendritic cell-based vaccines in patients with standard treatments-refractory non-small-cell lung cancer (ID 3215)

      16:30 - 16:35  |  Author(s): K. Teramoto, J. Hanaoka, N. Tezuka, Y. Daigo

      • Abstract
      • Presentation
      • Slides

      Background
      MUC1, a tumor antigen, has been considered to be a promising target antigen for cancer immunotherapy because it possesses a potent immunogenicity. It is processed and presented by antigen-presenting cells in a MHC-unrestricted pattern. Dendritic cell-based vaccine immunotherapy can elicit antigen-specific cytotoxic T lymphocytes in tumor-bearing hosts, and activated cytotoxic T lymphocytes are expected to attack cancer cells. In this study, we evaluated the efficacy of MUC1-targeted dendritic cell-based vaccine immunotherapy in patients with standard treatments-refractory advanced non-small-cell lung cancer (NSCLC).

      Methods
      The eligibility criteria of this immunotherapy were as follows: histologic or cytologic evidence of NSCLC that express MUC1 protein abundantly; an Eastern Cooperative Oncology Group performance status of 0-2; advanced stage of diseases refractory to any standard cancer treatments. The dendritic cells were prepared from peripheral blood mononuclear cells with cytokines interleukin-4 and granulocyte macrophage colony stimulating factor, pulsed with MUC1 peptides, and subsequently administered to patients by subcutaneous injection. The vaccinations were repeated bi-weekly, and assessable patients were received at least 6 vaccinations. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors. Adverse events were graded according to National Cancer Institute Common Toxicity Criteria.

      Results
      From June 2005 to December 2012, 36 patients were treated with dendritic cell-based vaccines, and 25 patients (69.4%) with median age of 61 years (range, 49-84 years) were assessable for tumor responses. The cohort consisted of 14 males and 11 females, and 22 patients had adenocarcinomas; 2 patients with squamous cell carcinomas and 1 patient with pleomorphic carcinoma. Among these patients, neither complete response nor partial response was obtained. Fourteen patients had progressive disease as the best response, and 10 patients had stable disease, yielding overall disease control rate of 40.0% (95%CI=20.8-59.2). Median survival time after the vaccines was 10.0 months, and 1-year survival rate was 32.3%. Adverse events related to the vaccines were less frequent. Immunological responses could be monitored in five patients, showing that MUC1-specific cytotoxic responses of effector immune cells were achieved in all of those patients, and the population of regulatory T lymphocytes in peripheral blood cells was decreased after the vaccines.

      Conclusion
      MUC1-targeted dendritic cell-based vaccine immunotherapy is feasible, and has a potential to control the diseases in patients with refractory NSCLC.

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      MO18.05 - DISCUSSANT (ID 3957)

      16:35 - 16:45  |  Author(s): P.M. Ellis

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MO18.06 - BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 1949)

      16:45 - 16:50  |  Author(s): V. Papadimitrakopoulou, I. Wistuba, J.J. Lee, A. Tsao, N. Kalhor, F. Fossella, J.V. Heymach, A. White, S.N. Gettinger, K.R. Coombes, P. Saintigny, X. Tang, E. Duffield, J. Boyer, C. Wei, G. Powis, D.J. Mauro, E.H. Rubiin, W.K. Hong, R. Herbst

      • Abstract
      • Presentation
      • Slides

      Background
      Effective therapeutic strategies for mutant KRAS and other biomarkers of resistance in refractory NSCLC remain an unmet medical need, while a personalized medicine approach is increasingly adopted in NSCLC guided by tumor molecular profiling. The BATTLE-2 clinical study is using EGFR, PI3K/AKT and MEK inhibitors and is designed to identify biomarkers for optimal patient selection for these therapies (ClinicalTrials.gov NCT01248247).

      Methods
      This is a four-arm, open-label, multi-center, biopsy-driven, adaptive randomization, phase II clinical trial in NSCLC pts that failed at least 1 prior line of therapy. Patients are adaptively randomized to 4 arms: erlotinib, erlotinib plus the AKT inhibitor MK-2206, MK-2206 plus the MEK inhibitor selumetinib, and sorafenib. The primary objective is 8-week disease control rate (DCR). The trial is conducted in 2 stages. In Stage 1, 200 evaluable pts are adaptively randomized (AR) based on observed 8-week DCR and KRAS mutation status while predictive biomarkers are being developed by means of gene expression profiling, targeted next generation sequencing and protein expression. EGFR sensitizing mutations and EML4/ALK translocation in pts that are erlotinib and crizotinib naïve are exclusion criteria, while erlotinib resistant patients are excluded from erlotinib monotherapy. In Stage 2, the AR model is refined to include the most predictive biomarkers tested in Stage 1, with subsequent Stage 2 AR based on the new algorithm, to a total of 400 evaluable pts. Selection of Stage 2 single and/or composite markers follows a rigorous, internally and externally reviewed statistical analysis that follows a training, testing methodology with validation in stage 2 of the trial. All Stage 1 and 2 randomization biomarker assays are CLIA-certified.

