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L. Horn

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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Author of

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    MO01 - Lung Cancer Biology - Techniques and Platforms (ID 90)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO01.07 - Inhibition of the IGF-1R signaling pathway potentiates responses to ALK inhibitors in both ALK TKI naive and ALK TKI resistant lung cancer (ID 1660)

      11:00 - 11:05  |  Author(s): L. Horn

      • Abstract
      • Presentation
      • Slides

      Background
      Oncogenic fusions involving the gene encoding the anaplastic lymphoma kinase (ALK) define a new clinically relevant molecular subset of lung cancer. The majority of patients with ALK+ lung cancer are highly responsive to ALK tyrosine kinase inhibitor (TKI) therapy, however, the efficacy of these ALK inhibitors is limited by the development of acquired resistance. Additional strategies using rationally selected therapeutic agents/combinations of agents are needed to both delay and overcome acquired resistance to ALK inhibition. Based upon an intriguing clinical observation from a patient with ALK+ lung cancer who had an ‘exceptional response’ to an IGF-1R monoclonal antibody (MAb), we report a novel therapeutic synergism between ALK inhibitors and IGF-1R inhibitors.

      Methods
      A series of experimental approaches including cell culture models, in vitro assays, and a study of patient tumor samples prior to and at the time of acquired resistance to ALK TKI therapy were employed to test the hypothesis that IGF-1R can be targeted therapeutically to enhance anti-tumor responses in ALK+ NSCLC.

      Results
      Across multiple different ALK+ lung cancer cell lines, including a novel ALK+ cell line developed from a patient prior to ALK TKI therapy, IGF-1R inhibitors (TKIs and MAbs) sensitized ALK+ lung cancer cells to the effects of ALK blockade as assessed by standard cell viability assays. Similar to IGF-1R, ALK fusions co-immunoprecipitated with the adaptor protein, IRS-1, and treatment with ALK inhibitors decreased IRS-1 protein levels. Furthermore, siRNA mediated knock-down of IRS-1 impaired the proliferation of ALK+ lung cancer cells and enhanced the anti-tumor effects of ALK inhibitors. The IGF-1R pathway was activated in cell culture models of ALK TKI resistance, and combined ALK/IGF-1R inhibition in the resistant cells blocked reactivation of downstream signaling and markedly improved therapeutic efficacy in vitro. Finally, IGF-1R and IRS-1 levels were increased in biopsy samples from a patient with advanced ALK+ lung cancer post crizotinib therapy.

      Conclusion
      Collectively, these data support a role for the IGF-1R/IRS-1 signaling pathway in both the ALK TKI sensitive and ALK TKI resistant states and suggest that this rationally selected combination of inhibitors may be an effective strategy to attempt to delay or overcome acquired resistance to therapeutic ALK inhibition. Intriguingly, the ‘second generation’ ALK TKI, LDK-378, which has demonstrated an overall response rate of 70% in patients with both crizotinib naïve and crizotinib resistant ALK+ lung cancer, can inhibit both ALK and IGF-1R in vitro. We speculate, based on these data, that this surprising response rate may be due to LDK-378’s ability to simultaneously inhibit both targets.

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    MO15 - Novel Genes and Pathways (ID 89)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO15.05 - Oncogenic ARAF mutation in lung adenocarcinoma (ID 2860)

      16:35 - 16:40  |  Author(s): L. Horn

      • Abstract
      • Presentation
      • Slides

      Background
      Targeted cancer therapies often induce “outlier” responses in molecularly defined patient subsets.

      Methods
      One patient with advanced-stage lung adenocarcinoma, who was treated with oral sorafenib, demonstrated a complete clinical and radiographic remission for five years. Whole genome sequencing (WGS) and RNA sequencing (RNA-seq) on primary tumor and normal samples from this patient was performed.

      Results
      We identified a somatic mutation, ARAF S214C, present in the cancer genome and expressed at high levels. Additional mutations affecting this residue of ARAF and a nearby residue in the related kinase RAF1 were demonstrated across 1% of an independent cohort of lung adenocarcinoma cases. The ARAF mutants were shown to transform immortalized human airway epithelial cells and were associated with in vitro sorafenib sensitivity.

      Conclusion
      These results suggest that mutant ARAF may be a novel oncogenic driver in lung adenocarcinoma and an indicator of sorafenib response.

