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D.P. Carbone

Moderator of

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    MS09 - Immune Therapies for Lung Cancer (ID 26)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Medical Oncology
    • Presentations: 5
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      MS09.0 - N/A - Chair Intro (ID 495)

      • Abstract

      Abstract not provided

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      MS09.1 - Biology of the B7 Family Members (CTLA4, PD1, PDL1) (ID 496)

      S. Antonia

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS09.2 - Treatment Targeting PD1/PDL1 and Toxicity (ID 497)

      J. Brahmer

      • Abstract
      • Presentation
      • Slides

      Abstract
      Tumors evade immune system attack through various different mechanisms. One such mechanism is through coopting inhibitory immune checkpoints.(1) These inhibitory checkpoints cause compromised T cell activation and effector function. The two immune checkpoints best known are CTLA-4 and PD-1.(2) CTLA-4 is the receptor that is expressed earlier on in T cell activation and whose ligands are B7.1 and B7.2. Tumor cells have not been known to express the CTLA-4 ligands which are only known to be expressed on antigen presenting cells (APC). CTLA-4 deficient mice die early on of massive lymphoproliferative disorders.(3) Alternatively, the PD-1 receptor is expressed later on in T cell activation in the periphery and binds to two ligands, PD-L1(B7-H1) and PD-L2 (B7-DC). Both ligands are known to be expressed in peripheral tissues on APCs as well as tumor cells. Both ligands are upregulated by type 1 and 2 interferons, particularly gamma interferon.(4) PD-1 deficient mice develop strain specific autoimmune diseases later on in life.(5) Antibodies developed to block the binding between co-inhibitory receptor and its ligands cause T cell activation. While CTLA-4 blockade via the antibody, ipilimumab, has yielded an improvement in survival in patients with melanoma, PD-1 blockade is earlier on its development.(6,7) Several antibodies are in various stages of development. Of the antibodies designed to bind to the PD-1 receptor, Nivolumab (BMS-936558) is furthest along in development. In the first in human, single dose study of nivolumab, no maximum tolerated dose was found.(8) The pharmacokinetics of the antibody revealed a 14 day half-life, but the antibody was found to occupy T cell receptors for up to 3 months after treatment leading to prolonged pharmacodynamic effects. The toxicities were relatively mild and consistent with the immune mechanism of action. Early signs of clinical activity were seen in patients with melanoma, colon cancer, non-small cell lung cancer (NSCLC), and renal cell cancer (RCC).(9) Two patients remain in a complete response even up to almost 5 years after their last treatment. One patient’s response was maintained up to 18 months after stopping treatment and when the cancer progressed, the patient was retreated with nivolumab resulting again in a response. More recently, a multidose phase I study of Nivolumab was performed.(10) Again, no maximum tolerated dose was found up to 10 mg/kg every two weeks. Toxicities again tended to be manageable and consistent with the immune mechanism of action. Because of initial signs of significant clinical activity, expansion cohorts in NSCCLC, RCC, and melanoma were enrolled. Exciting responses in NSCLC (17%) were seen. These responses were durable with a median duration of response of 17 months. Based on these results, two phase III trials have been initiated in the second line treatment setting comparing nivolumab to docetaxel in both squamous cell and non-squamous cell carcinomas. Another anti-PD-1 antibody, MK-3475, recently reported similar toxicities consistent with the immune mechanism of action as well as initial clinical activity in melanoma (47% response rate).(11) Further expansion cohorts were enrolled in NSCLC and information is forthcoming. Antibodies blocking the ligand, PD-L1, have also been developed. Theoretically there may be differences in activity and toxicities between the two groups of antibodies. By blocking the PD-L1, the interaction between PD-1 and PD-L2 remains intact. It remains to be seen if this is meaningful, clinically. The first in human study of once every two week dosing of BMS-936559 reported initial tumor activity in several tumor types including NSCLC (10%) as well as a tolerable safety profile.(12) Another PD-L1 antibody, MPDL3280A, initial phase I trial was reported at ASCO in 2013. Toxicities were mild, no MTD was reached, and initial clinical activity was seen in multiple tumor type including NSCLC (22%).(13) These trials demonstrate that the PD-1 pathway is important in tumor immune evasion, and by blocking this pathway, immune activation occurs which in turn can cause durable tumor control. References 1. Zou W: Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5:263-74, 2005 2. Chen L: Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol 4:336-47, 2004 3. Waterhouse P, Penninger JM, Timms E, et al: Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270:985-8, 1995 4. Keir ME, Butte MJ, Freeman GJ, et al: PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677-704, 2008 5. Nishimura H, Nose M, Hiai H, et al: Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141-51, 1999 6. Hodi FS, O'Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711-23, 2010 7. Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517-26, 2011 8. Brahmer JR, Drake CG, Wollner I, et al: Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 28:3167-75, 2010 9. Lipson EJ, Sharfman WH, Drake CG, et al: Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res 19:462-8, 2013 10. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443-54, 2012 11. Iannone R, Gergick K, Cong C, et al: Efficacy and safety of MK-3475 in patients with advanced melanoma, 9th International Congress of the Society for Melanoma Research. Los Angeles. California, 2012 12. Brahmer JR, Tykodi SS, Chow LQ, et al: Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455-65, 2012 13. Herbst R, Gordon M, Fine J, et al: A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors, ASCO Annual Meeting 2013. Chicago, I.L., 2013