      Results
      286 pts have been enrolled, 236 biopsies performed,172 pts randomized, and 167 pts treated. 144 pts are evaluable for the 8-week DCR endpoint. Within the randomized pts group KRAS mutation rate is 22.8%, and EGFR mutation rate 14.8%, while 36.3% patients have been previously treated with erlotinib. Treatment is well tolerated with no unanticipated toxicity.

      Conclusion
      Accrual updates, demographics, and further details will be presented at the meeting. (Supported by NCI R01CA155196-01A1)

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      MO18.07 - The Network Genomic Medicine: A prospective comprehensive molecular screening network for NSCLC (ID 2898)

      16:50 - 16:55  |  Author(s): M. Bos, M. Gardizi, L.C. Heukamp, S. Merkelbach-Bruse, H. Schildhaus, M. Scheffler, L. Nogová, C. Mattonet, M. Serke, W.J. Randerath, S. Krüger, T.H. Brümmendorf, U. Gerigk, J. Panse, Y.D. Ko, B. Kaminski, M. Reiser

      • Abstract
      • Presentation
      • Slides

      Background
      The potential of personalized medicine for improvement of lung cancer patient outcome has been paradigmatically shown by the treatment of advanced EGFR mutation- and ALK translocation positive NSCLC patients with the respective tyrosine kinase inhibitors. Furthermore numerous targeted drugs for molecular defined subgroups of NSCLC (e.g. ROS1- rearrangements) are in clinical development with the potential to improve outcome. Therefore one of the major challenges today is the implementation of comprehensive high-quality real time molecular diagnostics and personalized therapy for all NSCLC patients regardless of where they are treated.

      Methods
      To increase the availability of molecular testing and subsequently personalized treatment options for NSCLC patients in the catchment area of our cancer center, we established the Network Genomic Medicine (NGM) in January 2010. NGM is a collaborative network currently encompassing more than 40 different health care providers representing the full spectrum of lung cancer care in Germany including university hospitals, large non-university lung clinics and office based oncologists. NGM is based at the Center for Integrated Oncology (CIO), i.e. the joint comprehensive cancer center of the University Hospitals of Cologne and Bonn. At the NGM - headquarter genetic and clinical data are analysed and patients without approved targeted treatment options are screened for recruitment into NGM-linked personalized trials offered by the Lung Cancer Group Cologne (LCGC). Before the introduction of routine Next Generation Sequencing (NGS) within NGM in 06/2013 we screened lung adenocarcinomas (AD) via single gene assays for mutations in EGFR, KRAS, BRAF and PIK3CA, for amplifications in HER2 and translocations in ALK, ROS1 and RET. Squamous cell lung cancer (SCC) patients were screened for amplifications in FGFR1 and mutations in DDR2.

      Results
      We screened 5,145 lung cancer patients from January 2010 till April 2013. Genomic testing was feasible in 3,863 tumor samples (75%). 63% of the patients were male and 65% of samples were AD. In AD the following frequencies of genetic lesions were detected: EGFR 13.8% (288/2078); ALK 3.3% (54/1618); KRAS 33.8% (831/2457); BRAF 3.5% (76/2123); PIK3CA 3.1% (70/2190); HER2 amplified 3.6% (62/1717); RET 4.7% (4/85) and ROS1 5.1% (7/135). In SCC we found a frequency of 21% (279/1333) for FGFR1 amplification and 2.1% (11/505) for DDR2 mutations. Further we saw 18 KRAS/PIK3CA, 5 EGFR/PIK3CA, 5 BRAF/PIK3CA double mutant samples and 3 samples where a FGFR amplification was co-occurring with a DDR2 mutation. Overall 40% of NSCLC patients harboured a potentially targetable molecular alteration. In addition we could allocate more than 40 patients to early personalized clinical trials via the close collaboration of the partners within NGM and LCGC. *The frequencies of RET and ROS1 are biased, because of a preselection of pan negative patients.

      Conclusion
      NGM is one of the largest prospective molecular screening efforts for NSCLC worldwide, with currently more than 3000 samples analysed per year. Our experiences so far underline that central comprehensive high-quality real time molecular diagnostics is feasible in a large health care provider network and allows implementation of personalized medicine in routine clinical care of lung cancer patients.

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      MO18.08 - Phase II/III Biomarker-Driven Master Protocol for Second Line Therapy of Squamous Cell Lung Cancer (SCCA). (ID 1958)

      16:55 - 17:00  |  Author(s): V. Papadimitrakopoulou, D. Gandara, F. Hirsch, E. Sigal, M. Redman, J. Allen, P. Mack, I. Wistuba, R. Herbst

      • Abstract
      • Presentation
      • Slides

      Background
      There are few new effective therapeutic options for patients with advanced, lung SCCA; overall survival for metastatic disease being less than one year. The Cancer Genome Atlas (TCGA) project and similar studies have detected a significant number of somatic gene mutations/amplifications in patients with this disease, some of which are targetable by investigational agents. However, the frequency of these changes is low (5-20%) in these patients, making recruitment and treatment very challenging in the traditional single-agent trial setting. Our approach is to use a common platform (Next Generation DNA Sequencing) to enable a single “umbrella screening protocol” to efficiently find patients with varied, uncommon molecular changes.