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    MO18 - NSCLC - Targeted Therapies IV (ID 116)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 2
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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

      • 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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      MO18.03 - 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): L. Horn

      • 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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    MO19 - Lung Cancer Immunobiology (ID 91)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO19.09 - Molecular correlates of PD-L1 status and predictive biomarkers in patients with non-small cell lung cancer (NSCLC) treated with the anti-PDL1 antibody MPDL3280A (ID 1653)

      11:20 - 11:25  |  Author(s): L. Horn

      • Abstract
      • Presentation
      • Slides

      Background
      In NSCLC, antitumor immune response may be inhibited by PD-L1 expression. 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 binding to its receptors, PD-1 and B7.1.

      Methods
      Patients with squamous or nonsquamous NSCLC received MPDL3280A IV q3w up to 1 year as part of 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 tumor tissues were evaluated centrally by IHC for PD-L1 and CD8. A qPCR-based gene expression panel measuring ≈90 immune-related genes was used to characterize the tumor immune microenvironment at baseline and during MPDL3280A treatment.

      Results
      41 NSCLC patients first dosed at 1-20 mg/kg prior to Aug 1, 2012, were evaluable for efficacy with an ORR of 22%. Baseline tumor samples were available for IHC (n=33) and for gene expression analysis (n=29). Of patients with available tissue, 5 were PD-L1 tumor status positive and 28 were PD-L1 tumor status negative. Relationship between PD-L1 status and EGFR/KRAS status is described below (table). Elevated baseline PD-L1 expression was associated with response to MPDL3280A (80% ORR vs 14% ORR for PD-L1negative patients), and PD-L1 expression coordinated with CD8+ T cells. A Th1-type T-cell gene signature (including CD8, Granzyme-B and EOMES) was associated with treatment response. Non-responders exhibited at least a 2-fold higher ratio over CD8 of genes associated with immunosuppression, including RORC, FOXP3, TGFb1 and IL10 compared with responders. On treatment, responding tumors across indications showed increasing PD-L1 expression and a Th1-dominant immune infiltrate, providing evidence for adaptive PD-L1 up-regulation.

      Conclusion
      PD-L1 expression and a Th1 driven T-cell gene signature correlated with response to MPDL3280A in NSCLC, and MPDL3280A therapy led to T-cell reactivation and restored antitumor immunity. Additionally, expression of immune suppressive factors in NSCLC tumors is associated with a lack of benefit from MPDL3280A. These data provide mechanistic insights into immunotherapy and patient selection for MPDL3280A monotherapy. Preliminary observations suggest clinical activity and molecular characteristics may be associated with PD-L1 tumor expression. Updated data will be presented. Table: Relationship between PD-L1 status and EGFR/KRAS mutational status

      PD-L1-Positive (n = 5) PD-L1-Negative (n = 28) PD-L1 Unknown (n = 7) Overall (n = 40)*
      EGFRm, n 1 2 1 4
      EGFR WT, n 2 20 4 26
      EGFR Unknown, n 2 6 2 10
      KRASm, n 1 4 1 6
      KRAS WT, n 2 8 3 13
      KRAS Unknown, n 2 16 3 21
      * 1 patient had missing data.

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    MO21 - Prognostic and Predictive Biomarkers V - EGFR (ID 98)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO21.10 - Serial monitoring of plasma EGFR T790M levels and evaluation of EGFR mutational status in matched tissue and plasma from NSCLC patients treated with CO-1686 (ID 2498)

      11:25 - 11:30  |  Author(s): L. Horn

      • Abstract
      • Presentation
      • Slides

      Background
      Background: We explored the minimally-invasive detection of EGFR mutations in circulating free DNA from plasma and studied the concordance of EGFR mutation status between matched plasma and tumor tissue in a cohort of newly diagnosed or relapsed patients with advanced NSCLC. CO-1686 is an oral, potent, small-molecule irreversible tyrosine kinase inhibitor that selectively targets mutant forms of EGFR, including T790M and the common initial activating mutations, while sparing wild-type EGFR. Promising clinical activity has recently been reported from an on-going Phase I/II trial.