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      MS09.3 - Treatment Targeting CTLA4 Efficacy and Toxicity (ID 498)

      T. Lynch

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS09.4 - Lung Cancer Vaccines (ID 499)

      J.F. Vansteenkiste

      • Abstract
      • Presentation
      • Slides

      Abstract
      Surgical resection is the standard therapy for early stage NSCLC, but about half of the patients still develop a relapse and die of their cancer. In case of unresectable locally advanced disease, the combination of chemo- and radiotherapy may cure some patients, but the majority will relapse. Targeted agents have brought progress for patients with advanced NSCLC selected based on molecular factors such as EGFR or ALK mutation, but other novel approaches are needed. One is therapeutic cancer vaccination (TCV), which may become an important part in our future treatment armamentarium, especially for patients with local or locally advanced NSCLC. Cancer immunotherapy in a broad sense is any interaction with the immune system to treat cancer. A first approach is non-antigen-specific modulation of the immune system. Historical experience (BCG, C. parvum, interferon, interleukins, thymosin, etc.) was disappointing. Promising response rates in heavily pre-treated NSCLC patients were reported in recent phase I trials with agents acting on the interaction between antigen presenting cells, T-lymphocytes and tumor cells. Examples are antibodies against Cytotoxic T-lymphocyte Antigen 4 (CTLA-4) or against Programmed Death 1 receptor or its ligands. Antigen-specific immunotherapy aims at specific priming of immune system to recognize the tumor as foreign, thereby generating specific antibodies and/or cytotoxic T cells. This is “therapeutic cancer vaccination”. Conditions for optimal TCV are: 1/ specificity (well-defined target antigen in the tumor, not in other tissues); 2/ selectivity (use in the population expressing the target); 3/ immunogenicity (interaction with antigen leads to effective humoral and/or cellular response); 4/ tumor sensitive to immune kill in order to obtain improvement in patients’ outcome. Although the historical results of TCV for NSCLC were disappointing, knowledge from the last decades about the molecular pathology of tumors, of the immune system in general, and of tumor immunity in particular, has led to the introduction of several modern and more sophisticated TCVs. These vaccine formulations have shown encouraging data in phase II randomized clinical trials, and are now being studies in large phase III studies. Important examples are the MAGE-A3 vaccine in resected early stage NSCLC, the BLP-25 vaccine in locally advanced NSCLC after chemoradiotherapy, and e.g. belagenpumatucel-L and the TG4010 vaccine in advanced stage NSCLC. The MAGE-A3 protein is totally tumor-specific and present in about 35% of early stage NSCLC. In the hypothesis generating double-blind, randomized, placebo-controlled phase II study, 182 patients with completely resected MAGE-A3-positive stage IB-II NSCLC received recombinant MAGE-A3 protein combined with an immunostimulant (13 doses over 27 months) or placebo [1]. No significant toxicity was observed. There was a 24% - non-significant - improvement in disease-free survival (HR 0.76; 95% CI 0.48 to 1.21). Moreover, a predictive gene signature, initially described in advanced melanoma patients could be confirmed in early stage NSCLC [2].A large phase III study (n=2270) with MAGE-A3 vaccine is recruited and awaiting results (MAGRIT, NCT00480025). Mucins like the MUC1 protein are present in many epithelia, but MUC1 expression is altered (mainly by aberrant glycosylation) in many cancer types, including NSCLC. The tandem repeat MUC1-peptide liposomal vaccine BLP-25 has been studied in patients with stage IIIB-IV NSCLC [3]. Patients in disease control after conventional treatment with chemo(-radio)therapy were randomly assigned to BLP25 (8 weekly s.c. immunizations, followed by administration at 6-week intervals) plus BSC or BSC alone. While overall survival (OS) was not significantly different in the total group, a challenging effect was observed in stage IIIB patients (HR 0.524; 95%CI 0.261-1.052). No significant toxicity was observed. At the 2013 ASCO meeting, the double-blind, randomized, placebo-controlled phase III study was presented (START, NCT00409188) [4]. Patients not progressing after primary chemoradiotherapy for unresectable stage III NSCLC were randomized to BLP25 or placebo. In the primary analysis population (n=1239), OS was better with the vaccine (HR 0.88, 95%CI 0.75-1.03). In the predefined subgroup analysis in patients after concurrent chemoradiotherapy (n=806) there was a median OS difference of 10.2 months (HR 0.78, 95%CI 0.64-0.95). While the most obvious role for TCV is for patients with small residual disease after treatment, several compound are in phase III testing in advanced NSCLC as well. Belagenpumatucel-L is a vaccine based on a mixture of allogeneic tumor cells with TGF-β2 antisense blockade as adjuvant. In a phase II open trial, survival was related to the dose administered [5]. A phase III trial in patients with stage III-IV NSCLC in disease control after first-line therapy is now fully recruited (STOP, NCT00676507). TG4010 is a vaccine based on a recombinant viral vector (attenuated strain of vaccinia virus) expressing both the tumor-associated antigen MUC1 and interleukin-2. In a phase II randomized study, 148 patients with advanced NSCLC expressing MUC1 by immunohistochemistry received either up to 6 cycles of cisplatin-gemcitabine plus TG4010, or the same chemotherapy alone [6]. The primary endpoint, a 6-month progression-free survival more than 40% in the experimental arm was met. A confirmatory phase IIB-III trial is ongoing (TIME, NCT01383148). 1. Vansteenkiste J, Zielinski M, Linder A, et al. Adjuvant MAGE-A3 immunotherapy in resected non-small cell lung cancer: Phase II randomized study results. J Clin Oncol 2013; 31: 2396-2403. 2. Ulloa-Montoya F, Louahed J, Dizier B, et al. Predictive gene signature in MAGEA3 antigen-specific cancer immunotherapy. J Clin Oncol 2013; 31: 2388-2395. 3. Butts C, Murray N, Maksymiuk A, et al. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small cell lung cancer. J Clin Oncol 2005; 23: 6674-6681. 4. Butts CA, Socinski MA, Mitchell P et al. START: A phase III study of L-BLP25 cancer immunotherapy for unresectable stage III non-small cell lung cancer. J Clin Oncol 31 Suppl, abstract 7500. 2013. 5. Nemunaitis J, Dillman RO, Schwarzenberger PO, et al. Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small cell lung cancer. J Clin Oncol 2006; 24: 4721-4730. 6. Quoix E, Ramlau R, Westeel V, et al. Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small cell lung cancer: a controlled phase 2B trial. Lancet Oncol 2011; 12: 1125-1133.