      Methods
      Figure 1 This is a prospective, multi-substudy randomized Phase II/III Master Registration Protocol in which patients with advanced stage Lung SCCA (2[nd] line therapy)are randomized to biomarker-driven targeted therapy (TT) or standard of care (SOC) as shown in the schema after undergoing genomic screening. Genomic screening of a large patient resource provided by sites participating in the NCI North American Intergroup will identify molecular targets/biomarkers with an analytically validated diagnostic assay and a new drug match, leading to appropriate drug treatment-arm assignment. Archival FFPE tumor and/or core needle biopsies will be screened by a broad analytically validated next generation sequencing (NGS) platform centrally to establish eligibility within 10-14 days. This platform will be supplemented by individual immune-histochemical (IHC) protein assays performed in a CLIA setting as necessitated by the specific experimental agent used. Patients will be screened with homogeneous eligibility criteria. The overall trial objective is to establish a mechanism to genomically screen large but homogeneous cancer populations and subsequently assign and accrue simultaneously to multiple substudies comparing new TT to SOC therapy based on the identified therapeutic biomarker-drug combination. Each sub-study will function autonomously and will open and close independently of the other sub-studies. Drug combinations in the experimental arm will be allowed in appropriate settings and where appropriate the control arm may consist of FDA approved targeted therapy such as erlotinib. Each sub-study is independently powered for OS with an interim analysis for PFS to determine the “go-no go” decision to proceed from Phase II into Phase III. Each agent, along with the paired biomarker, that is successful at the interim analysis based on PFS will advance to a Phase III randomized registration trial (on behalf of the Master Protocol Steering Committee).

      Results
      NA

      Conclusion
      NA

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      MO18.09 - DISCUSSANT (ID 3958)

      17:00 - 17:10  |  Author(s): J.R. Brahmer

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MO18.10 - Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with pemetrexed in a phase 1/1B trial involving <em>KRAS</em>-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): efficacy and biomarker results (ID 2922)

      17:10 - 17:15  |  Author(s): J. Mazieres, D.R. Gandara, N.B. Leighl, J.J. Wheler, F. Barlesi, G. Zalcman, K. Kelly, K.L. Reckamp, M.S. Gordon, S. Hiret, F.A. Shepherd, F. Janku, B.C. Cho, K. Park, J.R. Infante, D.A. Richards, Y. Wu, D.J. Schramek, D.S. Cox, A.M. Piepszak, Y. Liu, O.S. Gardner, V.G.R. Peddareddigari, G.R. Blumenschein

      • Abstract
      • Presentation
      • Slides

      Background
      KRAS is the most frequently mutated oncogene in NSCLC and represents an unmet need for targeted therapy. Trametinib plus pemetrexed enhances growth inhibition and apoptosis of NSCLC cell lines with and without RAS/RAF mutations in vitro when compared with either agent alone.

      Methods
      This 2-part, multi-arm, open-label phase 1/1B study evaluated the safety and efficacy of trametinib plus chemotherapy (NCT01192165). Part 1 determined the recommended phase 2 dose (RP2D) for trametinib (1.5 mg daily) and pemetrexed (500 mg/m[2] every 3 weeks) in patients with advanced solid tumors. In part 2, patients with NSCLC were stratified as KRAS WT or KRAS-mutant and treated at the RP2D. Primary study objectives were safety and tolerability; secondary objectives were efficacy and pharmacokinetics (PK). Next-generation sequencing was used to perform exploratory mutational profiling on available archival tissue from 21 patients (50%). Plasma from 38 patients (90%) was analyzed both for tumor-derived mutations in cell-free DNA (eg, KRAS, EGFR) using BEAMing technology as well as cytokine and angiogenic factors using a Searchlight multiplex assay.

      Results
      A total of 42 patients with NSCLC (19 KRAS WT [79% ≥ 2 prior therapies; 74% prior pemetrexed; 16% squamous] and 23 KRAS-mutant [57% ≥ 2 prior therapies; 43% prior pemetrexed; 4% squamous]) were enrolled and treated at the RP2D until disease progression or unacceptable toxicity. Safety and PK data were previously reported (ASCO 2013). Response rate was 17% and disease control rate was 69% for the whole population of NSCLC. Of note, we observed disease control in 75% of patients previously treated with pemetrexed (including 4 partial responses [PRs]) and in 2 patients out of 4 with squamous histology (including one PR). Progression-free survival (PFS) was 5.1 months for all patients with NSCLC. Detailed efficacy results according to mutation status are shown in Table 1. Among KRAS WT, activity was seen in cancers with EGFR mutations or ALK rearrangement. Final biomarker analyses, including assessment of their potential correlation with therapeutic response or resistance, are ongoing and will be reported upon completion. Figure 1

      Conclusion
      MEK inhibition with trametinib + pemetrexed demonstrated activity in both KRAS-mutant and WT NSCLC; efficacy data are encouraging and warrant further study. There was no significant difference in activity or efficacy across KRAS mutation subtypes. Interestingly, activity with this combination was broad and was seen in patients with squamous histology, patients with prior pemetrexed treatment, and those with EGFR mutation or ALK translocation.