      Methods
      Methods: Matched tumor tissue and blood from 80 Stage IIIB/IV NSCLC patients, 41 treated with CO-1686, were tested using two allele-specific PCR assays, the cobas® EGFR FFPET and cobas® EGFR blood tests. Each test detects 41 mutations in EGFR, including the T790M resistance mutation, exon 19 deletions and L858R. We also used BEAMing, a highly quantitative and sensitive technology based on digital PCR, to assess a subset of 18 patients treated with CO-1686. BEAMing was compared to cobas analysis at baseline, and also used to serially monitor plasma EGFR mutation levels in response to CO-1686.

      Results
      Results: Using tissue as reference, the positive percent agreement between tissue and plasma was 76% (44/58) for activating mutations and 63% (17/27) for T790M. The cobas® EGFR blood test identified two patients with T790M mutations in plasma that were not detected in the corresponding tumor biopsy—likely because of tumor heterogeneity. The M1a/M1b status was known for 63 EGFR mutation-positive patients. Of the 44 with extrathoracic metastatic disease (M1b), 38 were found to have an activating mutation in plasma (86%). Conversely, only 53% (10/19) of EGFR mutation-positive patients with intrathoracic metastatic disease (M1a) had detectable activating mutations in plasma (p = 0.0081). For the 18 patients profiled by BEAMing, the overall percent agreement between BEAMing and the cobas® EGFR blood test was 94% (17/18) for T790M and 83% (15/18) for activating mutations. Nine of the 18 patients had detectable baseline plasma T790M levels, and several patients treated with CO-1686 had an initial decrease in plasma T790M by BEAMing.

      Conclusion
      Conclusions: Using the cobas® EGFR blood test, a high proportion of EGFR mutations identified in tissue were also detected in plasma. Mutations were more readily detectable in the plasma of patients with M1b rather than M1a disease. These findings suggest that the cobas® EGFR blood test and BEAMing can be useful tools for the non-invasive assessment and monitoring of EGFR mutations in NSCLC patients.

      EGFR mutation Evaluable patients Patients with tissue mutations* Patients with plasma mutations** Patients with same mutation detected in tissue and plasma Positive Percent Agreement***
      L858R, del19, S768I, G719X, or ex20ins 80 58 44 44 76%
      T790M 80 27 19 17 63%
      * identified by the cobas® EGFR tissue test
      ** identified by the cobas® EGFR blood test
      ***agreement of blood and tissue mutation-positive results with tissue as reference; although tissue is reference, some mutations may be missed due to tumor heterogeneity

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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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      P2.11-038 - Efficacy of nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with previously treated advanced non-small cell lung cancer (NSCLC): subpopulation response analysis in a phase 1 trial (ID 2751)

      09:30 - 09:30  |  Author(s): L. Horn

      • Abstract

      Background
      Lung cancer is the leading cause of cancer deaths globally, and NSCLC comprises 85% of lung cancers. Patients with advanced (stage IIIB or IV) NSCLC have a poor prognosis. Current second-line chemotherapeutics demonstrate a median overall survival (OS) of 8 months and 1-year survival of 30%. Factors that may influence clinical activity include age, ECOG performance status (PS), number of prior therapies, and EGFR- and KRAS-mutation status. The immune checkpoint receptor programmed death-1 (PD-1) negatively regulates T-cell activation upon interaction with its ligands PD-L1 and PD-L2. Nivolumab, a fully human IgG4, PD-1 receptor blocking monoclonal antibody, was evaluated in a phase 1 study (CA209-003; NCT00730639) in patients with various tumors, including previously treated advanced NSCLC. In this study, treatment with nivolumab demonstrated durable objective responses and prolonged stable disease in a portion of patients from this NSCLC cohort (Topalian S, et al. N Engl J Med. 2012;366:2443-54). We present the updated findings from assessment of clinical activity to nivolumab in subpopulations of the NSCLC cohort from this study.

      Methods
      Patients received nivolumab (1–10 mg/kg IV Q2W) for ≤12 cycles (4 doses/8W cycle) or until discontinuation criteria were met. An analysis of clinical activity by select patient characteristics was performed from the NSCLC cohort of this trial.

      Results
      129 patients with NSCLC (non-squamous [n=74], squamous [n=54], unknown histology [n=1]) received nivolumab at 1, 3, or 10 mg/kg as of March 2013 (Table). Association of clinical activity with baseline characteristics will be assessed for the following subgroups: age ≥70 and <70 years, gender, ECOG PS 0 and ≥1, number of prior therapies 1–2 and ≥3, prior tyrosine kinase inhibitor (TKI) therapy, EGFR-mutation status, and KRAS-mutation status.