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Author of

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    CF - A Focus on Lung Cancer - An Interactive Consumer Forum (ID 219)

    • Event: WCLC 2013
    • Type: Other Sessions
    • Track:
    • Presentations: 2
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      CF.1 - Standardising Lung Cancer Around the World (ID 5647)

      D.P. Carbone

      • Abstract
      • Slides

      Abstract not provided

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      CF.5 - Advances in Lung Cancer Treatments (ID 5651)

      D.P. Carbone

      • Abstract
      • Slides

      Abstract not provided

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    MO15 - Novel Genes and Pathways (ID 89)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 2
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      MO15.05 - Oncogenic ARAF mutation in lung adenocarcinoma (ID 2860)

      D.P. Carbone

      • 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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      MO15.06 - A prospective internet-based study of patients with lung cancer harboring baseline EGFR T790M to identify germline carriers and characterize familial risk (ID 1667)

      D.P. Carbone

      • Abstract
      • Presentation
      • Slides

      Background
      The EGFR T790M mutation, commonly seen with acquired resistance to EGFR kinase inhibitors, has also been described rarely as a germline mutation in association with familial lung cancer. In a prior study (Oxnard et al, JTO, 2012), the presence of EGFR T790M at diagnosis was associated with a 50% chance of carrying an underlying germline T790M mutation. This suggests that by studying patients whose cancer was shown to carry T790M at diagnosis, it is possible to efficiently screen for a germline allele that otherwise is rare among patients with non-small cell lung cancer. We therefore initiated a prospective trial to identify patients and families carrying germline EGFR mutations in order to characterize phenotype and cancer risk.

      Methods
      Subjects are eligible if they (1) have a cancer harboring EGFR T790M (excluding acquired T790M), (2) are a relative of a known germline carrier, or (3) are already known to carry a germline EGFR mutation on prior testing. Subjects may present at a participating cancer center or may enroll remotely using a study website (www.dana-farber.org/T790Mstudy/). Eligible subjects receive genetic counseling in person or over the phone, and then submit a saliva and/or blood specimen for central testing in a CLIA lab. Results are disclosed to the subject if they wish but do not enter the medical record. Those subjects carrying germline EGFR mutations are given the option of inviting relatives to participate. Chest CT scans are collected from germline carriers and analyzed centrally to study nodule prevalence and characteristics. Available tumor specimens are collected for central pathology review and advanced genomic analysis.