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      MO18.11 - Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with docetaxel in a phase 1/1B trial involving <em>KRAS</em>-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): efficacy and biomarker results (ID 2411)

      17:15 - 17:20  |  Author(s): J. Bennouna, N.B. Leighl, K. Kelly, G.R. Blumenschein, G. Zalcman, C. Audebert, C. Gomez-Roca, K.L. Reckamp, J.R. Infante, P. Lara, F.A. Shepherd, F. Janku, B.C. Cho, K. Park, F.S. Braiteh, R.M. Jotte, Y. Wu, D.J. Schramek, D.S. Cox, A.M. Piepszak, Y. Liu, O.S. Gardner, V.G.R. Peddareddigari, D.R. Gandara

      • Abstract
      • Presentation
      • Slides

      Background
      KRAS is the most frequently mutated oncogene in NSCLC and represents an unmet need for targeted therapy. Trametinib enhances docetaxel-induced growth inhibition and apoptosis of NSCLC cell lines. Cell lines with the KRAS G12C point mutation, the most common KRAS mutation subtype (≈50% of KRAS-mutant NSCLC or ≈10% of all NSCLC), are more responsive to apoptosis induced by this combination.

      Methods
      This 2-part, multi-arm, open-label phase 1/1B study evaluated the safety and efficacy of trametinib plus chemotherapy (NCT01192165). Part 1 determined the recommended phase 2 dose (RP2D) for trametinib (2.0 mg daily) and docetaxel (75 mg/m[2] every 3 weeks) in the presence of growth factors in patients with advanced solid tumors. In part 2, patients with NSCLC were stratified as KRAS WT or KRAS-mutant and treated at the RP2D. Primary study objectives were safety and tolerability; secondary objectives were efficacy and pharmacokinetics (PK). Next-generation sequencing was used to perform exploratory mutational profiling on available archival tissue from 17 patients (36%). Plasma from 42 patients (89%) was analyzed both for tumor-derived mutations in cell-free DNA (eg, KRAS, EGFR) using BEAMing technology as well as cytokine and angiogenic factors using a Searchlight multiplex assay.

      Results
      A total of 47 patients with NSCLC (22 KRAS WT [64% ≥2 prior therapies; 27% squamous] and 25 KRAS-mutant [40% ≥2 prior therapies; 0% squamous]) were enrolled and treated at the RP2D until disease progression or unacceptable toxicity. Safety and PK data were previously reported (ASCO 2013). Progression-free survival (PFS) was 4.2 months for all patients; efficacy results according to mutation status are shown in Table 1. Among KRAS-mutant patients, activity and efficacy were better in G12C compared with non-G12C subtypes. Among KRAS WT, activity was seen in cancers with EGFR mutations; clinical benefit was noted in 2 patients with ALK translocation (disease control 25 weeks and 60+ weeks). Final biomarker analyses, including assessment of their potential correlation with therapeutic response or resistance, are ongoing and will be reported upon completion. Figure 1

      Conclusion
      MEK inhibition with trametinib + docetaxel (+ growth factors) demonstrated activity in both KRAS-mutant and WT NSCLC; efficacy data are encouraging and warrant further study. Cancers carrying the KRAS G12C point mutation may have improved activity and efficacy compared with non-G12C subtypes, consistent with preclinical observations. Additionally, clinical benefit with this combination was broad and was seen in patients with squamous histology and those with EGFR mutation or ALK translocation.

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      MO18.12 - Impact of <em>KRAS</em> codon sub-types in a Phase II second-line trial in <em>KRAS</em>-mutant advanced non-small cell lung cancer (NSCLC) of selumetinib plus docetaxel versus docetaxel alone (ID 3331)

      17:20 - 17:25  |  Author(s): T. Liptrot, H. Mann, I. Smith, G. McWalter, B. Dougherty, J. Walker, M.C. Orr, D. Hodgson, A.T. Shaw, J. Rodrigues Pereira, G. Jeannin, J. Vansteenkiste, C.H.E. Barrios, F.A. Franke, L. Crinò, P.A. Jänne, P. Smith

      • Abstract
      • Presentation
      • Slides

      Background
      Phase II data from patients with KRAS mutation-positive NSCLC, selumetinib (AZD6244, ARRY-142886) plus docetaxel showed promising efficacy versus placebo plus docetaxel alone (Jänne et al. Lancet Oncol 2013;14:38–47). Median OS was 9.4 months (95% CI 6.8–13.6) in the selumetinib group and 5.2 months (95% CI 3.8–non-calculable) in the placebo group (HR for death 0∙80, 80% CI 0.56–1.14; one-sided p=0.21). Median PFS was 5.3 months (95% CI 4.6–6.4) and 2.1 months (95% CI 1.4–3.7), respectively (HR for progression 0∙58, 80% CI 0.42–0.79; one-sided p=0.014). 37% of patients in the selumetinib group and 0% in the placebo group had an objective response (two-sided p<0.0001). The KRAS mutation codon subtype might impact on prognosis and/or response to therapy. The BATTLE trial suggested that G12V or C KRAS mutations confer relatively poorer outcome within the KRAS mutant NSCLC sub-type (Ihle et al. J Natl Cancer Inst 2012;104:228–39). In cell lines carrying these codons, Akt phosphorylation but not ERK phosphorylation was low compared with other codons, suggesting these codons might confer greater dependence upon MEK/ERK signaling. We sought to understand if any codons or combinations of codons selected for striking treatment effects either between or within treatment groups in the Phase II study.

