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F.R. Hirsch



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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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      MO19.10 - Prevalence and prognostic association of PD-L1 protein and immune gene expression in NSCLC (ID 2437)

      11:25 - 11:30  |  Author(s): F.R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background
      Programmed Death Ligand 1 (PD-L1, CD274, B7-H1) is an immune checkpoint molecule that binds to the receptors PD-1 and B7.1 on activated T cells. Binding negatively regulates T-cell function in both physiological and pathological conditions. Recent clinical studies have suggested that numerous cancers, including NSCLC, may utilize PD-L1 expression to escape T-cell mediated cytotoxic activity. Inhibition of PD-L1 can restore anti-tumor immunity, leading to clinical responses. A better understanding of PD-L1 expression patterns, co-expression with other immune markers and actionable disease associated biomarkers may provide insight into the future design of cancer immunotherapy trials in NSCLC.

      Methods
      Expression of PD-L1 was measured by immunohistochemistry (IHC) in archival tumors and, in some cases, in paired metastases in 2 FFPE NSCLC tumor tissue collections. Set 1 (N=561) was collected from patients who were eligible for surgery with curative intent from 2003 to 2005 at MD Anderson Cancer Center. The samples from Set 2 (N=300) contained surgically resected NSCLC tissue collected between 2006 and 2011 (UCCC and Norwegian Radium Hospital). PD-L1 expression was analyzed in both malignant and non-malignant cells (e.g., infiltrating immune cells). In addition, a multiplex qPCR assay that measures ≈90 immune-related genes was used to characterize the tumor immune microenvironment in the NSCLC tumor samples. Disease associated biomarkers, including the mutation status of EGFR and KRAS, as well as expression of MET (by IHC) were also evaluated.

      Results
      Prevalence of PD-L1 was comparable between adenocarcinoma and squamous cell carcinoma (≈30% in tumor cells; ≈45% and ≈50%, respectively, in immune cells). PD-L1 prevalence varied depending on the pathological stage, and was higher in Stages I-IIIA than in Stages IIIB-IV. Similarly, the prognostic value of PD-L1 varied by both stage and histology. In adenocarcinoma, tumors with PD-L1–positive tumor cells had a higher frequency of KRAS mutation and high Met expression, and a lower frequency of EGFR mutation compared with PD-L1–negative tumors. In contrast, tumors with PD-L1–positive and PD-L1–negative immune cells had a comparable frequency of high Met expression. Expression of PD-L1 was frequently co-localized with CD8+ T-cell infiltrates. Gene expression profiling revealed differences in the tumor immune environment, including genes associated with cytotoxic T-cells, between adenocarcinomas and squamous cell carcinomas. PD-L1 protein and immune gene expression associations with patient characteristics will be described in further detail.

      Conclusion
      These data provide a comprehensive description of PD-L1 expression in the context of disease biology utilizing large independent cohorts of well-characterized lung cancer tissues. The results highlight the complexity of the tumor immune environment in NSCLC with particular emphasis on the association with factors such as pathological stage, histology and oncogenic mutational status. These analyses may help guide future development of immunotherapy trials in NSCLC.

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    O03 - NSCLC - Targeted Therapies I (ID 113)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O03.02 - Randomized Phase-3 trial (INSPIRE) of Necitumumab plus Cisplatin-Pemetrexed versus Cisplatin-Pemetrexed Alone as First-Line Therapy in Stage IV Non-Squamous NSCLC (ID 2337)

      10:40 - 10:50  |  Author(s): F.R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background
      Necitumumab is a human IgG1 anti-EGFR1 monoclonal antibody that competes for the binding of natural ligands to this receptor and prevents receptor activation. EGFR1 is detectable in approximately 85% of advanced NSCLC tumors. This phase 3 study investigated necitumumab in combination with first-line chemotherapy in advanced non-squamous NSCLC.

      Methods
      Patients with histologically or cytologically proven stage IV non-squamous NSCLC were randomized 1:1 to either Arm A: cisplatin 75mg/m[2] i.v.-pemetrexed 500mg/m[2] i.v. (Cis + PEM) on Day 1+ necitumumab 800mg i.v. on Days 1 and 8 of a 21-day cycle or Arm B: Cis+PEM alone. Patients received these regimens for up to six cycles. For patients in Arm A with at least stable disease, necitumumab continued until PD or intolerable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and EGFR protein expression level by immunohistochemistry (H-score) utilizing archived tumor tissue based on a mandatory tissue collection. The planned sample size of this study was 947 patients (assuming a hazard ratio [HR] of 0.8 would allow 85% power at 2-sided alpha level of 0.05). After 633 patients, enrollment was stopped (after Feb 2011) following an Independent Data Monitoring Committee (IDMC) recommendation.

