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D.S. Shames



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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): D.S. Shames

      • 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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    P1.01 - Poster Session 1 - Cancer Biology (ID 143)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.01-002 - Clinicopathological and biological significance of epiregulin expression in non-small cell lung cancer (ID 755)

      09:44 - 09:58  |  Author(s): D.S. Shames

      • Abstract

      Background
      KRAS mutations are one of the most common driver mutations in non-small cell lung cancer (NSCLC) and efficient therapeutic stratergies for oncogenic KRAS-driven NSCLC are urgently needed. We recently identified epiregulin (EREG) as one of several putative transcriptional targets of oncogenic KRAS signaling in KRAS-mutant NSCLC cells and immortalized bronchial epithelial cells expressing ectopic mutant KRAS. In the present study, we assessed clinicopathological and biological significance of EREG expression in NSCLC.

      Methods
      Seventy-eight lung cancer cell lines (23 small cell lung cancers [SCLCs] and 35 NSCLCs), five noncancerous bronchial epithelial cell lines and 174 surgical specimens from NSCLC patients (136 adenocarcinomas and 38 squamous cell carcinomas) were used for EREG expression analysis by real-time RT-PCR methods. In vitro cell growth was evaluated by MTT assay, colony-formation assay in liquid culture and soft agar assay. Apoptosis was evaluated by the DNA fragment detection method and the annexin-V-fluorescein staining method. The Kaplan-Meier method was used for analysis of disease-free survival (DFS) and overall survival (OS) and log-rank test was used for survival differences. Cox proportional hazards model was used to identify independent prognostic factors for PFS and OS.

      Results
      EREG is predominantly expressed in NSCLC lines harboring KRAS, BRAF or EGFR mutations whereas most SCLC lines lack EREG expression. Small interfering RNAs (siRNAs) targeting against these mutations resulted in down-regulation of EREG expression in NSCLC cells. EREG expression was significantly reduced by treatments with the inhibitors of MEK or ERK in EREG-overexpressing NSCLC cell lines, irrespective of mutation status of KRAS, BRAF and EGFR. EREG expression significantly correlated with KRAS copy number in KRAS-mutant NSCLC cell lines whereas EREG expression significantly correlated with EGFR copy number in NSCLC cell lines with wild-type KRAS/BRAF/EGFR. In the analysis of surgical specimens from NSCLC patients, EREG was predominantly expressed in lung adenocarcinomas. In a subgroup of adenocarcinomas, EREG expression was significantly higher in the tumors from elderly patients (≥70-year-old), males and smokers and was higher in the tumors with pleural involvement-, lymphatic permeation- or vascular invasion-positive. EREG was highly expressed in lung adenocarcinomas with KRAS mutation compared to those with EGFR mutation or wild-type EGFR/KRAS. Lung adenocarcinoma patients with high EREG expression had significantly shorter DFS and OS compared to those with low EREG expression. When the patients were divided into four groups according to EREG expression levels and KRAS mutation status, DFS and OS were significantly shorter in the patients with KRAS-mutant/EREG-high than those with wild-type KRAS/EREG-low. Cox regression analysis demonstrated that elevated EREG expression was an unfavorable prognostic factor. siRNA-mediated EREG silencing inhibited anchorage-dependent and -independent growth and induced apoptosis in KRAS-mutant and EREG-overexpressed lung adenocarcinoma cells.

      Conclusion
      Our findings suggest that oncogenic KRAS-induced EREG overexpression contributes to an aggressive phenotype and unfavorable prognosis in lung adenocarcinoma patients, and EREG could be a promising therapeutic target in oncogenic KRAS-driven NSCLC.

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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-005 - The High Incidence of Overlap between Actionable Biomarkers in NSCLC: Potential Impact on Future Clinical Trial Design (ID 360)

      09:30 - 09:30  |  Author(s): D.S. Shames

      • Abstract

      Background
      Recent advances in molecular profiling of non-small cell lung cancer (NSCLC) have led to the replacement of platinum-based chemotherapy with targeted therapies for certain genetic subsets of NSCLC (ALK rearrangements, some EGFR activating mutations). It is also known that myriad pathways can drive resistance, the unfortunate norm for most patients. A greater understanding of the overlap across multiple biomarker subsets, including activating mutations, signal transduction pathways, and immune system markers, might aid in prognostic assessment, predictive biomarker development and the design of combination or sequential treatment regimens.

      Methods
      The prevalence and prognostic significance of nine biomarkers (TTF1, p63, EGFR mutation, KRAS mutation, MET immunohistochemistry [IHC], PDL1 IHC, PTEN IHC, NaPi2B IHC, ECDH IHC) across two independent sample sets (Set 1, n=561; Set 2, n=300) were tested. With the exception of ECDH, all assays were IVD or companion diagnostics. Set 1 was collected from patients who were eligible for surgery with curative intent from 2003–2005 at MD Anderson Cancer Center in the USA. Samples from Set 2 were part of a collaboration between the University of Colorado Cancer Center, USA and The Norwegian Radium Hospital, and contained surgically-resected NSCLC tissues collected from 2006–2011.