      Methods
      Post-hoc analysis explored the hypotheses that patients whose tumours carried G12C or G12V KRAS mutations would have a worse prognosis and that these patients would have a better outcome with the addition of selumetinib. Clinical benefit was measured by PFS, OS and ORR.

      Results
      G12V or G12C mutations were present in 57% of patients and whilst not reaching statistical significance, trends for PFS, OS and ORR support the hypothesis (see table, PFS). Patients with G12V mutations responded better to selumetinib plus docetaxel than other patients as measured by change in tumour size at week 6 (G12V=-62%, G12C=-8%, G12D=+3%, reduction across all codons=-18%; two sided p=0.007). It is therefore possible that trends supporting the primary hypothesis were driven by effects in the small number of G12V codons (n=9). Table. Summary of analysis of progression-free survival (PFS): MITT by mutation subgroup

      Subgroup Selumetinib + docetaxel, n (number of PFS events) Docetaxel, n (number of PFS events) Selumetinib + docetaxel vs docetaxel, PFS HR (80% CI)
      G12C or G12V 24 (18) 23 (21) 0.48 (0.31–0.74)
      Other 19 (17) 17 (15) 0.72 (0.44–1.16)
      Overall 43 (35) 40 (36) 0.58 (0.42–0.79)

      Conclusion
      Any impacts of codon sub-type on the treatment effect in this trial were not sufficiently significant to be detected in this small Phase II trial of 87 patients, but the trends observed in this retrospective subgroup analysis warrant monitoring of the impact of specific codons or groups of codons in future clinical trials.

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      MO18.13 - DISCUSSANT (ID 3959)

      17:25 - 17:35  |  Author(s): E. Kim

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MO10 - Molecular Pathology II (ID 127)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      MO10.04 - High throughput parallel amplicon sequencing of common driver mutations from FFPE lung cancer samples in molecular pathological routine diagnostics for a regional health care provider network (ID 2145)

      16:30 - 16:35  |  Author(s): J. Wolf

      • Abstract
      • Presentation
      • Slides

      Background
      Treatment paradigms for non–small-cell lung cancer (NSCLC) have shifted from one based only on histology to one that incorporates molecular subtypes involving particular genetic alterations such as activating mutations in EGFR or translocations of ALK. The list of therapeutically targetable lesions is rapidly increasing including mutations in genes such as EGFR, HER2, KRAS, ALK, BRAF, PIK3CA, AKT1, ROS1, NRAS, FGFR1 and MAP2K1. Analysis of these potential targets is becoming a challenge in terms of work load, tissue availability as well as cost. Within the Network Genomic Medicine Lung Cancer (NGM), a regional molecular screening network of the Center for Integrated Oncology Köln Bonn, we aimed to improve on the sequential analysis of a set of 9 target amplicons by Sanger sequencing using bench top ultra-deep parallel sequencing platforms. We aimed to reduce 1) the time requirement for comprehensive molecular diagnostics, 2) the minimal amount of formalin fixed paraffin embedded (FFPE) derived input DNA, 3) while at the same time increasing the number of target regions analysed.

      Methods
      We established a multiplex PCR to amplify up to 640 lung cancer relevant target regions from at least 20ng of FFPE derived tumor DNA. The amplicon libraries were ligated to adapters encompassing medical identifier sequences that allowed multiplexing of up to 48 patients. The resulting libraries were sequenced on a benchtop Illumina platform (MiSeq). Mutations identified by parallel sequencing were confirmed by Sanger sequencing.

      Results
      330 patients were analyzed both by traditional single PCR based Sanger sequencing of 9 amplicons and the newly established parallel sequencing protocol. We found that the NGS approach worked reliably, was less prone to sequencing analysis errors and that the time needed to complete the mutation screening was significantly reduced to 7 working days from previously 21 days. A total of at least 300ng of DNA was needed to complete the analysis of 9 amplicons by Sanger sequencing compared to 20 to 100ng of DNA needed for up to 640 amplicons analyzed by parallel sequencing.

      Conclusion
      Newly multiplex PCR based parallel sequencing allows rapid comprehensive mutation testing in routine molecular pathological diagnostics even on small FFPE embedded transbronchial biopsies.

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    O04 - Molecular Pathology I (ID 126)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      O04.01 - Identification of CD74-NRG1, a new recurrent fusion gene in invasive mucinous lung adenocarcinomas of never smokers (ID 4022)

      10:30 - 10:40  |  Author(s): J. Wolf

      • Abstract
      • Presentation
      • Slides

      Background
      Lung adenocarcinoma (AD) of patients who have never smoked frequently bear targetable genome kinase alterations, such as EGFR mutations and translocations affecting ALK, ROS1, and RET genes. These mutations correlate with kinase inhibitor sensitivity in mouse models or in patients. Unfortunately, therapeutically relevant kinase alterations are not present in all lung cancer specimens. Thus, additional genome alterations need to be discovered in order to provide a therapeutic opportunity for the remaining patients.

      Methods
      We collected a cohort of 25 AD specimens of never smokers lacking mutations in KRAS or EGFR, in which we performed transcriptome sequencing with the aim of identifying new oncogenic driver genes.