      Results
      The trial was registered to clinicaltrials.gov (NCT01754025) and began accrual in December 2012. To date, 7 subjects have been enrolled and 5 are actively being screened, including 4 kindreds. More than half of the subjects have participated remotely via the study website. Of 4 probands with lung cancer and germline T790M, 3 have a family history of lung cancer, 2 of whom have children with CT scans showing multiple sub-centimeter ground-glass nodules. The fourth proband has no family history of lung cancer, suggesting variable penetrance or a de novo germline event. All cancers in germline T790M carriers have also harbored secondary EGFR kinase domain mutations.

      Conclusion
      Using a novel trial design, including remote accrual, genetic counseling by phone, and germline testing by mail, we have begun collecting a sizeable cohort of families affected by germline EGFR mutations. By leveraging referrals from commercial laboratories and contributing academic centers, we aim to study 100 patients over a three year period in order to better understand the natural history and risk associated with this unique familial cancer syndrome. Supported by grants from the Conquer Cancer Foundation of ASCO, the Bonnie J. Addario Lung Cancer Foundation, and the National Cancer Institute.

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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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      MO19.04 - DISCUSSANT (ID 3902)

      D.P. Carbone

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS20 - Small Cell Lung Cancer (ID 37)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Medical Oncology
    • Presentations: 1
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      MS20.2 - Small Cell Cancer Biology: Recent Insights (ID 552)

      D.P. Carbone

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    O08 - Preclinical Therapeutic Models I (ID 92)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      O08.04 - DISCUSSANT (ID 3905)

      D.P. Carbone

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.05-025 - EGFR blockade increases lung cancer stem cell-like cells by upregulation of Notch3 signaling. (ID 3487)

      D.P. Carbone

      • Abstract

      Background
      Blockade of genetic driver alterations in cell signaling pathways such as the epidermal growth factor receptor (EGFR) have led to dramatic tumor responses in the metastatic setting. However, these agents have unexpectedly failed to improve outcomes in clinical trails of early stage (BR.19) and locally advanced (S0023) NSCLC. In fact, survival was significantly worse among patients receiving gefitinib in the S0023 trial, and trended to be worse in BR.19. While it is clear that EGFR TKIs can reduce the tumor bulk and improve symptoms in the metastatic setting, these results raise the possibility that EGFR inhibition might somehow stimulate tumor growth either directly or indirectly.

      Methods
      We studied the fractions and numbers of ALDH+ cells and activation of stemcell signaling pathways in two EGFR mutated cell lines treated with erlotinib.

      Results
      Here, we report that treatment of EGFR-mutated lung cancer cell lines with erlotinib, while showing robust cell death, essentially increases the fraction and absolute number of ALDH+ clonogenic stem cell-like cells. This phenomenon can be abolished by inhibition of Notch3, while Notch1 inhibition has little effect or slightly increases ALDH+ cells. We demonstrate EGFR kinase activity-dependent coprecipitation of Notch and EGFR receptors and EGFR kinase dependent tyrosine phosphorylation of the Notch3 receptor. We further found that inhibition of EGFR activity leads to increased nuclear accumulation of gamma-secretase dependent Notch3 that correlates with the increase in ALDH+ cells.

      Conclusion
      These data suggest that while EGFR TKIs are very effective at debulking tumors in the metastatic setting, inhibition of EGFR paradoxically causes Notch activation and an increase in clonogenic stem cell-like cells. Therefore, curative-intent therapy may be best accomplished by dual targeting of EGFR and Notch3.

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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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      P3.05-017 - LKB1 loss induces characteristic pathway activation in human tumors and confers sensitivity to MEK inhibition due to attenuated PI3K-AKT-FOXO3 signaling. (ID 2847)

      D.P. Carbone

      • Abstract

      Background
      Inactivation of STK11/LKB1 is one of the most common genetic events in lung cancer, and understanding the cellular phenotypes and molecular pathways altered as a consequence will aid the development of therapeutic strategies targeting LKB1-deficient cancers.

      Methods
      We report the comprehensive analysis of gene and protein expression patterns associated with LKB1 loss in lung adenocarcinomas, through which we identify hallmarks of altered tumor metabolism and down-regulation of the PI3K/AKT pathway.

      Results
      Significant differences are observed between human tumors and those derived from a genetically engineered mouse model of LKB1 loss. A 16-gene signature is predictive of both mutational and non-mutational LKB1 loss in human tumors. Cell lines expressing this signature show increased sensitivity to MEK inhibition, independent of mutations in RAS and RAF family members. Restoration of LKB1 in lung cancer cell lines down-regulates the gene expression pattern, attenuates FOXO3, and induces resistance to MEK inhibition.

      Conclusion
      These findings identify characteristic phenotypic features of LKB1-deficient tumors and identify LKB1 loss as a novel determinant of MEK sensitivity.