      Table
      Baseline characteristic[a] NSCLC patient population (n=129)
      Median age (range), y 65 (38–85)
      Gender, n (%)
      Male 79 (61)
      Female 50 (39)
      ECOG PS, n (%)
      0 27 (21)
      1 100 (78)
      2 2 (2)
      Number of prior therapies, n (%)
      1 25 (19)
      2 34 (26)
      3 27 (21)
      ≥4 43 (33)
      Prior therapy, n (%)
      Platinum-based chemotherapy 128 (99)
      TKI 36 (28)
      [a]Data on EGFR- and KRAS-mutation status are pending.

      Conclusion
      Nivolumab demonstrated encouraging clinical activity in patients with previously treated advanced NSCLC. Clinical activity by patient subgroups may provide insights into the influence of patient and tumor characteristics on response to nivolumab. An update of the data regarding clinical activity of nivolumab therapy in these subgroups of the NSCLC cohort will be presented.

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    P2.13 - Poster Session 2 - SCLC (ID 201)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.13-002 - Randomized Phase II Study of Single Agent OSI-906, an Oral, Small Molecule, Tyrosine Kinase Inhibitor (TKI) of the Insulin Growth Factor-1 Receptor (IGF-1R) Versus Topotecan for the Treatment of Patients with Relapsed Small Cell Lung Cancer (SCLC) (ID 920)

      09:30 - 09:30  |  Author(s): L. Horn

      • Abstract

      Background
      SCLC typically presents with advanced (extensive stage) disease. Despite an initial response to chemotherapy, they all relapse and rarely survive beyond 2 years. Treatment of relapsed SCLC is limited (topotecan) and dependent on the response to initial chemotherapy (sensitive vs. refractory relapse). Downstream activation of PI3K-AKT, through IGF-1R pathway signaling plays a role in both, growth/survival and resistance to chemotherapy in SCLC. Growth inhibition and chemosensitization with IGF-1R inhibitors correlates with the PI3K-AKT inhibitory signaling and suggests AKT activation as a potential biomarker. OSI-906, is a well tolerated oral, small molecule, potent inhibitor of IGF-1R

      Methods
      A phase II randomized study comparing the efficacy of OSI-906 vs topotecan in patients with rSCLC is currently being conducted. Primary endpoint is PFS, summarized with the K-M method. An increase in median PFS from 2.5 to 4.175 months (in the experimental arm B) is proposed. A total of 95 patients are planned. Biomarkers of IGF-1R inhibition are explored in plasma, PBMC and using Radiomics. Eligible patients must have proven rSCLC, platinum sensitive (sen) or resistant (res) disease, ECOG PS 0-2 and adequate hematologic, renal and hepatic function. Fasting glucose <160 mg/dl, QTc < 450 msec and measurable disease by RECIST v1.1 are required. Pregnant, breast-feeding, diabetic and cirrhotic patients as well as those taking insulin/insulinotropic agents are excluded. Patients are randomized (2:1) to the experimental arm (B): OSI-906, 150 mg PO BID, until progression or to the standard arm (A): topotecan, 1.5 mg/m[2] IV daily x5 OR 2.3 mg/m[2] PO daily x5, for 4 cycles. Crossover to OSI-906 is allowed.

      Results
      Figure 1 Thirty-three patients have been enrolled; A=10 (res=6, PS 2=2) and B=23 (res=15, PS 2=4). M/F= 13/20; ECOG PS 0/1/2 = 8/19/6. Platinum sen/res = 12/21. Two patients were not treated (A/B = 1/1). Adverse events are described in Table 1. No responses have been observed. Only 2/6 and 1/15 patients in arms A and B respectively achieved SD at 6 weeks. Median PFS (A/B) was 2.1 (95% CI; 0.6, 3.6) and 1.3 (95% CI; 1.0, 1.4) months respectively (p = 0.0149). OS was not reached in arm A and 2.7 (95% CI; 1.5, …) months in arm B (p = 0.1716).

      Conclusion
      OSI-906 is safe in rSCLC patients. In our unselected, high risk population, efficacy in both arms, but particularly in arm B appears suboptimal. The study continues to accrue to reach the sample size and follow up time needed for more robust conclusions.