      Results
      We were able to identify known kinase fusions affecting ALK, ROS1 and RET genes in 3 cases each. Moreover, we detected one sample carrying a novel chimeric transcript fusing the first six exons of CD74 to the EGF-like domain of the NRG1 III-β3 isoform, leading to the expression of its EGF-like domain in an otherwise NRG1-negative tumor tissue. The fusion gene was further detected in four additional cases out of 94 pan-negative* ADs of never smokers. In total, all 5 cases were identified in stage I invasive mucinous lung adenocarcinomas (IMA) of never smoker females. This tumor type frequently presents with multifocal unresectable disease, for which no effective treatment has been yet established. IMA is highly associated with KRAS mutations; indeed, out of 15 IMA analysed, 6 carried a KRAS mutation (40%), and 4 the CD74-NRG1 fusion (27%). Given the fact that NRG1 signals through ERBB3 and ERBB4 receptors, we aimed to determine which receptor CD74-NRG1 provides the ligand for. We observed that ERBB4 was not expressed in the index case, while ERBB3 was relatively highly expressed and this expression also correlated with a positive phospho-ERBB3 (p-ERBB3) signal in the tumoral tissue of all 5 CD74-NRG1 positive cases. In order to test if this phosphorylation of ERBB3 was statistically significant, we stained a cohort of 241 ADs and found that p-ERBB3 was only positive in 6 of them (p-value<0.0001). Additionally, although both EGFR and ERBB2 were expressed in the index case, only ERBB2 expression correlated with a p-ERBB2 positive signal. These data suggest that CD74-NRG1 might provide the ligand for ERBB3, which may form heterodimers with ERBB2, since ERBB3 is devoid of intrinsic kinase activity and cannot support linear signaling in isolation. This is in line with previous studies showing that NRG1 induces an oncogenic signal through ERBB2-ERBB3 heterodimers engaging the PI3K-AKT pathway. This was further supported by the activation of the PI3K-AKT, but not the MAPK pathway, in CD74-NRG1 transduced H2052 lung cells, after 24h starvation. *pan-negative: EGFR, KRAS, ALK, HER2, BRAF, ROS1 and RET wild-type

      Conclusion
      Altogether, these data shows that CD74-NRG1 is a new recurrent oncogenic fusion gene, highly associated with IMA of never smokers. It also suggests that CD74-NRG1 fusion protein signals through the ERBB2-ERBB3 receptors complex leading to the activation of the PI3K-AKT pathway, providing a therapeutic opportunity for a tumor type with, so far, no effective treatment.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 3
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      P1.11-041 - Overall survival of ALK translocation - and of EGFR mutation positive NSCLC patients treated with and without personalized therapy. A retrospective analysis within the Network Genomic Medicine (ID 2916)

      09:30 - 09:30  |  Author(s): J. Wolf

      • Abstract

      Background
      Erlotinib, Gefitinib and Crizotinib have been approved by the European Medicines Agency (EMA) for the treatment of molecular defined patient subgroups with advanced EGFR mutation positive (EGFR M+) and ALK translocation positive (ALK +) NSCLC, respectively. In randomized clinical trials for ALK + and EGFR M+ patients comparing standard chemotherapy to TKI treatment so far no significant improvement in overall survival (OS) could be shown, based on the high crossover rate of patients initially treated in the standard chemotherapy arm into the TKI arms upon progression. Since prevention of crossover is obsolete due to ethical reasons, registry data may gain in importance for investigating the impact of new effective targeted drugs on OS in the near future.

      Methods
      Since January 2010 EGFR sequencing and ALK FISH analysis for lung adenocarcinoma was performed within the Network Genomic Medicine (NGM) as part of a broad genetic screening effort. This included mutation screening for EGFR, KRAS, BRAF and PIK3CA as well as HER2 amplification and recently also translocations of RET and ROS. Clinical and follow-up data were extracted from medical records, directly collected from physicians and patients and additionally matched with data of the Epidemiological Cancer registry of North Rhine-Westphalia, Germany.

      Results
      So far, we included a total of 44 ALK+ and 143 EGFR M+ patients into our analysis. The median age of the ALK + and EGFR M+patients was 53.5 yrs and 71 yrs, respectively. 39% of the ALK+ patients received crizotinib and 54% of the EGFR M+ patients received an EGFR TKI during the course of their disease. The median OS (mOS) of patients with an initial stage IIIb/IV was 14 months (95% CI 6.2 - 21.8) for ALK+ and 29 months (95% CI 16 - 41) for EGFR M+ patients. Both groups showed a significant difference in mOS when separated by targeted treatment status. ALK+ patients who received crizotinib had a mOS of 23 months (95% CI 12.2 - 33.8) and patients who did not receive crizotinib had a mOS of 8 months (95% CI 0.0 - 17.4) (p = 0.01). EGFR M+ patients who received an EGFR TKI had a mOS of 31 months (95% CI not computable) and patients who did not receive an EGFR TKI had a mOS of 9 months (95% CI 4.9 - 13.1) (p < 0.001). There were no significant differences with regard to treatment of a platinum-containing chemotherapy, age or sex between the two groups.