      Results
      The prevalence of each biomarker varied significantly by histology. For adenocarcinoma samples, the prevalence of each biomarker was: EGFR mutation (13%), KRAS mutation (29%), TTF1 IHC (83%), p63 IHC (7%), MET IHC (50%), PDL1 IHC (45%), PTEN loss IHC (11%), NaPi2B IHC (76%), EGFR IHC (FLEX cut-off, 11%). In squamous-cell carcinoma, the prevalence of each biomarker was: TTF1 IHC (2%), p63 IHC (87%), MET IHC (13%), PDL1 IHC (50%), PTEN loss IHC (13%), NaPi2B IHC (3%), EGFR IHC (FLEX cut-off, 40%). In addition, more than 67% of patients were positive for more than one biomarker and >33% were positive for at least three biomarkers. The diagnostic criteria for each biomarker and correlations with patient characteristics will be described in further detail. Figure 1. Biomarker Overlap in Adenocarcinoma in Set 1 (n=337) Figure 1

      Conclusion
      Collectively, these data suggest that the biomarker landscape in NSCLC is complex and will be increasingly dynamic as more experimental agents approach pivotal testing. Grant support: this study was partially funded by UT Lung Specialized Programs of Research Excellence grant (P50CA70907; IIW)

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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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      P3.11-014 - Safety, pharmacokinetics, and activity of the anti-NaPi2b antibody-drug conjugate DNIB0600A: A Phase I study in patients with non-small cell lung cancer and platinum-resistant ovarian cancer (ID 1477)

      09:30 - 09:30  |  Author(s): D.S. Shames

      • Abstract

      Background
      NaPi2b (SLC34A2) is a multi-transmembrane, sodium-dependent phosphate transporter highly expressed in non-small cell lung cancer (NSCLC) and ovarian cancer (OC). DNIB0600A is an antibody-drug conjugate consisting of a humanized anti-NaPi2b IgG1 monoclonal antibody and the anti-mitotic agent MMAE.

      Methods
      This study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DNIB0600A (0.2-2.8 mg/kg) given every 3 weeks (q3w) to patients (pts) with non-squamous NSCLC or platinum-resistant, non-mucinous OC. A traditional 3+3 design was used for dose escalation followed by expansions in NSCLC and OC at the recommended Phase 2 dose (RP2D). Tumor NaPi2b expression was evaluated in archival tissue by immunohistochemistry (IHC). Anti-tumor activity was evaluated per RECIST 1.1.

      Results
      As of 1 May 2013, 65 pts have enrolled (35 NSCLC; 30 OC), median age 62 (range 39-85), PS 0-1, median number of prior regimens 2 (1-8) in NSCLC pts, and 5 (1-12) in OC pts. Pts received a median of 4 (range 1-25) doses of DNIB0600A. One pt experienced a DLT (Grade 3 dyspnea) at 1.8 mg/kg; however, no additional DLTs occurred through the maximally administered dose of 2.8 mg/kg. Two patients had Grade 1 and 2 infusion-related reactions. The most common related AEs (all grades) were fatigue (55%), nausea (35%), peripheral neuropathy (32%), decreased appetite (29%), vomiting (25%), alopecia (20%), and diarrhea, dysgeusia, headache, and pain (each 15%). The majority of these AEs were Grade 1 and Grade 2. Two patients had serious AEs (SAE) which led to discontinuation (dyspnea; dehydration and hyperglycemia). Four other related SAEs (nausea, upper respiratory tract infection, abdominal pain, and headache) were noted in 2 pts. Preliminary PK results support a q3w dosing regimen with no accumulation observed. Expansion at 2.4 mg/kg was selected based on cumulative safety data and a benefit/risk assessment performed at time of expansion. Exposures of analytes monitored were dose-proportional over all dose levels, and no PK difference was observed between NSCLC or OC pts. Approximately 60% of NSCLC and 90% of OC pts expressed high levels (IHC 2+/3+) of NaPi2b. Anti-tumor activity with DNIB0600A was associated with tumor NaPi2b expression for both NSCLC and OC. Of the 40 pts with NaPi2b IHC Score of 2+ or 3+, treated at dose levels 1.8-2.8 mg/kg, 10 pts had a confirmed partial response (PR); 2 of 18 NSCLC and 8 of 22 OC pts, respectively. Additionally, 3 NSCLC and 3 OC pts have unconfirmed PRs. No pt was enrolled with NaPi2b IHC Score of 1+; no pt responded among the 13 pts with NaPi2b IHC Score of 0, treated at dose levels 1.8-2.8 mg/kg

      Conclusion
      DNIB0600A administered q3w has an encouraging safety, tolerability, and PK profile and evidence of anti-tumor activity in NSCLC and OC pts whose tumors express NaPi2b detectable by IHC. This data supports further clinical evaluation of DNIB0600A in NSCLC and OC together with a companion diagnostic.