      Results
      Between Nov 2009 and Feb 2011 633 patients were randomized (315 Arm A; 318 Arm B). Baseline characteristics were balanced between the arms; 67.0% were male and 33.0% female; ECOG-PS 0/1 94.2 % and PS 2 5.7 %. No difference between treatment arms was observed for OS (median 11.3 vs 11.5 months; HR 1.01 95%-CI [0.84, 1.21]), PFS (median 5.6 vs 5.6 months, HR 0.96 95%-CI [0.80, 1.16]) and ORR (31.1 vs 32.1%; Odds ratio 0.96 95%-CI [0.68, 1.34]). The exploratory analysis in 490 patients assessable for H-score revealed no association between H-score and differences in efficacy between treatment arms (H-score < 200: mOS 8.97 vs 9.72 months, HR 1.07, mPFS 4.90 vs 4.76 months, HR 0.95, ORR 27.1 vs 26.0%; H-score ≥ 200: mOS 15.01 vs 13.34 months, HR 1.03, mPFS 5.59 vs 5.62 months, HR 0.94, ORR 39.6 vs 39.4%). Grade ≥ 3 treatment-emergent adverse events (AEs) occurring more frequently in Arm A included skin or subcutaneous disorders (14.1 vs 0.3%), thromboembolic events (9.5 vs 6.4%), hypomagnesaemia (7.6 vs 2.2%), asthenia (6.9 vs 1.9%), vomiting (6.6 vs 3.2%), dyspnea (5.3 vs 2.6%) and diarrhea (4.3 vs 2.2%). The frequency of study drug related deaths was 4.9% and 2.9% in Arms A and B, respectively.

      Conclusion
      In this study, the addition of necitumumab did not improve the efficacy outcome over cisplatin plus pemetrexed alone in advanced non-squamous-NSCLC. The EGFR H-score did not seem to predict the efficacy outcomes of necitumumab in combination with cisplatin plus pemetrexed. The addition of necitumumab resulted in a higher frequency of grade ≥ 3 AE (skin reaction, GI, asthenia and other) and an imbalance of grade ≥ 3 thromboembolic events. Further biomarker studies are ongoing.

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    P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.05-023 - Treatment with the mTOR kinase inhibitor CC-223 overcomes resistance to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in non-small cell lung cancer cells (ID 3429)

      09:30 - 09:30  |  Author(s): F.R. Hirsch

      • Abstract

      Background
      Activation of the mTOR pathway is a common down-stream mechanism of resistance to Epidermal Growth Factor receptor (EGFR) tyrosine kinase inhibitors. CC-223 (Celgene) is an mTOR kinase inhibitor under clinical development. We evaluated CC-223 in combination with erlotinib to overcome resistance to EGFR tyrosine kinase inhibition in non-small cell lung cancer (NSCLC) cell lines and xenografts in nude mice.

      Methods
      A panel of 18 NSCLC cell lines was used to evaluate the effect of erlotinib and CC-223 treatment on cell growth using an MTT assay. Intermediately (IC50 >1 and <10 mM) and highly (IC50 >10 mM) resistant cell lines to erlotinib were used in analyses of additive/synergistic effects for the combination treatment with CC-223.

      Results
      CC-223 demonstrated anti-proliferative activity in NSCLC cell lines with various degrees of sensitivity as reflected in different IC50 values, ranging from 0.15 to 12 mM. In combination with erlotinib, CC-223 showed synergistic anti-proliferative effects in NSCLC cells resistant to erlotinib with combination indices as low as 0.1-0.2. In vivo studies in mice xenografts demonstrated a strong synergistic effect of the combination treatment of erlotinib and CC-223 with a 90% decrease of tumor volume compared to untreated and 88% compared to erlotinib treated for A549 cells. IHC analyses of apoptosis and proliferation in the tumors are ongoing; mature data will be presented at the meeting.

      Conclusion
      The mTOR kinase inhibitor CC-223 demonstrated anti-proliferative activity in a panel of NSCLC cell lines. In NSCLC cells resistant to the EGFR tyrosine kinase inhibitor erlotinib, combining erlotinib with CC-223 demonstrated a synergistic anti-proliferative effect. In vivo studies of tumors in xenografted mice also demonstrated synergistic anti-tumor effects with the combination treatment even in erlotinib resistant tumors. The present data suggest that mTOR inhibition using the mTOR kinase inhibitor CC-223 may be a therapeutic strategy to overcome resistance to EGFR tyrosine kinase inhibitors in NSCLC.