      Conclusion
      Screening patients for genetic driver mutations identified patients with EGFR mutations and ALK translocations that were not treated with a kinase inhibitor. Comparing these cohorts of patients that only received standard chemotherapy to those subsequently treated with a personalized approach showed a significant improvement in OS. This confirms the predictive value of ALK translocations and EGFR mutations for treatment with the respective TKIs

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      P1.11-042 - SORAVE: Sorafenib and everolimus for patients with solid tumors and with KRAS mutated NSCLC - results of a phase I study. (ID 3068)

      09:30 - 09:30  |  Author(s): J. Wolf

      • Abstract

      Background
      Inhibition of signaling pathways interfering with cell proliferation and angiogenesis may increase anti-tumor efficacy. Sorafenib as well as mTOR inhibitors showed preliminary activity in KRAS mutated NSCLC.

      Methods
      In the dose escalation part, patients with relapsed solid tumors were treated with escalating doses of everolimus from 2.5-10.0 mg daily p.o. in a 14 days run-in phase followed by the combination with a fixed dose of sorafenib 400 mg bid p.o. The extension phase is currently recruiting patients with KRAS mutated NSCLC. The KRAS mutation status is determined by PCR based high resolution melting curve analysis (HRM) on DNA extracted from FFPE material and validated using Sanger sequencing. HRM has now been replaced by multiplex PCR. Pharmacokinetic (PK) analyses are performed during run-in and during the combination. Treatment outcome is validated with CT scans on day 57.

      Results
      In the dose escalation part, 19 patients were recruited. The dose limiting toxicity (DLT) was not reached. At everolimus dose level of 10 mg/day, increased rates of grade 3 thrombocytopenia (3 patients), leukocytopenia (2 patients) and anaemia (2 patients) occurred after the DLT interval of 29 days. Based on these observations, the dose level of 7.5 mg/day everolimus in combination with 400 mg sorafenib bid was defined as a maximal tolerated dose. The AUC and Cmax values of everolimus at all dose levels were comparable on days 5 and 14. On day 29, AUC and Cmax of everolimus showed a 20 - 40% reduction when co-administered with sorafenib. The best treatment outcome on day 57 was stable disease in 11 patients. Median PFS and OS were 3.7 and 5.5 months, respectively. The extension phase in KRAS mutated NSCLC is currently ongoing. Nine patients have been recruited so far. The CT response at day 57 compared to the baseline of four evaluable patients is ranging from -22% to +5% in the sum of the longest diameter of all targeted lesions.

      Conclusion
      Treatment of patients with relapsed solid tumors with the combination of 7.5 mg everolimus p.o. daily and 400 mg sorafenib p.o. bid is safe and feasible. Current results of an extension phase in KRAS mutated NSCLC patients show preliminary clinical activity in this patient group with an unfavorable prognosis.

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      P1.11-043 - BARIS: A phase I trial to evaluate the safety and tolerability of combined BIBF 1120 and RAD001 in solid tumors and to determine the maximum tolerated dose (MTD) of the combination. (ID 3222)

      09:30 - 09:30  |  Author(s): J. Wolf

      • Abstract

      Background
      Simultaneious inhibition of several signalling pathways involved in angiogenesis as well as in tumor cell growth regulation by kinase inhibitor combination therapy may increase therapeutic efficacy. Here we evaluate the combination of the mTOR-inhibitor RAD001 (everolimus) and the triple kinase (FGFR, VEGFR, PDGFR) inhibitor BIBF 1120 in a phase I trial in advanced solid tumors. In addition we use DCE-MRI for early identification of patients with benefit from BIBF 1120.

      Methods
      This is an open-label, monocentric phase I trial with 3 dosage arms in a classical „3+3“-design: Patients in arm A receive 5 mg of RAD001 and 2 x 150 mg BIBF 1120, in arm B 10 mg RAD001 and 2 x 150 mg BIBF 1120 will be administered, whereas in arm C, 10 mg of RAD001 and 2 x 200 mg BIBF 1120 will be given. There is no interindividual dose escalation, and the enrollment of the patients will be performed sequentially. Eligible are all patients with relapsed or refractory advanced/metastatic solid tumors (UICC stage IV) and an ECOG performance state of 0-1 for whom no further standard therapies are available and who have predefined adequate organ functions. All patients will start with a 2-week run-in phase of 2 x 200 mg BIBF 1120. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scans will be performed at baseline staging, on day 3 and day 14. On day 14, there will also be 12 hours-pharmacokinetic (PK) assessment. Combination therapy within the forementioned dosage arms starts on day 15. After two weeks of combination therapy, on day 29, a DCE-MRI scan and 12-hours PK will be performed. Restaging for the evaluation of the efficacy will be performed on day 57. The safety of this combination will be assessed throughout the complete therapy phase using CTC-AE V4.0, with predefined dose-limiting toxicities (DLTs) being assessed until day 42. Patients who experience clinical benefit (i. e., response or stable disease) on day 57 with adequate tolerability of the combination will further receive the medication, as long as the benefit lasts.

      Results
      10 patients have been enrolled so far. In one patient with FGFR-amplified lung cancer, there was a partial response after six weeks of therapy. No DLTs were detected within the first dosage step. Tolerability of the combination was good, as there were no toxicities of CTC-AE grade 3 or greater. In arm B, there has been one DLT (elevation of transaminases), which turned out to be reversibel.

      Conclusion
      So far, the combination of BIBF 1120 and RAD001 seems tob e very good tolerated, demonstrating activity in a patient with NSCLC and FGFR1-amplification. Enrollment into the second dosage stage has already started. We expect the termination of the trial by winter 2013/2014.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-045 - TRY: A phase II study to evaluate safety and efficacy of combined trastuzumab and AUY922 in advanced non-small-cell lung cancer (NSCLC) with HER2 overexpression or amplification or mutation. (ID 3057)

      09:30 - 09:30  |  Author(s): J. Wolf

      • Abstract

      Background
      HER2 amplifications and/or mutations are rare genetic alterations in NSCLC accounting for approximately 4%. Preliminary clinical data suggested efficacy of trastuzumab in patients with HER2 IHC3+ status or FISH positivity. The heat shock protein HSP90 is a molecular chaperone that modulates stability and/or transport of intracellular client proteins including HER2. In breast cancer HSP90 inhibition has shown anticancer activity in HER2-positive patients after trastuzumab failure. Here we are investigating the efficacy of the combination of trastuzumab and the HSP90 inhibitor AUY922 in lung cancer patients with aberrant HER2.

      Methods
      This phase II study recruits metastatic NSCLC patients with HER2 overexpression (immunohistochemistry, DAKO-score 3+) or amplification (fluorescence in situ hybridization) or activating mutation after at least one previous standard treatment. In the first part of the study, patients are treated with trastuzumab only. CT scans are scheduled every 6 weeks during treatment. In case of disease progression, patients receive the combination of trastuzumab and AUY922.

      Results
      The study was initiated this year and NSCLC patients are screened within the Network of Genomic Medicine Lung Cancer on HER2 overexpression, amplifications and mutations. Until now, we tested 720 tumor samples by FISH and 63 by genomic sequencing. We identified 55 patients with HER2 amplification, 34 with HER2 overexpression (Dako score 3+) and 7 patients showed a mutation in the HER2 gene (1 exon 19; 6 exon 20).

      Conclusion
      HER2 overexpression, amplification or mutation is a rare genetic alteration in NSCLC patients. Data on treatment with HER2 antibody trastuzumab and HSP90 inhibitor AUY922 will be presented.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-050 - Sunitinib for the treatment of RET-translocated NSCLC: A case report (ID 693)

      09:30 - 09:30  |  Author(s): J. Wolf

      • Abstract

      Background
      RET-translocations have recently been identified as oncogenic drivers in a subset of non-small cell lung cancer (NSCLC). Up to now, there is limited information on the therapeutic value of RET-inhibitors in treating patients with RET-translocated NSCLC. Here we report on the clinical course of a patient with RET-translocated NSCLC treated with sunitinib, a multitarget tyrosinkinase-inhibitor with activity against RET.

      Methods
      A 65 year old woman with a non smoking history was diagnosed with adenocarcinoma of the left upper lobe in october 2009. Staging by CT and PET revealed stage II. Therefore the patient was referred to lobectomy plus lymphnode dissection. Pathologic work up in the following led to an upstaging to stage IIIA (pT1N2M0L1V0R0,GIII). The patient refused to get adjuvant chemotherapy but postoperative radiotherapy was applied. In may 2012 the patient developed left-sided pleural carcinomatosis and a thoracoscopic biopsy confirmed recurrence of the bronchial adenocarcinoma. Molecular workup of the available tissue showed EGFRwt and no evidence for ALK-translocation. As a platinum-based chemotherapy was not acceptable for the patient she was treated with pemetrexed monotherapy for 3 cycles leading to disease stabilization. At that timepoint the patient opted for a treatment holiday. In december 2012 CT-restaging showed progressive disease with increasing pleural tumor deposits. As the patient denied further cytostatic therapy, additional analyses for potential driver mutations were initiated and the existence of a KIF5B/RET-translocation was detected by FISH-analysis. As, at that timepoint, sunitinib was the only available RET-inhibitor at our site the patient was offered sunitinib treatment.

      Results
      Sunitinib was initiated in january 2013 (50mg qd, 4 weeks on/2 weeks off) with the patient at that timepoint not suffering from any symptoms (WHO 0). Due to severe toxicities (mucositis, fatigue, diarrhea) a dose reduction had to be performed allready during the first treatment cycle (37,5mg, 4/2 weeks). CT-restaging after 2 cycles showed stable disease. Treatment was continued, but, due to ongoing toxicities, the dose of sunitinib had to be further reduced (25mg qd, continously). In may 2013, with the patient free from tumor-associated symptoms, another CT-scan still revealed disease stabilization. At that timepoint the patient refused further treatment with sunitinib, due to subjectively inacceptable side effects (diarrhea, fatigue).

      Conclusion
      In this case of a patient with recurrent RET-translocated NSCLC treatment with sunitinib showed signs of clinical activity by inducing disease-stabilization for at least 4 months despite substantial dose reductions due to toxicities. As the patient withdrew further treatment, no further conclusions on the potential long term effects of such treatment can be drawn. Based on the preclinical evidence and the published case reports so far, testing of RET-inhibitors for the treatment of patients with RET-translocated NSCLC within prospective clinical trials is strongly recommended.